WO1995028389A1 - Spiro compound and medicinal composition thereof - Google Patents

Abstract

A spiro compound represented by general formula (I), a salt thereof, a hydrate thereof, or a solvate thereof, a typical example of which is the compound (a). It has an antagonistic effect against tachykinin receptors, especially substance P and/or neurokinin A receptors, and is useful as a preventive or remedy for respiratory diseases, central nervous system diseases, pains, and inflammatory diseases.

Description

 Description Spiro compounds and pharmaceutical compositions thereof

 The present invention relates to a novel spiro compound having a tachykinin receptor antagonistic action, particularly a substance P and Z or neurokinin A receptor antagonistic action, a salt thereof, a hydrate thereof or a solvate thereof. And a pharmaceutical composition containing the compound, and a raw material compound thereof. Background art

 Tachykinins are a general term for a group of peptides with similar structures, which are neuropeptides that are widely found in the nervous system.

 In recent years, it has been revealed that tachykinin has various physiological actions, such as airway constriction, airway hypersensitivity induction, mucus hypersecretion, vascular hyperpermeability, hissamine release from mast cells, cough induction, and painfulness. Have been. Therefore, tachykinin antagonists are useful treatments for diseases in which these effects are deeply related to their pathology, such as central illness, asthma, chronic bronchitis, rheumatoid arthritis, diabetes, irritable bowel syndrome, or widely inflammation. It has been suggested that it may be a drug.

 Tachykinins derived from mammals include substance P (SP), neurokinin A (NK A), and neurokinin B (NKB), which have various physiological actions via NK-1, NK-12 and NK-3 receptors, respectively. Is known to be involved in

For example, it is known that SP (NK-1 receptor) and NKA (NK-2 receptor) are involved in airway and nasal hypersensitivity in asthma and nasal allergy [Ichinose et al. Clinical Science Vol. 26, No. 10, No. 1, 248—1, 253 (1990)]. In addition, it is known that NK A (NK-2 receptor) is involved in central diseases such as anxiety [SC Strattoneta 1. 49 P (1993)].

 Furthermore, it has been reported that NK-1 receptor antagonists significantly suppress chemotherapeutic agents such as cisplatin, analgesics such as morphine, and various experimentally induced emesis such as X-ray irradiation. CB ountra , C. eta 1., Eur. J. Pharmaco 1., 24, R3-R4 (1993), FD T attera 11 etal., Eur, J. Pharma col., 250 R5-R6 (1993)]. Furthermore, it has been suggested that these antiemetic effects may be based on antagonism with tachykinin near the vomiting center such as the medullary medulla [Koichi Yoshioka et al., Neuropsychopharmacology Vol. 16, No. 1, 1 1-2-3 (1994)].

 Heretofore, compounds that antagonize each type of tachykinin receptor have been reported. For example, European Patent No. 5129001 describes a compound represented by the following general formula having a substance P, neurokinin A or neurokinin B receptor antagonistic action. Z

(For the symbols in the formula, see the above publication)

 In addition, Japanese Patent Application Laid-Open No. 4-261155 describes a compound represented by the following general formula having a neurokinin receptor (particularly, NK-2 receptor) antagonistic action.

R

 / ~ \ I

Y ― N- (CH ₂ ) _m -CH-CH ₂ -NTZ

 Ar '

(For the symbols in the formula, see the above publication)

Furthermore, Japanese Patent Application Laid-Open No. 5-140103 describes a compound represented by the following general formula having a substance P, neurokinin A or neurokinin B receptor antagonistic action.

(Refer to the above publication for symbols in the formula)

 However, although these compounds have a single ring containing a nitrogen atom, the compound of the present invention has a spiropiperidine skeleton of three rings as shown in the general formula (I) described later. In these respects, these compounds are structurally distinct. In addition, Japanese Patent Application Laid-Open No. 2-128487 describes a spirolactam derivative represented by the following general formula and having NK-1 or NK-2 receptor antagonistic activity.

. (CH ₂ ),.

RN '

 (For the symbols in the formula, see the above publication)

 However, the above compound is a bicyclic compound, but the compound of the present invention is structurally distinct in that it has a tricyclic spiropiperidine skeleton fused to a benzene ring. ―

 WO94 / 17545 published after filing the first country application of the present invention describes that a spiropiperidine derivative represented by the following general formula antagonizes a tachykinin receptor.

(Refer to the above publication for symbols in the formula)

However, this publication describes three spiropiperidine rings represented by the following formula. No specific pharmacological data is described for the tachykinin receptor antagonistic activity of these compounds.

The compounds of the present invention are structurally different from the compounds described in this publication in that they have a tricyclic spiperpiperidine ring having a different structure from these spiropiperidine rings. Furthermore, it has been confirmed by pharmacological tests by the present inventors that the tachykinin receptor antagonism is superior to the compounds disclosed in the above publications.

 Recently, peptide compounds having an antagonistic effect on both NK-1 and NK-2 receptors have been found, and their clinical utility due to having an antagonistic effect on both receptors has been reported. [PJ Barneseta 1., Br. J. Pharmacol., 108, 844-851 (1993)]. Further, Japanese Patent Publication No. 5-72852 also discloses a peptide compound having an antagonistic action on both NK-1 and NK-2 receptors.

On the other hand, various compounds having a spiropiperidine skeleton are also known. For example, European Patent Publication No. 431,943 describes a spiropiberidine compound having antiarrhythmic activity. In addition, Japanese Patent Application Laid-Open Nos. 50-89363 and 50-10.052 each disclose a spiropiperidine compound which can be used as a tranquilizer or an analgesic. Publications Nos. 414,289 and 188,055 disclose spiropiperidine compounds as antipsychotics, which are described in U.S. Pat.Nos. 3.686,186. A spiropiperidine compound which can be used as an antihypertensive agent is disclosed in Japanese Patent Application Laid-Open No. 55-139,980, and a spiropiperidine compound as an antiallergic agent is disclosed in U.S. Pat. , 2 3 3, 3 07, the specification states that God A spiropiperidine compound as a transsystemic drug or an antihypertensive agent is disclosed in Japanese Patent Application Laid-Open No. Sho 53-132578, a spiropiperidine compound as an antidepressant is disclosed in No. 55 discloses a spiropiperidine compound as an oxytocin antagonist, and EP-A-518 805 discloses a spiropiperidine compound as a centrally acting drug. , 857 describe spiropiperidine compounds as antihypertensive agents, respectively. However, it has not been reported that these compounds have tachykinin receptor antagonistic activity.

 As a result of intensive studies, the present inventors have found that a novel spiropiperidine compound has an excellent antagonistic effect on NK_1 and Z or NK-2 receptors. In particular, they also found that their antagonism to the NK-2 receptor was significantly superior to known NK-2 receptor antagonists. The present invention is based on these findings. The novel spiropiperidine compounds discovered by the present inventors are particularly useful for diseases involving both NK-1 and NK-12 receptors, including respiratory diseases such as asthma, rhinitis, chronic bronchitis, or airway hyperreactivity. Furthermore, it has high clinical utility for diseases in which one of the NK-1 and NK-2 receptors is more deeply involved. Disclosure of the invention

That is, the present invention provides a compound represented by the general formula (I) _:

_n -X ² -R ⁵ (I)

(The symbols in the formula represent the following meanings.

 N ": a nitrogen atom which may form a quaternary ammonium salt with a lower alkyl group or an aralkyl group, or which may be oxidized

Z: -C (R ⁸ R ⁹ ) -Z ¹ -or —CH ₂ — C (R ¹⁰ RH) —Z ² —

Z ¹ : oxygen atom or S (0), Z ² : Z ¹ , NR ¹² , or C (R ¹³ R ¹⁴ )

 s: 0, 1 or 2

 R: aryl group which may be substituted

 n: 0 or an integer from 1 to 5

p and Q: same or different, 0 or 1 (however, p and q are not 0 at the same time) X ¹ :-C (= 0)-,-C (= S) one,-S (= 0) -, - S 0 ₂ one, one ^{C (= NR 6) -,} - CH 2 primary, or - CH = CH- (where, X ¹ is - in the case of CH = CH one is, n and Q are both Is 0 and X ² is a single bond. X ² : oxygen atom, sulfur atom, one NR ⁷ -or single bond (provided that X ^{1 is} -C (= N

R ⁶ ) — and when n is 0, X ² is a sulfur atom, one NR ⁷ — or a single bond)

R ′, R ² , R ³ , R ⁴ , R ⁶ and IT: 1) The same or different, and a hydrogen atom or a lower alkyl group (when n is an integer of 2 to 5, a plurality of R ³ and R ⁴ may be the same or different), 2) R ¹ and R ² together form a lower alkylene group having 1 to 4 carbon atoms when p is 1 When P is 0, a lower alkylene group having 2 to 5 carbon atoms can be formed, or 3) n is 0 and X ^{1 is} -C (= 0)-, — C (= S)-, 1 S (= 0)-,-S 0 _{2 If} 1 or 1 C (= NR ⁶ ) —, then R ² and R ⁷ are united and have 2 carbon atoms. Can form ~ 4 lower alkylene groups

R ⁵ : a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group, an optionally substituted cycloalkyl group, An optionally substituted cycloalkenyl group or an optionally substituted heterocyclic group:

R ^8, R ^3,! ^^ and!? ^11: 1) the same or different, a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, human Dorokishi lower alkyl group, a mercapto group, low grade alkylthio group, or a mercapto-lower alkyl group, or 2) R ⁸ and R ⁹ Or R ^{1 β} and R ¹¹ together form an oxo group

R ^'2: a hydrogen atom, a lower alkyl group,' a lower alkoxycarbonyl group, a lower alkyl Rusuruhoniru group, a lower alkylsulfinyl group, a lower Arukanoiru group, Shikuroa Alkylcarbonyl group, optionally substituted arylcarbonyl group, or optionally substituted aryloxycarbonyl group

? 1 ¹³ and 1 _^14: 1) the same or different, a hydrogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group or a lower alkylthio group, 2) a hydroxyl group, lower pole alkoxy group is substituted with Melka but-group or a lower alkylthio group An optionally substituted lower alkyl group, or 3) an oxo group wherein R ¹³ and R ¹⁴ are

 B z: 1) unsubstituted benzene ring or 2) benzene ring substituted with 1 to 4 identical or different substituents

 Substituents: i) halogen atom, hydroxyl group, lower alkoxy group, mercapto group, lower alkylthio group, carboxy group, lower alkanoyl group, lower alkoxycarbonyl group, nitro group, amino group, lower alkanoylamino group and the like. Or a lower alkoxycarbonylamino group, ΰ) a lower alkyl group or a lower alkenyl group which may be substituted by the substituent of the above i), or iii) methylenedioxy by combining two adjacent substituents together. Group or ethylenedioxy group)

Or a salt thereof.

 Furthermore, the present invention also relates to a compound represented by the general formula (A) or a salt thereof, which is a starting compound of the compound of the present invention.

. Wherein, X: - 0-, -NH- or -S0 ₂ -

Z ³ : -CH ₂ — or 1 C (= 0) —

t: 0 or 1 (however, when t is 0, X is one S 0 _2— , and when Z ^{3 is-} C (= 0) one, X is one 0— Shall be) :)

Examples of the tachykinin receptor antagonist containing the spiro compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient include, in particular, substance P receptor and Z or neurokinin A receptor antagonist. Yes, tachykinin-mediated anxiety, Central nervous system disorders including depression, psychiatric disorders and schizophrenia: dementia in AIDS, Algeheimer-type senile dementia, Alzheimer's disease, Down's syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, Neurodegenerative diseases including peripheral neuropathy and neuralgia; chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, respiratory diseases including asthma; inflammatory bowel disease (IBD), psoriasis, fibrositis, osteoarthritis Inflammatory diseases, including rheumatoid arthritis, and rheumatoid arthritis; Allergic diseases, including eczema; and rhinitis; Hypersensitivity diseases, including hypersensitivity to vines: Conjunctivitis, spring conjunctivitis, Blood-aqueous humor associated with various inflammatory eye diseases Ophthalmological disorders including barrier destruction, increased intraocular pressure, and miosis: skin disorders including contact dermatitis, atopic dermatitis, juniper, and other eczema-like dermatitis; alcoholism Somatic disorders due to stress; reflex sympathetic dystrophy including shoulder-hand syndrome; mood swings; unwanted immune responses including graft rejection and immune enhancement including systemic lupus erythematosus; Is a disease related to immunosuppression; diseases due to abnormalities in the nerves regulating the internal organs, ulcerative colitis, digestive diseases including Crohn's disease: X-ray irradiation and chemotherapeutic agents, poisons, toxins, pregnancy, vestibular disorders, postoperative Vomiting, including vomiting induced by disease, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure, or side effects associated with the administration of various drugs: bladder dysfunction including urinary incontinence: collagen disease, Scleroderma, eosinophilia due to liver niece infection; Vasodilation including angina, migraine, and Reino's disease, or abnormal blood flow due to contraction: Pain nociception including migraine Pain: from An antagonist that is an agent for preventing or treating tachykinin-mediated diseases.

