JP7324953B2 - Pharmaceutical composition containing benzisoxazole derivative - Google Patents

Description

The present invention provides a benzisoxazole derivative having calcium channel inhibitory activity and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition or a therapeutic agent for Parkinson's disease or a therapeutic agent for essential tremor containing them as active ingredients. and a therapeutic agent for neuropathic pain.

Calcium channels on the cell membrane are one of a diverse superfamily of voltage-gated channel proteins, transmembrane subunit proteins that control the entry of Ca ²⁺ ions from the extracellular fluid into the cell. Voltage-dependent calcium channels present in living cells are activated at high voltages by the opening potential. L-type (Cav.1) and non-L-type (P/Q-type, N-type and R-type) (Cav.2) and T-type (Cav.3) activated at low voltage. L-type channels are expressed in skeletal muscle, heart, endocrine tissue, brain, retina, etc. Non-L-type channels are expressed in nerve cells, and T-type channels are widely and abundantly expressed in the brain (non-L-type channels). Patent document 1).

T-type calcium channels are associated with epilepsy, essential tremor, Parkinson's disease, cerebellar ataxia, neuropathic pain including hyperalgesia and allodynia, nociceptive pain, migraine, schizophrenia, autism, bipolar It has been reported to be involved in a variety of diseases and disorders, including disorders, depression, anxiety, sleep disorders, cardiac arrhythmia, hypertension, cancer, diabetes, infertility and sexual dysfunction (Non-Patent Documents 2, 3). and 4). At present, there are many therapeutic agents and therapeutic methods for these diseases and disorders, but their effects cannot be said to satisfy the patient's satisfaction with the treatment, and the appearance of better therapeutic agents is still eagerly awaited. I am where I am.

Patent Documents 1 and 2 describe benzisoxazole derivatives, but they have a different chemical structure from the compound represented by formula (1) described below.

Japanese Patent Application Laid-Open No. 53-77057 US 4172896

Pharmacological Reviews 57(4) 397-409 (2005) Drug Discovery Today 11(5/6) 245-253 (2006) Neuron 98(3) 466-481 (2018) Q. Ashton Acton, PhD. (Eds.), Ion Channels－Advances in Research and Application. 2013 Edition. Scholarly EditionsTM, Atlanta, Georgia, pp. 1-106. Bulletin of Urology 57, 125-128 (2011)

The subject of the present invention is a pharmaceutical composition containing a compound useful as a therapeutic agent for various nervous system diseases or psychiatric disorders, specifically a therapeutic agent for Parkinson's disease, a therapeutic agent for essential tremor, and a therapeutic agent for neuropathic pain. is to provide

As a result of intensive studies, the present inventors have found that a compound represented by the following formula (1) has T-type calcium channel inhibitory activity, and found that it has anti-Parkinson's disease action (enhancement of levodopa action and anti-tremor effect). action) and anti-essential tremor action, and found to be effective against chemotherapy-induced peripheral neuropathy, thereby completing the present invention. According to the present invention, a benzisoxazole derivative represented by the following formula (1) (hereinafter sometimes referred to as "the compound of the present invention") is provided.

That is, the present invention is as follows.

［式中、
Ｒ^１は、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２は、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表すか、あるいは
Ｒ^１及びＲ^２はそれらが結合する炭素原子と一緒になってＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を構成した基を表し、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］ [Section 1]
A pharmaceutical composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[In the formula,
R ¹ is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ² is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy or R ¹ and R ² together with the carbon atom to which they are attached represent C _3-6 cycloalkyl (the cycloalkyl being halogen, hydroxyl, C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and C _1-3 alkoxy),
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]

[Section 2]
R ¹ is hydrogen, fluorine, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a substituent of
R ² is fluorine, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with groups), or R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (the cycloalkyl being fluorine, hydroxyl, C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and C _1-3 alkoxy).
Item 1. The pharmaceutical composition according to item 1.

[Section 3]
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is fluorine, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein said cycloalkyl is fluorine, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is fluorine, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy);
3. The pharmaceutical composition according to Item 1 or 2.

[Section 4]
R ¹ is hydrogen, fluorine, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy; good) and
R ² is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); or R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein the cycloalkyl consists of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy (optionally substituted with 1 to 3 substituents independently selected from the group).
Item 4. The pharmaceutical composition according to any one of items 1 to 3.

[Section 5]
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, or C _1-3 alkoxy (wherein the alkoxy is optionally substituted with 1 to 3 fluorines);
Item 5. The pharmaceutical composition according to any one of items 1 to 4.

[Section 6]
R ¹ is hydrogen, fluorine, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy; good) and
R ² is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); or R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl, said cycloalkyl consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group),
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, or C _1-3 alkoxy (wherein the alkoxy is optionally substituted with 1 to 3 fluorines);
Item 1. The pharmaceutical composition according to item 1.

[Section 7]
Item 1. The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(benzo[d]isoxazol-3-yl)propane-2-sulfonamide (Example 2),
benzo[d]isoxazol-3-yl-fluoromethanesulfonamide (Example 3),
benzo[d]isoxazol-3-yl-difluoromethanesulfonamide (Example 4),
1-(benzo[d]isoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
1-(benzo[d]isoxazol-3-yl)propane-1-sulfonamide (Example 6),
1-(benzo[d]isoxazol-3-yl)butane-1-sulfonamide (Example 7),
1-(benzo[d]isoxazol-3-yl)-1-fluoroethane-1-sulfonamide (Example 8),
1-(benzo[d]isoxazol-3-yl)-2-methylpropane-1-sulfonamide (Example 9),
1-(5-methoxybenzo[d]isoxazol-3-yl)ethane-1-sulfonamide (Example 10),
1-(5-fluorobenzo[d]isoxazol-3-yl)ethane-1-sulfonamide (Example 11),
1-(5-chlorobenzo[d]isoxazol-3-yl)ethane-1-sulfonamide (Example 12),
(R)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide, or (S)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (performed Examples 13 or 14).

[Section 7a]
Item 1. The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(1,2-benzoxazol-3-yl)-1-fluoromethanesulfonamide (Example 3),
1-(1,2-benzoxazol-3-yl)-1,1-difluoromethanesulfonamide (Example 4),
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
1-(1,2-benzoxazol-3-yl)propane-1-sulfonamide (Example 6),
1-(1,2-benzoxazol-3-yl)butane-1-sulfonamide (Example 7),
1-(1,2-benzoxazol-3-yl)-1-fluoroethane-1-sulfonamide (Example 8),
1-(1,2-benzoxazol-3-yl)-2-methylpropane-1-sulfonamide (Example 9),
1-(5-methoxy-1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 10),
1-(5-fluoro-1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 11),
1-(5-chloro-1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 12),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

[Item 8]
Item 1. The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(benzo[d]isoxazol-3-yl)propane-2-sulfonamide (Example 2),
benzo[d]isoxazol-3-yl-fluoromethanesulfonamide (Example 3),
benzo[d]isoxazol-3-yl-difluoromethanesulfonamide (Example 4),
1-(benzo[d]isoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
1-(benzo[d]isoxazol-3-yl)-1-fluoroethane-1-sulfonamide (Example 8),
(R)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide, or (S)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (performed Examples 13 or 14).

[Section 8a]
Item 1. The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(1,2-benzoxazol-3-yl)-1-fluoromethanesulfonamide (Example 3),
1-(1,2-benzoxazol-3-yl)-1,1-difluoromethanesulfonamide (Example 4),
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
1-(1,2-benzoxazol-3-yl)-1-fluoroethane-1-sulfonamide (Example 8),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

[Item 9]
Item 1. The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(benzo[d]isoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(benzo[d]isoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
(R)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide, or (S)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (performed Examples 13 or 14).

[Section 9a]
Item 1. The pharmaceutical composition according to item 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

[Item 10]
Form I wherein the compound of formula (1) has diffraction angle (2θ°) peaks at 5.7° ± 0.2 and 17.3° ± 0.2° in X-ray powder diffraction. 2. The pharmaceutical composition according to item 1, which is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide in crystalline form.

[Item 11]
The compound represented by formula (1) has X-ray powder diffraction of 5.7°±0.2, 14.1±0.2°, 17.3°±0.2°, 19.1°± 0.2°, 19.3±0.2°, 21.6°±0.2°, 22.5±0.2°, 23.1°±0.2°, 23.3°±0. Form I crystalline form of (1R)-1-(1,2-benzoxazole having four or more diffraction angle (2θ°) peaks selected from 2°, and 26.5°±0.2° -3-yl)ethane-1-sulfonamide, the pharmaceutical composition according to item 1.

[Item 12]
Form II, wherein the compound of formula (1) has diffraction angle (2θ°) peaks at 8.7° ± 0.2° and 17.6° ± 0.2° in X-ray powder diffraction Item 2. The pharmaceutical composition according to Item 1, which is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide in the crystalline form of

[Item 13]
The compound represented by formula (1) has X-ray powder diffraction of 8.7° ± 0.2°, 13.5° ± 0.2°, 15.5° ± 0.2°, 17.6 °±0.2°, 20.3°±0.2°, 21.6°±0.2°, 22.6°±0.2°, 26.2°±0.2°, 26.8° The crystalline form of Form II, (1R)-1-(1, having four or more diffraction angle (2θ°) peaks selected from °±0.2°, and 35.2°±0.2°. Item 2. The pharmaceutical composition according to Item 1, which is 2-benzoxazol-3-yl)ethane-1-sulfonamide.

[Item 14]
Form III, wherein the compound of formula (1) has diffraction angle (2θ°) peaks at 11.1° ± 0.2° and 20.3° ± 0.2° in X-ray powder diffraction Item 2. The pharmaceutical composition according to Item 1, which is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide in the crystalline form of

[Item 15]
The compound represented by formula (1) has X-ray powder diffraction of 11.1° ± 0.2°, 13.8° ± 0.2°, 17.0° ± 0.2°, 20.3 °±0.2°, 21.4°±0.2°, 22.1°±0.2°, 22.4°±0.2°, 24.8°±0.2°, 26.3° The crystalline form of Form III (1R)-1-(1, having four or more diffraction angle (2θ°) peaks selected from °±0.2°, and 27.9°±0.2° Item 2. The pharmaceutical composition according to Item 1, which is 2-benzoxazol-3-yl)ethane-1-sulfonamide.

[Item 16]
A nerve induced by T-type calcium channel abnormality, containing as an active ingredient the compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof. A therapeutic and/or prophylactic agent for systemic or psychiatric disorders.

[Item 17]
Neurological or psychiatric disorders caused by abnormalities in T-type calcium channels include epilepsy, seizure disorders, motor dysfunction (disorders related to muscle spasms including convulsions, tremor, essential tremor, Huntington's disease, Myoclonus, tics, restless leg syndrome and dystonia), movement disorders including akinesia and rigidity syndrome and Parkinsonism (Parkinson's disease (tremor, muscle stiffness/rigidity, akinesia/oligokinesia, postural reflex disorder, olfactory disturbance) , REM sleep disorder, constipation, sleep disturbance, memory disturbance, depression, anxiety, headache, low back pain), idiopathic and drug-induced parkinsonism, post-encephalitis parkinsonism, progressive supranuclear palsy, multiple system atrophy , corticobasal degeneration, Lewy body dementia, cerebellar ataxia, parkinsonism-ALS dementia complex and basal ganglia calcification), drug-induced dyskinesias, nociceptive pain (traumatic pain, migraine, headache, chronic pain (lumbar back pain, rheumatoid arthritis, fibromyalgia, osteoarthritis, etc.), inflammatory pain), neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, Peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (post-spinal injury pain, post-stroke pain, etc.), pain associated with Guillain-Barré syndrome, multiple sclerosis pain associated with Parkinson's disease, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain), fatigue (parkinsonian fatigue, multiple sclerosis fatigue, fatigue caused by sleep disturbance or circadian rhythm disturbances, medication-induced parkinsonism) chronic fatigue syndrome including dyspraxia), migraine, schizophrenia, autism, Gilles de la Tourette syndrome, bipolar disorder, depression, anxiety (generalized anxiety disorder, panic disorder and obsessive-compulsive disorder) sleep disorders (including insomnia, hypersomnia, narcolepsy, and REM sleep disorders), cardiac arrhythmias, hypertension, cancer, diabetes, infertility and sexual dysfunction. 17. The therapeutic and/or prophylactic agent according to 16.

[Section 17a]
Neurological or psychiatric disorders caused by abnormalities in T-type calcium channels include epilepsy, seizure disorders, motor dysfunction (disorders related to muscle spasms including convulsions, tremor, essential tremor, Huntington's disease, Myoclonus, tics, restless leg syndrome and dystonia), movement disorders including akinesia and rigidity syndrome and Parkinsonism (Parkinson's disease (tremor, muscle stiffness/rigidity, akinesia/oligokinesia, postural reflex disorder, olfactory disturbance) , REM sleep disorder, constipation, sleep disturbance, memory disturbance, depression, anxiety, headache, low back pain), idiopathic and drug-induced parkinsonism, post-encephalitis parkinsonism, progressive supranuclear palsy, multiple system atrophy , corticobasal degeneration, Lewy body dementia, cerebellar ataxia, Parkinsonism-ALS dementia complex and basal ganglia calcification), levodopa-induced dyskinesia in Parkinson's disease, drug-induced dyskinesia, nociceptive Receptive pain (traumatic pain, migraine, headache, chronic pain (lumbar back pain, rheumatoid arthritis, fibromyalgia, osteoarthritis, etc.), inflammatory pain), neuropathic pain (shingles pain, trigeminal pain) Neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), Guillain-Barré syndrome pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain), fatigue (due to Parkinson's fatigue, multiple sclerosis fatigue, sleep disturbance, or disturbance of circadian rhythm) induced fatigue, chronic fatigue syndrome including medication-induced parkinsonism), migraines, schizophrenia, autism, Gilles de la Tourette syndrome, bipolar disorder, depression, anxiety (general anxiety sleep disorders (including insomnia, hypersomnia, narcolepsy, REM sleep disorder), sleep disorders in depression, cardiac arrhythmias, hypertension, cancer, diabetes, infertility and Item 17. The therapeutic and/or prophylactic agent according to Item 16, which is a variety of diseases and disorders including sexual dysfunction.

[Item 18]
Nervous system disease or psychiatric disease caused by abnormality of T-type calcium channel is Parkinson's disease disorder, memory impairment, depression, anxiety, headache, low back pain), essential tremor, or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy) , leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, and Parkinson's disease Item 17. The therapeutic and/or preventive agent according to Item 16, which is pain, hyperalgesia or allodynia associated with neuropathic pain.

[Section 18a]
Nervous system disease or psychiatric disease caused by abnormality of T-type calcium channel is Parkinson's disease levodopa-induced dyskinesia in Parkinson's disease, essential tremor, anxiety (generalized anxiety disorder), or neuropathic pain (shingles pain, trigeminal pain) Neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), Guillain-Barré syndrome Item 17. The therapeutic and/or prophylactic agent according to Item 16, which is pain associated with cancer, pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain.

[Item 19]
Item 17. The therapeutic agent and/or according to Item 16, wherein the nervous system disease or psychiatric disease caused by T-type calcium channel abnormality is tremor in Parkinson's disease, essential tremor, or chemotherapy-induced peripheral neuropathy. prophylactic agent.

[Section 19a]
Nervous system disease or psychiatric disease caused by abnormality of T-type calcium channel is Parkinson's disease (including tremor, muscle rigidity/rigidity, akinesia/limbism, postural reflex disorder), essential tremor, or chemical Item 17. The therapeutic and/or prophylactic agent according to Item 16, which is therapy-induced peripheral neuropathy.

[Section 20]
administering a therapeutically effective amount of a compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof, to a patient in need of treatment; A method for treating and/or preventing neurological or psychiatric disorders caused by abnormalities in T-type calcium channels, comprising:

[Section 21]
The method according to any one of Items 1 to 15 (including Items 7a to 9a) for producing a therapeutic and/or preventive agent for nervous system diseases or psychiatric diseases caused by T-type calcium channel abnormality. Use of the compound, or a pharmaceutically acceptable salt thereof.

[Section 22]
A compound according to any one of Items 1 to 15 (including Items 7a to 9a) for use in the treatment and/or prevention of neurological or psychiatric disorders caused by abnormalities in T-type calcium channels; or a pharmaceutically acceptable salt thereof.

[Section 23]
administering a therapeutically effective amount of a compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof, to a patient in need of treatment; Including, Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/liquidity, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and lumbago) ), essential tremor, or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, Treatment of central pain (pain after spinal cord injury, pain after stroke, etc.), pain associated with Guillain-Barre syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain, and / Or a method for prevention.

[Section 23a]
administering a therapeutically effective amount of a compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof, to a patient in need of treatment; Including, Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/liquidity, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and lumbago) ), levodopa-induced dyskinesia in Parkinson's disease, essential tremor, anxiety (generalized anxiety disorder), or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy) , leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, and Parkinson's disease A method for the treatment and/or prevention of pain, hyperalgesia or allodynia associated with neuropathic pain.

[Section 24]
Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/limbism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and low back pain), Essential tremor or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain) pain (post-spinal injury pain, post-stroke pain, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain) and/or or use of the compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof, for the manufacture of a prophylactic agent.

[Section 24a]
Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/limbism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and low back pain), Levodopa-induced dyskinesia in Parkinson's disease, essential tremor, anxiety (generalized anxiety disorder), or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy) etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, The compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutical product thereof, for manufacturing a therapeutic agent and/or preventive agent for hyperalgesia or allodynia associated with neuropathic pain Use of scientifically acceptable salts.

[Section 25]
Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/limbism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and lumbago), Essential tremor or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain) pain (post-spinal injury pain, post-stroke pain, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain) and/or A compound of any one of Sections 1-15 (including Sections 7a-9a), or a pharmaceutically acceptable salt thereof, for use in prophylaxis.

[Section 25a]
Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/limbism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and low back pain), Levodopa-induced dyskinesia in Parkinson's disease, essential tremor, anxiety (generalized anxiety disorder), or neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy) etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, A compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutical formulation thereof, for use in the treatment and/or prevention of hyperalgesia or allodynia associated with neuropathic pain permissible salt.

[Section 26]
administering a therapeutically effective amount of a compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof, to a patient in need of treatment; A method for treating and/or preventing tremor, essential tremor, or chemotherapy-induced peripheral neuropathy in Parkinson's disease, comprising:

[Section 26a]
administering a therapeutically effective amount of a compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof, to a patient in need of treatment; A method for treating and/or preventing Parkinson's disease (including tremor, muscle stiffness/rigidity, akinesia/limbism, postural reflex disorder), essential tremor, or chemotherapy-induced peripheral neuropathy, including .

[Section 27]
Any one of items 1 to 15 (including items 7a to 9a) for manufacturing a therapeutic and/or preventive agent for tremor, essential tremor, or chemotherapy-induced peripheral neuropathy in Parkinson's disease Use of the compound described in 1. or a pharmaceutically acceptable salt thereof.

[Section 27a]
To manufacture a therapeutic and/or prophylactic agent for Parkinson's disease (including tremor, muscle stiffness/rigidity, akinesia/hypokinesis, and postural reflex disorder), essential tremor, or chemotherapy-induced peripheral neuropathy or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 15 (including Items 7a to 9a).

[Section 28]
Any one of paragraphs 1-15 (including paragraphs 7a-9a) for use in the treatment and/or prevention of tremor, essential tremor, or chemotherapy-induced peripheral neuropathy in Parkinson's disease or a pharmaceutically acceptable salt thereof.

[Section 28a]
for use in the treatment and/or prophylaxis of Parkinson's disease (including tremor, muscle rigidity/rigidity, akinesia/limbism, postural reflex disorder), essential tremor, or chemotherapy-induced peripheral neuropathy; A compound according to any one of Items 1 to 15 (including Items 7a to 9a), or a pharmaceutically acceptable salt thereof.

[Section 29]
Abnormality of T-type calcium channel, characterized in that it is used in combination with at least one drug selected from drugs classified as drugs for treating Parkinson's disease, drugs for treating essential tremor, and drugs for treating neuropathic pain. A medicament containing a compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 15 (including Items 7a to 9a) for treating a disease involved.

[Item 30]
A medicament containing the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 15 (including Items 7a to 9a), a therapeutic agent for Parkinson's disease, a therapeutic agent for essential tremor, or A drug in combination with at least one drug selected from drugs classified as therapeutic drugs for neuropathic pain.

[Item 31]
A neurological disease or a psychiatric disease characterized by being used in combination with at least one drug selected from drugs classified as drugs for treating Parkinson's disease, drugs for treating essential tremor, or drugs for treating neuropathic pain. A medicament containing the compound of any one of Items 1 to 15 (including Items 7a to 9a) or a pharmaceutically acceptable salt thereof for treatment.

［式中、
Ｒ^１Ａは、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２Ａは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１ＡとＲ^２Ａは、異なる置換基であり、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］
で表される化合物またはその製薬学的に許容される塩の製造方法であって、下記の工程１～３を含む製造方法；
（工程１）式（３）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は、上記と同じ基を表す。］
で表される化合物またはその塩と式（４ａ）または（４ｂ）：

［式中、Ｒ^７は、２－（メトキシカルボニル）エチル、メシチレンカルボニロキシメチル、２－ベンゾチアゾイル（該基は、ベンゼン環上に、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、水酸基、シアノ、ニトロ、アミノ（該アミノは、Ｃ_１－３アルキルによって１～２個置換されていてもよい）、カルボン酸、カルバモイル（該カルバモイルは、アミノ部分がＣ_１－３アルキルによって１～２個置換されていてもよい）、Ｃ_１－６アルコキシカルボニルからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、２-ピリジル、２-ピリミジニルまたは２－（トリメチルシリル）エチルから選択されるスルフィン酸塩を放出することが可能な脱離基を表す。］
で表される化合物またはその塩を反応させて、式（５）：

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同じ基を表す。]
で表される化合物またはその塩を製造する工程、
（工程２）式（５）で表される化合物またはその塩を酸化して、式（６）：

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同じ基を表す。]
で表される化合物またはその塩を製造する工程、
（工程３）式（６）で表される化合物またはその塩のＲ^７を除去してスルホンアミド化して、式（２）で表される化合物またはその製薬学的に許容される塩を製造する工程。 [Item 32]
Formula (2):

[In the formula,
R ^1A is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ^2A is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group), wherein R ^1A and R ^2A are different substituents,
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]
A method for producing a compound represented by or a pharmaceutically acceptable salt thereof, comprising the following steps 1 to 3;
(Step 1) Formula (3):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as above. ]
A compound represented by or a salt thereof and formula (4a) or (4b):

[In the formula, R ⁷ is 2-(methoxycarbonyl)ethyl, mesitylenecarbonyloxymethyl, 2-benzothiazolyl (the group is halogen, C _1-6 alkyl (the alkyl is halogen, optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is a halogen , hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), hydroxyl, cyano, nitro, amino (the amino optionally substituted 1 to 2 times with C _1-3 alkyl), carboxylic acid, carbamoyl (wherein the carbamoyl is optionally substituted 1 to 2 times by C _1-3 alkyl on the amino moiety) , C _1-6 alkoxycarbonyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of), 2-pyridyl, 2-pyrimidinyl or 2-(trimethylsilyl)ethyl represents a leaving group capable of releasing a sulfinate salt. ]
By reacting a compound represented by or a salt thereof, the formula (5):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 2) The compound represented by formula (5) or a salt thereof is oxidized to give formula (6):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 3) The compound represented by formula (6) or a salt thereof is sulfonamidated by removing ^R7 to produce a compound represented by formula (2) or a pharmaceutically acceptable salt thereof. process.

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、項３２と同じ基を表し、Ｒ^８は、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニロキシメトキシを表す。]
で表される化合物またはその塩を、リパーゼ、エステラーゼ、アミダーゼ、またはプロテアーゼから選択される加水分解酵素を用いて光学選択的に加水分解し、式（３）で表される化合物を製造する工程。 [Item 33]
Item 33. The manufacturing method according to Item 32, comprising the following steps;
(Step 4a) Formula (7):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as in item 32, R ⁸ is C _1-6 alkyl (wherein said alkyl is halogen, hydroxyl group, C ₃ optionally substituted with 1 to 3 substituents independently selected from the group consisting of _-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy, C _1-6 alkylcarbonyloxy represents methoxy. ]
A step of optically hydrolyzing a compound represented by or a salt thereof with a hydrolase selected from lipase, esterase, amidase, or protease to produce a compound represented by formula (3).

[式中、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、項３２と同じ基を表す。]
で表される化合物またはその塩を、還元酵素、およびＮＡＤＨまたはＮＡＤＰＨから選択される補酵素を用いて光学選択的に還元し、式（３）で表される化合物を製造する工程。 [Item 34]
Item 33. The manufacturing method according to Item 32, wherein R ^1A is hydrogen and comprises the steps of;
(Step 4b) Formula (8):

[In the formula, R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as in Item 32. ]
A step of optically reducing a compound represented by or a salt thereof using a reductase and a coenzyme selected from NADH or NADPH to produce a compound represented by formula (3).

[Item 35]
Item 35. The production method according to any one of Items 32 to 34, wherein R ⁷ is 2-benzothiazolyl.

[Item 36]
Item 36. The production method according to Item 33 or 35, wherein ^R8 is methyl and the hydrolase is lipase.

[Item 37]
Item 36. The production method according to Item 34 or 35, wherein ^R2A is methyl and the reductase is carbonyl reductase or alcohol dehydrogenase.

［式中、
Ｒ^１Ａは、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２Ａは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１ＡとＲ^２Ａは、異なる置換基であり、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］
で表される化合物またはその製薬学的に許容される塩の製造方法であって、下記の工程１～２を含む製造方法；
（工程１）式（９）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は、上記と同じ基を表し、Ｘ^１Ａは、ハロゲンを表す。］
で表される化合物またはその塩と式（１０）：

［式中、Ｐ^１Ａは、２－インダノール－１－イル、２－フェニルエタン－１－オール－２－イル、または３－メチルブタン－１－オール－２－イルを表し、Ｐ^２Ａは、水素またはベンジル（該基は、ベンゼン環上に、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）を表す。］
で表される光学活性化合物またはその塩を反応させてジアステレオマー分割をして、式（１１）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｐ^１Ａ、およびＰ^２Ａは、上記と同じ基を表す。］
で表される化合物またはその塩を製造する工程、
（工程２）式（１１）で表される化合物またはその塩を脱保護して、式（２）で表される化合物またはその製薬学的に許容される塩を製造する工程。 [Item 38]
Formula (2):

[In the formula,
R ^1A is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ^2A is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group), wherein R ^1A and R ^2A are different substituents,
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]
A method for producing a compound represented by or a pharmaceutically acceptable salt thereof, comprising the following steps 1 to 2;
(Step 1) Formula (9):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as above, and X ^1A represents a halogen. ]
A compound represented by or a salt thereof and formula (10):

[In the formula, P ^1A represents 2-indanol-1-yl, 2-phenylethan-1-ol-2-yl, or 3-methylbutan-1-ol-2-yl, and P ^2A is hydrogen or benzyl (the group is optionally substituted on the benzene ring with 1 to 5 substituents independently selected from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy); represent. ]
An optically active compound represented by or a salt thereof is reacted to perform diastereomer resolution, and the formula (11):

[wherein R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ , P ^1A and P ^2A represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 2) A step of deprotecting the compound represented by formula (11) or a salt thereof to produce the compound represented by formula (2) or a pharmaceutically acceptable salt thereof.

[Item 39]
Item 39. A production method according to Item 38, wherein R ^1A is hydrogen and R ^2A is methyl.

[Item 40]
40. A process according to Item 38 or 39, wherein P ^1A is 2-indanol-1-yl and P ^2A is hydrogen.

［式中、
Ｒ^１Ａは、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２Ａは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１ＡとＲ^２Ａは、異なる置換基であり、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］
で表される化合物またはその製薬学的に許容される塩の製造方法であって、下記の工程１～３を含む製造方法；
（工程１）式（３－１）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は、上記と同じ基を表す。］
で表される化合物またはその塩と式（４ａ）または（４ｂ）：

［式中、Ｒ^７は、２－（メトキシカルボニル）エチル、メシチレンカルボニロキシメチル、２－ベンゾチアゾイル（該基は、ベンゼン環上に、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、水酸基、シアノ、ニトロ、アミノ（該アミノは、Ｃ_１－３アルキルによって１～２個置換されていてもよい）、カルボン酸、カルバモイル（該カルバモイルは、アミノ部分がＣ_１－３アルキルによって１～２個置換されていてもよい）、Ｃ_１－６アルコキシカルボニルからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、２-ピリジル、２-ピリミジニルまたは２－（トリメチルシリル）エチルから選択されるスルフィン酸塩を放出することが可能な脱離基を表す。］
で表される化合物またはその塩を反応させて、式（５－１）：

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同じ基を表す。]
で表される化合物またはその塩を製造する工程、
（工程２）式（５－１）で表される化合物またはその塩を酸化して、式（６－１）：

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同じ基を表す。]
で表される化合物またはその塩を製造する工程、
（工程３）式（６－１）で表される化合物またはその塩のＲ^７を除去してスルホンアミド化して、式（２－１）で表される化合物またはその製薬学的に許容される塩を製造する工程。 [Item 41]
Formula (2-1):

[In the formula,
R ^1A is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ^2A is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group), wherein R ^1A and R ^2A are different substituents,
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]
A method for producing a compound represented by or a pharmaceutically acceptable salt thereof, comprising the following steps 1 to 3;
(Step 1) Formula (3-1):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as above. ]
A compound represented by or a salt thereof and formula (4a) or (4b):

[In the formula, R ⁷ is 2-(methoxycarbonyl)ethyl, mesitylenecarbonyloxymethyl, 2-benzothiazolyl (the group is halogen, C _1-6 alkyl (the alkyl is halogen, optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is a halogen , hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), hydroxyl, cyano, nitro, amino (the amino optionally substituted 1 to 2 times with C _1-3 alkyl), carboxylic acid, carbamoyl (wherein the carbamoyl is optionally substituted 1 to 2 times by C _1-3 alkyl on the amino moiety) , C _1-6 alkoxycarbonyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of), 2-pyridyl, 2-pyrimidinyl or 2-(trimethylsilyl)ethyl represents a leaving group capable of releasing a sulfinate salt. ]
By reacting a compound represented by or a salt thereof, the formula (5-1):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 2) The compound represented by formula (5-1) or a salt thereof is oxidized to give formula (6-1):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 3) removing R ⁷ from the compound represented by formula (6-1) or a salt thereof to sulfonamidate the compound represented by formula (2-1) or a pharmaceutically acceptable The process of making salt.