 Hereinafter, the general formula (I) of the present invention will be described in more detail. (The symbols in the formula are the same as described above.)

Expression

In addition, below !? ⁸ and!? ^9, R ^ie and R ¹¹ represents a case where the Okiso group together.

Up

(Where

R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom, a lower alkyl group, or an oxo group;

R ^{1 (1} and R ¹¹ are a hydrogen atom or an integral oxo group,

R ¹² is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a lower alkanol group or a benzoyl group,

R ¹³ is a hydroxyl group, a mercapto group or a hydroxy lower alkyl group,

R ¹⁴ is a hydrogen atom or an oxo group together with R ¹³ )

A spiro compound or a salt thereof, which is a group represented by

 More preferably

formula

(Where

R ¹ ° and R ¹¹ are a hydrogen atom or an integral oxo group,

R ¹² is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a lower alkyl group or a benzoyl group)

Or a salt thereof.

 When N ′ represents a nitrogen atom, the spirocyclic group forms a tertiary amine, but the N * further forms a quaternary ammonium salt with a lower alkyl group or an aralkyl group. And may be oxidized.

When X ^{1 is} -CH = CH-, the general formula is as follows.

In addition, when X ¹ is —C (= NR ⁶ ) and n is 0, the following general formula is obtained.

(I-I b)

(I-c)

 Or

(I-d)

When p is 1, when R ¹ and R ² together form a lower alkylene group having 1 to 4 carbon atoms, one C (R) (R ¹ ) one (CH ₂ ) p one (NR ² ). The first is the following structure.

Further, when p is 0, when R ¹ and R ² together form a lower alkylene group having 2 to 5 carbon atoms, one C (R) (R ¹ ) one (CH ₂ ) p one (NR ² ). -Has the following structure.

n is 0, Q force "1, X ² gar NR ⁷ - and is, and X ¹ is - C (= 0) one, - C (= S) one, one S (= 0) - , -S 0 ₂ — or —C (= NR ⁶ ) —, when R ² and R ⁷ together form a lower alkylene group having 2 to 4 carbon atoms, — NR ² -X ¹ -NR ⁷ — has the following structure:

Preferably, p and q are 1 and R ¹ and R ² are combined to form a lower alkylene group having 1 to 4 carbon atoms or a spiro compound or a salt thereof, or!? ¹ and!? ² is a spiro compound or a salt thereof in which the same or different hydrogen atoms or lower alkyl groups are present.

 Hereinafter, the present invention will be described in more detail.

 In this specification, "low" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

 Accordingly, in the present invention, the “lower alkyl group” includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1 monoethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methyl Rupuropiru group, and a 1 Echiru 2 Mechirupuro propyl group. Particularly, a methyl group and an ethyl group are preferred.

The “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl (2-probenyl) group, a 1-propenyl group, an isopropyl group. Benzyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl Cyl-1 monopropyl group, 2-methylaryl group, 1-methyl-1 monopropyl group,

1-methylaryl group, 1,1-dimethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3- Butenyl group, 1,1-dimethylaryl group, 1,2-dimethyl-1-propenyl group,

2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-12-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4 1-hexenyl group, 5-hexenyl group, 1,1-dimethyl-1 butenyl group, 1,1 dimethyl-2-butenyl group, 1,1 dimethyl-3-butenyl group, 3,3-dimethyl-1-butenyl group , 1 —methyl-1 monopentenyl group, 1 —methyl-2-pentenyl group, 1 —methyl-3-pentenyl group, 1 —methyl-4 monopentenyl group, 4 monomethyl-1 1 pentenyl group, 4-methyl-2-pentenyl group, 4 -Methyl

3 One pentenyl group and the like can be mentioned.

 "Cycloalkyl group" or "cycloalkenyl group" is preferably a cycloalkyl group or cycloalkenyl group having 3 to 8 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexyl group. A butyl group, a cyclooctyl group, a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group and the like, and a cyclohexyl group or a cyclohexenyl group is preferable.

 The “aryl group” is preferably an aryl group having 6 to 14 carbon atoms, for example, a phenyl group, a biphenyl group, a naphthyl group, an anthryl group, a phenyl group and the like, and a phenyl group Or a naphthyl group is preferable.

 "Aralkyl group J is a group in which any hydrogen atom of the lower alkyl group is substituted with the above-mentioned aryl group, and is preferably a benzyl group.

The “heterocyclic group” is preferably an unsaturated 5- to 7-membered ring containing 1 to 5 (particularly 1 or 2) nitrogen, oxygen and Z or sulfur atoms as a hetero atom or a condensed ring thereof. It is a ring group. More preferably, it is a 5- or 6-membered monocyclic or bicyclic heterocyclic group. More specifically, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, benzimidazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, virazyl, Monocyclic or bicyclic unsaturated heterocyclic groups containing only nitrogen atoms such as quinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, and pyrimidazolyl groups, thiazolyl groups, isothiazolyl groups, and thiadiazolyl A monocyclic or bicyclic unsaturated heterocyclic group containing a nitrogen atom and a sulfur atom, such as a benzothiazolyl group, a benzoisothiazolyl group, an oxazolyl group, an isoxazolyl group, an oxdiazolyl group, a benzoxazolyl group, a benzy Units containing nitrogen and oxygen atoms such as soxazolyl groups Sulfur-containing heterocyclic groups such as a cyclic or bicyclic unsaturated heterocyclic group, a phenyl group, a phenyl group, a benzoyl group, a benzoyl group, and a benzopyrenyl group. And an oxygen heterocyclic group. Particularly preferred is a group represented by the following formula. The bond to X ² may come from any carbon atom constituting the hetero ring R ⁶ .

In the above formula, when forming a condensed ring with a benzene ring, only one type of condensing is shown. It may appear, and it is not limited to only the above-mentioned condensed ring.

 The “lower alkoxy group” is a lower alkoxy group having the lower alkyl group in the alkyl portion, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy group, pentyloxy (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group And hexoxy groups, and among them, a methoxy group, an ethoxy group or an isopropoxy group is preferable.

 The "lower alkanol group" is a lower acetyl group having 1 to 6 carbon atoms derived from a saturated aliphatic carboxylic acid, and includes, for example, formyl group, acetyl group, propionyl group, butylyl group, isoptyryl group, valeryl group, and isovaleryl. Group, a bivaloyl group or a hexanoyl group are preferred.

 The term "lower alkylthio group", "lower alkylsulfinyl group" or "lower alkylsulfonyl group" preferably means a thio group, a sulfinyl group or a sulfonyl group each having the lower alkyl group as an alkyl moiety.

 “Hydroxy lower alkyl group” or “mercapto lower alkyl group” means a group in which any one or two or more hydrogen atoms of the aforementioned lower alkyl group have been substituted with a hydroxyl group or a mercapto group, respectively.

 The “lower alkoxycarbonyl group” is a carbonyl group having the lower alkoxy group as an alkoxy moiety.

 The “cycloalkylcarbonyl group” or “arylcarbonyl group” is a carbonyl group having the above-mentioned cycloalkyl group or aryl group, respectively, and is preferably a cyclohexylcarbonyl group or a benzoyl group.

 An "aryloxycarbonyl group" is one having the above-mentioned aryl group in the oxycarbonyl group.

Among the optionally substituted aryl groups represented by R, preferred are an unsubstituted phenyl group or an unsubstituted naphthyl group, or a phenyl group substituted with 1 to 4 identical or different substituents. Examples of the substituent on R include: i) a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group. Group, carboxy group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, sorbamoyl group, cyano group, nitro group, amino group, mono-low-alkylamino group, di-lower-alkylamino group A lower or lower alkanoylamino group, ii) a lower alkyl group or a lower alkenyl group or a lower alkynyl group which may be substituted with the group of i), or iii) two adjacent substituents All together form an alkylene group having 3 to 4 carbon atoms, a methylenedioxy group or an ethylenedioxy group, particularly preferably a halogen atom, a trifluoromethyl group, a lower alkoxy group, a cyano group or An unsubstituted lower alkyl group or a methylenedioxy group consisting of two adjacent substituents Is mentioned.

 Here, the “halogen atom” is specifically a chlorine atom, a fluorine atom, a bromine atom or an iodine atom.

 A “mono-lower alkylamino group” or a “di-lower alkylamino group” is a group in which one or two hydrogen atoms of an amino group are substituted with a lower alkyl group. For example, specific examples of the amino group which is mono- or di-substituted with a lower alkyl group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, A mono-lower alkylamino group substituted with a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as an isoptylamino group, a pentylamino group, an isopentylamino group, a hexylamino group, and an isohexylamino group. Straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as dimethylamino, getylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, and dihexylamino. Disubstituted symmetric di-lower alkylamino, ethylmethylamino, methylpropylamino, ethylpro Asymmetrical di-substituted alkyl groups of 1 to 6 carbon atoms, such as lumino, butylmethylamino, butylethylamino, butylpropylamino, etc. Examples thereof include di-lower alkylamino groups, and among them, a dimethylamino group is particularly preferred.

The “lower alkyl group” is an amino group in which an arbitrary hydrogen atom is substituted with the lower alkyl group, and is preferably an acetylamino group. The “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-petynyl group and 2-butyl. 2-, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-11-butynyl, 2-methyl-3-butynyl group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 1,1-dimethyl-2-propynyl group, 1-hexynyl group, 2- Examples include a hexynyl group, a 3-hexynyl group, a 4-hexynyl group, and a 5-hexynyl group, and any hydrogen atom of these groups may be substituted with the group of the above i)) .

 Examples of the substituent on Bz include: i) a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, a carboxy group, a lower alkanoyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, A lower alkanoylamino group and a lower alkoxycarbonylamino group, and ΰ) a lower alkyl group or a lower alkenyl group which may be substituted by the group of the above i), or iii) two adjacent substituents Are taken together to form a methylenedioxy group or an ethylenedioxy group, particularly preferably an unsubstituted lower alkyl group.

 The “lower alkoxycarbonylamino group” is one in which the carbon atom of the carbonyl group of the carbonylamino group is bonded to the lower alkoxy group.

Examples of the substituent on the substituted aryl group or the substituted heterocyclic group represented by R ⁵ include i) a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, and a carboxy group. , Lower alkanol group, lower alkoxycarbonyl group, lower alkoxy lower alkoxy group, benzoyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, carbamoyl group, cyano group, nitrite group, amino group, mono-lower alkylamine Ii) a lower alkylamino group, a lower alkanoylamino group, and a phenyl group; andii) a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be replaced by the group of i) above, or iii) Two adjacent substituents are combined to form a methylenedioxy group or an ethyl group. And particularly preferably a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a benzoyl group, a carbamoyl group, a cyano group, A nitro group, an amino group, a di-lower alkylamino group, a lower alkylamino group, a lower alkoxy lower alkoxy group, an unsubstituted lower alkyl group, or two adjacent substituents And methylenedioxy groups.

 The “lower alkoxy lower alkoxy group” is one in which any hydrogen atom of the lower alkoxy group is substituted by a lower alkoxy group, and is preferably a methoxy methoxy group.

Examples of the substituent of R ⁵ as a substituted lower alkyl group, a substituted lower alkenyl group, a substituted cycloalkyl group or a substituted cycloalkenyl group include the groups described in i) above.

Examples of the substituted arylcarbonyl group or the substituted aryloxycarbonyl group as R ¹² include i) a halogen atom, a trifluoromethyl group, a lower alkoxy group, and ii) the above i) And a lower alkyl group which may be substituted with the above group.

 Among the compounds represented by the general formula (I), particularly preferred compounds are

 1 '-(2-C3- (3,4-dichlorophenyl) -1 1-[(3-Isopropoxyphenyl) acetyl] —3-Piperidyl] ethyl] 1 1' (a) -Methyl-

3, 4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidinium] salt,

 1 '-[2- [3- (3,4-dichlorophenyl) 1-1] [(3-isopropoxyphenyl) acetyl] -3-piridyl] ethyl] 1' (a) -methyl-3 Salts of oxo-3,4-dihydrospiro [isoquinolin-1 (2H), 4'-pyridinium],

 N- (2- (3,4-dichlorophenyl) -14- (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine) 1-1-1 ' Le) butyl] —N-methylbenzamide or a salt thereof,

 N_ [2- (3,4-dichloromouth phenyl) 1-4- (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] 1 1'-yl) Butyl] 1,3,4,5-trimethoxy N-methylbenzamide or a salt thereof,

1 '1 [4-(N-benzoyl-N-methylamino) 1 3-(3,4-dichloro Mouth phenyl) butyl] spiro [benzo [c] thiophene 1 (3H), 4'-piperidine] 2-year-old oxide or a salt thereof.