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、項４１と同じ基を表し、Ｒ^８は、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニロキシメトキシを表す。]
で表される化合物またはその塩を、リパーゼ、エステラーゼ、アミダーゼ、またはプロテアーゼから選択される加水分解酵素を用いて光学選択的に加水分解し、式（３－１）で表される化合物を製造する工程。 [Item 42]
Item 42. The manufacturing method according to Item 41, comprising the following steps;
(Step 4a) Formula (7):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as in Item 41, R ⁸ is C _1-6 alkyl (wherein said alkyl is halogen, hydroxyl group, C _{3 -6} cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), C _1-6 alkoxy, C _1-6 alkylcarbonyloxy represents methoxy. ]
A compound represented by or a salt thereof is optically hydrolyzed using a hydrolase selected from lipase, esterase, amidase, or protease to produce a compound represented by formula (3-1) process.

[式中、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、項４１と同じ基を表す。]
で表される化合物またはその塩を、還元酵素、およびＮＡＤＨまたはＮＡＤＰＨから選択される補酵素を用いて光学選択的に還元し、式（３－１）で表される化合物を製造する工程。 [Item 43]
Item 42. The manufacturing method according to Item 41, wherein R ^1A is hydrogen and comprises the steps of;
(Step 4b) Formula (8):

[In the formula, R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as in Item 41. ]
A step of optically reducing a compound represented by or a salt thereof using a reductase and a coenzyme selected from NADH or NADPH to produce a compound represented by formula (3-1).

[Item 44]
44. The production method according to any one of Items 41 to 43, wherein R ⁷ is 2-benzothiazolyl.

[Item 45]
Item 45. The production method according to Item 42 or 44, wherein ^R8 is methyl and the hydrolase is lipase.

[Item 46]
Item 45. The production method according to Item 43 or 44, wherein ^R2A is methyl and the reductase is carbonyl reductase or alcohol dehydrogenase.

［式中、
Ｒ^１Ａは、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２Ａは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１ＡとＲ^２Ａは、異なる置換基であり、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］
で表される化合物またはその製薬学的に許容される塩の製造方法であって、下記の工程１～２を含む製造方法；
（工程１）式（９）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は、上記と同じ基を表し、Ｘ^１Ａは、ハロゲンを表す。］
で表される化合物またはその塩と式（１０）：

［式中、Ｐ^１Ａは、２－インダノール－１－イル、２－フェニルエタン－１－オール－２－イル、または３－メチルブタン－１－オール－２－イルを表し、Ｐ^２Ａは、水素またはベンジル（該基は、ベンゼン環上に、ハロゲン、Ｃ_１－６アルキル、Ｃ_１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）を表す。］
で表される光学活性化合物またはその塩を反応させてジアステレオマー分割をして、式（１１－１）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｐ^１Ａ、およびＰ^２Ａは、上記と同じ基を表す。］
で表される化合物またはその塩を製造する工程、
（工程２）式（１１－１）で表される化合物またはその塩を脱保護して、式（２－１）で表される化合物またはその製薬学的に許容される塩を製造する工程。 [Section 47]
Formula (2-1):

[In the formula,
R ^1A is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ^2A is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group), wherein R ^1A and R ^2A are different substituents,
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]
A method for producing a compound represented by or a pharmaceutically acceptable salt thereof, comprising the following steps 1 to 2;
(Step 1) Formula (9):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as above, and X ^1A represents a halogen. ]
A compound represented by or a salt thereof and formula (10):

[In the formula, P ^1A represents 2-indanol-1-yl, 2-phenylethan-1-ol-2-yl, or 3-methylbutan-1-ol-2-yl, and P ^2A is hydrogen or benzyl (the group is optionally substituted on the benzene ring with 1 to 5 substituents independently selected from the group consisting of halogen, C _1-6 alkyl and C _1-6 alkoxy); represent. ]
Diastereomer resolution is performed by reacting an optically active compound or a salt thereof represented by the formula (11-1):

[wherein R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ , P ^1A and P ^2A represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 2) A step of deprotecting the compound represented by formula (11-1) or a salt thereof to produce a compound represented by formula (2-1) or a pharmaceutically acceptable salt thereof.

[Item 48]
Item 48. A production method according to Item 47, wherein R ^1A is hydrogen and R ^2A is methyl.

[Section 49]
Item 49. The production method according to Item 47 or 48, wherein P ^1A is 2-indanol-1-yl and P ^2A is hydrogen.

［式中、
Ｒ^１Ａは、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２Ａは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１ＡとＲ^２Ａは、異なる置換基であり、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］
で表される化合物またはその製薬学的に許容される塩の製造方法であって、下記の工程１～３を含む製造方法；
（工程１）式（３－２）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は、上記と同じ基を表す。］
で表される化合物またはその塩と式（４ａ）または（４ｂ）：

［式中、Ｒ^７は、２－（メトキシカルボニル）エチル、メシチレンカルボニロキシメチル、２－ベンゾチアゾイル（該基は、ベンゼン環上に、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、水酸基、シアノ、ニトロ、アミノ（該アミノは、Ｃ_１－３アルキルによって１～２個置換されていてもよい）、カルボン酸、カルバモイル（該カルバモイルは、アミノ部分がＣ_１－３アルキルによって１～２個置換されていてもよい）、Ｃ_１－６アルコキシカルボニルからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、２-ピリジル、２-ピリミジニルまたは２－（トリメチルシリル）エチルから選択されるスルフィン酸塩を放出することが可能な脱離基を表す。］
で表される化合物またはその塩を反応させて、式（５－２）：

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同じ基を表す。]
で表される化合物またはその塩を製造する工程、
（工程２）式（５－２）で表される化合物またはその塩を酸化して、式（６－２）：

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、上記と同じ基を表す。]
で表される化合物またはその塩を製造する工程、
（工程３）式（６－２）で表される化合物またはその塩のＲ^７を除去してスルホンアミド化して、式（２－２）で表される化合物またはその製薬学的に許容される塩を製造する工程。 [Item 50]
Formula (2-2):

[In the formula,
R ^1A is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ^2A is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group), wherein R ^1A and R ^2A are different substituents,
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]
A method for producing a compound represented by or a pharmaceutically acceptable salt thereof, comprising the following steps 1 to 3;
(Step 1) Formula (3-2):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as above. ]
A compound represented by or a salt thereof and formula (4a) or (4b):

[In the formula, R ⁷ is 2-(methoxycarbonyl)ethyl, mesitylenecarbonyloxymethyl, 2-benzothiazolyl (the group is halogen, C _1-6 alkyl (the alkyl is halogen, optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is a halogen , hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), hydroxyl, cyano, nitro, amino (the amino optionally substituted 1 to 2 times with C _1-3 alkyl), carboxylic acid, carbamoyl (wherein the carbamoyl amino moiety is optionally substituted 1 to 2 times by C _1-3 alkyl) , C _1-6 alkoxycarbonyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of), 2-pyridyl, 2-pyrimidinyl or 2-(trimethylsilyl)ethyl represents a leaving group capable of releasing a sulfinate salt. ]
By reacting a compound represented by or a salt thereof, the formula (5-2):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 2) The compound represented by formula (5-2) or a salt thereof is oxidized to give formula (6-2):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 3) removing R ⁷ from the compound represented by formula (6-2) or a salt thereof to sulfonamidate the compound represented by formula (2-2) or a pharmaceutically acceptable The process of making salt.

[式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、項５０と同じ基を表し、Ｒ^８は、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ、Ｃ_１－６アルキルカルボニロキシメトキシを表す。]
で表される化合物またはその塩を、酸または塩基を用いて加水分解し、式（３－２）で表される化合物を製造する工程。 [Section 51]
51. The manufacturing method according to Item 50, comprising the following steps;
(Step 4a) Formula (7):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as in item 50, R ⁸ is C _1-6 alkyl (wherein said alkyl is halogen, hydroxyl group, C ₃ optionally substituted with 1 to 3 substituents independently selected from the group consisting of _-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy, C _1-6 alkylcarbonyloxy represents methoxy. ]
A step of hydrolyzing a compound represented by or a salt thereof with an acid or base to produce a compound represented by formula (3-2).

[式中、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５およびＲ^６は、項５０と同じ基を表す。]
で表される化合物またはその塩を、還元剤を用いて還元し、式（３－２）で表される化合物を製造する工程。 [Section 52]
51. The manufacturing method according to Item 50, wherein R ^1A is hydrogen and comprises the steps of;
(Step 4b) Formula (8):

[In the formula, R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as in item 50. ]
A step of reducing a compound represented by or a salt thereof with a reducing agent to produce a compound represented by formula (3-2).

[Section 53]
53. The production method according to any one of Items 50 to 52, wherein R ⁷ is 2-benzothiazolyl.

[Section 54]
Item 54. The production method according to any one of Items 50 to 53, wherein R ^1A is hydrogen and R ^2A is methyl.

［式中、
Ｒ^１Ａは、水素、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
Ｒ^２Ａは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１ＡとＲ^２Ａは、異なる置換基であり、
Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は、同一又は異なって、水素、ハロゲン、シアノ、ニトロ、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す。］
で表される化合物またはその製薬学的に許容される塩の製造方法であって、下記の工程１～２を含む製造方法；
（工程１）式（９）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、およびＲ^６は、上記と同じ基を表し、Ｘ^１Ａは、ハロゲンを表す。］
で表される化合物またはその塩と式（１０－２）：

［式中、Ｐ^１ＢおよびＰ^２Ｂは、同一または異なって、水素または窒素原子の保護基を表す。］
で表される化合物またはその塩を反応させて、式（１１－２）：

［式中、Ｒ^１Ａ、Ｒ^２Ａ、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｐ^１Ｂ、およびＰ^２Ｂは、上記と同じ基を表す。］
で表される化合物またはその塩を製造する工程、
（工程２）式（１１－２）で表される化合物またはその塩を脱保護して、式（２－２）で表される化合物またはその製薬学的に許容される塩を製造する工程、ただし、Ｐ^１Ｂ、およびＰ^２Ｂがいずれも水素である場合は、本工程は不要である。 [Section 55]
Formula (2-2):

[In the formula,
R ^1A is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ^2A is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group), wherein R ^1A and R ^2A are different substituents,
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ]
A method for producing a compound represented by or a pharmaceutically acceptable salt thereof, comprising the following steps 1 to 2;
(Step 1) Formula (9):

[In the formula, R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ and R ⁶ represent the same groups as above, and X ^1A represents a halogen. ]
A compound or a salt thereof represented by the formula (10-2):

[In the formula, P ^1B and P ^2B are the same or different and represent a protecting group for a hydrogen or nitrogen atom. ]
By reacting a compound represented by or a salt thereof, the formula (11-2):

[wherein R ^1A , R ^2A , R ³ , R ⁴ , R ⁵ , R ⁶ , P ^1B and P ^2B represent the same groups as above. ]
A step of producing a compound represented by or a salt thereof,
(Step 2) deprotecting the compound represented by formula (11-2) or a salt thereof to produce a compound represented by formula (2-2) or a pharmaceutically acceptable salt thereof; However, when both P ^1B and P ^2B are hydrogen, this step is unnecessary.

[Section 56]
Item 56. A production method according to Item 55, wherein R ^1A is hydrogen and R ^2A is methyl.

Since the compounds of the present invention have T-type calcium channel inhibitory activity, they are useful in various neurological or psychiatric disorders (e.g., epilepsy, essential tremor, Parkinson's disease, cerebellar ataxia, levodopa-induced dyskinesia in Parkinson's disease). , drug-induced dyskinesias, neuropathic pain including hyperalgesia and allodynia, nociceptive pain, migraines, schizophrenia, autism, bipolar disorder, depression, anxiety, sleep disorders, sleep disorders in depression , cardiac arrhythmia, hypertension, cancer, diabetes, infertility, sexual dysfunction, etc.). The compounds of the present invention also have a levodopa-induced hyperlocomotion-enhancing action that is not dependent on monoamine oxidase B (hereinafter referred to as "MAOB") inhibitory action. Since the risk of calculi is reduced, it is useful as a combination drug with levodopa preparations for the treatment of Parkinson's disease with high safety. Furthermore, since the compound of the present invention suppressed the onset of dyskinesia in a levodopa-induced dyskinesia model, it is useful as a Parkinson's disease therapeutic and/or prophylactic agent with high safety, unlike existing concomitant drugs with levodopa. In addition, since it showed efficacy against Parkinson's disease tremor models and essential tremor models, it was suggested that tremor in Parkinson's disease, essential tremor, and parkinsonism observed in neurological or psychiatric disorders. It is also useful as a therapeutic and/or prophylactic agent. Furthermore, since it showed an anti-allodynia effect in an oxaliplatin-induced pain model, it is also useful as a therapeutic and/or preventive drug for neuropathic pain (in particular, pain and allodynia in chemotherapy-induced peripheral neuropathy).

1-1 shows an X-ray crystal structure diagram of the compound of Example 13 obtained in Example 15. FIG. FIG. 1-1 is a front view of the benzisoxazole ring. 1-2 shows an X-ray crystal structure diagram of the compound of Example 13 performed in Example 15. FIG. Figures 1-2 are side views of the benzisoxazole ring. 2 is an X-ray powder diffraction pattern of the compound of Example 13 (Form I) as performed in Example 23. FIG. The x-axis indicates the 2θ value and the y-axis indicates the intensity. 3 is an X-ray powder diffraction pattern of the compound of Example 13 (Form II) as performed in Example 23. FIG. The x-axis indicates the 2θ value and the y-axis indicates the intensity. 4 is an X-ray powder diffraction pattern of the compound of Example 13 (Form III) as performed in Example 23. FIG. The x-axis indicates the 2θ value and the y-axis indicates the intensity. 5 shows differential scanning calorimetry (DSC) for the compound of Example 13 (Form I) performed in Example 24. FIG. The x-axis shows temperature (° C.) and the y-axis shows heat flow (Watts/g). 6 shows differential scanning calorimetry (DSC) for the compound of Example 13 (Form II) performed in Example 24. FIG. The x-axis shows temperature (° C.) and the y-axis shows heat flow (Watts/g). 7 shows differential scanning calorimetry (DSC) for the compound of Example 13 (Form III) performed in Example 24. FIG. The x-axis shows temperature (° C.) and the y-axis shows heat flow (Watts/g). 8 shows a thermogravimetric analysis (TGA) for the compound of Example 13 (Form I) performed in Example 25. FIG. The x-axis shows temperature (°C) and the y-axis shows weight variation (%). 9 shows a thermogravimetric analysis (TGA) for the compound of Example 13 (Form II) performed in Example 25. FIG. The x-axis shows temperature (°C) and the y-axis shows weight variation (%). 10 shows a thermogravimetric analysis (TGA) for the compound of Example 13 (Form III) performed in Example 25. FIG. The x-axis shows temperature (°C) and the y-axis shows weight variation (%). 11 shows the dynamic vapor sorption (DVS) for the compound of Example 13 (Form I) performed in Example 26. FIG. The x-axis shows relative humidity (%) and the y-axis shows mass variation (%). 12 shows the dynamic vapor sorption (DVS) for the compound of Example 13 (Form II) performed in Example 26. FIG. The x-axis shows relative humidity (%) and the y-axis shows mass variation (%). 13 shows the dynamic vapor sorption (DVS) for the compound of Example 13 (Form III) performed in Example 26. FIG. The x-axis shows relative humidity (%) and the y-axis shows mass variation (%). 14 is a graph showing the enhancing effect of the compounds of Examples 1 to 5 on levodopa-induced hyperlocomotion in reserpine-induced Parkinson's disease model mice in Test Example 2. FIG. The white column represents the total exercise amount of the levodopa alone administration group as 100%, and the colored column represents the combined administration of levodopa and each dose (mg/kg) of the example compound or rasagiline relative to the total exercise amount of the levodopa alone administration group. Represents the percentage (%) of the total momentum in FIG. 15 shows the 6-hydroxydopamine (6-OHDA)-induced unilateral nigrostriatal dopamine nerve destruction model for the compounds of Examples 1, 2, 3, 5, 8, 13, and 14 in Test Example 3. FIG. 2 shows the duration-prolonging effect of levodopa-induced rotational behavior in mice. The vertical axis represents the number of late phase rotations (between 100 minutes and 120 minutes from the start of observation of rotation behavior). The white column (Veh) represents the group administered with levodopa alone, and the colored column represents the group administered with levodopa in combination with the Example compound, safinamide or rasagiline, together with the dose (mg/kg) of each compound used in combination. FIG. 16 shows the anti-tremor action of the compounds of Examples 1 and 13 in the tacrine-induced Parkinson's disease tremor model in Test Example 4. The vertical axis represents the number of mandibular tremors for 10 minutes from 10 minutes after tacrine administration. A white column (Vehicle) represents a group administered with tacrine alone, and a colored column represents a group administered with tacrine in combination with an example compound together with the dose (mg/kg) of each example compound. 17 is a graph showing the levodopa-induced dyskinesia inhibitory effects of the compounds of Examples 1 and 13 in Test Example 5. FIG. The vertical axis represents the total dyskinesia-like symptom score scored every 20 minutes from 20 minutes to 180 minutes after administration of levodopa. The white column (MC) represents the repeated administration group of levodopa and solvent, and the colored column represents the repeated administration group of combined administration of levodopa and the compound of the example or rasagiline together with the dose (mg/kg) of each compound used in combination. 18 is a graph showing the tremor-suppressing effect of the compounds of Examples 1, 13 and 14 in harmaline-induced essential tremor model mice in Test Example 7. FIG. The vertical axis represents the intensity of the harmaline-induced tremor. The white column (Vehicle) represents the harmaline single administration group, the hatched column (Propranolol) represents the combined administration group of harmaline and β-propranolol (10 mg/kg), and the colored column represents the combined administration group of harmaline and the example compound. , together with the dose (mg/kg) of each compound used in combination. 19 shows the anti-cold allodynia effect of the compound of Example 13 in a chemotherapy-induced peripheral neuropathy model in Test Example 8. FIG. The vertical axis represents the total score in the acetone test. White columns represent the oxaliplatin+solvent multiple administration groups before and after multiple oxaliplatin treatments, and colored columns represent the oxaliplatin+example compound or duloxetine multiple administration groups. FIG. 20 shows the anti-tremor action of the compound of Example 13 in Test Example 10 in the 6-OHDA unilateral nigrostriatal dopamine nerve destruction model. The vertical axis represents the number of mandibular tremors for 10 minutes in this model. A white column (Vehicle) represents a solvent-administered group, and a colored column represents an example compound-administered group together with its dosage (mg/kg). FIG. 21 is a graph showing the inhibitory action of the compound of Example 13 on neuronal firing in mouse brain slices in Test Example 11. FIG. The vertical axis indicates the ratio of spike firing frequencies in neurons before and after addition of the compound of the example, measured by the patch clamp technique, in percentage. A and B represent the results in subthalamic nucleus neurons and cerebellar Purkinje cells, respectively. Compound doses are given as concentrations (μmol/L) in the recording solution perfusing the brain slices. 22 is a diagram showing the anxiolytic action of the compound of Example 13 in Test Example 12. FIG. The vertical axis in FIG. 9A indicates the ratio of the open arm entry to the total number of arm entries, and the vertical axis in FIG. 9B indicates the ratio of the open arm stay time to the total search time. The white column (Vehicle) represents the solvent administration group, the hatched column (DZP_3) is the anxiolytic drug diazepam (diazepam) 3 mg/kg administration group used as a positive control substance, and the colored column is the administration group of Example 13. and the number at the lower limit of the column represents the dose. FIG. 23 shows (A) NREM sleep latency, (B) REM sleep latency, (C) awakening time, (D) NREM sleep time, and (E) REM sleep for the compound of Example 13 in Test Example 13. FIG. 10 is a diagram showing the effect on time; The vertical axis represents the total time in minutes up to 6 hours after administration. The white column represents the solvent-administered group, the gray column represents the compound dose group of Example 13, and the dose (mg/kg) is shown numerically.

The terms used in this specification are explained below.

In this specification, unless otherwise indicated, the description of each group also applies when that group is part or a substituent of another group.

"Halogen" includes, for example, fluorine, chlorine, bromine, or iodine. Fluorine or chlorine is preferred. Fluorine is more preferred.

“C _1-6 alkyl” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, “C ₆ alkyl” means alkyl having 6 carbon atoms means The same is true for other numbers. "C _1-6 alkyl" preferably includes "C _1-4 alkyl", more preferably "C _1-3 alkyl". Specific examples of “C _1-3 alkyl” include methyl, ethyl, propyl, 1-methylethyl and the like. Specific examples of "C _1-4 alkyl" include, in addition to those listed above as specific examples of "C _1-3 alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methyl propyl and the like. Specific examples of "C _1-6 alkyl" include, in addition to those listed above as specific examples of "C _1-4 alkyl", pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

“C _3-6 cycloalkyl” means a cyclic alkyl having 3 to 6 carbon atoms, including partially crosslinked structures. “C _3-6 cycloalkyl” preferably includes “C _3-5 cycloalkyl”. Specific examples of “C _3-5 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl and the like. Specific examples of “C _3-6 cycloalkyl” include, in addition to those exemplified above for ““C _3-5 cycloalkyl”, cyclohexyl and the like.

“C _1-6 alkoxy” means an oxy group substituted with the above “C _1-6 alkyl”. The “C _1-6 alkoxy group” preferably includes “C _1-4 alkoxy”, more preferably “C _1-3 alkoxy”. Specific examples of “C _1-3 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy and the like. Specific examples of "C _1-4 alkoxy" include, in addition to those listed above as specific examples of "C _1-3 alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl propoxy. Specific examples of "C _1-6 alkoxy" include, in addition to those listed above as specific examples of "C _1-4 alkoxy", penthyloxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethyl propoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

“C _1-6 alkoxycarbonyl” means a carbonyl group substituted with the above “C _1-6 alkoxy”. The “C _1-6 alkoxycarbonyl group” preferably includes “C _1-4 alkoxycarbonyl”, more preferably “C _1-3 alkoxycarbonyl”. Specific examples of “C _1-3 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl and the like. Specific examples of "C _1-4 alkoxycarbonyl" include, in addition to the specific examples of "C _1-3 alkoxycarbonyl", butoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1-methylpropoxy carbonyl, 2-methylpropoxycarbonyl. Specific examples of "C _1-6 alkoxycarbonyl" include, in addition to those given as specific examples of "C _1-4 alkoxycarbonyl" above, pentyloxycarbonyl, 3-methylbutoxycarbonyl, 2-methylbutoxycarbonyl , 2,2-dimethylpropoxycarbonyl, 1-ethylpropoxycarbonyl, 1,1-dimethylpropoxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl , hexyloxycarbonyl and the like.

“C _1-6 alkylcarbonyloxymethoxy” means a carbonyloxymethoxy group substituted with the aforementioned “C _1-6 alkyl”. The “C _1-6 alkylcarbonyloxymethoxy group” preferably includes “C _1-4 alkylcarbonyloxymethoxy”, more preferably “C _1-3 alkylcarbonyloxymethoxy”. Specific examples of “C _1-3 alkylcarbonyloxymethoxy” include methylcarbonyloxymethoxy, ethylcarbonyloxymethoxy, propylcarbonyloxymethoxy, 1-methylethylcarbonyloxymethoxy and the like. Specific examples of "C _1-4 alkylcarbonyloxymethoxy" include, in addition to the specific examples of "C _1-3 alkylcarbonyloxymethoxy", butoxycarbonyloxymethoxy, 1,1 -dimethylethylcarbonyloxymethoxy, 1-methylpropylcarbonyloxymethoxy, 2-methylpropylcarbonyloxymethoxy. Specific examples of "C _1-6 alkylcarbonyloxymethoxy" include, in addition to the specific examples of "C _1-4 alkylcarbonyloxymethoxy", pentylcarbonyloxymethoxy, 3-methyl butylcarbonyloxymethoxy, 2-methylbutylcarbonyloxymethoxy, 2,2-dimethylpropylcarbonyloxymethoxy, 1-ethylpropylcarbonyloxymethoxy, 1,1-dimethylpropylcarbonyloxymethoxy, 4-methylpentyl carbonyloxymethoxy, 3-methylpentylcarbonyloxymethoxy, 2-methylpentylcarbonyloxymethoxy, 1-methylpentylcarbonyloxymethoxy, hexylcarbonyloxymethoxy and the like.

Among R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , preferred ones are as follows, but the technical scope of the present invention is not limited to the compounds listed below.

A preferred embodiment of R ¹ and R ² is that R ¹ is hydrogen, fluorine, C _1-6 alkyl (wherein said alkyl is independently from the group consisting of fluorine, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy). or C _3-6 cycloalkyl (wherein the cycloalkyl is the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from
R ² is fluorine, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a group) or
Alternatively, R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein said cycloalkyl is from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy) (optionally substituted with 1 to 3 independently selected substituents).

A more preferred embodiment of R ¹ and R ² is that R ¹ is hydrogen, fluorine, or C _1-6 alkyl (wherein the alkyl is independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy 1 optionally substituted with ~3 substituents),
R ² is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); or
Alternatively, R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein said cycloalkyl is from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy) (optionally substituted with 1 to 3 independently selected substituents).

An even more preferred embodiment of R ¹ and R ² is that R ¹ _{is hydrogen or C 1-6 alkyl} (wherein the alkyl is 1 to optionally substituted with 3 substituents),
whether R ² is C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy); ,
Alternatively, R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein said cycloalkyl is from the group consisting of fluorine, hydroxy, C _1-3 alkyl and C _1-3 alkoxy) (optionally substituted with 1 to 3 independently selected substituents).

Examples of the C _3-6 cycloalkyl formed together with the carbon atoms to which R ¹ and R ² are attached include (2a) to (2d) below. (2a) or (2b) is preferred, and (2a) is more preferred.

In a preferred embodiment of R ³ , R ⁴ , R ⁵ and R ^{6 , R 3 , R 4 , R 5 and R 6 are the same or} different and are hydrogen, halogen (the halogen is fluorine, chlorine or bromine). is preferred), cyano, nitro, C _1-6 alkyl (wherein said alkyl has 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy ), C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy) optionally substituted with a substituent), or C _1-6 alkoxy (wherein the alkoxy is 1-3 independently selected from the group consisting of fluorine, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy) may be substituted with one substituent).

A more preferred embodiment of R ³ , R ⁴ , R ⁵ and R ⁶ is that R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen (the halogen is fluorine or chlorine). preferred), or C _1-3 alkoxy (the alkoxy may be optionally substituted with 1 to 3 fluorines).

In preferred embodiments of R ^1A and _R ^2A , R ^1A is hydrogen, fluorine, or C _1-6 alkyl (wherein the alkyl is 1 to optionally substituted with 3 substituents),
R ^2A is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); mentioned. Here, R ^1A and R ^2A are different substituents.

A more preferred embodiment of R ^1A and R ^2A is that R ^1A is hydrogen or C _1-6 alkyl (wherein the alkyl is 1 to 3 independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy). optionally substituted with one substituent),
R ^2A includes C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); . Here, R ^1A and R ^2A are different substituents.

In an even more preferred embodiment of R ^1A and R ^2A , R ^1A is hydrogen,
R ^2A includes methyl.

Preferred embodiments of R ⁷ include 2-(methoxycarbonyl)ethyl, mesitylenecarbonyloxymethyl, 2-benzothiazolyl (wherein the benzene ring has halogen, C _1-6 alkyl (wherein said alkyl is halogen, optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is a halogen , hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted with 1 to 3 substituents), 2-pyridyl, 2-pyrimidinyl or 2-(trimethylsilyl)ethyl.

A more preferred embodiment of R ⁷ is 2-benzothiazolyl (wherein the group is halogen, C _1-6 alkyl (wherein the alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and C _1- optionally substituted with ₁ to 3 substituents independently selected from the group consisting of 3alkoxy), optionally substituted with 1 to 3 substituents independently selected from the group consisting of good), 2-pyrimidinyl or 2-(trimethylsilyl)ethyl.

An even more preferred embodiment of R ⁷ includes 2-benzothiazolyl.

Preferred embodiments of R ⁸ include C _1-6 alkyl, and more preferred embodiments include methyl.

Preferred embodiments of X ^1A include halogen, more preferred embodiments include chlorine or bromine, and even more preferred embodiments include chlorine.

In preferred embodiments of P ^1A and P ^2A , P ^1A is 2-indanol-1-yl, 2-phenylethan-1-ol-2-yl, 3-methylbutan-1-ol-2-yl,
P ^2A includes hydrogen, 2,4-dimethoxybenzyl and p-methoxybenzyl.

In a more preferred embodiment of P ^1A and P ^2A , P ^1A is 2-indanol-1-yl or 2-phenylethan-1-ol-2-yl,
P ^2A includes hydrogen.

In a still more preferred embodiment of P ^1A and P ^2A , P ^1A is 2-indanol-1-yl,
P ^2A includes hydrogen.

Preferred embodiments of P ^1B and P ^2B are the same or different and are hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl (the benzyloxycarbonyl is substituted on the phenyl moiety with 1 to 5 C _1-6 alkoxy, may be substituted), benzyl (wherein the benzyl is optionally substituted with 1 to 5 C _1-6 alkoxy on the phenyl moiety).

More preferred embodiments of P ^1B and P ^2B are the same or different and include hydrogen, 2,4-dimethoxybenzyl or p-methoxybenzyl.

Preferred embodiments of hydrolases include lipases, esterases, amidases, or proteases.

A more preferred embodiment of the hydrolase is lipase.

Preferred embodiments of the reductase include carbonyl reductase and alcohol dehydrogenase, more preferably carbonyl reductase.

A preferred embodiment of the coenzyme includes NADH or NADPH, more preferably NADPH.

Preferred embodiments of the acid or base used in the hydrolysis reaction include hydrochloric acid, sulfuric acid, or trifluoroacetic acid as the acid, and sodium hydroxide, potassium hydroxide, or lithium hydroxide as the base.

Preferred embodiments of the reducing agent include sodium borohydride, lithium borohydride, and lithium aluminum hydride.

Preferred embodiments of the nitrogen atom-protecting group include tert-butoxycarbonyl, benzyloxycarbonyl (the benzyloxycarbonyl may be substituted by 1 to 5 C _1-6 alkoxy on the phenyl moiety), benzyl (the Benzyl optionally has 1 to 5 C _1-6 alkoxy substitutions on the phenyl moiety), preferably 2,4-dimethoxybenzyl or p-methoxybenzyl.

Among the compounds represented by formula (1), preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.

One aspect of the compound represented by Formula (1) includes the following (A).
(A)
R ¹ is hydrogen or halogen,
R ² is halogen or C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; ) and
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different, hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), or C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and (optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy) or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by Formula (1) includes the following (B).
(B)
R ¹ and R ² are C _1-6 alkyl, wherein the alkyl is 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; may be substituted) and
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different, hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), or C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and (optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy) or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by Formula (1) includes the following (C).
(C)
R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein said cycloalkyl is independently from the group consisting of halogen, hydroxy, C _1-3 alkyl and C _1-3 alkoxy; optionally substituted with 1 to 3 substituents selected by
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different, hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), or C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-3 alkoxy), C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and (optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy) or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by formula (1) includes the following (D).
(D)
R ¹ is hydrogen, fluorine, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy; good) and
R ² is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); or
Alternatively, R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein said cycloalkyl is from the group consisting of fluorine, hydroxy, C _1-3 alkyl and C _1-3 alkoxy) (optionally substituted with 1 to 3 independently selected substituents),
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen (preferably fluorine or chlorine as the halogen), or C _1-3 alkoxy (the alkoxy is 1 to 3 (optionally fluorine-substituted) or a pharmaceutically acceptable salt thereof.

One aspect of the compound represented by Formula (1) includes the following (E).
(E)
R ¹ is hydrogen or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); can be,
whether R ² is C _1-6 alkyl (the alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl and C _1-3 alkoxy); ,
Alternatively, R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (wherein said cycloalkyl is from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy) (optionally substituted with 1 to 3 independently selected substituents),
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen (preferably fluorine or chlorine as the halogen), or C _1-6 alkoxy (wherein the alkoxy is 1 to 3 optionally substituted) or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by Formula (1) includes the following compounds.
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(1,2-benzoxazol-3-yl)-1-fluoromethanesulfonamide (Example 3),
1-(1,2-benzoxazol-3-yl)-1,1-difluoromethanesulfonamide (Example 4),
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
1-(1,2-benzoxazol-3-yl)propane-1-sulfonamide (Example 6),
1-(1,2-benzoxazol-3-yl)butane-1-sulfonamide (Example 7),
1-(1,2-benzoxazol-3-yl)-1-fluoroethane-1-sulfonamide (Example 8),
1-(1,2-benzoxazol-3-yl)-2-methylpropane-1-sulfonamide (Example 9),
1-(5-methoxy-1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 10),
1-(5-fluoro-1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 11),
1-(5-chloro-1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 12),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

One embodiment of the compound represented by Formula (1) includes the following compounds.
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(1,2-benzoxazol-3-yl)-1-fluoromethanesulfonamide (Example 3),
1-(1,2-benzoxazol-3-yl)-1,1-difluoromethanesulfonamide (Example 4),
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
1-(1,2-benzoxazol-3-yl)-1-fluoroethane-1-sulfonamide (Example 8),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

One embodiment of the compound represented by Formula (1) includes the following compounds.
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide (Example 2),
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide (Example 5),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

One embodiment of the compound represented by Formula (1) includes the following compounds.
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 1),
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (Example 13), or (1S)-1-(1,2-benzoxazol-3-yl)ethane -1-sulfonamide (Example 14).

Polymorphism exists in some of the compounds of formula (I). The crystalline substance is subjected to X-ray powder diffraction (hereinafter “XRPD”) analysis, differential scanning calorimetry (hereinafter “DSC”), thermogravimetric analysis (hereinafter “TGA”), dynamic vapor adsorption (hereinafter “DVS ”), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, liquid phase and/or solid phase nuclear magnetic resonance spectroscopy. there is Also, the water content of the crystalline substance can be measured by Karl Fischer analysis.

For example, although polymorphs exist for the compound of Example 13 and three crystalline forms (Form I, Form II and Form III) are identified herein, the crystalline forms of the present invention are those crystalline forms. It is not limited.

A further aspect of the invention includes Form I crystalline form of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 5.7°±0.2 A crystalline form (Form I) having an X-ray powder diffraction pattern with characteristic peaks at .degree.

A further aspect of the present invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 17.3°±0.2 A crystalline form (Form I) having an X-ray powder diffraction pattern with characteristic peaks at .degree.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 5.7°±0.2 °, and 17.3° ± 0.2° with characteristic peaks at 17.3° ± 0.2°.

As a further aspect of the invention is Form I a crystalline form of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide, expressed in 2θ, of 5.7 °±0.2°, 14.1±0.2°, 17.3°±0.2°, 19.1°±0.2°, 19.3°±0.2°, 21.6° Characteristic at ±0.2°, 22.5°±0.2°, 23.1°±0.2°, 23.3°±0.2°, and 26.5°±0.2° Those having a powder X-ray diffraction pattern with peaks are included. The crystal is identified by having 4 or 5 selected from these 10 peaks.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having substantially the same X-ray powder diffraction pattern as shown in FIG. There is a crystalline form (Form I) that has an X-ray powder diffraction pattern.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a differential scanning calorimetry (DSC) of 144.0° C.±5 A crystalline form (Form I) that has an endothermic peak associated with melting with an extrapolated onset temperature (Tim) at °C.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a DSC thermogram substantially identical to the DSC thermogram shown in FIG. There is a crystalline form (Form I) with gram.

As a further aspect of the present invention, (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a TGA graph substantially the same as the TGA graph shown in FIG. crystalline form (Form I) having

As a further aspect of the invention, (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide has substantially the same DVS graph as shown in FIG. crystalline form (Form I) having

Form I of Example 13 can be prepared by concentrating an acetonitrile solution of Example 13 or by shaking an aqueous suspension of a mixture of Forms I and II of Example 13 at 25° C. for 9-11 days. .

A further aspect of the invention includes Form II crystalline form of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 17.6°±0.2 A crystalline form (Form II) having an X-ray powder diffraction pattern with characteristic peaks at .degree.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 8.7°±0.2 A crystalline form (Form II) having an X-ray powder diffraction pattern with characteristic peaks at .degree.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 8.7°±0.2 °, and 17.6° ± 0.2° with characteristic peaks at 17.6° ± 0.2°.

As a further aspect of the invention is Form II a crystalline form of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide, expressed in 2θ, of 8.7 °±0.2°, 13.5°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 20.3°±0.2°, 21.6° Characteristic at °±0.2°, 22.6°±0.2°, 26.2°±0.2°, 26.8°±0.2° and 35.2°±0.2° Those having a powder X-ray diffraction pattern with peaks are included. The crystal is identified by having 4 or 5 selected from these 10 peaks.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having substantially the same X-ray powder diffraction pattern as shown in FIG. There is a crystalline form (Form II) that has an X-ray powder diffraction pattern.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a differential scanning calorimetry (DSC) of 143.8° C.±5 A crystalline form (Form II) having an endothermic peak associated with melting with an extrapolated onset temperature (Tim) at °C.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a DSC thermogram substantially identical to the DSC thermogram shown in FIG. There is a crystalline form (Form II) with gram.

As a further aspect of the invention, (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a TGA graph substantially the same as the TGA graph shown in FIG. crystalline form (Form II).

As a further aspect of the invention, (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide has substantially the same DVS graph as shown in FIG. crystalline form (Form II).

Form II of Example 13 is prepared by heating an acetonitrile/water (1:1) or acetone/heptane (1:1) solution of Example 13 at about 80° C. for about 1 hour and standing at room temperature for 1 day. It can be manufactured by

A further aspect of the invention includes Form III crystalline form of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide.

A further aspect of the present invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 11.1°±0.2 A crystalline form (Form III) having an X-ray powder diffraction pattern with characteristic peaks at .degree.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 20.3°±0.2 A crystalline form (Form III) having an X-ray powder diffraction pattern with characteristic peaks at .degree.

A further aspect of the present invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide wherein the 2θ is at least 11.1°±0.2 °, and 20.3° ± 0.2° with characteristic peaks at 20.3° ± 0.2°.

As a further aspect of the invention, the crystalline form of Form III (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide, expressed in 2θ, is 11.1 °±0.2°, 13.8°±0.2°, 17.0°±0.2°, 20.3°±0.2°, 21.4°±0.2°, 22.1° Characteristic at °±0.2°, 22.4°±0.2°, 24.8°±0.2°, 26.3°±0.2°, and 27.9°±0.2° and those having a powder X-ray diffraction pattern with a peak. The crystal is identified by having 4 or 5 selected from these 10 peaks.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having substantially the same X-ray powder diffraction pattern as shown in FIG. There is a crystalline form (Form III) that has an X-ray powder diffraction pattern.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a differential scanning calorimetry (DSC) of 142.5° C.±5 There is a crystalline form (Form III) that has an endothermic peak associated with melting with an extrapolated onset temperature (Tim) at °C.

A further aspect of the invention is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a DSC thermogram substantially identical to the DSC thermogram shown in FIG. There is a crystalline form (Form III) with gram.

As a further aspect of the invention, (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide having a TGA graph substantially the same as the TGA graph shown in FIG. crystalline form (Form III) having

As a further aspect of the invention, (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide has substantially the same DVS graph as that shown in FIG. crystalline form (Form III) having

Form III of Example 13 is prepared by reacting a suspension of Example 13 in an organic solvent (such as ethanol, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, acetone and tetrahydrofuran/heptane mixture (1:1)) at about 50° C. It can be manufactured by shaking for 11 days. Alternatively, the organic solvent (acetonitrile, ethyl acetate, acetone, acetonitrile, ethyl acetate, acetone, acetone/water mixture (1:1), and tetrahydrofuran/heptane mixture (1:1), etc.) suspension of Example 13 was added at about 25 ° C. It can be manufactured by shaking for days. Alternatively, a suspension of a mixture of Forms I and II of Example 13 in organic solvents such as ethanol, 2-propanol, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, and a 1:1 tetrahydrofuran/heptane mixture. It can be prepared by shaking at about 50° C. for 9-11 days. or the organic solvent of the mixture of Forms I and II of Example 13 (2-propanol, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, acetone, methanol/water mixture (1:1), 2-propanol/water mixture (1:1) 1), acetone/water mixture (1:1), and tetrahydrofuran/heptane mixture (1:1))) can be prepared by shaking the suspension at about 25° C. for 9-11 days. Alternatively, it can be produced by heating the tert-butyl methyl ether solution of Example 13 at about 80° C. for about 1 hour and allowing it to stand at room temperature for 1 day. Form III is a restabilizing form because it can be reproducibly prepared by shaking a multi-solvent suspension of Forms I-III for 9-11 days.

The 2-theta values of X-ray powder diffraction patterns can vary slightly from instrument to instrument or sample to sample, so the numbers given here are not absolute (Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), see X-Ray Diffraction Procedures). Generally, the measurement error of diffraction angles in X-ray powder diffraction spectra is, for example, about ±0.2° in 2θ, and that degree of measurement error should be taken into account when considering X-ray powder diffraction data. . Furthermore, the intensity can vary depending on experimental conditions and sample preparation (preferred orientation). In the present application, measurements are given when carried out using copper radiation (Cu Kα1, λ=1.5406 Å, Kα2, λ=1.5444 Å).

It is also known that X-ray powder diffraction patterns can be obtained with one or more measurement errors depending on the measurement conditions (eg the instrumentation or equipment used). For example, grains with non-uniform sizes and aspect ratios greater than 30 microns can affect the relative intensities of the peaks. Also, the position of the reflection can be affected by the exact height at which the sample is placed in the diffractometer and the zero calibration of the diffractometer. The planarity of the sample surface can also have some effect. Thus, unless otherwise stated, the crystalline forms of the present invention described above are not limited to crystals that provide the X-ray powder diffraction patterns shown in FIGS. Any crystal that provides an X-ray powder diffraction pattern substantially the same as is included within the scope of the present invention.

Moreover, ±5° C. is allowed for the extrapolation start temperature (Tim) of differential scanning calorimetry (DSC), the endothermic peak temperature (Tpm), and the like. The extrapolation start temperature (Tim) of differential scanning calorimetry (DSC) refers to the temperature at the intersection of the extrapolated line of the rising portion of the endothermic peak curve and the baseline, and the endothermic peak temperature (Tpm) , refers to the peak top temperature of the endothermic peak.

"Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate and phosphate, or citrate, oxalate, phthalate, Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonic acid organic acid salts such as salts and camphorsulfonates; Base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine and diethanolamine. , triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylamine, and the like. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

Suitable salts and pharmaceutically acceptable salts of starting compounds and intermediates are the conventional non-toxic salts, including organic acid salts (e.g. acetates, trifluoroacetates, maleates, fumaric acid salts). salt, citrate, tartrate, methanesulfonate, benzenesulfonate, formate or para-toluenesulfonate, etc.) and inorganic acid salts (e.g. hydrochloride, hydrobromide, hydroiodide) , sulfates, nitrates or phosphates), salts with amino acids (eg arginine, aspartic acid or glutamic acid), alkali metal salts (eg sodium or potassium salts) and alkaline earth metals Metal salts such as salts (e.g. calcium salts or magnesium salts), ammonium salts, or organic base salts (e.g. trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts or N,N'-dibenzylethylenediamine salts, etc.) ), etc., can be appropriately selected by those skilled in the art.

When it is desired to obtain a salt of the compound of the present invention, when the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and when it is obtained in the free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended, and an acid or base may be added to form a salt by a conventional method.

In the present invention, a deuterium conversion product obtained by converting any one or two or more ¹ H of the compound represented by formula (1) to ² H(D) is also a compound represented by formula (1). subsumed.
The present invention includes a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. In addition, the compounds of the present invention may exist in the form of hydrates and/or solvates with various solvents (ethanolates, etc.), so these hydrates and/or solvates are also Included in the compounds of the invention. Furthermore, the present invention includes all tautomers, all existing stereoisomers, and all forms of crystalline forms of compound (1) of the present invention, as well as mixtures thereof.

The compound (1) of the present invention includes optical isomers based on an optically active center, atropisomers based on axial or planar chirality caused by restriction of intramolecular rotation, other stereoisomers, and tautomers. All possible isomers, racemates and mixtures thereof, including isomers, geometric isomers, etc., which may exist, are included within the scope of the present invention.

In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. If necessary, at an appropriate stage in the production process below, the corresponding starting material, intermediate or racemate of the final product can be physically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. or chemically into their optical antipodes. Specifically, for example, in the diastereomer method, two diastereomers are formed from a racemate by a reaction using an optically active resolving agent. The different diastereomers generally have different physical properties and can be resolved by known methods such as fractional crystallization.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じである。Ｐ^１は、２，４－ジメトキシベンジル、ｐ－メトキシベンジル、２－インダノール－１－イル、２－フェニルエタン－１－オール－２－イル、３－メチルブタン－１－オール－２－イル等の、酸性条件で除去することのできる窒素原子の保護基であり、Ｐ^２は、水素、または２，４－ジメトキシベンジル、ｐ－メトキシベンジル、２－インダノール－１－イル、２－フェニルエタン－１－オール－２－イル、３－メチルブタン－１－オール－２－イル等の、酸性条件で除去することのできる窒素原子の保護基である。） Manufacturing method 1
The compound of formula (I) [compound of formula (Ia) below] can be produced by the following production method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in Item 1. ^{P 1} is 2,4-dimethoxybenzyl, p-methoxybenzyl, 2-indanol -1-yl, 2 ^- phenylethan-1-ol-2-yl, 3-methylbutan-1-ol-2-yl, a nitrogen atom-protecting group that can be removed under acidic conditions; is hydrogen, or 2,4-dimethoxybenzyl, p-methoxybenzyl, 2-indanol-1-yl, 2-phenylethan-1-ol-2-yl, 3-methylbutan-1-ol-2-yl, etc. is a nitrogen atom-protecting group that can be removed under acidic conditions.)

Deprotection of compound (IIa) provides compound (Ia).

Deprotection of compound (IIa) can be carried out according to a conventional method. For example, this reaction can be achieved by reacting compound (IIa) with a strong organic acid such as trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or a strong inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid.

Deprotection of compound (IIa) is carried out in a solvent or without solvent. Specific examples of the solvent should be selected according to the type of starting compound, etc. Examples include toluene, THF, dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. Alternatively, it can be used as a mixed solvent. In addition to the 2,4-dimethoxybenzyl group as the protecting group of the compound (IIa), a protecting group that is cleaved under acidic conditions, such as a t-butoxycarbonyl group, a t-butyl group, and a p-methoxybenzyl group, may be substituted. . Although the reaction temperature varies depending on the type of starting compound used, it is usually about -30°C to about 150°C, preferably about -10°C to about 70°C. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じである。Ｐ^１及びＰ^２は、製造法１と同義である。） Manufacturing method 2
Compound (IIa) used in the above production method is produced according to the method shown by the following reaction scheme.

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in item 1. ^{P 1} and P ² are the same as in production method 1.)

(Step 1): Compound (VIIa) is reacted with hydroxylamine to obtain compound (VIa).

The reaction of step 1 can be carried out according to a conventional method. For example, this reaction is carried out by reacting compound (VIIa) with hydroxylamine in the presence or absence of a base in a suitable solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and include ethers such as Et ₂ O, THF, dioxane, and DME, alcohols such as methanol, ethanol, and isopropyl alcohol, water, and toluene. etc., and can be used singly or as a mixed solvent. Further, specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkoxy alkali metals such as potassium t-butoxy, sodium carbonate, potassium carbonate, lithium carbonate and the like. Organic bases such as alkali metal carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine and 4-dimethylaminopyridine can be mentioned. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 2): Compound (Va) is obtained by reacting compound (VIa) with chlorosulfuric acid.

The reaction of step 2 can be carried out according to a conventional method. For example, this reaction is accomplished by reacting compound (VIa) with chlorosulfuric acid in a solvent. Specific examples of the solvent should be selected according to the kind of the raw material compound, etc. Examples include Et ₂ O, THF, dioxane, DME, toluene, etc., and can be used alone or as a mixed solvent. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 3): Compound (IVa) is obtained by sulfonamidating compound (Va).

The reaction of step 3 can be carried out according to a conventional method. For example, this reaction is achieved by converting compound (Va) into a sulfonyl chloride and then reacting it with an amine. Conversion to sulfonyl chloride is carried out by reacting phosphorus oxychloride in a solvent or in the absence of solvent. Specific examples of the solvent should be selected according to the kind of the raw material compound, etc. Examples include Et ₂ O, THF, dioxane, DME, toluene, etc., and can be used alone or as a mixed solvent. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

The conversion of the intermediate sulfonyl chloride of step 3 to the sulfonamide, in a solvent with or without base, is carried out on the amine NHP ¹ P ² mono- or di-substituted by protecting groups that can be removed under acidic conditions. is performed by acting Specific examples of the solvent should be selected according to the _type of the raw material compound and the like. can be done. Further, specific examples of the base used include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkoxy alkali metals such as potassium t-butoxy, sodium carbonate, potassium carbonate, lithium carbonate and the like. Organic bases such as alkali metal carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine and 4-dimethylaminopyridine can be mentioned. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 4): Compound (IVa) is alkylated or halogenated to give compound (IIIa). However, this step is omitted when R ¹ is hydrogen.

The alkylation or halogenation reaction in step 4 can be carried out according to a conventional method. For example, in the alkylation reaction, compound (IVa) and alkyl halide R ¹ X are reacted in an appropriate solvent in the presence of a base, and in the halogenation reaction, compound (IVa) and a halogenating reagent are reacted in an appropriate solvent in the presence of a base. It is carried out by reacting. Specific examples of the solvent should be selected according to the type of the raw material compound, and include THF, dioxane, DME, HMPA, DMPU, etc., which can be used singly or as a mixed solvent. Specific examples of the base used include alkyllithium reagents such as n-butyllithium and s-butyllithium, alkalis such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydride and potassium t-butoxy. metal reagents. Specific examples of halogenating reagents include N-fluorobenzenesulfonimide, (diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride and the like. The reaction temperature is usually -100 to 50.degree. C., preferably -78 to 25.degree. The reaction time is usually 30 minutes to 24 hours.

(Step 5): Compound (IIa) is obtained by alkylating or halogenating compound (IIIa).

The alkylation or halogenation reaction in step 5 can be carried out according to a conventional method. For example, in the alkylation reaction, compound (IIIa) and alkyl halide R ² X are reacted in an appropriate solvent in the presence of a base, and in the halogenation reaction, compound (IIIa) and a halogenating reagent are reacted in an appropriate solvent in the presence of a base. It is carried out by reacting. Specific examples of the solvent should be selected according to the type of starting compound, and include THF, dioxane, DME, HMPA, DMPU, etc., which can be used singly or as a mixed solvent. Specific examples of bases to be used include alkyllithium reagents such as n-butyllithium and s-butyllithium, alkalis such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydride and potassium t-butoxy. metal reagents. Specific examples of halogenating reagents include N-fluorobenzenesulfonimide, (diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride and the like. The reaction temperature is usually -100 to 50.degree. C., preferably -78 to 25.degree. The reaction time is usually 30 minutes to 24 hours.

In compound (IIa), when R ¹ and R ² are different and at least one of P ¹ and P ² is an optically active substance, compound (IIa) is a diastereomeric mixture. When compound (IIa) is a diastereomeric mixture, it can be resolved according to conventional methods. For example, resolution of diastereomers is accomplished by chromatography, fractional crystallization, and the like.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、およびＰ^２は製造法１と同義である。Ｐ^１Ｂは、水素、または２，４－ジメトキシベンジル、ｐ－メトキシベンジル、２－インダノール－１－イル、２－フェニルエタン－１－オール－２－イル、３－メチルブタン－１－オール－２－イル等の、酸性条件で除去することのできる窒素原子の保護基であり、Ｐ^３は置換されていてもよいＣ_１－６アルキルまたは置換されていてもよいＣ_３－６シクロアルキル等の、酸素原子の保護基である。） Manufacturing method 3
Compound (IIa) used in production method 1 can also be produced according to the method shown by the following reaction scheme.

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and P ² are the same as in production method 1. P ^1B is hydrogen, or 2,4-dimethoxybenzyl, p- Protection of nitrogen atoms that can be removed under acidic conditions, such as methoxybenzyl, 2-indanol-1-yl, 2-phenylethan-1-ol-2-yl, 3-methylbutan-1-ol-2-yl, etc. and P ³ is an oxygen atom-protecting group such as optionally substituted C _1-6 alkyl or optionally substituted C _3-6 cycloalkyl.)

(Step 1): Compound (Va) is esterified to give compound (VIIIa).

The reaction of step 1 can be carried out according to a conventional method. For example, this reaction is carried out by reacting compound (Va) with an alkyl halide in the presence of a silver salt in a suitable solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and include ethers such as Et ₂ O, THF, dioxane, and DME, alcohols such as methanol, ethanol, and isopropyl alcohol, water, and toluene. , acetonitrile, DMF, NMP, DMSO, etc., and can be used alone or as a mixed solvent. Specific examples of silver salts used include silver oxide, silver chloride and silver bromide. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 2): Compound (VIIIa) is alkylated or halogenated to give compound (IXa). However, this step is omitted when R ¹ is hydrogen.

The alkylation or halogenation reaction in step 2 can be carried out according to the method described in step 4 of production method 2.

(Step 3): Compound (Xa) is obtained by alkylating or halogenating compound (IXa).

The alkylation or halogenation reaction in step 3 can be carried out according to the method described in step 5 of production method 2.

(Step 4): Compound (Xa) is de-esterified to give compound (XIa).

The reaction of step 4 can be carried out according to a conventional method. For example, this reaction is accomplished by reacting compound (Xa) with an alkali metal iodide salt in a suitable solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc. Examples include THF, dioxane, DME, toluene, acetonitrile, DMF, NMP, etc., and can be used alone or as a mixed solvent. . Specific examples of alkali metal iodide salts include sodium iodide and potassium iodide. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

(Step 5): Compound (IIa) is obtained by sulfonamidation of compound (XIa).

The reaction of step 5 can be carried out according to a conventional method. For example, this reaction can be achieved by converting compound (XIa) into a sulfonyl chloride or the like and then reacting it with an amine. Conversion to sulfonyl chloride is carried out by reacting phosphorus oxychloride in a solvent or in the absence of solvent. Specific examples of the solvent should be selected according to the kind of the raw material compound, etc. Examples include Et ₂ O, THF, dioxane, DME, toluene, etc., and can be used alone or as a mixed solvent. The reaction temperature is usually -100°C to 200°C, preferably 0°C to 150°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours. Conversion of the step 5 intermediate sulfonyl chloride to a sulfonamide can be carried out according to the method described in preparation 2, step 3.

In compound (IIa), when both R ¹ and R ² are hydrogen, the subsequent deprotection step is unnecessary.

In compound (IIa), when R ¹ and R ² are different and at least one of P ^1B and P ² is an optically active substance, compound (IIa) is a diastereomeric mixture. When compound (IIa) is a mixture of diastereomers, it can be resolved according to the method described in step 5 of preparation method 2.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じである。Ｘはハロゲン、トルエンスルホニロキシ、メタンスルホニロキシ、トリフルオロメタンスルホニロキシ等の脱離基を意味する。 Manufacturing method 4
Compound (XIa) used in production method 3 can also be produced by the following production method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in Item 1. X is halogen, toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy means a leaving group such as

(Step 1): Substitution reaction of compound (XIIa) gives compound (XIa).

The substitution reaction in step 1 can be carried out according to a conventional method. For example, it is carried out by reacting compound (XIIa) with a sulfite in a suitable solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc. Examples include THF, dioxane, acetonitrile, DMF, acetone, water, ethanol, methanol, etc., and may be used alone or as a mixed solvent. can be done. Sulfites used include sodium sulfite, sodium hydrogen sulfite, ammonium sulfite, methylamine sulfite, ethylamine sulfite, dimethylamine sulfite, triethylamine sulfite and the like. The reaction temperature is usually -100 to 150.degree. C., preferably 0 to 100.degree. The reaction time is usually 30 minutes to 1 week.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じである。Ｒ^７は２－（メトキシカルボニル）エチル、メシチレンカルボニロキシメチル、２－ベンゾチアゾイル（該基は、ベンゼン環上に、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシ（該アルコキシはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、水酸基、シアノ、ニトロ、アミノ（該アミノは、Ｃ_１－３アルキルによって１～２個置換されていてもよい）、カルボン酸、カルバモイル（該カルバモイルは、アミノ部分がＣ_１－３アルキルによって１～２個置換されていてもよい）、Ｃ_１－６アルコキシカルボニルからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、２－ピリジル、２－ピリミジニルまたは２－（トリメチルシリル）エチル等の適当な条件下で除去しスルフィン酸塩を放出することが可能な脱離基である。Ｍは金属イオンまたは４級アンモニウムイオンである。） Manufacturing method 5
Compound (Ia) used in Production Method 1 can also be produced by the following production method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in Item 1. R ⁷ is 2-(methoxycarbonyl)ethyl, mesitylenecarbonyloxymethyl, 2- benzothiazolyl (the group is independently selected from the group consisting of halogen, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-3 alkoxy on the benzene ring optionally substituted with 1 to 3 substituents), C _1-6 alkoxy (wherein said alkoxy is independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy) optionally substituted with 1 to 3 substituents), hydroxyl group, cyano, nitro, amino (wherein the amino is optionally substituted by 1 to 2 C _1-3 alkyl), carboxylic acid, 1 to 3 substituents independently selected from the group consisting of carbamoyl (wherein the carbamoyl is optionally substituted with 1 to 2 C _1-3 alkyl on the amino moiety), C _1-6 alkoxycarbonyl; M is a leaving group that can be removed under suitable conditions to release a sulfinate salt, such as 2-pyridyl, 2-pyrimidinyl or 2-(trimethylsilyl)ethyl. metal ions or quaternary ammonium ions.)

After decomposition of compound (XIIIa), reaction with an aminating reagent gives compound (Ia).