 The salt of the compound represented by the general formula (I) or the general formula (II) is an acid addition salt with an inorganic acid or an organic acid, or a salt with an inorganic or organic base. Preferably, the salt is acceptable. Specific examples of these salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid. Acid, fumaric acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, organic acid such as methanesulfonic acid or ethanesulfonic acid, or acidic amino acid such as aspartic acid or glutamic acid. Acid addition salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, organic bases such as methylamine, ethylamine, ethanolamine, and basic amino acids such as lysine and orditin And the like. Furthermore, it can be a 4-ammonium salt. The quaternary ammonium salt is specifically a salt with a lower alkyl halide, a lower alkyl triflate, a lower alkyl tosylate, a lower alkyl mesylate, a benzyl halide, or the like, and is preferably a methyl aldehyde, an ethyl sulfide or a benzyl halide. It is a salt with benzyl bromide.

 Further, the compound of the present invention has at least 1 to 5 asymmetric carbon atoms, and in some cases, one asymmetric nitrogen atom. Therefore, the compound (I) of the present invention exists in the form of an optically active substance or a diastereomer or a racemic mixture thereof. Further, depending on the type of the substituent, there are geometrical isomers based on a double bond ゃ cycloalkyl ring, and these are all included in the scope of the compound of the present invention.

 A racemic mixture or an optically active substance can be used as a starting material in the production method described below, and a stereoisomer in a product obtained by using the racemic mixture as a starting material can be obtained by ordinary chromatography or fractional crystallization. It can be separated by methods. The present invention also includes hydrates, various solvates, polymorphs, and the like of the compound of the general formula (I).

 Next, a method for producing the compound (I) of the present invention will be described.

The novel compound represented by the general formula (I) according to the present invention can be produced by various methods utilizing the characteristics of its basic skeleton and substituents. I will explain the typical production method of

 (1) First manufacturing method

-X ² -R ^E

During the above reaction scheme, Y is capable desorption upon N- alkylation reaction group, for example halogen atoms or R 'S 0 ₂ 0- group (R * is an alkyl group, Ariru group or Ararukiru group) in Yes, Β ζ, τ R, R ^{1 to} R ⁵ , X ′, X ² , n, p and Q have the same meanings as described above.

 In the first production method, a ring nitrogen atom of a compound represented by the general formula (Π) is N-alkylated by a compound represented by the general formula (I) as shown in the above reaction formula. To obtain the compound (I) of the present invention.

This N-alkylation reaction can be carried out in the presence or absence of a base such as potassium carbonate, tritylamine or the like, in a solvent such as dimethylformamide 2-butanone, or without a solvent. It is. The N-alkylation reaction can be carried out at 0 ° C. to 150 ° C., preferably at room temperature to 100 ° C., and more preferably at 50 ° C. to 100 ° C.

(2) Second manufacturing method

N-alkylation

Deprotection

 (V)

 Amidation, etc.

(I) In the above reaction formula, Y ¹ is Y—CH ₂ , Y ² is an amino-protecting group (for example, tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group) a Asechiru group, a formyl group, a benzyl group, etc.), B z, Z, Y , R, R 1, R 2, Z 1 and p are as defined above.

In this production method, as shown in the above-mentioned reaction formula, first, as a first step, a ring nitrogen atom of a compound represented by the general formula (E) is converted into a compound represented by the general formula (E) by the same method as the first production method. N-alkylation with the compound represented by the formula (W), and as a second step, the amino-protecting group Y ² is removed by a conventional deprotecting means such as acid or alkali hydrolysis, catalytic reduction, etc. The compound represented by (V) is obtained. Further, as a third step, the free amino group of the compound represented by the general formula (V) obtained in the first step is converted into amidated, uretized, urethanized, This is a method for obtaining the compound (I) of the present invention by thioamidation, alkylation, amidination or sulfonamidation. -Each reaction of the above-mentioned third step can be carried out as follows.

Amidation involves free carboxylic acids or reactive derivatives thereof, such as acid halides, acid azides, active esters (eg, 1-hydroxybenzotriazole, N-hydroxide). Roxysuccinimide, etc.), symmetrical acid anhydrides, and mixed acid anhydrides (eg, isobutyl carbonate). When a free carboxylic acid is used, a condensing agent such as N, N'-dicyclohexylcarpoimide, 1,1'-carbonyldiimidazole, N, N'-disuccinimidyl carbonate, 1 It is preferable to use (3-dimethylaminopropyl) 1-3-ethylcarbodiimide or N, N'-bis (2-oxo-13-oxazolidinyl) phosphinic chloride.

The urea formation can be carried out by reacting with an isocyanate isolated or prepared in a system from carboxylic acid azide or the like. The urethanation can be carried out by reacting with a methyl ester carbonate, or by a substitution reaction between a substituted or unsubstituted phenoxycarbonyl compound and alcohol. The thioamidation is carried out by reacting with dithiocarboxylic acid or thiocarboxylic acid under the same conditions as in the above-mentioned amidation, or by using an amide derivative to obtain linyl pentasulfide or 2,4-bis (4-medium). Toxylphenyl) 1,1,3-dithia1-2,4—diphosphethane-12.4—disulfide, etc., or by reacting with S— (thiocarbonyl (substituted) alkyl) thioglycolic acid or S— (thiocarbonyl) (Substituted) aryl) It can be carried out by reacting with thioglycolic acid. The alkylation in the second step can be carried out by carrying out the same reaction as in the above-mentioned first production method, or by reducing it with lithium aluminum hydride or borane via an amide derivative. The amidination can be carried out by reacting with a thioimidate, the thioperylation can be carried out by reacting with isothiosinate, and the sulfonamidation can be carried out by reacting with sulfonyl chloride. .

(3) Third manufacturing method

(1) N-alkylation + (1)

(2) Cyclization

(YD I, -X ² -R ⁵ (I-1)

nX ² -R ⁶ (1-2)

During the above reaction ^{formula, B z, R, R 1} ~ R 6, R 8 ~RH, X 1, X 2, n, p及Beauty Q have the same meanings as above.

In the third production method, as shown in the above reaction formula, a ring nitrogen atom of a compound represented by the general formula (W) is N-alkylated by a compound represented by the general formula (II), and By the cyclization reaction, the compound of the present invention (1 — 1) wherein Z is —C (R ⁸ R ⁹ ) 10 — in the general formula (I) or —CH ₂ —C (R ¹⁰ R ") 1 0—This is a method for obtaining the compound (1-2) of the present invention.

In this third production method, the alkylation can be carried out in the same manner as described in the first production method, and the cyclization is carried out in an acidic solution such as an aqueous sulfuric acid solution from room temperature under heating to reflux, or boron trifluoromethane. The reaction can be carried out in a solvent such as benzene or in the absence of a solvent in the presence of a Lewis acid such as a lidgetyl ether complex, from 0 to heating under reflux. Further, the cyclization reaction is carried out in the presence or absence of a base such as pyridine in a solvent such as thionyl chloride, p-toluenesulfonyl chloride or methanesulfonyl chloride with dichloromethane or tetrahydrofuran or in the absence of a solvent. From 20 ° C It is possible to carry out the reaction under heat reflux, preferably from 0 under heat reflux,

 (4) Fourth manufacturing method

NX ² -R ⁵

 (π) ()

Ν—alkylation

(I) In the above reaction formula, Y ³ and Y ⁴ are the same or different, a leaving group such as a halogen atom, and B z, Z, R, R ^{1 to} R ⁵ , X ¹ , X ² , n, p and Q have the same meaning as described above.

 In the fourth production method, as shown in the above reaction formula, a nitrogen atom of a compound represented by the general formula (W) is N-alkylated by a compound represented by the general formula (观). To obtain the compound (I) of the present invention. This fourth production method can be performed in substantially the same manner as the method described in the first production method.

 (5) Fifth manufacturing method Killing

Y ⁵ is a protecting group) etc.

In the above reaction formula, Y ⁵ is a protecting group for a hydrogen atom or an amino group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, acetyl group, formyl group, Bz, R, R ¹ to R ⁵ , R ^{10 to} R ¹² , X ¹ , X ² , n, p and Q have the same meanings as described above.

 In the fifth production method, as shown in the above reaction formula, one ring nitrogen atom of the compound represented by the general formula (K) is selectively generalized by a method similar to the second production method. formula

N-alkylation (deprotection if desired) with the compound represented by (Π), and further amide, urea, uretan, thioamid, alkyl, amidine, or other ring nitrogen atom The compound of the present invention wherein the Z group is one CH ₂ —C (R ^ R ¹¹ ) 1 N (R ¹² ) group in the general formula (I) by sulfonamide formation

It is a way to obtain (I-1 3).

 (6) Sixth manufacturing method

The sixth production method, among the groups represented by Z in the general formula (I), R ⁸ and R ^9, R ^ie and R ¹¹ or R ¹³ and R ⁴ compound is Okiso group becomes gar body Of the group represented by Z in the formula (I), ^{one of} R ⁸ and R ^s , R ^{1 ()} and R ¹¹ or R ¹³ and R ¹⁴ is hydrogen. Compound in which the atom is the other and the other is a hydroxyl group]. This reduction reaction is carried out using a reducing agent (for example, sodium hydride or lithium aluminum hydride) in a solvent such as methanol, ethanol, tetrahydrofuran or getyl ether at a temperature of 178 ° C. The reaction can be carried out under heating to reflux, preferably at 0 ° C. to heating under reflux.

(7) Seventh manufacturing method

In the above reaction formula, B z, R, R ¹ • R. X ¹ , X ² , n, p and Q have the same meanings as described above.

In the seventh production method, as shown in the above reaction formula, the unsaturated compound represented by the general formula (X) is reduced, and in the general formula (I), Z is —CH ₂ —CH ₂ — and converts the CH ₂ one at a saturated compound. This reduction reaction is carried out using a reduction catalyst (for example, palladium carbon or Raney nickel) in a solvent such as methanol, ethanol, water, or ethyl acetate at normal pressure to 50 kg / cm ² , preferably at normal pressure. The reaction can be performed under a hydrogen atmosphere of 0 to 3 kg / cm ² under heating to reflux from 0 ° C, preferably at room temperature to about 50 ° C.

 (8) Eighth manufacturing method

 a) Sulfoxidation and sulfonation

„-X ² -R ^E

b) N-oxidation

„-X ² -R ⁶

In the above reaction formula, Z ′ is one C (R ⁸ R ⁹ ) one or —CH ₂ —C (R ¹⁰ R) one, s ¹ is 1 or 2, B z, R, R ¹ to R ⁶ , X ¹ , X ² , n, p and Q have the same meanings as described above.

In the eighth production method, as shown in the above reaction formula, a) in the above general formula (I), a) a compound in which Z ¹ or Z ² is a sulfur atom is oxidized to form one SO— or one SO ₂ — It is converted to a certain compound, or b) oxidizes a tertiary nitrogen atom of a spiro ring represented by N ′ in the above general formula. This oxidation reaction is carried out by the compound (I-15) or (I-17) and its corresponding or excessive amount of sodium periodate, hydrogen peroxide, m-chloroperbenzoic acid or monoperphthalic acid. The reaction can be carried out in a solvent such as water, methanol, ethanol, benzene, dichloromethane or chloroform in the presence of an oxidizing agent for an organic peracid such as magnesium under heating and reflux at about −28 ° C.

(9) Ninth manufacturing method

„-X ² -R ⁵

In the above reaction formula, R ^b is a lower alkyl group or an aralkyl group, Q— is an anion, and B z, Z, R, R ¹ to R ⁵ , X ¹ , X ² , n, p and Q has the same meaning as described above.

 In the ninth production method, as shown in the above reaction formula, a spiro ring represented by N ′ in the general formula (I) is converted into a 4-nitrogen atom to convert it into a quaternary ammonium salt derivative. It is. This quaternization reaction is carried out by using an alkylating agent (for example, alkyl halide or alkyl triflate) in a solvent such as dimethylformamide, toluene, acetonitril or aceton, or without solvent. At about 0 ° C. under heating and reflux.

 (1 0) No. 10 manufacturing method

N-alkylation

 (XI)

„-X ² -R ⁵ (I-I)

In the above reaction formula, R ^b , QB z, Z, R, R ′ to R ⁵ , X ′, X ² , n, P and Q have the same meaning as described above.