Removal of the leaving group of compound (XIIIa) can be carried out according to a conventional method. For example, when R ⁷ is a 2-(methoxycarbonyl)ethyl group, it can be achieved by reacting with a base in a suitable solvent. Bases include sodium methoxide, sodium carbonate and the like. Also, when R ⁷ is a 2-pyridyl group, 2-pyrimidinyl group or 2-benzothiazolyl group, it can be achieved using a suitable nucleophile in a suitable solvent. Nucleophiles include sodium ethoxide, sodium ethanethiol, sodium borohydride, lithium aluminum hydride and the like. Alternatively, if R ⁷ is a 2-(trimethylsilyl)ethyl group, this can be accomplished using a suitable fluoride reagent in a suitable solvent. Fluoride reagents include tetrabutylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate and the like.

Conversion of the intermediate sulfinate to the sulfonamide can be accomplished by reacting ammonia or its salt with an oxidizing agent in the presence of a base in a solvent, or by reacting ammonia with a leaving group in the presence of a base in a solvent. is performed by acting Specific examples of the solvent should be selected according to the type of raw material compound, etc. Examples include ethanol, methanol, water, THF, dioxane, DME, DMF, acetonitrile, etc., and may be used alone or as a mixed solvent. can be done. Further, specific examples of the base used include sodium carbonate, sodium hydrogencarbonate, sodium acetate and the like. Examples of the oxidizing agent include meta-chloroperbenzoic acid (mCPBA) and the like. Specific examples of ammonia with a leaving group include hydroxylamine-O-sulfonic acid, O-mesitylenesulfonylhydroxylamine, monochloramine and the like. The reaction temperature is usually -100°C to 200°C, preferably -20°C to 100°C, although it varies depending on the kind of starting compound and reagent used. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じであり、Ｒ^７は製造法５と同義であり、Ｘは製造法４と同義である。 Manufacturing method 6
Compound (XIIIa) used in production method 5 can be produced by the following production method.

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in item 1, R ⁷ is the same as in production method 5, and X is the same as in production method 4. be.

(Step 1): Substitution reaction of compound (XIIa) gives compound (XIVa).

The substitution reaction in step 1 can be carried out according to a conventional method. For example, it can be achieved by reacting compound (XIIa) with an alkali metal salt of thiol (R ⁷ —SH) in a suitable solvent. Specific examples of alkali metal salts include lithium salts, sodium salts, potassium salts and the like. Specific examples of the solvent should be selected according to the type of the raw material compound, etc. Examples include THF, dioxane, acetonitrile, DMF, toluene, chlorobenzene, etc., and can be used alone or as a mixed solvent. The reaction temperature is usually -100 to 150.degree. C., preferably -20 to 100.degree. The reaction time is usually 30 minutes to 24 hours.

(Step 2): Compound (XIVa) is oxidized to give compound (XIIIa).

The oxidation reaction in step 2 can be carried out according to a conventional method. For example, it can be achieved by reacting compound (XIVa) with an oxidizing agent in a suitable solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc. Examples include dichloromethane, chloroform, acetonitrile, DMF, toluene, chlorobenzene, etc., and can be used alone or as a mixed solvent. The oxidizing agents used include potassium permanganate, sodium tungstate and hydrogen peroxide, mCPBA, magnesium bis(monoperoxyphthalate) hexahydrate, Oxone and the like. The reaction temperature is usually -100 to 150.degree. C., preferably -10 to 100.degree. The reaction time is usually 30 minutes to 48 hours.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じであり、Ｒ^７は製造法５と同義である。Ｒ^８はＣ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_１－６アルコキシまたはＣ_１－６アルキルカルボニロキシメトキシである。） Manufacturing method 7
Compound (XIVa) used in production method 6 can be produced by the following production method.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in item 1, R ⁷ is the same as in production method 5, R ⁸ is C _1-6 alkyl (said alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy), C _1-6 alkoxy or C _1-6 alkylcarbonyloxymethoxy.)

(Step 1): Compound (XVa) is hydrolyzed to give compound (XVIa).

The reaction of step 1 can be carried out according to a conventional method. For example, this reaction is achieved by reacting compound (XVa) in a suitable aqueous solvent in the presence of an acid or base. Specific examples of the aqueous solvent should be selected according to the type of the raw material compound, etc. Examples include solvents such as Et ₂ O, THF, dioxane, DME, DMF, acetonitrile, acetone, toluene, methanol, and ethanol. , can be used singly or in combination with water. Acids to be used include hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like, and bases to be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and the like. The reaction temperature is usually 0°C to 120°C, preferably 40°C to 100°C, although it varies depending on the kind of starting compounds and reagents used. The reaction time is usually 30 minutes to 24 hours.

When R ¹ and R ² are different, an optically active compound (XVIa) can be obtained by reacting the compound (XVa) with a hydrolase in an aqueous solvent. Specific examples of the solvent should be selected according to the type of the raw material compound and the like. For example, solvents such as THF, DMSO, acetonitrile, acetone, toluene, ethanol, hexane, etc., may be used singly or in combination with water. be able to. Moreover, lipase, esterase, amidase, protease, etc. are mentioned as a hydrolase to be used. The reaction temperature varies depending on the kind of raw material compounds and reagents used, but is usually 0°C to 100°C, preferably 20°C to 60°C. The reaction time is usually 30 minutes to 1 week.

(Step 2): Substitution reaction of compound (XVIa) gives compound (XIVa).

The substitution reaction in step 2 can be carried out according to a conventional method. For example, it can be achieved by reacting compound (XVIa) with a thiol (R ⁷ SH), Mitsunobu reagent and a phosphine reagent, or by reacting a disulfide (R ⁷ S—SR ⁷ ) with a phosphine reagent in a suitable solvent. . Specific examples of the solvent should be selected according to the type of the raw material compound, etc. Examples include THF, dioxane, acetonitrile, DMF, toluene, chlorobenzene, etc., and can be used alone or as a mixed solvent. Mitsunobu reagents used include diethyl azodicarboxylate, diisopropyl azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, 1,1'-(azodicarbonyl)dipiperidine and the like. . Phosphine reagents include triphenylphosphine and tri-n-butylphosphine. The reaction temperature is usually -100 to 150.degree. C., preferably -20 to 100.degree. The reaction time is usually 30 minutes to 24 hours.

（式中、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１の定義に同じであり、Ｒ^２Ｂは、ハロゲン、Ｃ_１－６アルキル（該アルキルはハロゲン、水酸基、Ｃ_３－６シクロアルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）、又はＣ_３－６シクロアルキル（該シクロアルキルはハロゲン、水酸基、Ｃ_１－３アルキル及びＣ_１－３アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）である。） Manufacturing method 8
Of compounds (XVIa) used in production method 7, (XVIb) in which ^R1 is hydrogen can also be produced by the following production method.

(In the formula, R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined in item 1, R ^2B is halogen, C _1-6 alkyl (wherein the alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy), or C _3-6 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, C ₁ optionally substituted with 1 to 3 substituents independently selected from the group consisting of _-3 alkyl and C _1-3 alkoxy).)

(Step 1): Compound (XVIIb) is obtained by reduction reaction of compound (XVIIb).

Reduction of compound (XVIIb) in step 1 can be carried out according to a conventional method. For example, it can be achieved by reacting compound (XVIIb) with a reducing agent in a suitable solvent. Specific examples of the solvent should be selected according to the type of starting compound, and include THF, acetonitrile, DMF, toluene, methanol, ethanol, 2-propanol, water, etc., which may be used alone or as a mixed solvent. can do. The reducing agent used includes sodium borohydride, lithium borohydride, lithium aluminum hydride and the like. The reaction temperature is usually -100 to 150.degree. C., preferably -10 to 100.degree. The reaction time is usually 30 minutes to 48 hours.

An optically active compound (XVIb) can be obtained by asymmetric reduction. For example, this reaction can be achieved by reacting compound (XVIIb) with a reductase and a coenzyme in an aqueous solvent. Specific examples of the solvent should be selected according to the type of the raw material compound and the like. For example, solvents such as THF, DMSO, acetonitrile, acetone, toluene, ethanol, hexane, etc., may be used singly or in combination with water. be able to. Moreover, carbonyl reductase, alcohol dehydrogenase, etc. are mentioned as a reductase to be used. Examples of coenzymes include NADH and NADPH. The reaction temperature varies depending on the kind of raw material compounds and reagents used, but is usually 0°C to 100°C, preferably 20°C to 60°C. The reaction time is usually 30 minutes to 1 week.

In addition, the intermediates or final products in the above production method are required to convert their functional groups as appropriate, and in particular, to extend various side chains from amino, hydroxyl, carbonyl, halogen, etc., and at that time, It is also possible to lead to other compounds included in the present invention by performing the above protection and deprotection according to the above. Transformation of functional groups and elongation of side chains can be carried out by conventional methods (see, for example, Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999), etc.).

The compound of the present invention represented by formula (1) or a pharmaceutically acceptable salt thereof may be asymmetric or have a substituent having an asymmetric carbon. There are optical isomers. The compounds of the present invention include mixtures and isolated isomers of these isomers, and can be produced according to conventional methods. The production method includes, for example, a method using a raw material having an asymmetric point, or a method of introducing asymmetry in an intermediate step. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution or the like at an appropriate stage in the production process. As an optical resolution method, for example, when the compound represented by formula (1) or an intermediate thereof has a basic functional group, in an inert solvent (e.g., methanol, ethanol, alcoholic solvent such as 2-propanol , ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), optical activity acids (e.g., monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid; dicarboxylic acids such as tartaric acid, o-diisopropylidenetartaric acid and malic acid; sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) A diastereomer method is used to form a salt. When the compound of the present invention represented by formula (1) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (eg, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, Optical resolution can also be performed by forming a salt with an organic amine such as strychnine.

The temperature at which the salt is formed is selected from the range of -50°C to the boiling point of the solvent, preferably from 0°C to the boiling point of the solvent, more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once raise the temperature to near the boiling point of the solvent. When the precipitated salt is collected by filtration, the yield can be improved by cooling as necessary. The amount of optically active acid or amine to be used is appropriately in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, crystals are placed in an inert solvent (e.g., alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. In addition, if necessary, the optically resolved salt can be treated with an acid or base in a conventional manner to obtain a free form.

Among the raw materials and intermediates in each of the production methods described above, those for which the production method is not described again are commercially available compounds, or methods known to those skilled in the art from commercially available compounds, or methods according to them. can be synthesized by the method.

Since the novel benzisoxazole derivatives of the present invention have T-type calcium channel inhibitory activity, various nervous system diseases or psychiatric diseases (e.g., epilepsy, seizure disorders, exercise disorders) caused by abnormalities in T-type calcium channels Dysfunction (disorders related to muscle spasms, including spasticity, tremor, essential tremor, Huntington's chorea, myoclonus, tics, restless leg syndrome and dystonia), movement disorders and parkinsonism, including akinesia and rigor syndrome (Parkinson's disease (including symptoms of tremor, muscle stiffness/rigidity, akinesia/limbism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, and lumbago) , idiopathic and drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, dementia with Lewy bodies, cerebellar ataxia, parkinsonism-ALS dementia complex and basal ganglia calcification), drug-induced dyskinesia, nociceptive pain (traumatic pain, migraine, headache, chronic pain (lumbar back pain, rheumatoid arthralgia, fibromyalgia, osteoarthritis, etc.) ), inflammatory pain), neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central nervous system pain (e.g. pain after spinal cord injury, pain after stroke), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain), fatigue (Parkinson fatigue, multiple sclerosis fatigue, fatigue caused by sleep disturbances or circadian rhythm disturbances, chronic fatigue syndrome including medication-induced parkinsonism), migraine, schizophrenia, autism, Gilles de Ra・Tourette syndrome, bipolar disorder, depression, anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), sleep disorders (including insomnia, hypersomnia, narcolepsy, and REM sleep disorder), psychology various diseases and disorders including arrhythmia, hypertension, cancer, diabetes, infertility and sexual dysfunction, etc.).
The novel benzisoxazole derivative of the present invention is preferably used for essential tremor, Parkinson's disease (tremor, muscle stiffness/rigidity, akinesia/hybridism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, depression, anxiety, headache, low back pain), neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), Chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), pain associated with Guillain-Barré syndrome, pain associated with multiple sclerosis, pain associated with Parkinson's disease, neuropathic It is useful as a therapeutic and/or prophylactic agent for hyperalgesia or allodynia associated with pain).
The novel benzisoxazole derivatives of the present invention are more preferably useful as therapeutic and/or prophylactic agents for essential tremor, tremor in Parkinson's disease, and chemotherapy-induced peripheral neuropathy.

The novel benzisoxazole derivatives of the present invention are useful for epilepsy, seizure disorders, motor dysfunction (disorders related to muscle spasms including spasms, tremors, essential tremors, Huntington's chorea, myoclonus, tics, restless legs). syndrome and dystonia), movement disorders including akinesia and rigidity syndrome, and Parkinsonism (Parkinson's disease (tremor, muscle stiffness/rigidity, akinesia/hybridism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, (including symptoms of sleep disturbance, memory disturbance, depression, anxiety, headache, low back pain), idiopathic and drug-induced parkinsonism, post-encephalitis parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration , Lewy body dementia, cerebellar ataxia, parkinsonism-ALS dementia complex and basal ganglia calcification), levodopa-induced dyskinesia in Parkinson's disease, drug-induced dyskinesia, nociceptive pain (traumatic pain , migraine, headache, chronic pain (lumbar back pain, rheumatoid arthritis, fibromyalgia, osteoarthritis, etc.), inflammatory pain), neuropathic pain (shingles pain, trigeminal neuralgia, complex regional pain syndrome , peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (post-spinal injury pain, post-stroke pain, etc.), pain associated with Guillain-Barre syndrome, multiple sclerosis pain associated with disease, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain), fatigue (parkinsonian fatigue, multiple sclerosis fatigue, fatigue caused by sleep disturbance or circadian rhythm disturbances, medication-induced chronic fatigue syndrome including Parkinsonism), migraine, schizophrenia, autism, Gilles de la Tourette syndrome, bipolar disorder, depression, anxiety (generalized anxiety disorder, panic disorder and obsessive-compulsive disorder) sleep disorders (including insomnia, hypersomnia, narcolepsy, REM sleep disorders), sleep disorders in depression, cardiac arrhythmias, hypertension, cancer, diabetes, infertility and sexual dysfunction. It is useful as a therapeutic and/or prophylactic agent for diseases, disorders, and the like.
The novel benzisoxazole derivative of the present invention is preferably used for Parkinson's disease (tremor, muscle rigidity/rigidity, akinesia/limbism, postural reflex disorder, olfactory disorder, REM sleep disorder, constipation, sleep disorder, memory disorder, etc.). , depression, anxiety, headache, low back pain), levodopa-induced dyskinesia in Parkinson's disease, essential tremor, anxiety (generalized anxiety disorder), or neuropathic pain (shingles pain, trigeminal neuralgia, complex Regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (post-spinal injury pain, post-stroke pain, etc.), pain associated with Guillain-Barré syndrome, It is useful as a therapeutic and/or prophylactic agent for pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain).
The novel benzisoxazole derivatives of the present invention are more preferably used for Parkinson's disease (including tremor, muscle rigidity/rigidity, akinesia/limbism, postural reflex disorder), essential tremor, or chemotherapy-induced It is useful as a therapeutic and/or prophylactic agent for peripheral neuropathy.

The compound of the present invention also has a levodopa-induced hyperlocomotion-enhancing action that is not dependent on the MAOB inhibitory action, and the preferred compound has a reduced risk of kidney stones due to the attenuation of the carbonic anhydrase inhibitory action, and thus is highly safe. It is useful as a combination drug with levodopa preparations for treating Parkinson's disease. The compound of the present invention further suppressed the onset of dyskinesia in a levodopa-induced dyskinesia model, and therefore, unlike existing concomitant drugs with levodopa, which have a high risk of developing drug-induced dyskinesia, a therapeutic agent for Parkinson's disease with high safety and / or It is useful as a prophylactic agent. In addition, since it showed efficacy against Parkinson's disease tremor model and essential tremor model, tremor in Parkinson's disease, essential tremor, and parkinsonism observed in nervous system disease or psychiatric disease It is also useful as a therapeutic and/or prophylactic agent for In addition, the compounds of the present invention showed anti-anxiety-like effects in the elevated plus maze and shortened non-REM sleep latency and awakening time in sleep electroencephalogram evaluations. It is also useful as a therapeutic and/or prophylactic agent for motor symptoms. Furthermore, since it showed an anti-allodynia effect in an oxaliplatin-induced pain model, it is also useful as a therapeutic and/or preventive drug for neuropathic pain (in particular, pain and allodynia in chemotherapy-induced peripheral neuropathy).
In the present invention, "prevention" means the act of administering the active ingredient of the present invention to a healthy person who has not developed a disease, for example, for the purpose of preventing the development of a disease. be. “Treatment” is the act of administering the active ingredient of the present invention to a person (patient) diagnosed by a doctor as having a disease. The action taken by a patient suffering from such a disease to suppress seizures associated with such a disease also falls under "prevention" or "treatment" herein.

Since the novel benzisoxazole derivative of the present invention has weaker MAOB inhibitory activity than rasagiline and safinamide, which are MAOB inhibitors, it is a safe drug that does not easily cause dyskinesia when repeatedly administered in combination with levodopa. be. As used herein, "weak MAOB inhibitory activity" means that the _IC50 value is 70 μmol/L or more when the MAOB inhibitory activity is measured under the conditions described in Test Example 6 of this specification. Preferably, it means a value of 100 µmol/L or more.

In a preferred embodiment of the novel benzisoxazole derivative of the present invention, the CA-II inhibitory activity is weaker than topiramate and acetazolamide, which are carbonic anhydrase inhibitors, so it is a safe drug with a low risk of urinary calculi. is. As used herein, "weak CA-II inhibitory activity" means that the _IC50 value is 1 μmol/L or more when the CA-II inhibitory activity is measured under the conditions described in Test Example 9 of this specification. preferably 3 μmol/L or more, more preferably 10 μmol/L or more.

The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose varies depending on the type of compound, administration method, symptoms and age of the patient, and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per 1 kg body weight of humans or mammals can be administered in 1 to several divided doses. For parenteral administration such as intravenous injection, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per 1 kg body weight of a human or mammal can be administered.

When the compound of the present invention is used for pharmaceutical purposes as described above, it is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. As pharmaceutical carriers, non-toxic substances commonly used in the pharmaceutical field and which do not react with the compounds of the present invention are used. Specific examples include citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and aluminum metasilicate. Magnesium acid, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose , polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, Veegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, Refined lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid, water and the like.

Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, ointments, patches, inhalants and the like. These formulations can be prepared according to a conventional method. Liquid formulations may be dissolved or suspended in water or other suitable medium at the time of use. Tablets and granules may also be coated by well-known methods. In addition, these formulations may contain other therapeutically valuable ingredients.

The compounds of the present invention can be used in combination with at least one or more drugs classified as drugs for treating Parkinson's disease, drugs for essential tremor, or drugs for treating neuropathic pain. The term "combination" as used herein refers to a form in which a preparation prepared separately from the compound of the present invention is administered. may be administered after
Drugs classified as drugs for treating Parkinson's disease include, for example, levodopa, carbidopa, entacapone, MAOB inhibitors (e.g., selegiline, rasagiline, safinamide, etc.), dopamine receptor agonists (e.g., bromocriptine, pergolide, talipexole, cabergoline, pramipexole). , ropinirole, rotigotine, apomorphine, etc.), amantadine, droxidopa, istradefylline, anticholinergics (eg, trihexyphenidyl, biperiden, etc.), and the like.
Drugs classified as essential tremor drugs include, for example, arotinolol, primidone, propranolol, and the like.
Drugs classified as neuropathic pain drugs include, for example, serotonin/noradrenaline reuptake inhibitors (e.g., duloxetine, venlafaxine, milnacipran, etc.), tricyclic antidepressants (e.g., amitriptyline, imipramine , clomipramine, nortriptyline, desipramine, etc.), serotonin reuptake drugs (e.g., paroxetine hydrochloride, escitalopram, fluvoxamine maleate, sertraline hydrochloride, etc.), mirtazapine, vaccinia virus-inoculated rabbit inflammatory skin extract, tramadol, buprenorphine, gabapentin , pregabalin, carbamazepine, oxcarbazepine, sodium valproate, lamotrigine, topiramate, dextromethorphan hydrobromide, mexiletine hydrochloride, vitamin B12 and the like.

The present invention will be described in more detail with reference examples, examples and test examples below, but the present invention is by no means limited thereto. The compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description of the specification, the following abbreviations may be used in Reference Examples, Examples, and tables in Examples. THF is tetrahydrofuran, DMSO is dimethylsulfoxide, TFA is trifluoroacetic acid, Et ₂ O is diethyl ether, DMF is N,N-dimethylformamide, DME is 1,2-dimethoxyethane, NMP is N-methylpyrrolidone, HMPA is Hexamethyl phosphate triamide, HMPU means dimethyl propylene urea. The symbols used in NMR are as follows: s is a singlet, d is a doublet, dd is a doublet of doublets, t is a triplet, td is a doublet of triplets, q is a quartet, m is multiplet, br is broad, brs is broad singlet, brs is broad multiplet and J is coupling constant. As a term used when synthesizing an optically active substance, ee means enantiomeric excess.

Various data described in Reference Examples and Examples were obtained with the following equipment.

NMR spectrum: [ ¹ H-NMR] 400 MHz: JEOL JNM-AL series AL400
LC-MS spectra: Waters ACQUITYTM UltraPerformance LC, Agilent 1260 InfinityHPLC - Agilent 6120 Quadrupole LC/MS
Optical purity measurement: Shimadzu LC-20AT HPLC system, Agilent 1200 HPLC system

High performance liquid chromatographic mass spectrometer; LCMS measurement conditions are as follows, where the observed mass spectrometry value [MS (m/z)] is indicated by MH ⁻ and the retention time is indicated by Rt (min).

Measurement conditions (i)
Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×30 mm column
Solvent: A solution: 0.05% HCOOH/ _H2O , B solution: _CH3CN
Gradient conditions: 0.0 to 1.3 min; A/B = 90/10 to 5/95 (linear gradient) 1.3 to 1.5 min; A/B = 90/10
Flow rate: 0.80 mL/min
UV: 220nm, 254nm
Column temperature: 40℃
Measurement conditions (ii) Column: ZORBAX SB-C18 2.1 x 50 mm 1.8 μm
Solvent: A solution: 0.1% HCOOH/ _H2O , B solution: _CH3CN
Gradient conditions: B% 5% (ini) → 90% (5-6 minutes) → 5% (6-10 minutes)
Flow rate: 0.60 mL/min
UV: 210nm, 254nm, 280nm
Column temperature: 40℃

４－ヒドロキシ－２Ｈ－クロメン－２－オン（１．００ｇ）、エチレンジアミン四酢酸二水素二ナトリウム二水和物（０．１８ｇ）を硫酸ヒドロキシルアミン（２．０３ｇ）、水（５．６ｍＬ）、２５％水酸化ナトリウム水溶液（２．７ｍＬ）の混合液に加え、８５℃加温下で４時間撹拌した。溶液を硫酸で酸性に調整後、ジクロロエタンで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮して表題化合物（８６２ｍｇ）を得た。
^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６）δ ：４．０９（ｓ，２Ｈ），７．３９（ｄｄ，１Ｈ），７．６５（ｄｄｄ，１Ｈ），７．７３（ｄ，２Ｈ），７．８４（ｄ，１Ｈ） Reference example 1 :
2-(benzo[d]isoxazol-3-yl)acetic acid (IUPAC name: (1,2-benzoxazol-3-yl)acetic acid)

4-Hydroxy-2H-chromen-2-one (1.00 g), disodium dihydrogen ethylenediaminetetraacetate dihydrate (0.18 g), hydroxylamine sulfate (2.03 g), water (5.6 mL), The mixture was added to a mixed solution of 25% aqueous sodium hydroxide solution (2.7 mL) and stirred for 4 hours under heating at 85°C. After acidifying the solution with sulfuric acid, it was extracted with dichloroethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (862 mg).
¹ H-NMR (DMSO-d ₆ ) δ: 4.09 (s, 2H), 7.39 (dd, 1H), 7.65 (ddd, 1H), 7.73 (d, 2H), 7.73 (d, 2H), 84 (d, 1H)

Reference example 2-4 :
The compounds shown in Table 1 were obtained by reacting and treating in the same manner as in Reference Example 1 using the corresponding starting compounds.

参考例１で得られた化合物（１７．０ｇ）のトルエン（１５０ｍＬ）／酢酸エチル（２５ｍＬ）混合溶媒懸濁液に、クロロ硫酸（９．６ｍＬ）の１，２－ジクロロエタン（５０ｍＬ）溶液を室温で滴下後、８０度加温下で２時間撹拌した。析出固体をろ取し、トルエンで洗浄後乾燥し、表題化合物（２０．５ｇ）を得た。
ＭＳ（ｍ／ｚ）２１２（ＭＨ－），Ｒｔ＝０．２８ｍｉｎ． Reference example 5 :
Benzo[d]isoxazol-3-ylmethanesulfonic acid (IUPAC name: (1,2-benzoxazol-3-yl)methanesulfonic acid)

To a toluene (150 mL)/ethyl acetate (25 mL) mixed solvent suspension of the compound (17.0 g) obtained in Reference Example 1, a solution of chlorosulfuric acid (9.6 mL) in 1,2-dichloroethane (50 mL) was added at room temperature. After dropping at , the mixture was stirred for 2 hours under heating at 80°C. The precipitated solid was collected by filtration, washed with toluene and dried to give the title compound (20.5 g).
MS (m/z) 212 (MH-), Rt = 0.28 min.

Reference example 6-8 :
Using the corresponding starting compounds, the compounds shown in Table 2 were obtained by reacting and treating in the same manner as in Reference Example 5.

参考例５で得られた化合物（５．３０ｇ）のトルエン（８０ｍＬ）懸濁液に、オキシ塩化リン（２２．９ｇ）を加え２時間加熱還流後、減圧濃縮した。残渣をＴＨＦ（８０ｍＬ）に溶解し、トリエチルアミン（１３．９ｍｌ）、４－ジメチルアミノピリジン（０．３０ｇ）、ビス（２，４－ジメトキシベンジル）アミン（７．８９ｍＬ）のＴＨＦ（８０ｍＬ）へ滴下後、室温で１２時間撹拌した。不溶物を濾別し、濾液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；１：２）で精製することにより、表題化合物（５．０５ｇ）を固体として得た。
^１Ｈ－ＮＭＲ（ＣＤＣｌ_３）δ ：３．７７（ｓ，６Ｈ），３．７７（ｓ，６Ｈ），４．３１（ｓ，４Ｈ），４．４５（ｓ，２Ｈ），６．３９－６．４１（ｍ，４Ｈ），７．１８（ｄ，２Ｈ），７．３１（ｄｄｄ，１Ｈ），７．５２－７．５４（ｍ，２Ｈ），７．８８（ｄ，１Ｈ） Reference Example 9 :
1-(benzo[d]isoxazol-3-yl)-N,N-bis(2,4-dimethoxybenzyl)methanesulfonamide (IUPAC name: 1-(1,2-benzoxazol-3-yl)-N , N-bis[(2,4-dimethoxyphenyl)methyl]methanesulfonamide)

Phosphorus oxychloride (22.9 g) was added to a toluene (80 mL) suspension of the compound (5.30 g) obtained in Reference Example 5, and the mixture was heated under reflux for 2 hours and then concentrated under reduced pressure. The residue was dissolved in THF (80 mL), and triethylamine (13.9 mL), 4-dimethylaminopyridine (0.30 g) and bis(2,4-dimethoxybenzyl)amine (7.89 mL) were added dropwise to THF (80 mL). After that, the mixture was stirred at room temperature for 12 hours. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 1:2) to give the title compound (5.05 g). was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 3.77 (s, 6H), 3.77 (s, 6H), 4.31 (s, 4H), 4.45 (s, 2H), 6.39- 6.41 (m, 4H), 7.18 (d, 2H), 7.31 (ddd, 1H), 7.52-7.54 (m, 2H), 7.88 (d, 1H)

Reference Example 10-12 :
Using the corresponding starting compounds, the compounds shown in Table 3 were obtained by reacting and treating in the same manner as in Reference Example 9.

参考例９で得られた化合物（４．６９ｇ）のＴＨＦ（４０ｍＬ）溶液にｎ－ブチルリチウム（１．５５ｍоｌ／Ｌヘキサン溶液、７．１ｍｌ）を窒素雰囲気下－７８℃で加え、そのままの温度で１時間撹拌した。－７８℃冷却下でヨードメタン（０．６３ｍＬ）を加えた後に、ゆっくりと室温に戻しながら１２時間撹拌した。飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；２：１）で精製し、表題化合物（４．２６ｇ）を油状物として得た。
^１Ｈ－ＮＭＲ（ＣＤＣｌ_３）δ ：１．８１（ｄ，３Ｈ），３．７４（ｓ，６Ｈ），３．７７（ｓ，６Ｈ），４．２０（ｄ，２Ｈ），４．３３（ｄ，２Ｈ），４．６０（ｑ，１Ｈ），６．３６－６．４０（ｍ，４Ｈ），７．１６（ｄ，２Ｈ），７．２６－７．３０（ｍ，１Ｈ），７．４９－７．５５（ｍ，２Ｈ），７．９８（ｄ，１Ｈ） Reference Example 13 :
1-(benzo[d]isoxazol-3-yl)-N,N-bis(2,4-dimethoxybenzyl)ethane-1-sulfonamide (IUPAC name: 1-(1,2-benzoxazol-3-yl )-N,N-bis[(2,4-dimethoxyphenyl)methyl]ethane-1-sulfonamide)

To a THF (40 mL) solution of the compound (4.69 g) obtained in Reference Example 9 was added n-butyllithium (1.55 mol/L hexane solution, 7.1 mL) under a nitrogen atmosphere at -78°C, and the temperature was kept as it was. and stirred for 1 hour. After adding iodomethane (0.63 mL) under cooling at −78° C., the mixture was stirred for 12 hours while slowly returning to room temperature. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 2:1) to give the title compound (4.26 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.81 (d, 3H), 3.74 (s, 6H), 3.77 (s, 6H), 4.20 (d, 2H), 4.33 ( d, 2H), 4.60 (q, 1H), 6.36-6.40 (m, 4H), 7.16 (d, 2H), 7.26-7.30 (m, 1H), 7 .49-7.55 (m, 2H), 7.98 (d, 1H)

Reference Examples 14-21 :
Using the corresponding starting compounds, the compounds shown in Table 4 were obtained by reacting and treating in the same manner as in Reference Example 13.

参考例９で得られた化合物（２．００ｇ）のＴＨＦ（３０ｍＬ）溶液に窒素気流下－７８℃でナトリウムビス（トリメチルシリル）アミド（１．０ｍоｌ／ｌＴＨＦ溶液、４．２９ｍＬ）を加えた後に、０℃冷却下で２０分撹拌した。再度－７８℃へ冷却し、Ｎ－フルオロベンゼンスルホンイミド（１．２９ｇ）のＴＨＦ（１５ｍＬ）溶液を滴下した。ゆっくりと室温へ昇温し１２時間撹拌した後に、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し無水硫酸ナトリウムで洗浄後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；１：１）で精製し、表題化合物（１．９８ｇ）を油状物として得た。
^１Ｈ－ＮＭＲ（ＣＤＣｌ_３）δ ：３．８０（ｓ，６Ｈ），３．８２（ｓ，６Ｈ），４．３２（ｄ，２Ｈ），４．６１（ｄ，２Ｈ），６．２２（ｄ，１Ｈ），６．４５－６．４７（ｍ，４Ｈ），７．２０（ｄ，２Ｈ），７．３２－７．３６（ｍ，１Ｈ），７．５３－７．６１（ｍ，２Ｈ），８．０１（ｄ，１Ｈ） Reference example 22 :
1-(benzo[d]isoxazol-3-yl)-N,N-bis(2,4-dimethoxybenzyl)-1-fluoromethanesulfonamide (IUPAC name: 1-(1,2-benzoxazole-3- yl)-N,N-bis[((2,4-dimethoxyphenyl)methyl]-1-fluoromethanesulfonamide)

Sodium bis(trimethylsilyl)amide (1.0 mol/l THF solution, 4.29 mL) was added to a THF (30 mL) solution of the compound (2.00 g) obtained in Reference Example 9 at -78°C under a nitrogen stream, The mixture was stirred for 20 minutes under cooling at 0°C. After cooling to −78° C. again, a solution of N-fluorobenzenesulfonimide (1.29 g) in THF (15 mL) was added dropwise. After slowly raising the temperature to room temperature and stirring for 12 hours, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, washed with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to give the title compound (1.98g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 6H), 3.82 (s, 6H), 4.32 (d, 2H), 4.61 (d, 2H), 6.22 ( d, 1H), 6.45-6.47 (m, 4H), 7.20 (d, 2H), 7.32-7.36 (m, 1H), 7.53-7.61 (m, 2H), 8.01 (d, 1H)

Reference Examples 23-24 :
The compounds shown in Table 5 were obtained by reacting and treating in the same manner as in Reference Example 22 using corresponding starting compounds.

参考例２１で得られた化合物（４．６４ｇ）のＴＨＦ（５０ｍＬ）溶液に窒素気流下０℃でリチウムアルミニウムヒドリド（１ｍоｌ／ｌ ＴＨＦ溶液、７．９４ｍＬ）を加え、そのままの温度で１時間撹拌した。飽和硫酸ナトリウム水溶液を加え還元剤を失活させたのちに、析出した固体をセライト濾過により除去した。濾液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；１：１９）で精製することにより、表題化合物（３．１３ｇ）をアモルファスとして得た。
^１Ｈ－ＮＭＲ（ＣＤＣｌ_３）δ ：２．４４－２．５３（ｍ，１Ｈ），２．５６－２．６５（ｍ，１Ｈ），３．６５－３．７０（ｍ，１Ｈ），３．７４（ｓ，６Ｈ），３．７６（ｓ，６Ｈ），４．１８（ｄ，２Ｈ），４．２４（ｄ，２Ｈ），４．７８（ｄｄ，１Ｈ），６．３６－６．３９（ｍ，４Ｈ），７．１４（ｄ，２Ｈ），７．２８（ｄｄｄ，１Ｈ），７．４９－７．５６（ｍ，２Ｈ），７．９５（ｄ，１Ｈ） Reference Example 25 :
1-(benzo[d]isoxazol-3-yl)-N,N-bis(2,4-dimethoxybenzyl)-3-hydroxypropane-1-sulfonamide (IUPAC name: 1-(1,2-benzoxazole -3-yl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]-3-hydroxypropane-1-sulfonamide)

Lithium aluminum hydride (1 mol/l THF solution, 7.94 mL) was added to a THF (50 mL) solution of the compound (4.64 g) obtained in Reference Example 21 at 0°C under a nitrogen stream, and the mixture was stirred at that temperature for 1 hour. did. A saturated sodium sulfate aqueous solution was added to deactivate the reducing agent, and then the precipitated solid was removed by Celite filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 1:19) to give the title compound (3.13 g) as an amorphous.
¹ H-NMR (CDCl ₃ ) δ: 2.44-2.53 (m, 1H), 2.56-2.65 (m, 1H), 3.65-3.70 (m, 1H), 3 .74 (s, 6H), 3.76 (s, 6H), 4.18 (d, 2H), 4.24 (d, 2H), 4.78 (dd, 1H), 6.36-6. 39 (m, 4H), 7.14 (d, 2H), 7.28 (ddd, 1H), 7.49-7.56 (m, 2H), 7.95 (d, 1H)

参考例２５で得られた化合物（３．１３ｇ）のジクロロメタン（３０ｍＬ）溶液に窒素気流下で１－クロロ－Ｎ，Ｎ，２－トリメチルプロペニルアミン（１．１２ｍＬ）を加え、室温で２時間撹拌後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ｎ－ヘキサン：酢酸エチル；１：１）で精製することにより、表題化合物（３．１２ｇ）を油状物として得た。
^１Ｈ－ＮＭＲ（ＣＤＣｌ_３）δ ：２．７２－２．７９（ｍ，２Ｈ），３．１６－３．２２（ｍ，１Ｈ），３．５０－３．５５（ｍ，１Ｈ），３．７６（ｓ，６Ｈ），３．７７（ｓ，６Ｈ），４．２１（ｄ，２Ｈ），４．２５（ｄ，２Ｈ），４．７１（ｄｄ，１Ｈ），６．３８－６．４２（ｍ，４Ｈ），７．１６（ｄ，２Ｈ），７．２９（ｄｄｄ，１Ｈ），７．５０－７．５７（ｍ，２Ｈ），７．８６（ｄ，１Ｈ） Reference example 26 :
1-(benzo[d]isoxazol-3-yl)-3-chloro-N,N-bis(2,4-dimethoxybenzyl)propane-1-sulfonamide (IUPAC name: 1-(1,2-benzoxazole -3-yl)-3-chloro-N,N-bis[(2,4-dimethoxyphenyl)methyl]propane-1-sulfonamide)

1-Chloro-N,N,2-trimethylpropenylamine (1.12 mL) was added to a solution of the compound (3.13 g) obtained in Reference Example 25 in dichloromethane (30 mL) under a stream of nitrogen, and the mixture was stirred at room temperature for 2 hours. After that, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate; 1:1) to give the title compound (3.12 g) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 2.72-2.79 (m, 2H), 3.16-3.22 (m, 1H), 3.50-3.55 (m, 1H), 3 .76 (s, 6H), 3.77 (s, 6H), 4.21 (d, 2H), 4.25 (d, 2H), 4.71 (dd, 1H), 6.38-6. 42 (m, 4H), 7.16 (d, 2H), 7.29 (ddd, 1H), 7.50-7.57 (m, 2H), 7.86 (d, 1H)

参考例２６で得られた化合物（３．１２ｇ）のＴＨＦ（５０ｍＬ）溶液にｎ－ブチルリチウム（２．６５ｍоｌ／Ｌヘキサン溶液、２．５ｍＬ）を窒素雰囲気下－７８℃で加えた後に、１時間かけ室温へ昇温した。室温で終夜撹拌後、飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；１：１）で精製し、表題化合物（２．８６ｇ）をアモルファスとして得た。
^１Ｈ－ＮＭＲ（ＣＤＣｌ_３）δ ：１．４０（ｄｄ，２Ｈ），１．８１（ｄｄ，２Ｈ），３．６０（ｓ，６Ｈ），３．７１（ｓ，６Ｈ），４．１８（ｓ，４Ｈ），６．１８（ｄ，２Ｈ），６．２４（ｄｄ，２Ｈ），７．０９（ｄ，２Ｈ），７．３０－７．３５（ｍ，１Ｈ），７．４９－７．５４（ｍ，２Ｈ），８．０６（ｄ，１Ｈ） Reference Example 27 :
1-(benzo[d]isoxazol-3-yl)-N,N-bis(2,4-dimethoxybenzyl)cyclopropane-1-sulfonamide (IUPAC name: 1-(1,2-benzoxazole-3- yl)-N,N-bis[(2,4-dimethoxyphenyl)methyl]cyclopropane-1-sulfonamide)

To a THF (50 mL) solution of the compound (3.12 g) obtained in Reference Example 26 was added n-butyllithium (2.65 mol/L hexane solution, 2.5 mL) at -78°C under a nitrogen atmosphere. The temperature was raised to room temperature over time. After stirring overnight at room temperature, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to give the title compound (2.86 g) as an amorphous substance.
¹ H-NMR (CDCl ₃ ) δ: 1.40 (dd, 2H), 1.81 (dd, 2H), 3.60 (s, 6H), 3.71 (s, 6H), 4.18 ( s, 4H), 6.18 (d, 2H), 6.24 (dd, 2H), 7.09 (d, 2H), 7.30-7.35 (m, 1H), 7.49-7 .54 (m, 2H), 8.06 (d, 1H)

参考例１３で得られた化合物（４．２６ｇ）のトルエン（３０ｍＬ）溶液にトリフルオロ酢酸（２０ｍＬ）を加え室温で３時間撹拌後、反応溶液を減圧濃縮した。残渣に酢酸エチル（１００ｍＬ）を加え撹拌後、不溶物を濾別した。濾液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン：酢酸エチル；１：１）で精製し、表題化合物（１．１６ｇ）を固体として得た。
^１Ｈ－ＮＭＲ（ＤＭＳＯ－ｄ_６）δ ：１．８１（ｄ，３Ｈ），４．９２（ｑ，１Ｈ），７．１７（ｓ，２Ｈ），７．３８－７．４２（ｍ，１Ｈ），７．６３－７．６７（ｍ，１Ｈ），７．７４－７．７６（ｍ，１Ｈ），７．９６－７．９８（ｍ，２Ｈ）
ＭＳ（ｍ／ｚ）２２５（ＭＨ－），Ｒｔ＝０．５０ｍｉｎ． Example 1 :
1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (IUPAC name: 1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide)

Trifluoroacetic acid (20 mL) was added to a toluene (30 mL) solution of the compound (4.26 g) obtained in Reference Example 13, and the mixture was stirred at room temperature for 3 hours, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (100 mL) was added to the residue, and after stirring, the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate; 1:1) to give the title compound (1.16 g) as a solid.
¹ H-NMR (DMSO-d ₆ ) δ: 1.81 (d, 3H), 4.92 (q, 1H), 7.17 (s, 2H), 7.38-7.42 (m, 1H ), 7.63-7.67 (m, 1H), 7.74-7.76 (m, 1H), 7.96-7.98 (m, 2H)
MS (m/z) 225 (MH-), Rt = 0.50 min.

Examples 2-12 :
The compounds shown in Table 6 were obtained by reacting and treating in the same manner as in Example 1 using corresponding starting compounds.

実施例１の化合物をダイセル社製ＣＨＩＲＡＬＰＡＫ^TM ＡＹ－Ｈ（移動相：１００％アセトニトリル）で分取し、前ピーク（エナンチオマーＡ、絶対配置未決定）及び後ピーク（エナンチオマーＢ、絶対配置未決定）を得た。
実施例１３（エナンチオマーＡ）：保持時間 3.46分、Chiral HPLC（Chiralpak^TM AY-H、0.46 cm I.D.×25 cm L、移動相：100 %アセトニトリル、流量：1.0 mL/min、温度：40℃、波長：238 nm)
実施例１４（エナンチオマーＢ）：保持時間 4.15分、Chiral HPLC（Chiralpak^TM AY-H、0.46 cm I.D.×25 cm L、移動相：100 %アセトニトリル、流量：1.0 mL/min、温度：40℃、波長：238 nm) Examples 13 and 14 :
(R)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (IUPAC name: (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfone amide) and (S)-1-(benzo[d]isoxazol-3-yl)ethane-1-sulfonamide (IUPAC name: (1S)-1-(1,2-benzoxazol-3-yl)ethane- 1-sulfonamide)

The compound of Example 1 was fractionated with Daicel CHIRALPAK ^™ AY-H (mobile phase: 100% acetonitrile), and the front peak (enantiomer A, absolute configuration undetermined) and the rear peak (enantiomer B, absolute configuration undetermined) were obtained. got
Example 13 (enantiomer A): retention time 3.46 min, Chiral HPLC (Chiralpak ^™ AY-H, 0.46 cm ID x 25 cm L, mobile phase: 100% acetonitrile, flow rate: 1.0 mL/min, temperature: 40°C, wavelength : 238 nm)
Example 14 (enantiomer B): retention time 4.15 minutes, Chiral HPLC (Chiralpak ^™ AY-H, 0.46 cm ID x 25 cm L, mobile phase: 100% acetonitrile, flow rate: 1.0 mL/min, temperature: 40°C, wavelength : 238 nm)

The specific rotations of the compounds of Examples 13 and 14 were measured under the following conditions.
Measuring equipment: JASCO P-1020 Polarimeter
Temperature: 21.6℃
Solution concentration: 10 mg/mL
Measurement solvent: MeOH
Wavelength: 589nm
Cell length: 50mm
Example 13 (Enantiomer A): Specific rotation -30.1886
Example 14 (enantiomer B): specific rotation +31.4743

Example 15:
Single crystal X-ray crystal structure analysis of Example 13 Single crystal X-ray diffraction at -173 ° C. using a diffractometer (pinpoint structure measuring device) for the single crystal of Example 13 to determine the structure of the crystal Measurements were made.

Obtaining Single Crystals Example 13 (0.01-0.03 g) was added to a glass screw tube, tetrahydrofuran (about 0.02 mL) was added, the screw tube was capped and the suspension was heated at about 50°C. After shaking for about 10 days, a single crystal of Example 13 was obtained.

Single crystal X-ray crystal structure analysis The single crystal of Example 13 was attached to a diffractometer, and a diffraction image was measured in an inert gas stream at -173°C using X-rays of a predetermined wavelength. Next, from the set of surface index and diffraction intensity calculated from the diffraction image, structure determination by direct method and structure refinement by least squares method [Acta Cryst. A64, 112 (2008)] to obtain the molecular structure and the crystal structure. From the results of X-ray crystal structure analysis, the absolute configuration of the compound of Example 13 (enantiomer A with a specific rotation of −30.1886) at the α-position of benzisoxazole was R. The results of the analysis are shown in Table 7, Figures 1-1 and 1-2.

標題の化合物を以下に記載する工程により製造した：
（ｉ）プロパン－２－イル （１，２－ベンゾオキサゾール－３－イル）メタンスルホネート

（１，２－ベンゾオキサゾール－３－イル）メタンスルホン酸(13.00 g) のアセトニトリル(130 ml) 溶液に酸化銀（16.96 g）と２－ヨウ化プロピル（7.32 ml）を加え室温で１時間撹拌した。不溶物をセライトろ過で除きろ液を濃縮した。残渣をシリカゲルクロマトグラフィー(ヘキサン：酢酸エチル； １９：１→１：１)で精製し黄色固体の表題化合物を13.00 g得た。収率84 %。
¹H NMR (400 Hz, CDCl₃) δ 1.34 (d, J=6.4 Hz, 6H), 4.75 (s, 2H), 4.85 (dt, J=12.8, 6.4 Hz, 1H), 7.38 (t, J=8.0, 6.0, 2.4 Hz, 1H), 7.56-7.62 (m, 2H), 7.90 (d, J= 8.0 Hz, 1H), Example 16:
Preparation of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (alternative to Example 13)

The title compound was prepared by the steps described below:
(i) propan-2-yl (1,2-benzoxazol-3-yl) methanesulfonate

Silver oxide (16.96 g) and 2-propyl iodide (7.32 ml) were added to a solution of (1,2-benzoxazol-3-yl)methanesulfonic acid (13.00 g) in acetonitrile (130 ml) and stirred at room temperature for 1 hour. did. Insoluble matter was removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate; 19:1→1:1) to obtain 13.00 g of the title compound as a yellow solid. Yield 84%.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.34 (d, J=6.4 Hz, 6H), 4.75 (s, 2H), 4.85 (dt, J=12.8, 6.4 Hz, 1H), 7.38 (t, J= 8.0, 6.0, 2.4Hz, 1H), 7.56-7.62 (m, 2H), 7.90 (d, J = 8.0Hz, 1H),

実施例１６工程（ｉ）で得られた化合物(13.00 g, 50.9 mmol)の ＴＨＦ（255 ml）溶液に水素化ナトリウム（2.222 g, 50.9 mmol）を0℃で加え、同温度で10分撹拌した。そこへヨウ化メチル（3.80 ml, 61.1 mmol）を加え 0℃で1時間撹拌した。飽和塩化アンモニウム水溶液でクエンチし酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後濃縮した。残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル；１９：１→３：１）で精製し黄色オイル状の標題化合物を10.60 g得た。収率77％。
¹H NMR (400 Hz, CDCl₃) δ 1.20 (d, J=6.2 Hz, 3H), 1.27 (d, J=6.2 Hz, 3H), 1.95 (d, J=7.2 Hz, 3H), 4.72 (sep, 6.2 Hz, 2H), 4.82 (q, J=7.2 Hz, 1H), 7.27-7.32 (m, 1H), 7.49-7.55 (m, 2H), 7.89 (d, J= 8.0 Hz, 1H),
MS(m/z): 270.2 [M+1]+ , Rt=0.99 min. (ii) propan-2-yl 1-(1,2-benzoxazol-3-yl)ethane-1-sulfonate

Sodium hydride (2.222 g, 50.9 mmol) was added to a solution of the compound (13.00 g, 50.9 mmol) obtained in step (i) of Example 16 in THF (255 ml) at 0°C and stirred at the same temperature for 10 minutes. . Methyl iodide (3.80 ml, 61.1 mmol) was added thereto, and the mixture was stirred at 0°C for 1 hour. It was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate; 19:1→3:1) to obtain 10.60 g of the title compound as a yellow oil. Yield 77%.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.20 (d, J=6.2 Hz, 3H), 1.27 (d, J=6.2 Hz, 3H), 1.95 (d, J=7.2 Hz, 3H), 4.72 (sep , 6.2 Hz, 2H), 4.82 (q, J=7.2 Hz, 1H), 7.27-7.32 (m, 1H), 7.49-7.55 (m, 2H), 7.89 (d, J= 8.0 Hz, 1H),
MS(m/z): 270.2 [M+1]+ , Rt=0.99 min.

実施例１６工程（ｉｉ）で得られた化合物（7.80 g, 29.0 mmol）のアセトン（250 ml）溶液にヨウ化ナトリウム（4.34 g, 29.0 mmol）を加え、4時間加熱還流した。白色析出物をろ取しアセトンでかけ洗いして白色固体の表題化合物（6.60 g, 91 % yield）を得た。
¹H NMR (400 Hz, DMSO-d₆) δ 1.65 (d, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.57 (dt, J=8.8, 1.2 Hz, 1H), 765 (d, J= 8.8 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H)
MS(m/z): 228.1 [M-21]+, Rt=0.48 min. (iii) sodium 1-(1,2-benzoxazol-3-yl)ethane-1-sulfonate

Sodium iodide (4.34 g, 29.0 mmol) was added to a solution of the compound (7.80 g, 29.0 mmol) obtained in step (ii) of Example 16 in acetone (250 ml), and the mixture was heated under reflux for 4 hours. The white precipitate was collected by filtration and spray-washed with acetone to obtain the title compound (6.60 g, 91 % yield) as a white solid.
¹ H NMR (400 Hz, DMSO-d ₆ ) δ 1.65 (d, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.57 (dt, J=8.8, 1.2Hz, 1H), 765 (d, J= 8.8Hz, 1H), 8.09 (d, J= 8.0Hz, 1H)
MS(m/z): 228.1 [M-21]+, Rt=0.48 min.

３－（１－ブロモエチル）－１，２－ベンゾオキサゾール（226 mg）、亜硫酸ナトリウム（189 mg）およびヨウ化カリウム（17 mg）をＴＨＦ（0.5 mL）、水（1 mL）に懸濁し50℃で80時間撹拌した。冷却後、反応液に酢酸エチル（1 mL）を加えて混合し、分液した。水層を濃縮乾固し、掲題化合物の混合物416 mgを得た。収率96 %。
¹H NMR (400 Hz, DMSO-d6) δ 1.65 (d, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.57 (dt, J=8.8, 1.2 Hz, 1H), 765 (d, J= 8.8 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H) (iii-a) sodium 1-(1,2-benzoxazol-3-yl)ethane-1-sulfonate (alternative to Example 16 step (iii))

3-(1-Bromoethyl)-1,2-benzoxazole (226 mg), sodium sulfite (189 mg) and potassium iodide (17 mg) were suspended in THF (0.5 mL) and water (1 mL) at 50°C. and stirred for 80 hours. After cooling, ethyl acetate (1 mL) was added to the reaction mixture and the mixture was separated. The aqueous layer was concentrated to dryness to obtain 416 mg of the title compound mixture. Yield 96%.
¹ H NMR (400 Hz, DMSO-d6) δ 1.65 (d, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 7.57 ( dt, J=8.8, 1.2Hz, 1H), 765 (d, J= 8.8Hz, 1H), 8.09 (d, J= 8.0Hz, 1H)

実施例１６工程（ｉｉｉ）で得られた化合物（600 mg, 2.408 mmol）のＴＨＦ（10 ml）懸濁液に塩化チオニル（0.210 ml, 2.89 mmol）とＮ，Ｎ‐ジメチルホルムアミド（9.32μl, 0.120 mmol）を加え、４時間加熱還流した。室温に冷却した後、反応液を酢酸エチルで希釈し冷水で3回洗浄した。有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥し濃縮し、褐色オイル状の表題化合物（606.00 mg、収率102 %）を得た。
MS(m/z): 246.1 [M+1]+, Rt=1.00 min. (iv) 1-(1,2-benzoxazol-3-yl)ethane-1-sulfonyl chloride

Thionyl chloride (0.210 ml, 2.89 mmol) and N,N-dimethylformamide (9.32 μl, 0.120 μl) were added to a THF (10 ml) suspension of the compound (600 mg, 2.408 mmol) obtained in Example 16 step (iii). mmol) was added and heated under reflux for 4 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with cold water three times. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to give the title compound (606.00 mg, yield 102%) as a brown oil.
MS(m/z): 246.1 [M+1]+, Rt=1.00 min.

（１Ｓ，２Ｓ）－（＋）－ｔｒａｎｓ－１－アミノ－２－インダノール（359 mg, 2.406 mmol）とＮ，Ｎ－ジイソプロピルエチルアミン（0.880 ml）のアセトニトリル（10 ml）溶液に実施例１６工程（ｉｖ）で得られた化合物（591 mg, 2.406 mmol）のアセトニトリル（10 ml）溶液を加え、室温で１５時間撹拌した。10％クエン酸水溶液で希釈し酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル； １９：１→１：１)で精製し、白色固体の表題化合物（174 mg、収率20.18 %)とそのジアステレオマーである（１Ｓ）－１－（１，２－ベンゾオキサゾール－３－イル）－Ｎ－［（１Ｓ，２Ｓ）－２－ヒドロキシ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］エタン－１－スルホンアミド（192.00 mg、収率22.27 %）を得た。
（１Ｒ）－１－（１，２－ベンゾオキサゾール－３－イル）－Ｎ－［（１Ｓ，２Ｓ）－２－ヒドロキシ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］エタン－１－スルホンアミド
¹H NMR (400 Hz, CDCl₃) δ 2.10 (d, J=7.2 Hz, 3H), 2.89 (dd, J=15.2, 9.2 Hz, 1H), 3.20 (dd, J=16.0, 8.0 Hz, 1H), 4.27-4.35 (m, 1H), 4.36 (d, 9.6 Hz, 1H), 4.63 (d, 3.6 Hz, 1H), 4.74 (dd, J=9.6, 7.2 Hz, 1H), 5.14 (q, J=7.2 Hz, 1H), 7.13-7.17 (m, 1H), 7.21-7.24 (m, 2H), 7.32-7.35 (m, 1H), 7.38-7.42 (m, 1H), 7.62 (d, J=3.6 Hz, 2H), 8.03 (dd, J=9.2, 1.2 Hz, 1H)
MS(m/z): 359.2 [M+1]+, Rt=0.92 min.
（１Ｓ）－１－（１，２－ベンゾオキサゾール－３－イル）－Ｎ－［（１Ｓ，２Ｓ）－２－ヒドロキシ－２，３－ジヒドロ－１Ｈ－インデン－１－イル］エタン－１－スルホンアミド
¹H NMR (400 Hz, CDCl₃) δ 2.13 (d, J=7.2 Hz, 3H), 2.84 (dd, J=16.0, 8.0 Hz, 1H), 3.24 (dd, J=16.0, 8.0 Hz, 1H), 3.59 (d, 3.2 Hz, 1H), 4.36-4.42 (m, 1H), 4.48 (d, J=9.2 Hz, 1H), 4.62 (dd, J=8.8, 6.8 Hz, 1H), 5.07 (q, 7.2 Hz, 1H), 7.15-7.19 (m, 1H), 7.22-7.30 (m, 3H), 7.38-7.42 (m, 1H), 7.59-7.65 (m, 2H), 7.97-8.00 (m, 1H)
MS(m/z): 359.2 [M+1]+, Rt=0.90 min. (v) (1R)-1-(1,2-benzoxazol-3-yl)-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]ethane -1-sulfonamide

A solution of (1S,2S)-(+)-trans-1-amino-2-indanol (359 mg, 2.406 mmol) and N,N-diisopropylethylamine (0.880 ml) in acetonitrile (10 ml) was added to Example 16 step ( An acetonitrile (10 ml) solution of the compound (591 mg, 2.406 mmol) obtained in iv) was added, and the mixture was stirred at room temperature for 15 hours. The mixture was diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate; 19:1→1:1) to give the title compound (174 mg, yield 20.18%) as a white solid and its diastereomer (1S)-1. -(1,2-benzoxazol-3-yl)-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]ethane-1-sulfonamide (192.00 mg , yield 22.27%).
(1R)-1-(1,2-benzoxazol-3-yl)-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]ethane-1- Sulfonamide
¹ H NMR (400 Hz, CDCl ₃ ) δ 2.10 (d, J=7.2 Hz, 3H), 2.89 (dd, J=15.2, 9.2 Hz, 1H), 3.20 (dd, J=16.0, 8.0 Hz, 1H) , 4.27-4.35 (m, 1H), 4.36 (d, 9.6 Hz, 1H), 4.63 (d, 3.6 Hz, 1H), 4.74 (dd, J=9.6, 7.2 Hz, 1H), 5.14 (q, J= 7.2Hz, 1H), 7.13-7.17 (m, 1H), 7.21-7.24 (m, 2H), 7.32-7.35 (m, 1H), 7.38-7.42 (m, 1H), 7.62 (d, J=3.6Hz , 2H), 8.03 (dd, J=9.2, 1.2Hz, 1H)
MS(m/z): 359.2 [M+1]+, Rt=0.92 min.
(1S)-1-(1,2-benzoxazol-3-yl)-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]ethane-1- Sulfonamide
¹ H NMR (400 Hz, CDCl ₃ ) δ 2.13 (d, J=7.2 Hz, 3H), 2.84 (dd, J=16.0, 8.0 Hz, 1H), 3.24 (dd, J=16.0, 8.0 Hz, 1H) , 3.59 (d, 3.2 Hz, 1H), 4.36-4.42 (m, 1H), 4.48 (d, J=9.2 Hz, 1H), 4.62 (dd, J=8.8, 6.8 Hz, 1H), 5.07 (q, 7.2 Hz, 1H), 7.15-7.19 (m, 1H), 7.22-7.30 (m, 3H), 7.38-7.42 (m, 1H), 7.59-7.65 (m, 2H), 7.97-8.00 (m, 1H)
MS(m/z): 359.2 [M+1]+, Rt=0.90 min.

実施例１６工程（ｖ）で得られた化合物（51 mg, 0.142 mmol）のトルエン（1 ml）懸濁液に0℃でトリフルオロメタンスルホン酸（0.252 ml, 2.85 mmol）加え0℃で0.5時間撹拌した。アセトニトリル1 mLを加え、 酢酸エチルで希釈して分液した。有機層を水で3回洗浄し、硫酸マグネシウムで乾燥した後濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；１９：１→１：１）で精製し、白色固体の表題化合物（27.50 mg、収率85 %、>99% ee）を得た。 (vi) (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide

Trifluoromethanesulfonic acid (0.252 ml, 2.85 mmol) was added to a toluene (1 ml) suspension of the compound (51 mg, 0.142 mmol) obtained in step (v) of Example 16 at 0°C and stirred at 0°C for 0.5 hours. did. 1 mL of acetonitrile was added, diluted with ethyl acetate and separated. The organic layer was washed with water three times, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate; 19:1→1:1) to give the title compound (27.50 mg, yield 85%, >99% ee) as a white solid.