 In the tenth production method, as shown in the above reaction formula, a ring tertiary nitrogen atom of a compound represented by the general formula (X) is alkylated with a compound represented by the general formula (Π). Thus, a quaternary ammonium salt derivative is obtained by quaternization. This quaternization reaction can be carried out in a solvent such as dimethylformamide, toluene, acetonitrile or acetone, or without a solvent, at about 0 to under reflux with heating.

 (1 1) 1st manufacturing method

In the first production method, among the groups represented by Z in the general formula (I), one of R ⁸ and R ⁹ , and one of R ^1β and R ¹¹ or R ¹³ and R ¹⁴ is a hydrogen atom. The other is a hydroxyl group of a compound wherein the hydroxyl group is reduced to form a dehydroxy derivative (the above-mentioned general formula

In which R ⁸ and R ⁹ of the radicals represented by Ζ in (I), R ¹⁰ and R ¹¹ or R ¹³ and R ¹⁴ are converted into both represent hydrogen atoms]. This reduction reaction is a reduction catalyst

(E.g., palladium carbon, Raney nickel, etc.) in a solvent such as methanol, ethanol, water, ethyl dichloride, acetic acid, etc. in the presence or absence of a mineral acid such as hydrochloric acid, or an organic acid such as acetic acid. The reaction can be carried out in the presence, from normal pressure to 100 kg gZcm ² , under a hydrogen atmosphere from 0 to 100. In the presence of a mineral acid such as hydrochloric acid or sulfuric acid, an organic acid such as acetic acid or trifluoroacetic acid, or a Lewis acid such as boron trifluoride dimethyl ether complex, a reducing agent such as triethylsilane or lithium aluminum hydride is used. The reaction can be carried out in a solvent such as dichloromethane, dichloroethane or tetrahydrofuran ethyl ether under heating and refluxing at a temperature of from 120 ° C, preferably from 0 ° C.

(1 2) 1st 2nd manufacturing method n-X ² -R ⁵

Reductive amination-(I) In the above reaction formula, Ι ^ Κ 'Ι ^ Χ' Χ ² ! ^ Ρ and q have the same meanings as above It is.

 In the 12th production method, as shown in the above-mentioned reaction formula, the compound represented by the general formula (XII) is subjected to reductive amination with the compound represented by the general formula (Π). This is a method for obtaining the compound (I) of the present invention.

 This reductive amination reaction is based on titanium (IV) isopropoxide, titanium

() Sodium cyanoborohydride in the presence or absence of a Lewis acid such as chloride, boron trifluoride dimethyl ether complex, or an acid such as sulfuric acid or hydrochloric acid, or a dehydrating agent such as molecular sieves; Using a reducing agent such as sodium trisodium borohydride or sodium borohydride in a solvent such as methanol, ethanol, dichloromethane, tetrahydrofuran, etc. under heating and reflux at 120 ° C. Can be performed at 0 ° C to 50 ° C. In addition, in the presence or absence of an acid such as acetic acid or hydrochloric acid, using a reducing catalyst (for example, palladium carbon, Raney nickel, etc.) in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, and normal pressure. To 50 g / cm ² , preferably normal pressure to 5 k / cm ² under a hydrogen atmosphere at 0 ° C. to 100 ° C., preferably at room temperature to 50 ° C. .

 Another method is to use a compound represented by the general formula (XII) instead of the compound represented by the general formula (XII).

A compound represented by the formula (IV), wherein Y ¹ is CHO, subjected to reductive amination in the same manner as described above, followed by the second and third steps of the second production method Similarly, it can be manufactured by deprotection and amidation.

 (13) 13th manufacturing method

X ² -R ⁵

In the above reaction formula, Y ⁶ is a hydroxy group, a hydride, a lower alkoxy group, and R, R ¹ ′ R ⁵ , n, p and Q have the same meanings as described above.

In the thirteenth production method, a compound represented by the general formula (Π) as shown in the above reaction formula is used. And reducing the amide obtained by amidating the compound represented by the general formula (XIII) to obtain the compound (I) of the present invention.

 In this 13th production method, amidation can be carried out in the same manner as in the 3rd step of the 2nd production method, and reduction is carried out by using a reducing agent such as lithium aluminum hydride, borane, etc. 0 in a solvent such as tyl ether. The reaction can be carried out from C to under reflux with heating, preferably from room temperature to under reflux with heating.

Further, as another method, a compound represented by the general formula (IV) wherein Y ¹ is Y ⁶ —C 0 is used instead of the compound represented by the general formula (XIII), After performing amidation and reduction in the same manner as in the above, deprotection and amidation can be carried out in the same manner as in the second and third steps of the second production method.

 The starting compounds used in the first to thirteenth production methods are known per se, or when they are novel compounds, can be prepared by known methods. For example, the chain compounds represented by the general formulas (Π), (W), (Cor), (XII) and (XIII) are all known compounds, or are known methods from known compounds. Can be easily prepared.

 Further, the piperidine compounds represented by the general formulas (Π), (VI), (K) and (XI) are described, for example, in US Pat. Nos. 3,745,165 and 3,30. 1, 857, each specification, European Patent Publication Nos. 51-805 and 414,289, or Journal Medical Chemistry, 35 (1 1), 20 33-203 9 (1992) or the like, or can be easily prepared from the compounds described therein by a known method.

 Among the various starting compounds used in the first to thirteenth production methods, they are represented by the following formulas (A-1), (A-2), (A-3) and (A-4) Each compound is a new compound. I ―

The compounds represented by the formulas (A-1), (A-2), (A-3) and (A-4) are also known per se by the following methods (a), (b) and (c. ) Or (d).

Production method (a)

During the reaction scheme, the Upsilon ⁷ is a halogen atom (e.g., bromine atom, chlorine atom or iodine atom), an oxygen atom, a sulfur atom, one C00_ or - S0 ^₂ -, Z ₂ 'is an oxygen atom, It is a sulfur atom, a nitrogen atom or a group represented by the formula -NH-, wherein Y ² has the same meaning as described above.

 First, the compound represented by the general formula (XIV) is lithiated. Lithiation is carried out in the presence of an organolithium reagent such as n-butyllithium or methyllithium, or a metal lithium or the like, in a solvent such as tetrahydrofuran, geethylether or hexane, or a mixture thereof. — It can be carried out at a temperature of not more than 120 and under ice-cooling, preferably at a temperature of 100 ° C. to 170 ° C.

When the thus-obtained lithio-form and the N-protected piperidone are reacted in a solvent such as tetrahydrofuran, getyl ether or hexane or a mixture thereof at —120 or at room temperature, The compound represented by the general formula (XV) can be obtained. Subsequently, the cyclization is carried out in the presence of an acid such as sulfuric acid or trifluoroacetic acid, in a solvent such as water, methanol or dichloromethane, or in the absence of a solvent, at 120 ° C under heating to reflux, or boron trifluoride dimethyl. The reaction can be carried out in the presence of a Lewis acid such as an ether complex, in a solvent such as benzene or without a solvent, at a temperature other than 0 or under reflux with heating. In addition, this cyclization is carried out in the presence or absence of a base such as pyridine or triethylamine, in the presence or absence of a base such as thionyl chloride, p-toluenesulfonyl chloride or methanesulfonyl chloride and a solvent such as dichloromethane or methane or tetrahydrofuran. The reaction is carried out in a medium or solvent-free condition under-20 to reflux under heating, and then under heating and refluxing from 120 in the presence or absence of a base such as pyridine, triethylamine, dichloromethane or tetrahydrofuran. It is also possible to carry out. The obtained compound is subjected to catalytic reduction, acid or alkali hydrolysis by a conventional method, and when Z ¹⁴ is a sulfur atom, is subjected to the oxidation described in the eighth production method to obtain the compound represented by the formula (A- The compound represented by 4) can be obtained.

Production method (b)

In the above reaction formula, Y ² has the same meaning as described above. The amino compound represented by the formula (XVI) is subjected to dehydration condensation as required. The dehydration condensation can be carried out in the presence or absence of an acid such as acetic acid or a Lewis acid such as boron trifluoride dimethyl ether complex in a solvent such as benzene or toluene at room temperature or under reflux with heating. . Preferably, the reaction can be carried out using a Dian-Stark dehydrator under heating and reflux.

Cyclization is carried out in the presence of an acid such as sulfuric acid or trifluoroacetic acid, or in the presence of a Lewis acid such as boron trifluoride dodecyl ether complex, in a solvent such as methanol or dichloroethane, or without a solvent, at room temperature or by heating. _c can be carried out under reflux Further, the presence of such poly-phosphate, Celsius to 5 0 ° in a suitable solvent or without a solvent 2 0 0 ° C, preferably from ~ 1 6 0 ° in 1 0 0 Can be done in C. The resulting compound is The compound represented by the formula (A-3) can be obtained by deprotection by a conventional method.

Here, when the protecting group is a benzyl group, the deprotection is carried out using a reducing catalyst (for example, palladium carbon, palladium hydroxide carbon or Raney nickel) using a solvent such as methanol, ethanol, water or acetic acid. The reaction can be carried out in a hydrogen atmosphere of normal pressure to 5 kcm ² at room temperature to 50 ° C. to obtain the compound represented by the formula (A-3).

Production method (c)

The compound represented by the formula (XVII) is reduced. The reduction can be carried out in the same manner as in the first to third production methods. Thus, the compound represented by the formula (A-3) can be obtained. Production method (d)

In the above reaction formula, Y ⁵ is as defined above. The oxidation reaction of the compound represented by the formula (XVII) is performed by using sodium periodate, hydrogen peroxide, m-chloroperbenzoic acid or monoperoxybenzoic acid. The reaction can be carried out in a solvent such as water, methanol, ethanol, benzene, dichloromethane or dichloromethane, in the presence of an oxidizing agent such as magnesium perphthalate, at a temperature of about −28 under reflux with heating. When Y ⁵ is a protecting group, the compound represented by the formula (A-4) can be further deprotected by a conventional method to obtain a compound represented by the formula (A-4).

To isolate and purify the product from the reaction mixture obtained by each of the above production methods, Solvent extraction, concentration, recrystallization, chromatography and the like are appropriately used.

 Further, the salt of the compound of the present invention can be easily produced by subjecting the salt to a usual salt formation reaction. Industrial applications

The compound of the present invention represented by the above general formula (I) has a tachykinin receptor antagonistic action, in particular, a substance P (NK-1 receptor) antagonistic action and a Z or neurokinin A (NK-2 receptor) antagonistic action. In addition, because of its superior antagonism to previously known compounds, tachykinin-mediated diseases include diseases of the central nervous system, such as anxiety, depression, psychiatric disorders and schizophrenia; neurodegenerative diseases, such as Dementia in AIDS, senile dementia of Alzheimer's type, Alzheimer's disease, Down's syndrome, demyelinating disease, e.g., amyotrophic lateral sclerosis and other neuropathies, e.g., diabetic, AIDS, chemotherapy, etc. Disorders and other peripheral neuropathies and neuralgia: respiratory diseases, such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma: inflammatory diseases, For example, inflammatory bowel disease (IBD), psoriasis, connective tissue inflammation, osteoarthritis, and rheumatoid arthritis: allergic diseases, such as eczema, and respiratory distress: hypersensitivity diseases, such as hypersensitivity to vines; ophthalmic diseases For example, conjunctivitis, spring conjunctivitis, blood-aqueous-water barrier destruction due to various inflammatory eye diseases, increase in intraocular pressure, miosis, etc .: skin diseases such as contact dermatitis, atopic dermatitis, Measles and other eczema-like dermatitis: addiction, eg, alcoholism: somatic disease due to stress; reflex sympathetic dystrophy, eg, shoulder-hand syndrome: mood swings: unwanted immune response, eg, Diseases associated with transplant rejection and immune enhancement or immunosuppression, such as systemic lupus erythematosus; gastrointestinal disorders, such as disorders of the internal organs regulating nerves Ulcerative colitis, Crohn's disease: X-ray irradiation, chemotherapeutics, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure or Vomiting such as vomiting induced by side effects associated with the administration of various drugs; bladder dysfunction such as urinary incontinence: collagen disease, scleroderma, eosinophilia due to fascioliasis: blood due to vasodilation or contraction. It is useful for the prevention or treatment of diseases caused by abnormal flow, such as angina, migraine, and Leino's disease: pain nociception, such as migraine pain. It is for.

 (Pharmacological action)

 It was confirmed by the following test method that the compound of the general formula (I) exhibited excellent NK-1 and NO or NK-2 receptor antagonistic activity.

 (1) Method of receptor binding test

The receptor binding test was performed by the method of Burcher et al. [John Bian Jianluob Pharmacol., 1, 28, 165-17-177 (19896)] with some modifications. went. Namely, the inhibitory effect of ¹²⁵ I-Bolton-Hunter-substance P ²⁵ I-BH-SP on binding to guinea pig bladder membrane preparation (NK-1 receptor) and ¹²⁶ I-diurokinin The inhibitory effect of A ( ¹²⁵ I-NKA) on the binding to hamster bladder membrane preparation (NK-2 receptor) was examined.