標題の化合物を以下に記載する工程により製造した：
（ｉ）１－（１，２－ベンゾオキサゾール－３－イル）エチル アセテート

３－（１－ブロモエチル）－１，２－ベンゾオキサゾール（4.52 g）、酢酸ナトリウム（3.28 g）およびヨウ化カリウム（3.32 g）にDMF（20 mL）を加えて50℃で14時間撹拌した。冷却後、反応液をチオ硫酸ナトリウム五水和物（2 g）の水（40 g）溶液を加え、酢酸エチル（40 mL）で抽出した。水層を酢酸エチル（20 mL）で2回抽出し、合わせた有機層をチオ硫酸ナトリウム五水和物（1 g）の水（20 g）溶液で洗浄した。有機層に硫酸ナトリウムを加えて乾燥し、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→７０：３０）で精製し、無色オイル状の標題化合物3.72 g（収率91 %）を得た。
¹H NMR (400 Hz, CDCl₃) δ 1.79 (d, J=6.8 Hz, 3H), 2.144 (s, 3H), 6.39 (q, J=6.8 Hz, 1H), 7.34 (ddd, J=8.0, 6.4, 1.6 Hz,1H), 7.54-7.61 (m, 2H), 7.78 (d, J= 8.8 Hz, 1H). Example 17:
Preparation of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (alternative to Example 13)

The title compound was prepared by the steps described below:
(i) 1-(1,2-benzoxazol-3-yl)ethyl acetate

DMF (20 mL) was added to 3-(1-bromoethyl)-1,2-benzoxazole (4.52 g), sodium acetate (3.28 g) and potassium iodide (3.32 g), and the mixture was stirred at 50°C for 14 hours. After cooling, a solution of sodium thiosulfate pentahydrate (2 g) in water (40 g) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL). The aqueous layer was extracted twice with ethyl acetate (20 mL), and the combined organic layers were washed with a solution of sodium thiosulfate pentahydrate (1 g) in water (20 g). The organic layer was dried by adding sodium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→70:30) to obtain 3.72 g of the title compound as a colorless oil (yield 91%).
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.79 (d, J=6.8 Hz, 3H), 2.144 (s, 3H), 6.39 (q, J=6.8 Hz, 1H), 7.34 (ddd, J=8.0, 6.4, 1.6 Hz, 1H), 7.54-7.61 (m, 2H), 7.78 (d, J= 8.8 Hz, 1H).

実施例１７工程（ｉ）で得られた化合物（1.54 g）のメタノール（15 mL）溶液に氷冷下1N 水酸化ナトリウム水溶液 （7.5 mL）を加えて室温で4時間撹拌した。反応液をある程度濃縮した後、酢酸エチル（25 mL）で3回抽出した後、有機層に硫酸ナトリウムを加えて乾燥し、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→７０：３０） で精製し、無色オイル状の標題化合物1.20 gを得た。収率98 ％。
¹H NMR (400 Hz, CDCl₃) δ 1.77 (d, J=6.4 Hz, 3H), 2.32 (d, J=4.8 Hz, 1H), 5.39 (ddd, J=13.6, 6.8, 4.8 Hz, 1H), 7.33 (ddd, J=8.0, 6.0, 2.0 Hz, 1H), 7.56-7.60 (m, 2H), 7.89 (dd, J= 8.0, 1.2 Hz, 1H) (ii) 1-(1,2-benzoxazol-3-yl)ethan-1-ol

To a solution of the compound (1.54 g) obtained in step (i) of Example 17 in methanol (15 mL) was added 1N aqueous sodium hydroxide solution (7.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was concentrated to some extent, it was extracted three times with ethyl acetate (25 mL), and the organic layer was dried by adding sodium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→70:30) to obtain 1.20 g of the title compound as a colorless oil. Yield 98%.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.77 (d, J=6.4 Hz, 3H), 2.32 (d, J=4.8 Hz, 1H), 5.39 (ddd, J=13.6, 6.8, 4.8 Hz, 1H) , 7.33 (ddd, J=8.0, 6.0, 2.0 Hz, 1H), 7.56-7.60 (m, 2H), 7.89 (dd, J= 8.0, 1.2 Hz, 1H)

実施例１７工程（ｉｉ）で得られた化合物（1.42 g）と二酸化マンガン（7.58 g）のジクロロメタン（20 g）溶液を室温で20時間撹拌した。反応液をセライトろ過し、ろ液を濃縮乾固して標題化合物を1.31 g（収率93 %）を得た。
¹H NMR (400 Hz, CDCl₃) δ 2.81 (s, 3H), 7.41-7.469 (m, 1H), 7.58-7.67 (m, 2H), 8.24 (dd, J= 8.0, 1.2 Hz, 1H) (iii) 1-(1,2-benzoxazol-3-yl)ethan-1-one

A dichloromethane (20 g) solution of the compound (1.42 g) obtained in Example 17 step (ii) and manganese dioxide (7.58 g) was stirred at room temperature for 20 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated to dryness to obtain 1.31 g of the title compound (yield 93%).
¹ H NMR (400 Hz, CDCl ₃ ) δ 2.81 (s, 3H), 7.41-7.469 (m, 1H), 7.58-7.67 (m, 2H), 8.24 (dd, J= 8.0, 1.2 Hz, 1H)

リン酸二水素ナトリウム・2水和物（1.25 g）、リン酸水素二ナトリウム・12水和物（2.87 g）および硫酸マグネシウム（38 mg）を脱イオン水（160 g）に室温で溶解した。Codexis社製ケトリダクターゼ(KRED P1-B05)（200 mg）およびＮＡＤＰ^＋（80 mg）を加えて室温で撹拌して溶解した。実施例１７工程（ｉｉｉ）で得られた化合物(10.00 g）のイソプロピルアルコール（31.5 g）溶液を加えて35℃で41時間撹拌した。反応液をある程度濃縮した後、クロロベンゼン（200 g）を加えてセライトろ過したろ液を分液した。有機層を水（200 g）で洗浄した後、有機層を硫酸ナトリウムで乾燥し、ろ過、濃縮した。淡黄色オイル状の掲題化合物を含む混合物9.61 gを得た。混合物1gをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→９６：４）で精製し、無色オイル状の標題化合物901 mgを得た。収率85 ％, 99.3 %ee。 (iv) (1S)-1-(1,2-benzoxazol-3-yl)ethan-1-ol

Sodium dihydrogen phosphate dihydrate (1.25 g), disodium hydrogen phosphate dodecahydrate (2.87 g) and magnesium sulfate (38 mg) were dissolved in deionized water (160 g) at room temperature. Codexis ketoreductase (KRED P1-B05) (200 mg) and NADP ⁺ (80 mg) were added and dissolved by stirring at room temperature. A solution of the compound (10.00 g) obtained in step (iii) of Example 17 in isopropyl alcohol (31.5 g) was added and stirred at 35°C for 41 hours. After concentrating the reaction mixture to some extent, chlorobenzene (200 g) was added and filtered through celite, and the filtrate was separated. After washing the organic layer with water (200 g), the organic layer was dried over sodium sulfate, filtered and concentrated. 9.61 g of a mixture containing the title compound was obtained as a pale yellow oil. 1 g of the mixture was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→96:4) to obtain 901 mg of the title compound as a colorless oil. Yield 85%, 99.3% ee.

カルボニル還元酵素スクリーニングキット（ＣＯＤＥＸ（登録商標）、ＣＯＤＥＸＩＳ社）を用いて、表８に示す１－２４に示すカルボニル還元酵素と補酵素の組み合わせを用いて、実施例１７工程（ｉｉｉ）で得られた化合物の還元反応を行った。
表８に示すカルボニル還元酵素１－１９においては、以下の操作を行った。
補酵素混合物（128 mM リン酸ナトリウム、1.7 mM 硫酸マグネシウム、1.1 mM ＮＡＤＰ^＋, pH 7.0）（０．６ｇ）の脱イオン水（３３ｇ）溶液を調製し、そのうち０．９ｍＬずつをカルボニル還元酵素１－１９（１０ｍｇ）にそれぞれ添加し、溶解するまで撹拌した。実施例１７工程（ｉｉｉ）で得られた化合物（１６１ｍｇ）のイソプロピルアルコール（４ｍＬ）溶液を調整し、そのうち０．１ｍＬずつを上記反応系にそれぞれ添加し、３０℃で２０時間撹拌した。酢酸エチルを加えて混合し、遠心分離を行い、酢酸エチル層をＨＰＬＣにて分析した。
表８に示すカルボニル還元酵素２０－２４においては、以下の操作を行った。
補酵素混合物（263 mM リン酸ナトリウム、1.7 mM 硫酸マグネシウム、1.1 mM ＮＡＤＰ^＋、1.1 mM ＮＡＤ^＋、80 mM Ｄ－グルコース、4.3 U/mL グルコース脱水素酵素、pH 7.0）（０．３ｇ）の脱イオン水（６ｇ）溶液を調製し、実施例１７工程（ｉｉｉ）で得られた化合物（４８ｍｇ）のＤＭＳＯ（０．３ｍＬ）溶液と混合した。混合液１ｍＬずつをカルボニル還元酵素２０－２４（１０ｍｇ）にそれぞれ添加し、３０℃で２０時間撹拌した。酢酸エチルを加えて混合し、遠心分離を行い、酢酸エチル層をＨＰＬＣにて分析した。
表８に示す通り、カルボニル還元酵素（１－２４）と補酵素（ＮＡＤＰＨまたはＮＡＤＨ）の組み合わせにおいて、実施例１７工程（ｉｉｉ）で得られた化合物が光学選択的に還元されることを確認した。

(iv-a) (1S)-1-(1,2-benzoxazol-3-yl)ethan-1-ol

Using a carbonyl reductase screening kit (CODEX (registered trademark), CODEXIS), using a combination of a carbonyl reductase and a coenzyme shown in 1-24 shown in Table 8, obtained in Example 17 step (iii) A reduction reaction of the compound was carried out.
For carbonyl reductase 1-19 shown in Table 8, the following operations were performed.
A solution of coenzyme mixture (128 mM sodium phosphate, 1.7 mM magnesium sulfate, 1.1 mM NADP ⁺ , pH 7.0) (0.6 g) in deionized water (33 g) was prepared, and 0.9 mL of each solution was added to carbonyl reductase 1. -19 (10 mg) and stirred until dissolved. A solution of the compound (161 mg) obtained in step (iii) of Example 17 in isopropyl alcohol (4 mL) was prepared, 0.1 mL of which was added to the above reaction system and stirred at 30° C. for 20 hours. Ethyl acetate was added and mixed, centrifugation was performed, and the ethyl acetate layer was analyzed by HPLC.
For the carbonyl reductases 20-24 shown in Table 8, the following operations were performed.
Desorption of coenzyme mixture (263 mM sodium phosphate, 1.7 mM magnesium sulfate, 1.1 mM NADP ⁺ , 1.1 mM NAD ⁺ , 80 mM D-glucose, 4.3 U/mL glucose dehydrogenase, pH 7.0) (0.3 g) A solution of ionized water (6 g) was prepared and mixed with a solution of the compound (48 mg) obtained in Example 17 step (iii) in DMSO (0.3 mL). Each 1 mL of the mixture was added to carbonyl reductase 20-24 (10 mg) and stirred at 30° C. for 20 hours. Ethyl acetate was added and mixed, centrifugation was performed, and the ethyl acetate layer was analyzed by HPLC.
As shown in Table 8, in the combination of carbonyl reductase (1-24) and coenzyme (NADPH or NADH), it was confirmed that the compound obtained in Example 17 step (iii) was optically reduced. .

実施例１７工程（ｉ）で得られた化合物（3.50 g）にリン酸緩衝液 （pH 7.0）（35 mL）とノボザイム435（0.70 g）を加え37℃で7時間撹拌した。反応液をろ過した後、ろ液を酢酸エチル（70 mL、35 mL×2）で抽出し、有機層を合わせて硫酸ナトリウムで乾燥、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→７０：３０）で精製し、無色オイル状の（Ｒ）－酢酸 １－（１，２－ベンゾオキサゾール－３－イル）エチル 1.74 g（収率50 %, 97.4% ee）とともに、無色オイル状の標題化合物1.37 g（収率49 %, 99.1 % ee）を得た。
¹H NMR (400 Hz, CDCl₃) δ 1.77 (d, J=6.4 Hz, 3H), 2.32 (d, J=4.8 Hz, 1H), 5.39 (ddd, J=13.6, 6.8, 4.8 Hz, 1H), 7.33 (ddd, J=8.0, 6.0, 2.0 Hz, 1H), 7.56-7.60 (m, 2H), 7.89 (dd, J= 8.0, 1.2 Hz, 1H) (iv-b) (1S)-1-(1,2-benzoxazol-3-yl)ethan-1-ol (alternative to Example 17 step (iv))

Phosphate buffer (pH 7.0) (35 mL) and Novozym 435 (0.70 g) were added to the compound (3.50 g) obtained in step (i) of Example 17, and the mixture was stirred at 37°C for 7 hours. After filtering the reaction mixture, the filtrate was extracted with ethyl acetate (70 mL, 35 mL×2), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→70:30) to give 1-(1,2-benzoxazol-3-yl)ethyl (R)-acetate 1.74 as a colorless oil. 1.37 g (49% yield, 99.1% ee) of the title compound as a colorless oil were obtained.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.77 (d, J=6.4 Hz, 3H), 2.32 (d, J=4.8 Hz, 1H), 5.39 (ddd, J=13.6, 6.8, 4.8 Hz, 1H) , 7.33 (ddd, J=8.0, 6.0, 2.0 Hz, 1H), 7.56-7.60 (m, 2H), 7.89 (dd, J= 8.0, 1.2 Hz, 1H)

実施例１７工程（ｉｖ）または（ｉｖ－ｂ）で得られた化合物（979 mg）とジベンゾチアゾイルジスルフィド（2.39 g）のＴＨＦ（20 mL）懸濁液に水冷下トリｎ－ブチルホスフィン（1.78 mL）を10分かけて滴下し、室温で2時間撹拌した。反応液に酢酸エチル（50 mL）および5%炭酸水素ナトリウム水溶液（50 mL）を加えて分液した。水層を酢酸エチル（50 mL）で2回抽出し、有機層を合わせて5%炭酸水素ナトリウム水溶液（50 mL）で洗浄した。有機層を硫酸ナトリウムで乾燥し、ろ過、濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→８２：１８）で精製し、無色ガム状の標題化合物1.873 gを得た。収率100 %、98.0 %ee。
¹H NMR (400 Hz, CDCl₃) δ 2.07 (d, J=6.4 Hz, 1H), 5.74 (q, J=7.2 Hz, 1H), 7.28-7.35 (m, 2H), 7.44 (dt, J= 7.6, 1.2 Hz, 1H), 7.52-7.60 (m, 2H), 7.76 (d, J= 8.0Hz, 1H), 7.90 (dd, J= 8.0, 1.2 Hz, 1H), 7.92 (d, J= 8.0Hz, 1H) (v) 3-{(1R)-1-[(1,3-benzothiazol-2-yl)sulfanyl]ethyl}-1,2-benzoxazole

A THF (20 mL) suspension of the compound (979 mg) obtained in Example 17 step (iv) or (iv-b) and dibenzothiazolyl disulfide (2.39 g) was added with tri-n-butylphosphine (1.78 mL) was added dropwise over 10 minutes and stirred at room temperature for 2 hours. Ethyl acetate (50 mL) and 5% aqueous sodium hydrogencarbonate solution (50 mL) were added to the reaction mixture to separate the layers. The aqueous layer was extracted twice with ethyl acetate (50 mL), and the organic layers were combined and washed with 5% aqueous sodium hydrogencarbonate solution (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→82:18) to obtain 1.873 g of the title compound as a colorless gum. 100% yield, 98.0% ee.
¹ H NMR (400 Hz, CDCl ₃ ) δ 2.07 (d, J=6.4 Hz, 1H), 5.74 (q, J=7.2 Hz, 1H), 7.28-7.35 (m, 2H), 7.44 (dt, J= 7.6, 1.2 Hz, 1H), 7.52-7.60 (m, 2H), 7.76 (d, J= 8.0Hz, 1H), 7.90 (dd, J= 8.0, 1.2 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H)

実施例１７工程（ｖ）で得られた化合物（250 mg）のクロロベンゼン(7.5 g)溶液にビス(モノペルオキシフタル酸)マグネシウム六水和物（0.95 g）の水（5 g）溶液を加えて室温で4日間撹拌した。ビス(モノペルオキシフタル酸)マグネシウム六水和物（0.24 g）の水（1.25 g）溶液を追加し室温で8時間撹拌した後、亜硫酸水素ナトリウム水溶液（0.24 g/1 g）を水冷下に滴下してクエンチした。クロロベンゼン（20 g）、水（20 g）を加えて分液した。有機層をリン酸二水素カリウム（272 mg）とリン酸水素二カリウム（87 mg）の水（10 g）溶液で洗浄し、続いて水（10 g）で洗浄した。有機層を硫酸ナトリウムで乾燥し、ろ過、濃縮した。濃縮残渣をクロロベンゼン（2 g）およびヘプタン（4 g）でリスラリーした後析出結晶をろ取し、ヘプタン（1 g）でかけ洗いした。40℃で真空乾燥し、標題化合物（10.44 g）を白色結晶として得た。収率72 %、99.8 %ee。
¹H NMR (400 Hz, CDCl₃) δ 2.11 (d, J=7.6 Hz, 1H), 5.37 (q, J=7.2 Hz, 1H), 7.33-7.37 (m, 1H), 7.56-7.60 (m, 3H), 7.62-7.66 (m, 1H), 7.91-7.97 (m, 2H) 8.24 (d, J= 8.4Hz, 1H) (vi) 3-[(1R)-1-(1,3-benzothiazole-2-sulfonyl)ethyl]-1,2-benzoxazole

To a solution of the compound (250 mg) obtained in step (v) of Example 17 in chlorobenzene (7.5 g) was added a solution of magnesium bis(monoperoxyphthalate) hexahydrate (0.95 g) in water (5 g). Stirred at room temperature for 4 days. A solution of magnesium bis(monoperoxyphthalate) hexahydrate (0.24 g) in water (1.25 g) was added and stirred at room temperature for 8 hours. and quenched. Chlorobenzene (20 g) and water (20 g) were added for liquid separation. The organic layer was washed with a solution of potassium dihydrogen phosphate (272 mg) and dipotassium hydrogen phosphate (87 mg) in water (10 g), followed by water (10 g). The organic layer was dried over sodium sulfate, filtered and concentrated. The concentrated residue was reslurried with chlorobenzene (2 g) and heptane (4 g), and the precipitated crystals were collected by filtration and spray-washed with heptane (1 g). It was dried under vacuum at 40°C to give the title compound (10.44 g) as white crystals. Yield 72%, 99.8% ee.
¹ H NMR (400 Hz, CDCl ₃ ) δ 2.11 (d, J=7.6 Hz, 1H), 5.37 (q, J=7.2 Hz, 1H), 7.33-7.37 (m, 1H), 7.56-7.60 (m, 3H), 7.62-7.66 (m, 1H), 7.91-7.97 (m, 2H) 8.24 (d, J= 8.4Hz, 1H)

塩化マグネシウム（0.69 g）のＮＭＰ（20 g）溶液に実施例１７工程（ｖｉ）で得られた化合物（5.0 g）を加えて懸濁させたものを、０℃に冷やした水素化ホウ素ナトリウム（1.10 g）のエタノール（22.5 g）懸濁液に滴下し、ＮＭＰ（2.5 g）で洗い込んだ後、０℃で２時間反応させた。０℃に冷やした酢酸ナトリウム（11.91 g）とヒドロキシアミン－Ｏ－スルホン酸（16.42 g）の水（62.5 g）溶液に、上記の反応液を滴下し、水（5 g）で洗い込んだ後、０℃で３．５時間反応させた。反応液に６Ｍ塩酸（25 g）および酢酸エチル（90 g）を加えて分液した。水層を酢酸エチル（45 g）で２回抽出した後、有機層を１Ｍ塩酸（90 g）で洗浄した。有機層に活性炭（0.25 g）を加えて1時間撹拌した後、ろ過し濃縮した。酢酸エチルを加えて全量を22.5 gに調製し、２０℃でヘプタンを20 g滴下して結晶化させた。０℃まで冷却した後、析出結晶をろ取し、ヘプタン-酢酸エチル（5 g/2.5 g）混合液でかけ洗いした。結晶を４０℃で真空乾燥し、粗結晶2.40 gを帯黄白色結晶として得た。
粗結晶（2.0 g）に酢酸イソプロピル（19.6 g）を加え５０℃で１時間撹拌した後１０℃に冷却し３時間撹拌した。不溶物をろ去した後酢酸イソプロピル0.5 gで洗浄した。ろ液を濃縮した後、酢酸イソプロイルを加えて全量を4.4 gに調製し、５０℃で４時間懸濁撹拌した。０℃まで冷却した後、析出結晶をろ取し、酢酸イソプロピル(1.5 g)でかけ洗いした。結晶を４０℃で真空乾燥し、標題化合物10.44 gを白色結晶として得た。収率37.6 %、98.5 %ee。 (vii) (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide

A suspension of the compound (5.0 g) obtained in Example 17 step (vi) in a solution of magnesium chloride (0.69 g) in NMP (20 g) was added to sodium borohydride ( 1.10 g) in ethanol (22.5 g), washed with NMP (2.5 g), and reacted at 0° C. for 2 hours. The above reaction solution was added dropwise to a solution of sodium acetate (11.91 g) and hydroxylamine-O-sulfonic acid (16.42 g) in water (62.5 g) cooled to 0°C, and washed with water (5 g). and 0° C. for 3.5 hours. 6M Hydrochloric acid (25 g) and ethyl acetate (90 g) were added to the reaction mixture to separate the layers. After the aqueous layer was extracted twice with ethyl acetate (45 g), the organic layer was washed with 1M hydrochloric acid (90 g). Activated carbon (0.25 g) was added to the organic layer and the mixture was stirred for 1 hour, filtered and concentrated. Ethyl acetate was added to adjust the total amount to 22.5 g, and 20 g of heptane was added dropwise at 20° C. to crystallize. After cooling to 0°C, precipitated crystals were collected by filtration and spray-washed with a heptane-ethyl acetate (5 g/2.5 g) mixed solution. The crystals were vacuum dried at 40°C to obtain 2.40 g of crude crystals as yellowish white crystals.
Isopropyl acetate (19.6 g) was added to the crude crystals (2.0 g), and the mixture was stirred at 50°C for 1 hour, cooled to 10°C, and stirred for 3 hours. The insoluble matter was removed by filtration and washed with 0.5 g of isopropyl acetate. After concentrating the filtrate, isopropyl acetate was added to adjust the total amount to 4.4 g, and the suspension was stirred at 50°C for 4 hours. After cooling to 0°C, precipitated crystals were collected by filtration and spray-washed with isopropyl acetate (1.5 g). The crystals were vacuum dried at 40°C to obtain 10.44 g of the title compound as white crystals. Yield 37.6%, 98.5% ee.

標題の化合物を以下に記載する工程により製造した：
（ｉ）３－｛（１Ｒ）－１－［（ピリミジン－２－イル）スルファニル］エチル｝－１，２－ベンゾオキサゾール

トリフェニルホスフィン(531 mg)のトルエン(1.5 mL)溶液に０℃でアゾジカルボン酸ジイソプロピル(90 %, 420μL)を滴下して０℃で１５分撹拌した。実施例１７工程（ｉｖ）または（ｉｖ－ａ）で得られた化合物(245mg)のトルエン(2 mL)溶液を滴下して０℃で３０分撹拌した。反応液にピリミジン－２－チオール(227 mg)を加えて０℃で５時間撹拌した。析出物をろ去し、ろ液を濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；８０：２０→７０：３０）で精製して表題化合物を290 mg得た。収率75％、100 %ee。
¹H NMR (400 Hz, CDCl₃) δ 1.98 (d, J=7.2 Hz, 3H), 5.64 (q, J=7.2 Hz, 1H), 7.01 (t, J=5.0, 1H), 7.27-7.31 (m, 1H), 7.53-7.58 (m, 2H), 7.87 (dd, J=8.0, 1.2 Hz, 1H), 8.56 (d, J= 5.2Hz, 2H) Example 18:
Preparation of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (alternative to Example 13)

The title compound was prepared by the steps described below:
(i) 3-{(1R)-1-[(pyrimidin-2-yl)sulfanyl]ethyl}-1,2-benzoxazole

To a solution of triphenylphosphine (531 mg) in toluene (1.5 mL) was added dropwise diisopropyl azodicarboxylate (90%, 420 µL) at 0°C, and the mixture was stirred at 0°C for 15 minutes. A toluene (2 mL) solution of the compound (245 mg) obtained in Example 17 step (iv) or (iv-a) was added dropwise and stirred at 0° C. for 30 minutes. Pyrimidine-2-thiol (227 mg) was added to the reaction mixture and the mixture was stirred at 0°C for 5 hours. The precipitate was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate; 80:20→70:30) to obtain 290 mg of the title compound. 75% yield, 100% ee.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.98 (d, J=7.2 Hz, 3H), 5.64 (q, J=7.2 Hz, 1H), 7.01 (t, J=5.0, 1H), 7.27-7.31 ( m, 1H), 7.53-7.58 (m, 2H), 7.87 (dd, J=8.0, 1.2Hz, 1H), 8.56 (d, J= 5.2Hz, 2H)

実施例１８工程（ｉ）で得られた化合物(257 mg)のジクロロメタン(5 mL)溶液に氷冷下ｍ－クロロ過安息香酸(542 mg)を加えて室温で5時間撹拌した。酢酸エチル(5 mL)、チオ硫酸ナトリウム5水和物(250 mg)と炭酸水素ナトリウム(250 mg)の水(5 mL)溶液を加えて分液した。水層を酢酸エチル(2 mL)で２回抽出し、有機層を合わせてチオ硫酸ナトリウム5水和物(250 mg)と炭酸水素ナトリウム(250 mg)の水(5 mL)溶液で２回洗浄した。有機層を硫酸ナトリウムで乾燥後濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；８０：２０→２０：８０）で精製して表題化合物を238 mg得た。収率82％、99.3 %ee。
¹H NMR (400 Hz, CDCl₃) δ 2.08 (d, J=7.2 Hz, 3H), 5.57 (q, J=7.2 Hz, 1H), 7.38 (ddd, J=8.4, 6.4, 2.0 Hz 1H), 7.53-7.60 (m, 3H), 8.05 (d, J=8.0 Hz, 1H), 8.91 (d, J=4.8Hz, 2H) (ii) 3-[(1R)-1-(pyrimidine-2-sulfonyl)ethyl]-1,2-benzoxazole

To a solution of the compound (257 mg) obtained in Step (i) of Example 18 in dichloromethane (5 mL) was added m-chloroperbenzoic acid (542 mg) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. A solution of ethyl acetate (5 mL), sodium thiosulfate pentahydrate (250 mg) and sodium hydrogencarbonate (250 mg) in water (5 mL) was added to separate the layers. The aqueous layer was extracted twice with ethyl acetate (2 mL), and the organic layers were combined and washed twice with a solution of sodium thiosulfate pentahydrate (250 mg) and sodium hydrogencarbonate (250 mg) in water (5 mL). did. The organic layer was dried over sodium sulfate and then concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate; 80:20→20:80) to obtain 238 mg of the title compound. Yield 82%, 99.3% ee.
¹ H NMR (400 Hz, CDCl ₃ ) δ 2.08 (d, J=7.2 Hz, 3H), 5.57 (q, J=7.2 Hz, 1H), 7.38 (ddd, J=8.4, 6.4, 2.0 Hz 1H), 7.53-7.60 (m, 3H), 8.05 (d, J=8.0Hz, 1H), 8.91 (d, J=4.8Hz, 2H)

実施例１８工程（ｉｉ）で得られた化合物(28.9 mg)と塩化マグネシウム(28.6 mg)のＤＭＦ(300μL)溶液に１０℃で水素化ホウ素ナトリウム(22.7 mg)のエタノール(300μL)を滴下して２０℃で１時間撹拌した後１０℃に冷却した。酢酸ナトリウム(82 mg)を加えた後、ヒドロキシルアミン－Ｏ－スルホン酸(113 mg)の水(600μL)溶液を滴下し、２０℃で1時間撹拌した。反応液を１Ｎ塩酸(1.5 mL)に加え、酢酸エチル(3 mL)で抽出した。有機層を１Ｎ塩酸(1.5 mL)で洗浄した後、硫酸ナトリウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル88/12-0-100)で精製して標題化合物17 mgを白色結晶として得た。収率75 %、25.2 %ee。 (iii) (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide

To a DMF (300 µL) solution of the compound (28.9 mg) obtained in Example 18 step (ii) and magnesium chloride (28.6 mg) was added dropwise ethanol (300 µL) of sodium borohydride (22.7 mg) at 10°C. After stirring at 20°C for 1 hour, the mixture was cooled to 10°C. After adding sodium acetate (82 mg), a solution of hydroxylamine-O-sulfonic acid (113 mg) in water (600 μL) was added dropwise, and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was added to 1N hydrochloric acid (1.5 mL) and extracted with ethyl acetate (3 mL). The organic layer was washed with 1N hydrochloric acid (1.5 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 88/12-0-100) to give 17 mg of the title compound as white crystals. 75% yield, 25.2% ee.