 Bladder extirpated from Hartley guinea pigs or Syrian Golden hamsters were treated with 50 mM Tris-HCl containing 10% (W / V) saccharose and 1 mM EDTA (pH 7. After homogenization in 4), the obtained homogenate was spun down at 48, 0.000 g and 4 ° C for 20 minutes. The obtained pellet was suspended in 10 volumes of 50 mM Tris-HCl (pH 7.4) containing 300 mM 300 mM KCl and 10 mM EDTA, and incubated at 4 ° C for 1 hour. After incubation, the mixture was centrifuged at 48, 1000 g and 4 for 20 minutes. The obtained pellet was washed twice with 50 mM tris-hydrochloric acid (pH 7.4), and then suspended in 10 volumes of 50 mM tris-hydrochloric acid (pH 7.4). Until — stored at 80.

A 2% (/ v) membrane preparation was prepared using 0.1% serum albumin (BSA), 40 g gZm 1 cytosine, 4 g / m 1 leuptin, 4 g 1 chymostatin and 3 mM-Mn C 1 5 containing ₂ (TmM preparative squirrel hydrochloride (p H 7. 4) and in the reaction solution of the radioligand (1 X 1 0- '° M ) and 2 0 min 2 5 ° C ( ¹²⁵ I — BH — SP) or incubated for ¹²⁵ min ( ¹²⁵ 1 — NKA) The reaction was pre-treated with 0.1% polyethyleneimine or 0.5% filtered off with suction using a Luther, further, 3 mm- washed with Mn C 1 ₂ 5 0 mM Bok squirrel hydrochloride containing (PH 7. 4) 3 m 1 , the radioactivity one in the filter Ganmakau It was measured with a computer. The radioactivity in the presence of 1 // M non-radioactive ligand was regarded as non-specific binding, and the concentration (IC ₅₀ ) at which the specific binding was inhibited by ₅₀ % was calculated by pseudo-hill equation (pseudo-Hill equation). .

 (2) NK-1 receptor antagonism

Tray male guinea pigs (550-850 g) were sacrificed by head bruising and blood removal, and the ileum was removed. To prepare a specimen having a length of about 2 cm, in _{9 5% 0 2 + 5%} C 0 internal volume 1 0 m 1 in M agnus vessel containing ₂ mixed gas Ty rode solution at 37 that was bubbled It was suspended at a static tension of 1.0 g. Note that endogenous Asechiruko Li down, to remove the involvement of histamine and prostaglandin, atto port pin (5 X 1 0 one ⁶ M), Mepirami emissions ^{(5 X 1 0 - 6 M} ) and Indome evening Singh (5 X 1 0 - ⁶ M) was used including Ty r 0 de solution. It was allowed to act repeatedly - ⁽⁸ M 1 0) with 1 5 minute intervals tension from a stable to about 9 0 minutes later, Substance P. After the contraction height due to substance P became constant, various concentrations of the drug were added and the mixture was incubated for 10 minutes, and then substance P was applied again. The control was defined as the height of the two contractions immediately before the drug was added, and the inhibition rate due to the drug was determined. The ₅₀ % inhibitory concentration (IC ₆₀ ) was determined from the concentration-effect curve of the drug by the Probit method.

 (3) NK-2 receptor antagonism

Male Syrian 'Golden hamsters (150-200 g) were killed by head bruising and blood removal, and their trachea was removed. To produce a ring-shaped specimens having a width of about 5 mm, 9 of _{5% 0 2 + 5% C} 0 inner capacity 1 0 m 1 containing ₂ mixed gas Ty r 0 de solution 3 7 ° C which was bubbled Ma gnus The suspension was suspended in the tank at a static tension of 0.5 g. After the tension was stabilized, neurokinin A - it was allowed to act repeatedly (1 0 ⁷ M) in 1 5-minute intervals. After the contraction height due to lip kinin A became constant, various concentrations of drugs were added, incubated for 15 minutes, and neurokinin A was allowed to act again. The suppression rate due to the drug was determined using the shrinkage height twice immediately before the addition of the drug as a control. From the concentration effect curve of the drug, 50% inhibitory concentration rate (IC _5.) Was determined by probit preparative method.

The results of the above pharmacological tests are shown below. (1) Receptor binding test

Comparative compound A (WO 9 4 1 7 0 4 5 EXAMPL E 1 (racemic mixture))

Comparative compound B (WO 94/170 4 5 EXAMPL E 16 (racemic mixture))

(2) NK-1 receptor antagonist test

Comparative compound C (EP 5 1 2 9 0 1, EXAMP LE 2)

(3) NK-2 receptor antagonist test

 Comparative compound D (Japanese Patent Application Laid-Open No. Hei 4-26 1155, Example 70)

Based on these results, the compounds of the present invention are selective for NK-1 or NK-2 receptors. It was found to be an antagonist, and also to include those having excellent antagonism at both NK-1 and NK-2 receptors.

 In addition, excellent results were obtained in a receptor antagonism test on an isolated organ, and therefore, the compound of the present invention is useful for a disease involving the NK-1 or NK-2 receptor or both. It can be a useful prophylactic or therapeutic agent.

 For the treatment, the compound (I) of the present invention is used in the form of a pharmaceutical preparation mixed with a pharmaceutically acceptable carrier such as a commonly used organic or inorganic solid or liquid excipient. can do. Pharmaceutical preparations include capsules, tablets, pills, granules, powders, fine granules, oral solutions, suspensions, emulsions, injections, suppositories, inhalants, eye drops, eye ointments, transdermal solutions, It is prepared as an oral or parenteral preparation such as a softening agent, transdermal patch, transmucosal solution, or transmucosal patch. If desired, auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives may be included in the formulation. The dosage is a power which is appropriately determined according to the individual case in consideration of the symptoms, age of the administration subject, gender, etc., and in the case of usual oral administration, 0.01 to 100 mgZkg per adult per day, preferably The dose is about 0.1 to 1 OmgZkg, which is administered once or divided into 2 to 4 times. In the case of intravenous administration, the dose is usually in the range of 0.001 to 10 mg / kg, preferably 0.05 to 5 mgZkg, once or more per day per adult per day. Furthermore, in the case of administration by recruitment, the usual components are administered in the range of 0.001 to 10 mg kg, preferably 0.01 to 1.0 mg kg, once or more times a day per day. You.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such solid compositions, one or more of the active ingredients may be an inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium aluminate. In accordance with the usual practice, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizers such as lactose. A solubilizing agent such as glutamate or aspartic acid may be contained. Tablets or pills may be sucrose, gelatin, hydroxypropylcellulose, hydroxyp if necessary It may be coated with a film of a gastric or enteric substance such as oral propyl methylcellulose phthalate, or may be coated with two or more layers. Further, capsules made of an absorbable substance such as gelatin may be used.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, for example, purified Contains water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.

 Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, and suspensions include, for example, distilled water for injection and physiological saline. Includes insoluble solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). Good. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.

 When used as a nasal preparation, the preparation can be produced according to a method known per se. For example, small amounts of pH adjusters, preservatives or thickeners (eg, natural gums, cellulosic derivatives, acrylic acid polymers, vinyl polymers, etc.) or excipients are added.

 The intranasal preparation containing the compound of the present invention is formed into a solid, liquid or semi-solid. In the case of a solid state, the above components may be mixed to form a simple powdery composition, but may be a lyophilized product, and a particle having a particle size of about 5 to 250 microns is preferred. In the case of a liquid, an aqueous solution, an aqueous suspension or an oil suspension is preferred. In the case of semi-solid, an aqueous or oily gel or ointment is preferred.

As a method of administering a nasal formulation, in the case of a solid formulation, turnover filled with powder A method in which the cell is set in a special spraying device equipped with a needle and the needle is penetrated, thereby making small holes on the top and bottom of the capsule, and then sending air with a rubber ball to eject the powder into the true cavity. And the like. In the case of a liquid preparation, there may be mentioned a method in which the preparation is placed in a point calculation container, a spray container, or a similar container suitable for intranasal application of such a liquid, and is dropped or sprayed into the true cavity. . In the case of a semi-solid preparation, fill the preparation into a tube and attach it to the mouth of the tube at the time of administration, and administer the preparation directly into the other cavity, or take a certain amount of the preparation using a forest cavity insertion tool. Methods for administration into the true cavity can be mentioned. The dose of the compound of the present invention varies depending on the type or disease state, but the amount of the preparation is about 5 mg to 10 O mg for a solid preparation and about 0.05 ml for a liquid preparation at one time. The appropriate range is about 0.5 to 0.5 ml, and about 50 mg to 500 mg for semi-solid preparations.

 The solid preparation can be produced by a method known per se. For example, a shaping agent is put in a mixer, and a compound dissolved in a mixture of the compound of the present invention and a small amount of water or ethanol is gradually added and kneaded. Thereafter, it is dried at an appropriate temperature under vacuum, and the dried product is pulverized to obtain a solid preparation. Alternatively, water or an ethanol mixture is added to the mixed powder of the compound of the present invention and the excipient to completely dissolve the mixture, followed by freeze-drying or dehydration-drying by spray-drying, and appropriately pulverizing the dried product to obtain a solid preparation.

 Examples of the excipient include glucose, mannitol, inositol, sucrose, hydration, fructose, starch, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolyl, and the like. Don and the like.

 The liquid preparation can be produced according to a method known per se. For example, an aqueous solution for transmucosal preparation can be produced by dissolving, suspending or emulsifying the compound of the present invention in water, a buffer solution or an aqueous solution. An oily suspension for transmucosal preparation can be produced by suspending or emulsifying the compound of the present invention in an oily base.

Oily bases include, for example, sesame oil, olive oil, corn oil, soybean oil, cottonseed oil, peanut oil, lanolin, vaseline, paraffin, isoper, silicone oil, and C6-C30 fatty acids or These include esters of glycerin or alcohol, and these may be used alone or as a mixture of two or more. May be.

As a method for producing a semi-solid preparation, an aqueous or oily gel or ointment can be produced according to a method known per se. For example to prepare a transmucosal aqueous gels aqueous solution or aqueous suspension, p H adjusting agent if necessary to this is added a preservative such as _c bisects the solution, dissolving or aqueous gel base on one Disperse and moderately heat or cool to form a stable gel. An aqueous gel can be produced by dissolving the compound of the present invention in the other solution and uniformly mixing the two. The adjustment of pH in the above can be performed, for example, by adding an acid, a base, a buffer and the like during the production process of the preparation.

 Examples of the aqueous gel base include natural gums (eg, tragacanth gum, akasha gum, karaya gum, Irish moss, guaiac gum, xanthan gum, locust gum, etc.), cellulose derivatives (eg, methyl cellulose, carboxymethyl cellulose, etc.). , Acrylic acid polymer (eg, polyacrylic acid, polymethacrylic acid, etc.), vinyl polymer (eg, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, carboxypolymethylene, etc.), synthetic polysaccharide ( Examples include polysaccharide, polyglucose, polylactose, etc., starch, dextrin, pectin, sodium alginate, and proteins (gelatin, collagen). These bases may be used as a mixture of two or more kinds as appropriate.

 The oily ointment for transmucosal preparation can be produced by uniformly dispersing the compound of the present invention in a heat-melted oily base, and cooling while stirring. Examples of the oil base include the same as those described above. Preservatives may be added to the preparation. Examples of the preservatives include phenolic substances such as paraoxybenzoates, phenol and cresol, chlorobutanol, phenylethyl alcohol, and propylene glycol. Alcohols such as alcohol, benzalkonium chloride, reversible soaps such as benzethonium chloride, benzoic acid, sorbic acid, dehydroacetic acid, sulfurous acid and salts thereof, and acids such as sodium hydrogen sulfite or salts thereof. Can be. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, Production Examples of the compound (I) of the present invention will be described in detail with reference to Examples. Ma Since the novel compounds are also contained in the starting compounds used for producing the compound (I) of the present invention, production examples of the starting compounds will be described as reference examples. The compound required in the process of producing the compound of the present invention can be produced by a conventional method in the same manner as in the production method described in the present specification or in Reference Examples described later.

 The following abbreviations are used in the following Reference Examples and Examples.

 DMF: N, N-dimethylformamide

 H 0 B T; 1-hydroxybenzotriazole

 TH F; Tetrahydrofuran

 The compound of the present invention is not limited to the compounds described in the following Examples, and further includes a compound represented by the general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, a geometry thereof, and an optical structure thereof. It includes all isomers and polymorphs.