標題の化合物を以下に記載する工程により製造した：
（ｉ）３－［（１Ｒ）－１－｛［２－（トリメチルシリル）エチル］スルファニル｝エチル］－１，２－ベンゾオキサゾール

（ｉ－１）実施例１７工程（ｉｖ）または（ｉｖ－ａ）で得られた化合物(979 mg)とＮ，Ｎ，Ｎ’，Ｎ’－テトラメチルアゾジカルボキサミド(1550 mg)のＴＨＦ(10 mL)溶液にチオ酢酸(0.67 mL)を加え撹拌した。水冷下、トリｎ－ブチルホスフィン(2.27 mL)を滴下し、室温で６時間撹拌した。水(25mL)で希釈した後、酢酸エチル(25mL)で３回抽出した。有機層を硫酸ナトリウムで乾燥した後濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９４：６→７０：３０）で精製してチオ酢酸 （Ｒ）－Ｓ－（１，２－ベンゾキサゾール－３－イル）エチル）を285 mg得た。収率21 ％、99.6 %ee。
¹H NMR (400 Hz, CDCl₃) δ 1.87 (d, J=7.2 Hz, 3H), 2.39 (s, 1H), 4.58 (quin, J=7.0 Hz, 1H), 7.34 (ddd, J=8.0, 6.0, 1.6 Hz 1H), 7.53-7.59 (m, 2H), 7.88 (dd, J=8.0, 1.2 Hz, 1H)
（ｉ－２）実施例１９工程（ｉ－１）で得られた化合物(221 mg)のメタノール(2 mL)溶液に１Ｎ水酸化ナトリウム水溶液(1 mL)を滴下し室温で２時間撹拌した。反応液を濃縮し、水(1 mL)を加え、１Ｎ塩酸(1 mL)を滴下しpH＜3にし、酢酸エチル(4.5 mL)で３回抽出した。有機層を水(2 mL)で洗浄した後、有機層を硫酸ナトリウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９４：６→７０：３０）で精製して、（Ｒ）－１－（１，２－ベンゾオキサゾール－３－イル）エタンチオールを140 mg得た。収率78％。
¹H NMR (400 Hz, CDCl₃) δ 1.92 (d, J=6.8 Hz, 3H), 2.22 (d, J=7.2 Hz, 1H), 5.24 (q, J=3.2 Hz, 1H), 7.31 (ddd, J=8.0, 5.6, 1.6 Hz 1H), 7.53-7.59 (m, 2H), 7.71 (d, J=8.0 Hz, 1H)
（ｉ－３）実施例１９工程（ｉ－２）で得られた化合物(139 mg)、トリメチルシリル(ビニル)シラン(93mg)および２，２’－アゾビス（イソブチロニトリル）（ＡＩＢＮ）(2.6 mg)を混合し、７０℃で６時間撹拌した。トリメチルシリル(ビニル)シラン(93 mg)およびＡＩＢＮ(2.6 mg)を追加し、７０℃で２時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→８２：１８）で精製して表題化合物を117 mg得た。収率54％。
¹H NMR (400 Hz, CDCl₃) δ -0.06 (s, 9H), 0.69-0.77 (m, 1H), 0.83-0.91 (m, 1H), 1.80 (d, J=7.6 Hz, 3H), 2.37-2.48 (m, 2H), 4.45 (q, J=7.2 Hz, 1H), 7.31 (ddd, J=8.0, 6.0, 2.0 Hz 1H), 7.52-7.59 (m, 2H), 7.94 (dt, J=8.0, 1.2 Hz, 1H) Example 19:
Preparation of (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide (alternative to Example 13)

The title compound was prepared by the steps described below:
(i) 3-[(1R)-1-{[2-(trimethylsilyl)ethyl]sulfanyl}ethyl]-1,2-benzoxazole

(i-1) The compound (979 mg) obtained in Example 17 step (iv) or (iv-a) and N,N,N',N'-tetramethylazodicarboxamide (1550 mg) in THF ( 10 mL) solution was added with thioacetic acid (0.67 mL) and stirred. Under water cooling, tri-n-butylphosphine (2.27 mL) was added dropwise, and the mixture was stirred at room temperature for 6 hours. After diluting with water (25 mL), it was extracted three times with ethyl acetate (25 mL). The organic layer was dried over sodium sulfate and then concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate; 94:6→70:30) to obtain (R)-S-(1,2-benzo-thioacetic acid). 285 mg of xazol-3-yl)ethyl) was obtained. Yield 21%, 99.6% ee.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.87 (d, J=7.2 Hz, 3H), 2.39 (s, 1H), 4.58 (quin, J=7.0 Hz, 1H), 7.34 (ddd, J=8.0, 6.0, 1.6Hz 1H), 7.53-7.59 (m, 2H), 7.88 (dd, J=8.0, 1.2Hz, 1H)
(i-2) To a solution of the compound (221 mg) obtained in step (i-1) of Example 19 in methanol (2 mL) was added dropwise 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, water (1 mL) was added, 1N hydrochloric acid (1 mL) was added dropwise to adjust the pH to <3, and the mixture was extracted with ethyl acetate (4.5 mL) three times. After washing the organic layer with water (2 mL), the organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate; 94:6→70:30) to obtain 140 mg of (R)-1-(1,2-benzoxazol-3-yl)ethanethiol. . Yield 78%.
¹ H NMR (400 Hz, CDCl ₃ ) δ 1.92 (d, J=6.8 Hz, 3H), 2.22 (d, J=7.2 Hz, 1H), 5.24 (q, J=3.2 Hz, 1H), 7.31 (ddd , J=8.0, 5.6, 1.6 Hz 1H), 7.53-7.59 (m, 2H), 7.71 (d, J=8.0 Hz, 1H)
(i-3) Compound (139 mg) obtained in Example 19 step (i-2), trimethylsilyl(vinyl)silane (93 mg) and 2,2'-azobis(isobutyronitrile) (AIBN) (2.6 mg) were mixed and stirred at 70° C. for 6 hours. Additional trimethylsilyl(vinyl)silane (93 mg) and AIBN (2.6 mg) were added, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→82:18) to obtain 117 mg of the title compound. Yield 54%.
¹ H NMR (400 Hz, CDCl ₃ ) δ -0.06 (s, 9H), 0.69-0.77 (m, 1H), 0.83-0.91 (m, 1H), 1.80 (d, J=7.6 Hz, 3H), 2.37 -2.48 (m, 2H), 4.45 (q, J=7.2 Hz, 1H), 7.31 (ddd, J=8.0, 6.0, 2.0 Hz 1H), 7.52-7.59 (m, 2H), 7.94 (dt, J= 8.0, 1.2Hz, 1H)

実施例１９工程（ｉ）で得られた化合物(112 mg)のｎ－ブタノール－水(1 mL/1 mL))溶液に氷冷下、ビス(モノペルオキシフタル酸)マグネシウム六水和物(476 mg)を加え室温で５時間撹拌した。１Ｍチオ硫酸ナトリウム水溶液(2 mL)を加えてクエンチし酢酸エチル（2 ｍL)で３回抽出した。有機層を５％炭酸水素ナトリウム水溶液(2 mL)で洗浄した後、硫酸ナトリウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル；９８：２→７０：３０）で精製して表題化合物を126 mg得た。収率100 ％、93.1 %ee。
¹H NMR (400 Hz, CDCl₃) δ -0.01 (s, 9H), 0.92-1.11 (m, 2H), 2.01 (d, J=7.2 Hz, 3H), 2.78-2.90 (m, 2H), 4.86 (q, J=7.2 Hz, 1H), 7.38 (ddd, J=8.0, 6.0, 2.0 Hz 1H), 7.58-7.64 (m, 2H), 7.99 (d, J=8.0 Hz, 1H) (ii) 3-{(1R)-1-[2-(trimethylsilyl)ethanesulfonyl]ethyl}-1,2-benzoxazole

To a solution of the compound (112 mg) obtained in step (i) of Example 19 in n-butanol-water (1 mL/1 mL) was added magnesium bis(monoperoxyphthalate) hexahydrate (476 mg) was added and stirred at room temperature for 5 hours. A 1M sodium thiosulfate aqueous solution (2 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (2 mL) three times. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution (2 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate; 98:2→70:30) to obtain 126 mg of the title compound. 100% yield, 93.1% ee.
¹ H NMR (400 Hz, CDCl ₃ ) δ -0.01 (s, 9H), 0.92-1.11 (m, 2H), 2.01 (d, J=7.2 Hz, 3H), 2.78-2.90 (m, 2H), 4.86 (q, J=7.2Hz, 1H), 7.38 (ddd, J=8.0, 6.0, 2.0Hz 1H), 7.58-7.64 (m, 2H), 7.99 (d, J=8.0Hz, 1H)

実施例１９工程（ｉｉ）で得られた化合物(31.1 mg)のＴＨＦ(300μL)溶液に１０℃で1 mol/Lのフッ化テトラブチルアンモニウム(300μL)を加えて２０℃で５時間撹拌した後、１０℃に冷却した。酢酸ナトリウム(41 mg)を加えた後、ヒドロキシルアミン－Ｏ－スルホン酸(57 mg)の水(600μL)溶液を滴下し、２０℃で２時間撹拌した。反応液に水(3 mL)を加え、酢酸エチル(3 mL)で３回抽出した。有機層を硫酸ナトリウムで乾燥し濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル；８８／１２→０：１００) で精製して標題化合物13 mgを白色結晶として得た。収率58 %、0 %ee。 (iii) (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide

To a solution of the compound (31.1 mg) obtained in step (ii) of Example 19 in THF (300 µL) was added 1 mol/L tetrabutylammonium fluoride (300 µL) at 10°C and the mixture was stirred at 20°C for 5 hours. , and cooled to 10°C. After adding sodium acetate (41 mg), a solution of hydroxylamine-O-sulfonic acid (57 mg) in water (600 μL) was added dropwise, and the mixture was stirred at 20° C. for 2 hours. Water (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL) three times. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate; 88/12→0:100) to give 13 mg of the title compound as white crystals. Yield 58%, 0% ee.

Example 20:
Preparation of Form I of Example 13 Fractionating the compound of Example 1 with Daicel CHIRALPAK® AY-H (mobile phase: 100% acetonitrile) and concentrating the obtained acetonitrile solution of Example 13 Form I of the compound of Example 13 was isolated at and characterized as discussed below.

Example 21:
Preparation of Form II of Example 13 Add Example 13 (0.01-0.03 g) to a glass screw tube, add acetone/heptane mixture (1:1) (approximately 0.02 mL) and add to the screw tube. It was capped and the solution was heated at about 80° C. for about 1 hour. The screw tube was uncapped and allowed to stand at room temperature for 1 day to isolate Form II of the compound of Example 13 and characterized as discussed below.

Example 22:
Example 13 Preparation of Form III Example 13 (0.01-0.03 g) is added to a glass screw tube, ethyl acetate (about 0.02 mL) is added, the screw tube is capped and the suspension is Shake at about 50° C. for about 10 days. Form III of the compound of Example 13 was isolated and characterized as discussed below.

Characterization of Crystal Forms The crystalline forms of the present invention can be characterized by various analytical techniques including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). , was characterized using the procedure described below.

Example 23:
X-ray powder analysis (XRPD) of the compounds obtained in Examples 20-22
XRPD analysis of Forms I to III of Example 13 was performed under the following measurement conditions.
X-ray powder diffraction (measurement conditions A): XRPD analysis was performed with a diffractometer (Bruker AXS D8 ADVANCE, Bruker, Billerica, Massachusetts, America) with copper radiation (Cu Kα1, λ=1.5406 Å, Kα2, λ=1. 5444 Å). Samples were prepared for analysis by placing the powdered sample in the center of a steel holder with a zero background plate. The generator was operated at a voltage of 40 kV and an amperage of 40 mA. The slits used were Soller slit 2.500 rad, anti-scatter 1.0°, and divergence. The sample rotation speed was 0.25 revolutions/second. Scans were performed from 2 to 40 degrees 2-theta for 10 minutes with a step size of 0.015 degrees 2-theta. Data analysis was performed using DIFFRAC. Performed by EVA (Bruker, Billerica, Massachusetts, USA).

X-ray powder diffraction (measurement conditions B): XRPD analysis was performed on a diffractometer (PANanalytical XPERT-PRO, PANanalytical B.V., Almelo, Netherlands) using copper radiation (Cu Kα, λ=1.5418 Å) carried out. Samples were prepared for analysis by placing the powdered sample in the center of a steel holder with a zero background plate. The generator was operated at a voltage of 40 kV and an amperage of 40 mA. The slits used were Soller slit 2.500 rad, anti-scatter 1.0°, and divergence. The sample rotation speed was 0.25 revolutions/second. Scans were performed from 4 to 40 degrees 2-theta for 10 minutes with a step size of 0.015 degrees 2-theta. Data analysis was performed by HigiScore Plus ver. 4.9 (Malvern PANalytical B.V., Almelo, Netherlands).

XRPD analysis of Form I of Example 13 was performed according to measurement conditions A. The XRPD pattern of Form I of Example 13 is shown in Table 9 and FIG.

XRPD analysis of Form II of Example 13 was performed according to measurement conditions B. The XRPD pattern of Form II of Example 13 is shown in Table 10 and FIG.

XRPD analysis of Form III of Example 13 was performed according to measurement conditions A. The XRPD pattern of Form III of Example 13 is shown in Table 11 and FIG.

Example 24:
Differential scanning calorimetry (DSC) of the compounds obtained in Examples 20-22
Differential scanning calorimetry of Forms I-III of Example 13 was performed by the following procedure.
Differential Scanning Calorimetry: Thermal properties were evaluated using a Differential Scanning Calorimetry (DSC) instrument (DSCQ1000, TA Instruments, New Castle, DE, USA). Approximately 1-10 mg of solid sample was placed in a pinhole vented standard aluminum pan for each experiment and heated at a rate of 5-10° C./min under a nitrogen purge of 50 mL/min. Data analysis was performed using Universal Analysis 2000 Version 4.1D (TA Instruments, New Castle, DE, USA).

The DSC of Form I of Example 13 is shown in FIG. Form I has a melting point of 100° C. or higher and high crystalline stability.

The DSC of Form II of Example 13 is shown in FIG. Form II has a melting point of 100° C. or higher and high crystalline stability.

The DSC of Form III of Example 13 is shown in FIG. Form III has a melting point of 100° C. or higher and high crystalline stability.

Example 25:
Thermogravimetric analysis (TGA) of the compounds obtained in Examples 20-22
Thermogravimetric analysis of Forms I-III of Example 13 was performed by the following procedure.
Thermogravimetric analysis: Thermogravimetric analysis (TGA) was performed on a TGA instrument (TGA Q500, TA Instruments, New Castle, DE, USA). Approximately 1-10 mg of solid sample was placed in an open aluminum pan for each experiment and heated at a rate of 5-10° C./min under a nitrogen purge of 60 mL/min. Data analysis was performed using Universal Analysis 2000 Version 4.1D (TA Instruments, New Castle, DE, USA).

The TGA of Form I of Example 13 is shown in FIG. Form I has no weight loss up to the melting temperature and is suitable for formulation.

The TGA of Form II of Example 13 is shown in FIG. Form II has no weight loss up to its melting temperature and is suitable for formulation.

The TGA of Form III of Example 13 is shown in FIG. Form III has no weight loss up to its melting temperature and is suitable for formulation.

Example 26:
Dynamic Vapor Sorption (DVS) of the Compounds Obtained in Examples 20-22
Dynamic Vapor Sorption measurements of Forms I-III of Example 13 were performed by the following procedure.
Dynamic Vapor Sorption: Hygroscopicity was evaluated at room temperature using a dynamic vapor sorption (DVS) instrument (IGAsorp, Hiden Isochema, Warrington, England). Water adsorption and desorption were studied at 25° C. over the range 0-90% as a function of relative humidity (RH). The relative humidity in the chamber was increased by 10% RH and held until the solids and atmosphere reached equilibrium. Equilibrium testing continued until passed or failed after 5 or 10 hours. At this point the RH was increased by 10% and the process was repeated until 90% RH was reached and equilibrated. Moisture sorption was monitored during this period. For desorption, the relative humidity was reduced in a similar fashion to measure a complete sorption/desorption cycle. Cycles were repeated as necessary. All experiments were operated in dm/dt mode (mass variation over time) to determine equilibration endpoints. Approximately 5-10 mg of solid was used. Data analysis was performed using Hisorp v4.02 (Hiden Isochema, Warrington, England).

The DVS of Form I of Example 13 is shown in FIG. Form I has a weight change of within 1% from 0-90% RH and is suitable for formulation.

The DVS of Form II of Example 13 is shown in FIG. Form II has a weight change of within 1% from 0-90% RH and is suitable for formulation.

The DVS of Form III of Example 13 is shown in FIG. Form III has a weight change of within 1% from 0-90% RH and is suitable for formulation.

Example 27: Preparation of Form III of Example 13 (alternative)
Form I, Form II and Form III of Example 13 (0.08-0.12 g) were each added to a glass screw tube and treated with ethanol, 2-propanol, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, acetone and tetrahydrofuran/heptane. The 1:1 mixture (approximately 0.02 mL) was added, the screw tube was capped, and the suspension was shaken at 45-55° C. for approximately 9-11 days. As a result, Form III of the compound of Example 13 was isolated in all glass screw tubes.

The pharmacological test results of representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are described, but the present invention is not limited to these test examples.

Test example 1. T-type calcium channel inhibitory activity The inhibitory activity of the compounds of the present invention against T-type calcium channels was evaluated using HEK293 cells expressing human Cav3.1, human Cav3.2 and human Cav3.3 (source of HEK293 cells: ATCC, Manassas, VA, USA, expression cell builder: ChanTest Corporation., Cleveland, OH, USA), and measured by whole-cell patch clamp technique. The HEK293 cell culture solution contains 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, and 500 μg/mL G418 in Dulbecco's modified Eagle's medium/Ham's F-12 mixed medium. mL was used. The IonWorks Barracuda system and Population Patch Clamp (both from Molecular Device Corporation, Union City, Calif., USA) were used for evaluation of whole-cell currents. Hank's buffered salt solution was used as an extracellular recording solution during recording. The internal recording solution contained 50 mmol/L CsCl, 90 mmol/L CsF, 5 mmol/L MgCl ₂ , 1 mmol/L glycol etherdiaminetetraacetic acid (EGTA) and 10 mmol/L 4-(2-hydroxyethyl) Piperazine-1-ethanesulfonic acid (HEPES, pH 7.2) was used. After maintaining a holding voltage of -90 mV, the holding voltage was changed to -65 mV, and after 60 seconds a pulse of -20 mV was applied for 200 ms. Calcium currents were induced by activating channels on the cell membrane using the IonWorks Barracuda system. The measurement was performed twice before and after the addition of the compound.When measuring after the addition of the compound, the current was recorded after exposure to the recording solution containing the compound for 5 minutes or longer.For the analysis, the current was measured before the addition of the compound. The ratio of post-compound amperometric readings to values was subtracted from 1 and converted to percentages, and normalized by considering similar values obtained for positive control compound and vehicle treatment as 100% and 0% inhibition, respectively. The obtained value was defined as the inhibition rate of each compound.TTA-A2, known as a T-type calcium channel inhibitor, was used as a positive control compound.The _IC50 value was calculated by applying the Hill equation.

Table 12 shows the inhibition rate (%) of the compound of the present invention at the evaluation concentration (600 μmol/L) (IC ₅₀ value (μmol/L) calculated from the dose-response test) for the T-type calcium channel.

Test example 2. Potentiating Effect on Levodopa-Induced Hyperlocomotion in Reserpine-Induced Parkinson's Disease Model Mice Mice depleted of dopamine by reserpine treatment are model animals that reflect hypokinesis symptoms of Parkinson's disease, and levodopa (L-DOPA) alleviates these symptoms. The enhancing effect of the compound of the present invention on the effect of levodopa was verified.

In this test, male Crl:CD1 (ICR) mice (Charles River Laboratories Japan, Inc.) were used. Reserpine (3 mg/kg) was administered intraperitoneally 20 to 24 hours before starting locomotion measurements. The compound of the present invention (Examples 1, 2, 3, 4 and 5, 12.5 mg/kg or 25 mg/kg, respectively) was orally administered 1 hour before the exercise amount measurement, and immediately before starting the exercise amount measurement, levodopa concentration in terms of free body concentration was reduced. Levodopa (200 mg/kg) containing 1/4 of the amount of benserazide was administered intraperitoneally. The amount of exercise was measured for 90 minutes, and the total amount of exercise was compared. The results are shown in FIG. 14. The compounds of Examples 1, 2, 3, 4 and 5 significantly exhibited the action of levodopa on increasing locomotion in hypokinetic mice. On the other hand, rasagiline (3 mg/kg or 10 mg/kg), an MAOB inhibitor clinically used as a therapeutic agent for Parkinson's disease, showed a tendency to increase the amount of exercise, but no statistically significant difference was observed.

This result indicates the possibility that the compound of the present invention enhances the effect of levodopa used for treating Parkinson's disease. Similarly, in humans, levodopa is expected to enhance the therapeutic effect of Parkinson's disease using a conventionally known protocol.
In FIG. 14, (A) N = 7 or 8, (B) N = 8, (C) N = 7, (D) N = 13 or 14, (E) N = 6, 7 or 8, (F) N=7 or 8. In addition, # represents p<0.05 in a statistical comparison (Dunnett's test) with the L-DOPA single administration group.

Test Example 3. Effect of 6-Hydroxydopamine (6-OHDA) on Prolonging Duration of Levodopa-Induced Rotational Behavior in Unilateral Nigrostriatal Dopaminergic Destruction Model 6-OHDA is a neurotoxin that specifically destroys dopaminergic neurons . By injecting 6-OHDA into the unilateral medial forebrain bundle (MFB), a model animal in which the dopaminergic nerves projecting from the substantia nigra to the striatum on one side was destroyed, the dopaminergic nervous system in the brain, such as levodopa and dopamine receptor agonists, was destroyed. It is known that activating drugs for treating Parkinson's disease exhibit rotational behavior, and the usefulness of the drug for treating Parkinson's disease can be evaluated using this rotational behavior as an index. Prolonging rolling behavior time by levodopa leads to prolongation of ON time in Parkinson's disease. In order to evaluate the ON time prolongation effect of the compounds of the present invention, this model was used to evaluate the prolongation of levodopa-induced rotational behavior time.

In this test, male Slc:Wistar rats (Japan SLC, Inc.) were used. Desipramine (25 mg/kg) was intraperitoneally administered 30 minutes before anesthesia when performing the destruction surgery. Under anesthesia, rats were fixed in a brain fixation device, and 6-OHDA (containing 0.02% ascorbic acid) was injected into the medial forebrain bundle (starting from bregma, AP: -4.4 mm, ML: 1.5 mm, DV: 7.8 mm). μg/4 μL was administered over 4 minutes. Two weeks after the operation, apomorphine hydrochloride (0.5 mg/kg) was subcutaneously administered, and rotational movements were observed.

The compounds of the present invention (Examples 1, 2, 3, 5, 8, 13 and 14, 10 mg/kg or 30 mg/kg, respectively) were orally administered to these rats 60 minutes before observation of rotation behavior. Levodopa methyl ester hydrochloride (5 mg/kg in terms of levodopa-free body weight) containing 1/4 amount of benserazide in terms of weight of levodopa was intraperitoneally administered 20 minutes before observation of rotation behavior. Rotating behavior was observed for 120 minutes, and the number of rotations between 100 and 120 minutes after the start of observation was totaled as the number of late phase rotations.

The results are shown in FIG. 15, and the compounds of Examples 1, 2, 13, and 14 and the MAOB inhibitor rasagiline (0.6 mg/kg) significantly increased the late phase turnover number. In addition, the compounds of Examples 3, 5, and 8 and the MAOB inhibitor safinamide showed a tendency to increase the late phase turnover number, although no statistically significant difference was observed.

This result indicates that the compound of the present invention can prolong the effect of levodopa used for treating Parkinson's disease. Similarly, in humans, using a conventionally known protocol, levodopa is expected to have the effect of prolonging the ON time in treating Parkinson's disease.
In FIG. 15, (A) N = 12, (B) N = 10, 11 or 12, (C) N = 9 or 11, (D) N = 7 or 12, (E) N = 10 or 11, ( F) N=12 or 16, (G) N=12 or 16, (H) N=10, 11 or 12, (I) N=10 or 11. # and ## represent p<0.05 and p<0.01 in statistical comparison (Dunnett's test) with the L-DOPA single administration group, respectively.

Test example 4. Anti-tremor effect in a tacrine-induced Parkinson's disease tremor model One of the causes of the tremor observed in Parkinson's disease is considered to be the overactivity of the acetylcholine nervous system due to a decrease in the amount of dopamine in the brain. there is In this model, an acetylcholinesterase inhibitor activates the acetylcholine nervous system and disrupts the balance between dopamine and acetylcholine in the brain, causing tremor symptoms. widely known as Using this model, the effect of the compound of the present invention on suppressing tremor in Parkinson's disease was evaluated.

In this test, male Slc:SD rats (Japan SLC, Inc.) were used. The compound of the present invention (Example 1 (10 mg/kg, 30 mg/kg or 100 mg/kg), Example 13 (3 mg/kg, 10 mg/kg, 30 mg/kg or 100 mg/kg)) After oral administration, 1 hour later, tacrine (2.5 mg/kg) was intraperitoneally administered. The number of mandibular tremors was counted for 10 minutes from 10 minutes after tacrine administration. The results are shown in FIG. The compounds of Examples 1 and 13 significantly reduced the number of mandibular tremors per unit time.

This result indicates that the compounds of the present invention may alleviate tremor symptoms in Parkinson's disease by oral administration. Similarly, in humans, a therapeutic effect for Parkinson's disease tremor is expected using a conventionally known protocol.
In FIG. 16, (A) N=9 or 10, (B) N=10 or 12. In addition, # and ## represent p<0.05 and p<0.01 in statistical comparison (Dunnett's test) with the tacrine single administration group, respectively.

Test example 5. Levodopa-induced dyskinesia inhibitory effect A unilateral nigrostriatal dopamine nerve destruction model by 6-hydroxydopamine (6-OHDA), as described in Test Example 2, is widely used for efficacy evaluation of drugs for treating Parkinson's disease. On the other hand, repeated administration of levodopa to this model is known to induce dyskinesia, which is similar to the clinical long-term administration of levodopa that causes dyskinesia in patients with Parkinson's disease. Using this model, the effect of the compound of the present invention on dyskinesia induction by repeated administration of levodopa was evaluated.

As described in Test Example 2, a unilateral nigrostriatal dopamine nerve destruction model was created. Levodopa methyl ester hydrochloride (5.86 mg/kg) containing benserazide hydrochloride (22.8 mg/kg) (4:1 in terms of free body weight) was administered intraperitoneally on the day before the start of repeated administration of levodopa, and rolling behavior was observed. Observations were made from 20 minutes to 140 minutes after administration. From individuals who showed rotational behavior, the total number of rotations (20 to 140 minutes after administration), the late rotation period (120 to 140 minutes after administration), and the duration of rotation were used to equalize the distribution in each group. grouped.

Two days after grouping, levodopa methyl ester hydrochloride (6 mg/kg) and benserazide hydrochloride (12 mg/kg) were repeatedly administered once daily for two weeks. In addition, the compound of Example 1 (30 mg/kg or 100 mg/kg) and the compound of 13 (30 mg/kg or 100 mg/kg) and the MAOB inhibitor rasagiline (0.2 mg/kg or 0.6 mg/kg ) was orally administered daily 1 hour prior to levodopa administration.

Dyskinesia assessment was performed at 1 and 2 weeks of repeated dosing. After administration of L-DOPA, each rat was placed in a transparent cylindrical cage for dyskinesia measurement, and behavior was observed for 1 minute every 20 minutes from 20 minutes after administration to score dyskinesia-like symptoms. Scoring was performed based on Abnormal Involuntary Movement Scales for rats (AIMS; Neurobiology of Disease 10, 165-186 (2002)) ] Involuntary bending and stretching, palm opening and closing, wrist up and down, chorea-like tremor, dystonia-like stiffness, [Body axis state] Upper body and neck twisting to the opposite side of destruction, losing balance and falling down, dystonia [Mouth and tongue] Involuntary abnormal movement of the jaw, forward protrusion of the tongue [Scoring] 0: None, 1: Less than 30 seconds, 2: More than 30 seconds, 3: Always (canceled by stimulation such as sound), 4: always expressed (not ceased by stimulation such as sound)). Observations were made up to 180 minutes after administration of levodopa.

The results are shown in FIG. In the repeated administration groups of the compounds of Examples 1 and 13, the onset of dyskinesia due to repeated administration of levodopa was suppressed, and a statistically significant difference was observed in comparison with the repeated administration of solvent group. On the other hand, in the MAOB inhibitor rasagiline repeated administration group, dyskinesia due to repeated administration of levodopa was significantly exacerbated. This result indicates that repeated oral administration of the compound of the present invention may suppress the development of levodopa-induced dyskinesia in Parkinson's disease. Similarly, in humans, it is expected to have the effect of suppressing the onset of drug-induced dyskinesia caused by long-term administration of levodopa using a conventionally known protocol.
In FIG. 17, (A) N=10, (B) N=10 or 11, (C) N=10. ## represents p<0.01 in the statistical comparison (Dunnett's test) between L-DOPA and the repeated solvent administration group.

Test example 6. Monoamine Oxidase B (MAOB) Inhibitory Activity MAOB is an enzyme involved in the oxidative deamination of endogenous monoamine neurotransmitters such as dopamine. MAOB inhibitors increase dopamine concentration in the brain by inhibiting dopamine degradation, thereby improving parkinsonism. The inhibitory activity against rat striatal and monkey striatal MAOB in compounds of the present invention was evaluated.