Reference Example 1: tert-butyl (earth) — N— [2- (3,4-dichlorophenyl) 1-41 (spiro [isobenzofuran 1 (3H), 4'-piperidine] 1 1'-1 Preparation of N-methylcarbamate

tert-Butyl (earth) 1 N— [2- (3,4-dichlorophenyl) -14-hydroxybutyl] 1-N-methylcarbamate (20.0 g), triethylamine (12.0 ml) ) And dichloromethane (200 ml) were added with methanesulfonyl chloride (5.55 ml) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling and then at room temperature for 2 hours. Water was added to the reaction mixture, and the product was extracted with chloroform. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Spiro [isobenzofuran-1- (3H), 4'-piperidine] (16.3 g), triethylamine (24.0 ml) and DMF (100 ml) were added to the obtained residue, and the mixture was added with 70 ml. Stirred overnight at ° C. Saline was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography (eluent; chloroform: methanol = 24: 1), and tert-butyl (earth) -N- [2- (3,4-dichlorophenol) is purified. 1- (spiryl [isobenzofuran 1 (3H), 4'-piperidine] 1'-yl) butyl] 1-N-methylcarbamate (18.7 g) Was obtained as a brown oil.

MS: m / z 5 19 C (M + H) ⁺ ]

 NMR (CD C 1) <5: 1.39 (s, 9H), 1.73 to 1.77 (m, 4H), 1.90 to 1.98 (m, 3H ), 2.26-2.38 (m, 4 4), 2.64-2.83 (m, 5Η), 2.94 to 3.49 (m, 3Η), 5 0 5 (s, 2 Η), 7.0 3 to 7.38 (m, 7 Η)

Reference Example 2: Preparation of (±) — 1 '— [3- (3,4-dichlorophenyl) -1-methylaminobutyl] spiro (isobenzofuran-1 (33), 4'-piperidine) Made

 tert-butyl (earth) 1 N— [2- (3,4-dichlorophenyl) 1 4-1 (spiro [isobenzofuran 1 (3H), 4'-piperidine] 1 1'-yl)) butyl Trifluoroacetic acid (10 ml) was added to a mixture of 1-N-methyl carbamate (1.64 g) and dichloromethane (20 ml) under ice cooling, and the mixture was cooled for 15 minutes under ice cooling. After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. A 0.5N aqueous sodium hydroxide solution was added to the obtained residue, and the product was extracted with ethyl acetate. The extract is washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (Sat) 1-1 '-[3- (3,4-dichloromouth phenyl) -14-methylaminobutyl] Spiro [isobenzofuran-1 (3H), 4'-piperidine] (1.40 g) was obtained as a pale yellow amorphous solid.

MS: m / z 4 1 8 [(M + H) +]

 NMR (CDC 1) 5: 1.8 to 2.08 (m, 6H), 2.45 to 2.6

3 (m, 7H), 2.8 u 3.04 (m, 5H), 5.06 (s.2H), 7.07 to 7.41 (m, 7H)

Reference Example 3: 1 '1-benzyl-1,4-dihydrospiro [isoquinoline 1 (2 H),

Preparation of 4'-piperidine] dihydrochloride

A mixture of phenethylamine (20.0 g) ^ 1-benzyl-4-piperidone (31.2 g) and toluene (500 ml) was stirred overnight while heating and refluxing using a Dean-Stark dewatering apparatus. After that, the mixture was concentrated under reduced pressure. The obtained residue was added to polyphosphoric acid (220 g), and the mixture was stirred overnight at 160 ° C. Pour the reaction mixture onto ice and add carbonic acid Potassium and potassium hydroxide were added sequentially to make the liquid alkaline, and the product was extracted with getyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: black form: methanol = 99: 1), 4N hydrochloric acid-dioxane solution was added, and the mixture was crystallized from ethyl acetate. The obtained crude crystals were recrystallized from methanol to give 1'-benzyl-3,4-dihydrospiro [isoquinoline-1-1 (2H), 4'-piperidine] dihydrochloride (3.23 g) ) Was obtained as colorless crystals.

Sublimation point: 202 ° C

Elemental analysis (as _{C 20 H 2S N 2 C 1} 2) (%):

Theoretical value: C = 6 5.75, H = 7.17, = 7.67, C1 = 19.44 Experimental value: C = 6 5.5, H = 7. 17, N = 7.61, C1 = 19.18 Reference Example 4: Preparation of ethyl 4-hydroxy-1-4- [2- (2-hydroxyxethyl) phenyl] piperidine-1-carboxylate

 To a mixture of 2-bromophenethyl alcohol (2.01), THF (10 ml) and dimethyl ether (10 ml), add n-butyllithium-hexane solution (1 .6.3M.12.9m1) was added and the mixture was stirred at 178 ° C for 1 hour. Add the reaction mixture to a mixture of 1-ethoxycarbone and 4-piperidone at

(1.88 g) and getyl ether (10 ml) were added, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture, brine was added under ice-cooling, and the product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent: hexane

: Ethyl acetate = 1: 1), and then crystallized from a mixture of ether and hexane to give ethyl 4-hydroxy41- [2- (2-hydroxyxethyl) phenyl] piperidine-1-carboxy. The lart (1.34 g) was obtained as colorless crystals. Melting point: 1 38 to 140

Elemental analysis (as _{C 16 H 23 N0 4) (} %):

Theoretical value: C = 6 5.5 1, H = 7.90, N = 4.77

Experimental values: C = 6 5.38, H = 7.88, N = 4.74 The following compounds were obtained in the same manner as in Reference Example 4.

Reference Example 5: Ethyl 4-hydroxy 4- (2-hydroxymethyl 4-methyl phenyl) piperidine

MS: m / z 2 9 3 (M ⁺ )

 NMR (CDC 13) δ: 1.27 (t, 3H, J = 7.0Hz), 1.87-1.89 (m, 2H), 2.00-2.0 4 (m, 2 H), 2.31 (s, 3 H), 3.25 to 3.35 (m, 2 H), 3.93-4.16 (m, 4 H) , 4.87 (s, 2H), 7.09 (s, 1H), 7.10 (d, 1H, J = 7.9Hz), 7.18 (d, 1 (H, J = 7.9 Hz)

Reference Example 6: Preparation of 1'-benzylspiro [1H-2-benzopyran-1,4'-piperidine] 13 (4H) monoone hydrochloride

 To a mixture of 2-bromodiacetic acid (10.8 g) and THF (200 ml) was added n-butyllithium-hexane solution (1.60 M, 63.0 m 1) was added and the mixture was stirred at 178 ° C. for 2 hours. To the reaction mixture was added 1-benzyl-4-piperidone (13.2 g) and THF (25 ml) at 160 ° C or lower, and the mixture was stirred at 170 at room temperature for 1 hour and then at room temperature overnight. . The reaction mixture was poured into water and washed with geetyl ether. Concentrated hydrochloric acid was added to the aqueous layer to make the liquid acidic (pH = 2), and then washed with diethyl ether. The aqueous layer was stirred for 2 hours under heating and refluxing, and a 2N aqueous sodium hydroxide solution was added thereto under ice cooling to make the liquid property alkaline (pH = 11). The product was extracted with black-mouthed form, the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, a 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was crystallized from ethyl acetate. The resulting crude crystals were recrystallized from methanol to give 1'-benzylspiro [1H-2-benzopyran-1,4'-piperidine] _3 (4H) monoone hydrochloride (1.9 0 g) were obtained as colorless crystals. Sublimation point:> 220 ° C

Elemental analysis (as _{C 20 H 22 NO 2 C 1} ) (%):

Theoretical value: C = 69.86, H = 6.45, N = 4.07, C1 = 10.3.1 Experimental value: C = 69.8, H = 6.38 , N = 4.13, C1 = 10.3.2 Reference Example 7: ethyl 3,4-dihydrospiro [1H—2-benzopyran—1,4 ' -Piperidine) Preparation of 1 1'-carboxylate

 Ethyl 4-hydroxy-4-1- [2- (2-hydroxyxethyl) phenyl] piperidine-1-carboxylate (300 mg), a mixture of pyridine (182/1) and dichloromethane (5 ml) Then, p-toluenesulfonyl chloride (214 mg) was added thereto under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture were added pyridin (821) and p-toluenesulfonyl chloride (194 mg) under ice cooling, and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water, an aqueous solution of sodium hydrogen carbonate, an aqueous solution of citric acid and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give ethyl 3,4-dihydrospiro [1H-2-benzopyran-1,4'-piperyl. Zin] 1 ′ ′-carboxylate (206 mg) was obtained as a colorless oil.

MS: m / z 2 7 5 (M ⁺ )

 NMR (CDC 13) <5: 1.31 (t, 3Η, J = 9.0Η ζ), 1.85 to 1.94 (m, 4Η), 2.84 (t, 2 Η, J = 5.4 Η), 3.20 (br, 2 Η), 3.91 (t, 2 Η, J = 5.4 Η ζ), 4.06 (br, 2 Η)

, 4.17 (q, 2 Η, J = 7.1 Η ζ), 7.0 7 to 7.1 1 (m, 2 Η), 7.13 to 7.2 1 (m, 2 Η )

 The following compounds were obtained in the same manner as in Reference Example 7.

Reference Example 8: Ethyl 5-methylspiro [isobenzofuran 1 (3Η), 4'-piperidine] 1 1'-carboxylate

MS: m / z 2 7 5 (M ⁺ )

 NMR (CDC 1) 5: 1.28 (t. 3 H, J = 7.0 Hz), 1.70 to 1.72 (m, 2 H), 1.79 to 1.8 5 (m, 2 H), 2.36 (s, 3 H) 3.1 9 to 3.2 3 (m, 2 H), 4.08 to 4.19 (m, 4 H), 5.04 (s, 2 H), 6.97 (d, 1 H, J = 8.0 Hz), 7.03 (s, 1 H), 7.08 (d, 1 H , J = 8.0 Hz)

Reference Example 9: Preparation of 1'-ethoxycarbonylspiro [benzo [c] thiophene-1 (3H) .4'-piperidine] 2,2-dioxide Ethyl spiro (benzo !: c) thiophene 1 (3H), 4'-piperidine] 1'-carboxylate (1.0 g) and 31% hydrogen peroxide solution (8001) Then, the mixture was stirred for 2 hours at TC. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline in this order. Then, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform), and 1'-ethoxycarbonylspiro [benzo [c] thiophene-1 (3H), 4'-piperidine] 2,2-dioxy (931 mg) was obtained as colorless crystals.

Melting point: 1 2 1 ~ 1 22 ° C

Elemental analysis (as _{C 15 H ia N0 4 S)} (%):

Theoretical value: C = 5 8.23, H = 6.19, N = 4.5, S = 1 0.33 Experimental value: C = 5 8.19, H = 6.13, N = 4.51, S = 10.23 Reference Example 10: 3,4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] dihydrochloride 0.3 Preparation of hydrate

1'-Benzyl-1,3-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] dihydrochloride (500 mg :), 20% palladium hydroxide monocarbon (500 mg ), Methanol (12 ml) and water (1.5 ml) were stirred under a hydrogen (3 k / cm ² ) atmosphere for 3-(TC overnight). The insolubles in the reaction mixture were filtered off. After removing the filtrate and concentrating the filtrate under reduced pressure, methanol was added to the obtained residue for crystallization, and the obtained crude crystal was recrystallized from methanol to give 3,4-dihydrospiro (isoquinoline). — 1 (2H), 4′-piperidine] dihydrochloride 0.3 trihydrate (345 mg) was obtained as colorless crystals.

Melting point:> 210 ° C (decomposition)

Elemental analysis (as _{C 13 H 20 N 2 C 12} ' over _{0.- 3 H 2 0) (%} ):

Theoretical value: C = 55.6, H = 7.40, N = 9.98, C1 = 25.27 Experimental value: C = 55.68, H = 7.22 , N = 9.94, C 1 = 2 5.07 The following compounds were obtained in the same manner as in Reference Example 10 described above.

Reference Example 11 1: Spiro [1H-2-benzopyran-1,4'-piperidine] 13 (4H) monoone hydrochloride Melting point: 235 ° C (decomposition)

Elemental analysis (as _{C 13 H ie N0 2 C 1} ) (%)

Theoretical value: C = 6 1.54, H = 6.3, N = 55, C1 = 1 3 9 7 Experimental value: C = 6 1.16, H = 6.35, N = 5 4 9, C 1 = 1 0 2 example 1 2: 3, 4 - dihydric Dorosupiro UH- 2-benzopyran one 1 _4, preparation of over piperidone Jin] hydrochloride

 Ethyl 3,4-dihydrospiro [1H-2-benzobenzopyran-1,4'-piperidine] 1 'in aqueous sodium hydroxide solution (5.0M, 2.0m1) under ice-cooling One carboxylate (190 mg) and ethanol (2 ml) were added, and the mixture was stirred overnight while heating under reflux. The reaction mixture was concentrated under reduced pressure, brine was added to the obtained residue, and the product was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 4N dioxane hydrochloride solution was added to the obtained residue, and the mixture was crystallized from a mixture of methanol and ethyl acetate. The obtained crude crystals were recrystallized from a mixture of methanol and ethyl acetate to give 3,4-dihydrospiro [1H-2-benzobenzopyran-1,4'-piperidine] hydrochloride (78 mg) as colorless crystals. As obtained.

Melting point: 229-230 ° C

Elemental analysis value (as C ₁₃ Hi ₈ NO C 1) (%):

Theoretical value: C = 65.1, H = 7.5, N = 5.84 C1 = 1.4.79 Experimental value: C = 65.16, H = 7.53, N = 5.87 C 1 = 1.4.88 In the same manner as in Reference Example 12, the following compounds of Reference Examples 13 and 14 were obtained.

Reference Example 13 3: 5-Methylspiro [isobenzofuran-1 (3H), 4'-piperidine] hydrochloride 0.1 monohydrate

Elemental analysis (as _{C l 3 H l 8 NO C} 1 · 0. 1 H 2 0) (%):

Theoretical value: C = 6 4. 6 4. H = 7.59, N = 5.8 0, C 1 = 1. 4.68 Experimental value: C = 6 4.60, H = 7 57, N = 5.81, C1 = 14.42 NMR (DMS 0- d6) δ175 (d, 2H, J = 14.1 Hz), 2.09 (dt, 2 H, J = 14.14.3 Hz), 2.32 (s, 3H), 3.07 -3.12 (m, 2H), 32 9 to 3.3 1 (m, 2 H), 4.99 9 (s , 2 H), 7.05 (d, 1 H, J = 7.3 Hz), 7.12 to 15 .5 (m, 2 H)

Reference Example 14 4: 3,4-Dihydrospiro [1H-2-benzothiopyran-1. 4'-piperidine] hydrochloride

 MS: m / z 2 19 (M +)

NMR (DMS 0- d ₆ ) <5: 1.97 (d, 2 H, J = 14.7 Hz), 2.59 (dt, 2 H, J = 1 3.8, 3. 8 Hz), 2.84 (t, 2H, J = 5.8Hz), 3.06 (t, 2H, J = 6.0Hz), 3.16-3. 28 (m, 4H), 7.16-7.21 (m, 2H), 7.28 (t, 1H, J = 7.5Hz), 7.47 (d, 1 H, J = 8.0 Hz), 8.98 (br, 1 H), 9.3 3 (br, 1 H)

Reference Example 15: Preparation of spiro [benzo [c] thiophene-1 (3H), 4'-piperidine] 2,2-dioxide 0.5 fumarate

 To a mixture of spiro [benzo [c] thiophene-1 (3H), 4'-piperidine) 2,2-dioxide (101 mg) and methanol obtained in the same manner as in Reference Example 12, fumaric acid ( 47 mg) and crystallized from methanol. The obtained crude crystals were recrystallized from methanol, and spiro [benzo [c] thiophene-1 (3H), 4'-piperidine] 2,2-dioxide 0.5 fumarate (113 mg) was removed. Obtained as colored crystals.

Melting point: 2 3 7 ~ 240

Elemental analysis (as _{C 14 H 17 N0 4 S)} ():

Theoretical value: C = 5 6.93, H = 5.80, N = 4.74, S = 10.8.6 Experimental value: C = 5 6.80, H = 5.77, N = 4.70, S = 10.8.8 Reference Example 16: Preparation of tert-butyl spiro [benzo [c] thiophen-1 (3H), 4'-piperidine) 1 1'-carboxylate

Spiro [benzo [c] thiophene-1 (3H), 4'-piperidine] (1.68 g), tritylamine (1.7 lm1) and dichloromethane (40 ml) were mixed with ice, Under cooling, di-tert-butyl dicarbonate (2.14 g) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and water and 10% aqueous citric acid were added. After sequentially washing with a solution and saturated saline, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1), and tert-butyl spiro [benzo [c] thiophene-1 (3H), 4'— Piperidine] 1'-carboxylate (1.25 g) was obtained as colorless crystals.

Melting point: 12.6-12.9 ° C

Elemental analysis (as _{C 17 H 23 N0 2 S)} (%):

Theoretical value: C = 6 6.8, H = 7.5, N = 4.59, S = 1.0.50 Experimental value: C = 6 6.8 2, H = 7.63, N = 4.51, S = 10.6.4 Reference Example 17: 1'-tert-butoxycarbonylspiro [benzo (c) thiophene-1 (3H), 4'-piperidine] 2—Preparation of oxide

 tert-Butyl spiro [benzo [c] thiophene 1 (3H), 4'-piperidine) 1'-carboxylate (1.00 g), methanol (20 ml) and ethanol (10 m 1), add sodium periodate aqueous solution under ice-cooling

(0.50 M, 6.8 m 1) and stirred at room temperature overnight. Water was added to the reaction mixture, and the product was extracted with chloroform. The extract was washed successively with a 5% aqueous solution of sodium thiosulfate and saturated saline. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1'-tert-butoxycarbonylspiro [benzo]

[C] Thiophene-11 (3H), 4'-piperidine] 2-oxide (1.17 g) was obtained as a colorless oil.

MS: m / z 3 2 2 C (M + H) +]

 NMR (CDC 1) (5: 1.50 (s, 9H), 1.58 to 1.61 (m, 1H), 1.87 to 1.92 (m, 1H) , 2.18 to 2.23 (m, 1H), 2.42 to 2.45 (m, 1H), 3.21 (br, 2Η), 4.05 (d , 1 Η. J = 20 Η ζ), 4.19 (br, 2 Η), 4.37 (d, 1 Η, J = 20 2 Η), 7.23 to 7.2 6 (m, 1Η), 7.32 to 7.37 (m, 3Η) The following compounds were obtained in the same manner as in Reference Example 17.

Reference Example 18: 3,4-Dihydrospiro [1Η-2_benzothiopyran-1.4 .'- piperidine] 2-year-old oxide MS: m / z 2 3 6 ((M + H) ⁺ )

 NMR (CDC 13) <5: 1.77 (dd, 1 H, J = 15.3, 2.3 Hz), 2.15 to 2.48 (m, 3 H), 2. 8.92 (m, 2 H), 2.97 to 3.01 (m, 1H), 3.09 to 3.13 (m, 1H), 3.18 ( dt, 1 H, J = 1 2.3, 3.0 H z), 3.25 to 3.4.4 (m, 2 H), 3.6 4 to 3.7 1 (m, 1 H) , 7.15 to 7.20 (m, 2 H), 7.2 3-7. 32 (m, 1 H), 7.47 (d, 1 H, J = 8.0 Hz )

Reference Example 19 9: tert-butyl (earth) —N— [2- (3,4-dichlorophenyl) -4-1 (3,4-dihydrospiro [isoquinolin-1 (2H), 4'- Preparation of (piperidine) -1'-yl) butyl--1-N-methylcarbamate

 To an aqueous solution of 3,4-dihydrospiro (isoquinolin-1- (2H), 4'-piperidine) dihydrochloride (539 mg) was added an aqueous solution of hydroxylated water to make the solution alkaline. The extract was washed with saturated sodium chloride solution, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 3,4-dihydrospiro [isoquinoline. 1 (2H), 4'-piperidine] was obtained.

 tert-butyl (sat) 1 N— (2- (3,4-dichlorophenyl) -4-1hydroxybutyl] 1-N-methylcarbamate (1.01 g), triethylamine (485 / To a mixture of 1) and dichloromethane (20 ml) was added methylsulfonyl chloride (2131) under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. After washing successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was mixed with the crude 3,4-dihydrospiro obtained above. (Isoquinoline 1 (2

H), 4'-piperidine], triethylamine (8071) and DMF (3m

I) was added and the mixture was stirred at 70 ° C for 4 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated saline in this order, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent; chloroform: methanol = 49: 1), and tert-butyl (earth) -N- [2- (3,4- 1- (3,4-Dihydrospiro (isoquinoline-1 (2H), 4'-pyridin) 1 1'-yl) butyl) 1 N-methyl Cyl carbamate (382 mg) was obtained as a colorless oil.

MS: m / z 5 3 2 ((M + H) +)

 NMR (CDC 1) δ: 1.40 (s, 9H), 1.55 to 1.78 (m, 6Η), 1.90 to 2.30 (m, 6Η), 2.64 to 2.76 (m, 6Η), 2.94-3.03 (m, 2Η), 3.28 to 3.5 1 (m, 2Η), 7. 0 4 to 7.20 (m, 4 Η), 7.3 1 to 7.38 (m, 3 Η)

Reference Example 20: Ethyl (Sat) —Ν— [2— (3,4-dichlorophenyl) 1-4 1 (3,4-dihydrospiro) [isoquinolin-1 1 (2Η), 4'—piperidine Preparation of 1 '-(yl) butyl) olebamate dihydrochloride

 Ethyl (sat) obtained in the same manner as in Reference Example 19— —_ [2- (3,4-dichloromouth phenyl) -14-1 (3,4-dihydrospiro [isoquinolin-1 1 (2 2), 4-N-piperidine]-1'-yl) butyl was added to 4X dioxane hydrochloride solution, and the mixture was crystallized from a mixture of methanol and ethyl acetate. The obtained crude crystals were recrystallized from a mixed solution of methanol and acetate nitrile, and ethyl (sat) 1 〔— [2— (3,4—dichloromouth phenyl) 14 1 (3,4-dihydrospiro) was recrystallized. [Isoquinoline-11 (2Η), 4′-piperidine] 1-1′-yl) butyl] Carbamate dihydrochloride was obtained as pale brown crystals.

MS: m / z 490 [(M ~ + H) ⁺ ]

NMR (DMS 0- d ₆ ) 6: I.10 (t, 3 H. J = 7.0 Hz), 2.14 to 2.30 (m, 2 H), 2.39 to 2.43 (m. 2 H), 2.79 to 2.91 (m, 4 H), 3.08 to 3.24 (m, 5 H), 3.41 (br, 2H), 3.50 to 3.56 (m, 2H), 3.67 to 3.76 (m.2H), 3.93 (q, 2H, J = 7. 0 Hz), 7.2 2 to 7.37 (m, 4 H), 7.49 to 7.5 1 (m, 1 H), 7.55 1 to 7.60 (m, 4 H) 2 H), 10.26 (br, 1 H), 10.0.4, 1 1.59 (br and 1 H together)

Reference Example 21: (±) — _ [3- (3,4-dichlorophenyl) -14-methylmethylaminobutyl] 1,3,4-dihydrospiro [isoquinoline-1 (2Η), 4 ' — Piperidine]

tert-butyl (earth) 1 N— (2— (3, 4 diphenyl phenyl) 1 4— (3,4-Dihydrospiro [isoquinolin-1- (2Η), 4'-piperidine] -11'-yl) butyl] —Ν-methylcarbamate (37 Omg) and dichloromethane (3 ml ) Was added to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and concentrated under reduced pressure. Water was added to the obtained residue, and carbonic acid hydration and hydroxylation hydration were added to adjust the liquid property to pH (pH> 12), and then the product was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to (±) —1 '-[3- (3,4-dichlorophenyl) -14-methylaminobutyl One, 3,4-dihydrospiro [isoquinolin-l 1 (2H), 4'-piperidine] (284 mg) was obtained as a pale yellow oil.