A mitochondrial synaptosome fraction containing MAOB was prepared by the following method. Male Slc: The striatum of Wistar rats (Japan SLC, Inc.) and male cynomolgus monkeys (Hamley Inc.) was homogenized by adding 10 mL of 0.32 mol/L sucrose aqueous solution per 1 g of tissue wet weight. The supernatant obtained by centrifuging the homogenate at 1,000 g for 10 minutes at 4°C was centrifuged again at 17,200 g for 20 minutes at 4°C. The resulting precipitate was added with 10 mL of preparation buffer (10 mmol/L Tris-HCl buffer (pH 7.4), 0.25 mol/L sucrose aqueous solution, 0.5 mmol/L EDTA-2K) per 1 g of original tissue wet weight. was added and suspended, and centrifuged again at 17,200 g for 20 minutes at 4°C. To the resulting precipitate, 40 mL of preparation buffer was added per 1 g of the original wet weight of the tissue, suspended, and used as an enzyme homogenate solution.

¹⁴ C-labeled β-phenylethylamine ([ ¹⁴ C]β-PEA) was used as a degradation substrate for MAOB. After incubating [ ¹⁴ C]β-PEA and the compound of the present invention diluted to each concentration together with the enzyme homogenate solution at 37° C. for a predetermined time, the reaction was stopped by adding 3 mol/L of ice-cold HCl. let me The reaction product was extracted with a 1:1 mixture of water-saturated toluene and ethyl acetate. The organic layer supernatant was separated, a liquid scintillation cocktail (ACSII, GE Life Sciences) was added, and radioactivity was quantified with a liquid scintillation counter (TRI-CARB 3100TR, Packard). IC ₅₀ values for compounds were determined by fitting percent inhibition data for each concentration from multiple tests to a two-parameter logistic model. Safinamide, a selective MAOB inhibitor, was used as a positive control compound in the experimental system.

The results are shown in Table 13. While safinamide exhibits strong MAOB inhibitory activity, all the compounds of the present invention exhibit extremely weak MAOB inhibitory activity. Comprehensive consideration of this result and the results of [Test Example 1] and [Test Example 2] indicates that the compound of the present invention is a levodopa potentiator that does not depend on MAOB inhibition.

Test example 7. Anti-tremor effect in the harmaline-induced essential tremor model Studies of harmaline administration are widely used as an animal model of essential tremor. By overactivating the inferior olivary nucleus of the medulla oblongata, harmaline induces network abnormalities in the cerebellar-thalamic-cortical loops involved in motor control, and induces action tremor characteristic of essential tremor. The inhibitory effect of the compounds of the present invention on tremor induced by acute harmaline administration was investigated.

Harmaline (30 mg/kg) was intraperitoneally administered to male Crl:CD1 mice (6-7 weeks old) (Charles River Laboratories Japan, Inc.) to induce tremor. Compounds of the present invention (Example 1 (25 mg/kg or 50 mg/kg), Example 13 (25 mg/kg or 50 mg/kg), Example 14 (3.125 mg/kg, 6.25 mg/kg, 12.5 mg /kg or 25 mg/kg)) was orally administered 1 hour before harmaline administration. Physiological saline or positive control compound β-propranolol (10 mg/kg) was also administered intraperitoneally 20 minutes before harmaline administration. Mice were placed in measurement cages (horizontally grounded acrylic cylinders, φ65 mm, length 145 mm) in a soundproof box of a startle response apparatus (O'hara & Co., Ltd., Tokyo) 35 min before harmaline administration. mm). Mouse-induced vibration data were recorded over time as tremor events. Recordings were made for 20 minutes immediately before harmaline administration (PRE) and 20 minutes immediately after administration (POST) after the animals were placed. Frequency analysis was performed on the time-series signal data using VitalTracer and BIMUTAS II-A (both Kissei Comtech Co., Ltd., Matsumoto City) as analysis software. The spectral content of 12-15 Hz or 12-18 Hz was extracted as a value that increases with tremor, and the tremor intensity T of each individual was calculated by the following formula.
T = POST/PRE

The results are shown in FIG. The compounds of Examples 1, 13 and 14 inhibited harmaline-induced tremors. β-propranolol, which is clinically used as a therapeutic agent for essential tremor, also significantly suppressed harmaline-induced tremor. These facts indicate that the compounds of the present invention are effective against essential tremor. Similarly, in humans, a therapeutic effect for essential tremor is expected using a conventionally known protocol.
In FIG. 18, (A) N=11 or 12, (B) N=16, (C) N=7, 13 or 14. Moreover, ** represents p<0.01 in a statistical comparison (Welch's t-test) with the harmaline single administration group. # and ## represent p<0.05 and p<0.01 in statistical comparison (Dunnett's test) with harmaline single administration group, respectively.

Test example 8. Anti-allodynic action in chemotherapy-induced peripheral neuropathy models One type of chemotherapy-induced peripheral neuropathy is sensory disturbance due to neuronal somatic disorder caused by platinum agents such as anticancer drugs cisplatin and oxaliplatin. are difficult to recover from, even after drug discontinuation. We investigated the therapeutic effect of repeated administration of oxaliplatin on sensory disturbance.

Male Crl:CD (SD) rats (7 weeks old) (Charles River Laboratories Japan, Inc.) were intraperitoneally administered oxaliplatin (5 mg/kg) twice a day for a total of 6 times. To create a chemotherapy-induced peripheral neuropathy model. The compound of Example 13 (100 mg/kg) was orally administered once daily for a total of 17 times. On the days of administration of oxaliplatin, the compound of Example 13 was administered 1 hour before administration of oxaliplatin. The positive control substance duloxetine (30 mg/kg) was administered orally 1 hour before the acetone test. An acetone test was performed 18 days after the start of oxaliplatin treatment. In the acetone test, 0.1 mL of acetone was sprayed onto the plantar of the hind paw of the rat, and the reaction was evaluated by scoring (Cold Score). Observation was performed for 20 seconds after the injection of acetone, and if no reaction was observed, the observation was terminated with a score of 0. If any reaction was observed within 20 seconds, observation was continued until 40 seconds after injection, and scoring was performed according to the evaluation scale. . Acetone injection was performed twice on each of the right and left hind legs, and the total score was calculated.

The rating scale is as follows.
Score 0: No response, Score 1: Shows behavior (instantaneous or once) such as Stamping, Flicking, Score 2: Shows behavior such as continuous or multiple Stamping, Flicking, Score 3: Licking, Biting, etc. Shows escape behavior with action.

The results are shown in FIG. The compound of Example 13 showed a significantly lower Cold Score by repeated oral administration than in the repeated solvent administration group. In addition, the cold score of the duloxetine single-dose group, which is clinically used for the treatment of allodynia caused by chemotherapy-induced peripheral neuropathy, was also significantly lower. This indicates that the compound of Example 13 is effective against chemotherapy-induced peripheral neuropathy (cold allodynia). Similarly, in humans, therapeutic effects on chemotherapy-induced peripheral neuropathy are expected using conventionally known protocols.
In FIG. 19, N=12. In addition, ## represents p<0.01 in the statistical comparison (Wilcoxon test) with the oxaliplatin + solvent repeated administration group.

Test example 9. Carbonic Anhydrase (CA) Inhibitory Activity CA is a family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and protons. Compounds with a sulfonamide skeleton such as acetazolamide and topiramate often have CA inhibitory activity, and CA inhibitors inhibit CA in the renal tubules, causing hypercalciuria and increased urine pH, leading to urinary calculi. It is known to cause serious side effects (Non-Patent Document 5). Since the compounds of the present invention also have a sulfonamide skeleton, their CA inhibitory activity was evaluated by the following method. Here, CA-II, which is known to be a highly active CA isozyme expressed systemically and strongly inhibited by acetazolamide, was examined.

4-Nitrophenylacetic acid was used as a degradation substrate for CA-II. 4-Nitrophenylacetic acid is dehydrated by CA-II to produce 4-nitrophenol. Commercially available human CA-II (recombinant protein, 2184-CA, R&D Systems, Inc. USA) was diluted with preparation buffer (12.5 mmol/L Tris, 75 mmol/L NaCl, pH 7.5) to a final concentration of 2 μg/ Diluted to mL. 4-Nitrophenylacetic acid (final concentration 5 mmol/L) and the compound of the present invention adjusted to each concentration were added and incubated at 37° C. for 30 minutes in the dark. A buffer solution (12.5 mmol/L Tris, pH 8.0) was added to stop the reaction, and the amount of 4-nitrophenol as a reaction product was quantified by spectrophotometry (410 nm). Compound IC ₅₀ values were determined by fitting percent inhibition data for each concentration from multiple tests to a two-parameter logistic model. The CA inhibitors topiramate and acetazolamide were used as positive control compounds in the experimental system.

The results are shown in Table 14. Both topiramate and acetazolamide exhibited strong CA-II inhibitory activity. On the other hand, the CA-II inhibitory activity of the compounds of the present invention was found to be generally weak except for the compounds of Examples 3, 4 and 8. This result suggests that the compounds of the present invention have a low risk of urolithiasis in humans.

Test Example 10. Anti-tremor action in unilateral nigrostriatal dopaminergic nerve destruction model by 6-hydroxydopamine (6-OHDA) The unilateral nigrostriatal dopaminergic nerve destruction model by 6-OHDA is described in Test Example 3. As mentioned above, it is widely used for efficacy evaluation of Parkinson's disease treatment drugs. In addition, this model is known to produce mandibular tremor that matches the tremor cycle of Parkinson's disease patients, and is expected to be a tremor model for Parkinson's disease. Using this model, the effect of the compound of the present invention on suppressing tremor in Parkinson's disease was evaluated.

As described in Test Example 3, a unilateral nigrostriatal dopamine nerve destruction model was created. The compound of Example 13 (3 mg/kg) was orally administered, and one hour later, the number of mandibular tremors was counted for 10 minutes. The results are shown in FIG. The compound of Example 13 significantly decreased the number of mandibular tremors per unit time.

This result indicates that the compound of the present invention may alleviate tremor symptoms in Parkinson's disease by oral administration. Similarly, in humans, a therapeutic effect for Parkinson's disease tremor is expected using a conventionally known protocol.
In FIG. 20, N=8. In addition, * represents p<0.05 in a statistical comparison (Dunnett's test) with the solvent-administered group.

Test Example 11. Inhibition of nerve cell firing in mouse brain slices It has been suggested that the motor symptoms of neurological disorders such as Parkinson's disease and essential tremor are related to motor circuit dysregulation due to hyperexcitability of the subthalamic nucleus and cerebellum. The regulating action of the compounds of the present invention on the spontaneous firing frequency in subthalamic nucleus neurons and cerebellar Purkinje cells was measured by patch-clamp measurement on mouse brain slices. Brain tissue was excised from male C57BL/6J mice (>7 weeks old) (Charles River Laboratories Japan, Inc.), and brain slices were prepared in sectioning solution (composition of sectioning solvent: 92 mmol/L N- Methyl-D-glucamine (NMDG), 25 mmol/L D-glucose, 20 mmol/L HEPES, 30 mmol/L NaHCO ₃ , 0.5 mmol/L CaCl ₂ , 10 mmol/L MgSO _{4.7H 2} O, 2.5 mmol/L mmol/L KCl, 1.25 mmol/L NaH ₂ PO _{4.2H 2} O, 2 mmol/L thiourea, 5 mmol/L ascorbic acid, 3 mmol/L pyruvic acid, 12 mmol/L N-acetyl-L-cysteine ( NAC) (pH 7.4, aerated with a mixed gas of 5% CO ₂ and 95% O ₂ )).The brain slices were recorded in a recording solution heated to 37°C (composition of recording solvent: 11.9 mmol/L NaCl, 0.2 mmol/L). CaCl ₂ , 0.2 mmol/L MgSO _{4.7H 2} O, 0.25 mmol/L KCl, 0.125 mmol/L NaH ₂ PO 4.2H ₂ O (aerated with a mixed gas of 5% _{CO 2} 95% O ₂ )). After incubation for 30 minutes at room temperature, the same recording _solution was perfused at room temperature and patch clamp measurements were performed. Using 10 mmol/L HEPES, 4 mmol/L D-glucose, and 123 mmol/L potassium gluconate (pH 7.4), the electrode was brought into close contact with the cell to be recorded, and a gigaohm-level seal resistance was formed. The potential was fixed near the resting membrane potential, and a negative pressure was applied to the electrode to perforate the cell membrane.As a stimulation protocol, a current of +200 pA or +400 pA was applied for 400 ms to evoked action potentials. The above stimulation protocol was performed 10 times for each current amount.Action potentials were digitized with a digitizer (Digidata 1400A) via an amplifier (MultiClamp 700B).Stimulation control and digitization were performed. Clampex (Version 10.2) software was used for recording action potentials (both from Molecular Device Corporation, Union City, Calif., USA). Action potential recording was performed twice before and after addition of the compound of Example 13 (500 μmol/L). In the measurement after addition of the compound of Example 13, action potentials were recorded after the recording solution containing the compound of Example 13 was perfused for 10 minutes or longer. For analysis, the ratio of the spike firing frequency (Hz) during current stimulation after addition of the compound of Example 13 to the spike firing frequency (Hz) during current stimulation before addition of the compound of Example 13 was converted into a percentage, and The rate of change in spike firing frequency was used.

The results are shown in FIG. The compound of Example 13 significantly suppressed the spike firing frequency of (A) subthalamic nucleus neurons and (B) cerebellar Purkinje cells. These results suggest that the compounds of the present invention are effective in treating motor symptoms in neurological disorders.
In FIG. 21, (A) N=10 or 11, (B) N=5 or 6. In addition, * indicates that p<0.05 in statistical comparison (Welch's t-test) with the solvent-added group.

Test example 12. Anti-anxiety-like effects Psychiatric symptoms (depression and anxiety) are known to be one of the non-motor symptoms of Parkinson's disease. The anti-anxiety-like action of the product of the present invention was evaluated using a mouse elevated plus maze. This test method is widely used as a method for evaluating the anti-anxiety-like effects of drugs.

In this test, male Crl:CD1 (ICR) mice (Charles River Laboratories Japan, Inc.) were used. Vehicle, the compound of Example 13 (3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg) or the positive control substance diazepam (3 mg/kg) was administered one hour before the start of the test. ) was administered orally. The test was initiated by placing mice on a central platform (illuminance adjusted to 80-100 Lux level) with their heads facing the closed arms and allowed to explore freely for 5 minutes. When 1/3 of the mouse body entered the arm, it was counted as arm entry, and the time spent in the open arm was measured with a stopwatch. The ratio of the number of open arm entries to the total number of arm entries and the ratio of open arm stay time to the search time of 5 minutes were calculated. In the elevated plus maze, mice prefer not to enter or explore open arms because they feel uneasy in open arms without walls. Therefore, when evaluated by the ratio of the open arm entry to the total number of arm entries and the ratio of the open arm staying time to the total search time, the value becomes small. If the proportion of these substances is higher in the drug-administered group than in the solvent-administered group, it can be determined that the drug has anxiolytic-like action.

The results are shown in FIG. Diazepam (DZP) significantly increased the percentage of open arm entries and the percentage of open arm stay time, indicating that this test was established as an evaluation system for anxiolytic-like effects. The compound of Example 13 significantly increased the percentage of open arm entries and the percentage of open arm stay time from a dose of 10 mg/kg. This result suggests that the compound of Example 13 has anxiolytic-like effects.
In FIG. 22, Vehicle: N=13, DZP: N=11, Example 13: 3 mg/kg N=7, 10 mg/kg N=13, 30 mg/kg N=12, 100 mg/kg N=13. ** indicates p<0.01 in the statistical comparison (Student's t-test) between the vehicle-administered group and the diazepam-administered group. # and ## represent p<0.05 and p<0.01 in a statistical comparison (Dunnett's test) between the solvent-administered group and the Example 13-administered group.

Test example 13. Effect on sleep/wakefulness stages In Parkinson's disease, sleep disturbances such as insomnia (inability to fall asleep, awakening in the middle of the night, etc.) are known as non-motor symptoms, and it is important to improve the quality of sleep. The effect of the product of the present invention on sleep was evaluated by measuring rat sleep electroencephalograms.

In this test, male Crlj:WI rats (Charles River Laboratories Japan, Inc.) were used. A radio wave transmitter (HD-S02, Data Science International, Inc.) was placed in the peritoneal cavity of anesthetized rats, and two electroencephalogram measurement electrodes were stereotactically fixed inside the skull (frontoparietal electrodes: from bregma 2 mm anterior and 2 mm left of midline, parietal electrode: 5 mm posterior to bregma and 2 mm right of midline). Electromyographic recording electrodes were placed in the dorsal neck muscles. After a recovery period of at least one week after the operation, it was used for sleep electroencephalogram measurement.

The compound of Example 13 (30 mg/kg or 100 mg/kg) was orally administered to rats just before the light period, and electroencephalograms and electromyograms were recorded at 500 Hz for 6 hours in rearing cages in a soundproof box. The recorded signals were classified into 3 stages of wakefulness, REM sleep, and non-REM sleep every 10 seconds using a sleep analysis program, Sleepsign (version 3, Kissei Comtec Co., Ltd.), and tabulated. Specifically, if there was a myoelectric response greater than or equal to a threshold determined for each individual, it was considered as wakefulness, and otherwise as sleep. In sleep, when the power value of delta waves (0.5-4 Hz) in the frequency component of brain waves exceeds the threshold set in advance for each individual, it is called non-REM sleep, and the power value of theta waves (4-8 Hz) is 0. REM sleep was classified as greater than 40% of the total 0.5-80 Hz power value.

The results are shown in FIG. The compound of Example 13 dose-dependently and significantly shortened the NREM sleep latency, increased the NREM sleep time, and significantly shortened the awakening time. On the other hand, it showed a tendency to prolong REM sleep latency and significantly shortened REM sleep time in a dose-dependent manner. These results indicate the possibility that the compound of Example 13 can improve sleep disorders such as sleep onset disorders and nocturnal awakenings.
In FIG. 23, each group N=8. *, ** and *** are p < 0.05 and p < 0.01 respectively in the statistical comparison (One-way ANOVA, followed by parametric Dunnett's test) between the solvent-administered group and the Example 13-administered group and p<0.001.

Since the compounds of the present invention have T-type calcium channel inhibitory activity, they are useful as therapeutic and/or prophylactic agents for various nervous system diseases or psychiatric diseases. In addition, it has a levodopa-induced hyperlocomotion-enhancing effect that is not dependent on the MAOB inhibitory effect, and the preferred compound reduces the risk of kidney stones due to the attenuation of the carbonic anhydrase inhibitory effect. It is useful as a concomitant drug with levodopa preparations. In addition, since it suppressed the onset of dyskinesia in a levodopa-induced dyskinesia model, it is useful as a Parkinson's disease therapeutic and/or prophylactic drug that is highly safe, unlike existing concomitant drugs with levodopa. In addition, since it showed efficacy against Parkinson's disease tremor models and essential tremor models, it is found in tremor therapeutics in Parkinson's disease, essential tremor, and neurological or psychiatric disorders. It is also useful as a therapeutic and/or prophylactic agent for parkinsonism. In addition, it showed anti-anxiety-like effects in the elevated plus maze and shortened non-REM sleep latency and awakening time in sleep electroencephalogram evaluations. and/or as a prophylactic agent. Furthermore, since it showed an anti-allodynia effect in an oxaliplatin-induced pain model, it is also useful as a therapeutic and/or preventive drug for neuropathic pain (in particular, pain and allodynia in chemotherapy-induced peripheral neuropathy).

Claims (26)

A pharmaceutical composition containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[In the formula,
R ¹ is hydrogen, halogen, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy It may be substituted with a substituent of
R ² is halogen, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy or R ¹ and R ² together with the carbon atom to which they are attached represent C _3-6 cycloalkyl (the cycloalkyl being halogen, hydroxyl, C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and C _1-3 alkoxy),
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, cyano, nitro, C _1-6 alkyl (where alkyl is halogen, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein said cycloalkyl is halogen, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is halogen, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy); ] R ¹ is hydrogen, fluorine, C _1-6 alkyl (the alkyl being 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl (wherein the cycloalkyl is 1 to 3 independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with a substituent of
R ² is fluorine, C _1-6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _3-6 cycloalkyl and C _1-3 alkoxy; or C _3-6 cycloalkyl, wherein the cycloalkyl has 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy or R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl (the cycloalkyl being fluorine, hydroxyl, C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and C _1-3 alkoxy).
A pharmaceutical composition according to claim 1 . R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different, hydrogen, halogen, cyano, nitro, C _1-6 alkyl (wherein said alkyl is fluorine, hydroxyl group, C _3-6 cycloalkyl and C _1-3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _3-6 cycloalkyl (wherein the cycloalkyl is fluorine, hydroxyl, C _1-3 alkyl and C _{1 -3} alkoxy optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _1-6 alkoxy (wherein said alkoxy is fluorine, hydroxyl, C _3-6 cycloalkyl and optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-3 alkoxy;
A pharmaceutical composition according to claim 1 . R ¹ is hydrogen, fluorine, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy; good) and
R ² is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); or R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl, said cycloalkyl consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy (optionally substituted with 1 to 3 substituents independently selected from the group).
A pharmaceutical composition according to claim 1 . R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, or C _1-3 alkoxy (wherein the alkoxy is optionally substituted with 1 to 3 fluorines);
A pharmaceutical composition according to claim 1 . R ¹ is hydrogen, fluorine, or C _1-6 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy; good) and
R ² is fluorine or C _1-6 alkyl (the alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, hydroxyl group and C _1-3 alkoxy); or R ¹ and R ² together with the carbon atom to which they are attached are C _3-6 cycloalkyl, said cycloalkyl consisting of fluorine, hydroxyl, C _1-3 alkyl and C _1-3 alkoxy optionally substituted with 1 to 3 substituents independently selected from the group),
R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, halogen, or C _1-3 alkoxy (wherein the alkoxy is optionally substituted with 1 to 3 fluorines);
A pharmaceutical composition according to claim 1 . The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide,
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide,
1-(1,2-benzoxazol-3-yl)-1-fluoromethanesulfonamide,
1-(1,2-benzoxazol-3-yl)-1,1-difluoromethanesulfonamide,
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide,
1-(1,2-benzoxazol-3-yl)propane-1-sulfonamide,
1-(1,2-benzoxazol-3-yl)butane-1-sulfonamide,
1-(1,2-benzoxazol-3-yl)-1-fluoroethane-1-sulfonamide,
1-(1,2-benzoxazol-3-yl)-2-methylpropane-1-sulfonamide,
1-(5-methoxy-1,2-benzoxazol-3-yl)ethane-1-sulfonamide,
1-(5-fluoro-1,2-benzoxazol-3-yl)ethane-1-sulfonamide,
1-(5-chloro-1,2-benzoxazol-3-yl)ethane-1-sulfonamide,
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide, or (1S)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide . The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide,
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide,
1-(1,2-benzoxazol-3-yl)-1-fluoromethanesulfonamide,
1-(1,2-benzoxazol-3-yl)-1,1-difluoromethanesulfonamide,
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide,
1-(1,2-benzoxazol-3-yl)-1-fluoroethane-1-sulfonamide,
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide, or (1S)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide . The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is selected from the following compounds:
1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide,
2-(1,2-benzoxazol-3-yl)propane-2-sulfonamide,
1-(1,2-benzoxazol-3-yl)cyclopropane-1-sulfonamide,
(1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide, or (1S)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide . The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is 1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is (1S)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide. Form I, wherein the compound of formula (1) has diffraction angle (2θ°) peaks at 5.7° ± 0.2 and 17.3° ± 0.2° in X-ray powder diffraction. 2. The pharmaceutical composition of claim 1, which is (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide in crystalline form. The compound represented by formula (1) has X-ray powder diffraction of 5.7°±0.2, 14.1±0.2°, 17.3°±0.2°, 19.1°± 0.2°, 19.3±0.2°, 21.6°±0.2°, 22.5±0.2°, 23.1°±0.2°, 23.3°±0. Form I crystalline form of (1R)-1-(1,2-benzoxazole having four or more diffraction angle (2θ°) peaks selected from 2°, and 26.5°±0.2° -3-yl)ethane-1-sulfonamide. Form II, wherein the compound of formula (1) has diffraction angle (2θ°) peaks at 8.7° ± 0.2° and 17.6° ± 0.2° in X-ray powder diffraction (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide in the crystalline form of The compound represented by formula (1) has X-ray powder diffraction of 8.7° ± 0.2°, 13.5° ± 0.2°, 15.5° ± 0.2°, 17.6 °±0.2°, 20.3°±0.2°, 21.6°±0.2°, 22.6°±0.2°, 26.2°±0.2°, 26.8° The crystalline form of Form II, (1R)-1-(1, having four or more diffraction angle (2θ°) peaks selected from °±0.2°, and 35.2°±0.2°. 2. The pharmaceutical composition of claim 1, which is 2-benzoxazol-3-yl)ethane-1-sulfonamide. Form III, wherein the compound of formula (1) has diffraction angle (2θ°) peaks at 11.1° ± 0.2° and 20.3° ± 0.2° in X-ray powder diffraction (1R)-1-(1,2-benzoxazol-3-yl)ethane-1-sulfonamide in the crystalline form of The compound represented by formula (1) has X-ray powder diffraction of 11.1° ± 0.2°, 13.8° ± 0.2°, 17.0° ± 0.2°, 20.3 °±0.2°, 21.4°±0.2°, 22.1°±0.2°, 22.4°±0.2°, 24.8°±0.2°, 26.3° The crystalline form of Form III (1R)-1-(1, having four or more diffraction angle (2θ°) peaks selected from °±0.2°, and 27.9°±0.2° 2. The pharmaceutical composition of claim 1, which is 2-benzoxazol-3-yl)ethane-1-sulfonamide. A therapeutic and/or prophylactic agent for nervous system diseases or psychiatric diseases caused by abnormal T-type calcium channels, comprising the pharmaceutical composition according to any one of claims 1 to 18. Neurological or psychiatric disorders caused by abnormalities in T-type calcium channels include epilepsy, seizure disorders, motor dysfunction (disorders related to muscle spasms including convulsions, tremor, essential tremor, Huntington's disease, Myoclonus, tics, restless leg syndrome and dystonia), movement disorders including akinesia and rigidity syndrome and Parkinsonism (Parkinson's disease (tremor, muscle stiffness/rigidity, akinesia/oligokinesia, postural reflex disorder, olfactory disturbance) , REM sleep disorder, constipation, sleep disturbance, memory disturbance, depression, anxiety, headache, low back pain), idiopathic and drug-induced parkinsonism, post-encephalitis parkinsonism, progressive supranuclear palsy, multiple system atrophy , corticobasal degeneration, Lewy body dementia, cerebellar ataxia, Parkinsonism-ALS dementia complex and basal ganglia calcification), levodopa-induced dyskinesia in Parkinson's disease, drug-induced dyskinesia, nociceptive Receptive pain (traumatic pain, migraine, headache, chronic pain (lumbar back pain, rheumatoid arthritis, fibromyalgia, osteoarthritis, etc.), inflammatory pain), neuropathic pain (shingles pain, trigeminal pain) Neuralgia, complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (pain after spinal cord injury, pain after stroke, etc.), Guillain-Barré syndrome pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain), fatigue (due to Parkinson's fatigue, multiple sclerosis fatigue, sleep disturbance, or disturbance of circadian rhythm) induced fatigue, chronic fatigue syndrome including medication-induced parkinsonism), migraines, schizophrenia, autism, Gilles de la Tourette syndrome, bipolar disorder, depression, anxiety (general anxiety sleep disorders (including insomnia, hypersomnia, narcolepsy, REM sleep disorder), sleep disorders in depression, cardiac arrhythmias, hypertension, cancer, diabetes, infertility and 20. A therapeutic and/or prophylactic agent according to claim 19 for various diseases and disorders including sexual dysfunction. Nervous system disease or psychiatric disease caused by abnormality of T-type calcium channel is Parkinson's disease disorder, memory impairment, depression, anxiety, headache, low back pain), levodopa-induced dyskinesia in Parkinson's disease, essential tremor , generalized anxiety disorder, or neuropathic pain (shingles pain, trigeminal neuralgia) , complex regional pain syndrome, peripheral neuropathy (diabetic neuropathy, leprosy, etc.), chemotherapy-induced peripheral neuropathy, phantom pain, central pain (post-spinal injury pain, post-stroke pain, etc.), Guillain-Barré syndrome pain associated with multiple sclerosis, pain associated with Parkinson's disease, hyperalgesia or allodynia associated with neuropathic pain). Nervous system disease or psychiatric disease caused by abnormality of T-type calcium channel is Parkinson's disease (including tremor, muscle stiffness/rigidity, akinesia/hybridism, postural reflex disorder), essential tremor, or chemical 20. The therapeutic and/or prophylactic agent according to claim 19, which is therapy-induced peripheral neuropathy. Use of the pharmaceutical composition according to any one of claims 1 to 18 for producing a therapeutic and/or preventive agent for nervous system diseases or psychiatric diseases caused by T-type calcium channel abnormality. Abnormality of T-type calcium channel, characterized in that it is used in combination with at least one drug selected from drugs classified as drugs for treating Parkinson's disease, drugs for treating essential tremor, and drugs for treating neuropathic pain. A medicament containing a pharmaceutical composition according to any one of claims 1 to 18 for treating diseases in which it is involved. It is selected from a medicament containing the pharmaceutical composition according to any one of claims 1 to 18 and a drug classified as a drug for treating Parkinson's disease, a drug for treating essential tremor, or a drug for treating neuropathic pain A medicine in combination with at least one drug. A neurological disease or a psychiatric disease characterized by being used in combination with at least one drug selected from drugs classified as drugs for treating Parkinson's disease, drugs for treating essential tremor, or drugs for treating neuropathic pain. A medicament containing the pharmaceutical composition according to any one of claims 1 to 18 for treatment.