 MS: m / z 4 3 2 [(M + H) +]

 NMR (CDC 13) (5: 1.68 to 1.78 (m, 3H), 1.89 to 1.97 (m, 1H), 2.05 to 2.12 ( m, 2 H), 2.20 to 2.39 (m, 7 H), 2.66-2.90 (m, 7 H), 3.0 3 (t, 2 Η, J = 9.8 Η ζ), 7.04-7.23 (m, 4 Η), 7.30 to 7.40 (m, 3 Η) Reference Example 22: [2- (3,4-dichlorophenyl) 1-4 1 (2-formyl-1,3,4-dihydrospiro (isoquinolin-1 1 (2Η), 4'-pyridine)-1'-yl Preparation of butyl) fumarate fumarate 0.2 pentahydrate

A mixture of acetic anhydride (5 ml) and formic acid (5 ml) was stirred at 60 ° C for 1 hour. The reaction mixture was added under water cooling to ethyl (Sat) — N— (2— (3,4-dichloromouth phenol) 1-41 (3,4-dihydrospiro [isoquinolin-1- (2H), 4 '-Pyridine]-1' -yl) butyl] Carbamate (944 mg), triethylamine (400 // 1) and THF (30 ml) were added, and the mixture was stirred at room temperature overnight. . The reaction mixture was poured into water, neutralized by adding sodium hydrogen carbonate, and then the product was extracted with a chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and ethyl (earth) —N— [2- (3,4-dichlorophenyl) 1-4— (2— Formyl-13,4-dihydrospiro [isoquinolin-1- (2H) 4′-piperidine] —1′-yl) butyl] carbamate (1.00 g) was obtained. Ethyl (Sat) 1 N—C 2-(3,4-Dichloromouth phenyl) 1 4- (2—Formyl-1 3,4 —Dihydrospiro (Isoquinoline 1 1 (2H), 4'-Pi Lysine] -1'-yl) butyl] carbamate (74 mg), fumaric acid (16 mg) was added, and the mixture was crystallized from a mixture of 2-propanol and getyl ether. Was recrystallized from acetonitrile to give ethyl (Sat) 1 N— [2— (3,4-dichloromethanephenyl) —4-1 (2—formyl-1,3,4-dihydrospiro (isoquinolinyl 1 1) 2H), 4'-Piperidine] 1'-yl) butyl] Carbamethotofumarate 0.25 hydrate (50 mg) was obtained as colorless crystals.

Melting point: 166-168 ° C

Elemental analysis (as _{C 31 H 37 N S 0 7} C 1 2 · 0. 2 5 Η 2 0) (%): theory: C = 5 8. 2 6, H = 5. 9 1, N = 6 5 8, C 1 = 1 1.10 Experimental value: C = 58.11, H = 5.8 3, N = 6-59, C 1 = 1.0.93 Reference example 2 3: (±) — 1 '1 [3-(3, 4-dichlorophenyl) 1-4-methylaminobutyl] 1-2-methyl-3, 4-dihydrospiro [isoquinoline-1 (2 H), 4'-piperi Preparation of

 To a mixture of lithium aluminum hydride (400 mg) and THF (5 ml) was added ethyl (earth) —N— (2- (3,4-dichlorophenyl) — 4-— under water cooling.

(2-Formyl-1,4, -dihydrospiro [isoquinolin-1- (2H) .4'-piperidine] -11'-yl) butyl] carbamate (915 mg) and THF

(10 ml), and the mixture was stirred at room temperature for 2 hours and 20 minutes, and then under heating and refluxing for 1 hour and 30 minutes. Sodium sulfate was added to the reaction mixture under ice-cooling, and the insoluble material was removed by filtration. The mixture was concentrated under reduced pressure to give (Sat)-1 '1 [3- (3, 4-dichloromouth phenyl)-4 1 Methylaminobutyl] 1-methyl-3,4-dihydrospiro [isoquinoline

1 (2H), 4'-piperidine] (879 mg) was obtained as a pale yellow oil. MS m / z 4 4 6 [(M + H) +]

_{NMR (CD C 1 3) 5} :. 1. 6 8~1 9 6 (m, 7 H), 2. 1 8~ 2. 4 0 (m, 9 H), 2. 6 4- 2. 6 8 (m, 2 H), 2.75 5-2.84 (m, 4 H), 3.14-3.16 (m, 2 H), 3.68 to 3.7 0 (m , 2 H), 7.0 4 to 7.29 (m, 7 H) Reference Example 24: (Sat) 1-N- [2- (3,4-dichlorophenyl) -14-hydroxyloxybutyl] -1,3,4,5-trimethoxy N-methylbenzamide

 (Earth) 1 N— [2- (3,4-dichlorophenyl) -14-hydroxybutyl) —N-methylamine (50 Omg), triethylamine (1.3 lml) and dichloromethane (5 3,4,5-Trimethoxybenzoyl chloride (2.17 g) and dichloromethane (2 ml) were added to the mixture of m 1) under ice-cooling, and the mixture was stirred at room temperature for 12 hours under an argon atmosphere. Water was added to the reaction mixture, and the product was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the obtained residue, methanol (5 ml) and a 1 N aqueous solution of sodium hydroxide (10 ml) were added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the product was extracted with black form. The extract was washed successively with a 1N aqueous solution of sodium hydroxide and a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: black form: methanol = 49: 1), and (Sat) 1 N— (2- (3,4 dichloromouth phenyl) [1-Hydroxybutyl]] 1,3,4,5-trimethoxy N-methylbenzamide (582 mg) was obtained as a colorless solid.

MS: m / z 4 4 2 (M ⁺ )

 NMR (CDC 1) 5: 1.70 to 2.05 (m, 2 H), 2.65 to 2.85 (m, 3 H), 3.10 to 3.95 (m , 6H), 3.79 (s, 6H), 3.83 (s, 3H), 6.28 (s, 2H), 6.90 to 7.60 (m, 3H) The following compounds were obtained in the same manner as in Reference Example 24.

Reference Example 25: (Sat) 1N— [2- (3,4-dichlorophenyl) —4-hydroxylbutyl] 13,4-dimethoxy-1-N-methylbenzamide

MS: m / z 4 1 2 (M ⁺ )

NMR (CDC 1) δ: 1.68 to 2.05 (m, 2 H), 2.81 (br, 3 H), 3.15 to 3.80 (m, 6 H), 3.84 (s, 3H), 3.88 (s, 3H), 6.68 (d, 1H, J = 1.5Hz), 6.74 to 6.85 (m, 2H), 7.0 to 7.21 (m, 1H), 7.22 to 7.49 (m, 2H) The following compounds were prepared in the same manner as in Reference Example 46 below. Obtained. Reference Example 26 6: (Sat) 1 N—C 2— (3,4 phenyl phenyl) 1-4 Hydroxybutyl] 1 N—Methyl—3-thiophenecarboxamide

MS: m / z 3 5 7 (M ⁺ )

 NMR (CDC 1) δ: 1.84 to 2.45 (m, 3H), 2.8 to 2.97 (m, 3H), 3.11 to 3.98 (m, 3H) 5 H), 6.8 1 -7. 3 8 (m, 9 H)

 The following compounds were obtained in the same manner as in Reference Example 24.

Reference Example 27: (Sat) 1 N— [2- (4-bromophenyl) —4-hydroxyl] 1 N-methylbenzamide

MS: m / z 36 1 (M ⁺ )

 NMR (CDC 1) δ: 1.57 to 2.16 (m, 4H), 2.62 to 3.07 (m, 3H), 3.32 to 4.02 (m , 4 H), 6.79 to 7.43 (m,

9 H)

Reference Example 28: Preparation of (Sat) -I-N- [2 (3,4-dichlorophenyl) -14-hydroxylbutyl] benzamide

 (Earth) 1 al 1 — rac— 2 (3, 4 — dichloromouth phenyl) 1-41 (tetrahydro 2-viranyloxy) ptyramine (3.18 g), triethylamine (1.67 ml) and Benzoyl chloride (1.28 ml) and dichloromethane (5 ml) were added to a mixture of dichloromethane (30 ml) under ice cooling, and the mixture was stirred for 30 minutes under ice cooling and at room temperature for 4 hours. Brine was added to the reaction mixture, and the product was extracted with chloroform. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the obtained residue and methanol (24 ml) was added 4N hydrochloric acid-dioxane solution (6.0 ml) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography— (eluent: pore-form: methanol = 49: 1) to give (Sat) 1 N— [2 — (3,4-dichlorophenyl) — 4-hydroxybutyl] benzamide (3.20 g) was obtained as a colorless oil.

MS: m / z 3 3 7 (M ⁺ ) NMR (CDC 1 s) 6: 1.82-1.90 (m, 1 H), 1.98-2.06 (m, 1 H), 3.1 1 3.18 (m , 1 H), 3.48 (ddd, 1 H, J = 1 3. 7, 5.4, 2.4 H z), 3.57 (ddd, 1 H, J = 1 3.2, 5.4, 2.9 Hz), 3.72 (ddd, 1 H, J = 1 1.2, 5.9, 5.4 Hz), 3.87 (ddd, 1 H, J = 1 3.7, 6.4, 5.9 Hz),

6.24 (br, 1H), 7.09 (dd, 1H, J = 8.3, 2.0Hz),

7.35 to 7.5 1 (m, 5 H), 7.64-7.66 (m, 2 H)

Reference Example 29: Preparation of methyl (earth) 13- (4-chlorophenyl) 14-pentenoate

 To a mixture of 3- (4-chlorophenyl) 1-2-propene-1-ol (823 mg) and toluene (15 ml) was added trimethyl orthoacetate (3.73 ml) and propionic acid (3.73 ml). 36 1) were sequentially added, and the mixture was stirred for 18 hours under heating and reflux. To the reaction mixture, trimethyl orthoacetate (3.73 ml) and propionic acid (3651) were added, and the mixture was stirred with heating under reflux for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the product was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography— (eluent; hexane: ethyl acetate = 9—: 1), and methyl (±) —3— (4-chlorophenyl) 14-pentenoate was obtained. (941 mg) was obtained as a colorless oil.

MS: m / z 2 2 4 (M ⁺ )

 NMR (CDC 13) 5: 2.71 (dd, 2 H, J = 8.2, 1.8 H z), 3.6 1 (s, 3 H), 3.65-4.0 0 (m, 1 H), 4.99 (dt, 1 H, J = 7.1, 1.4 Hz), 5.13 to 5.18 (m, 1 H), 5.7 6 to 6.14 (m, 1 H), 7.0 8 7 .-- 3 4 (m, 4 H)

Reference Example 30: Preparation of (Sat) 13- (4-chlorophenyl) 14-pentene-1-ol

To a mixture of methyl (sat) 14- (4-chlorophenyl) 14-pentenoate (926 mg) and THF (15 ml), at 170 to diisobutylaluminum hydride Xanth solution (0.93 M, 10.6 m 1) Stirred for 0 minutes. A 1 N aqueous solution of ammonium chloride was added to the reaction mixture, the insolubles in the reaction mixture were removed, and the product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1), and (Sat) 13- (4-chlorophenyl) 14-pentene-1 1 —Ol (389 mg) was obtained as a colorless oil.

MS: m / z 19 6 (M ⁺ )

 NMR (CDC 1) δ: 1.26 (t, 1 H, J = 4.9 Hz), 1.87 (dd, 1 H, J = 6.1, 1.5 Hz), 1 9 7 to 2.07 (m, 1H), 3.35 to 3.71 (m, 3H), 4.95 to 5.02 (m, 1H), 5.1 2 to 5.15 (m, 1 H), 5.75 to 6.14 (m, 1 H), 7.08 to 7.34 (m, 4 H)

Reference Example 31 1: (Sat) 1 5-(tert-butyldimethylcyclohexyl)-3-(4-chlorophenyl) 1-Preparation of 1-pentene

 (Earth) 14- (4-chlorophenyl) 14-pentene-11-ol (388 mg), imidazole (198 mg) and DMF (5 ml) were mixed under ice-cooling. Tert-butyldimethylsilyl chloride (351 mg) was added, and the mixture was stirred at room temperature for 19 hours. Brine was added to the reaction mixture, and the product was extracted with getyl ether. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 19: 1) to give (Sat) 15- (tert-butyldimethylsilyloxy) 13- (4 Phenyl) -1-pentene (603 mg) was obtained as a colorless oil.

MS: m / z 3 1 1 [(M + H) ⁺ ]

 NMR (CD C 1) δ 0.00 (s, 6H), 0.88 (s, 9H), 1.77 to 2.00 (m, 2Η), 3.33 to 3.76 (m, 3Η), 4.9 to 4.98 (m, 1 1), 5.10 (br, 1Η), 5.73 to 6.1.2 (m, 1 Η) 7.06 ~ 7.3 2 (m, 4 Η)

Reference Example 3 2: (Sat) 1 5-(tert -butyldimethyloxy) 1 3-(4-1 Preparation of pentane-1 mono-ol

 (Earth) 15- (tert-butyldimethylsiloxy) 13- (4-chlorophenyl) 11-pentene (31 1 mg) and THF (1 Oml) were added to a mixture under ice-cooling. Monoborabicyclo [3.3.1] nonane-hexane solution (0.5 M, 4 ml) was added, and the mixture was stirred at room temperature for 2 hours. Ethanol (2 ml), a saturated aqueous solution of sodium hydrogen carbonate (5 ml) and a 31% aqueous solution of hydrogen peroxide (1 ml) were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, a saturated aqueous solution of sodium sulfite (20 ml) and water were sequentially added, and the product was extracted with ethyl ether. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: 1) to give (Sat) 15- (tert-butyldimethylsiloxane) 13- (4 —Chlorophenyl) pentan-1-ol (295 mg) was obtained as a colorless oil.

MS: m / z 329 [(M + H) ⁺ ]

_{NMR (CDC l 3) (5} : -. 0. 02 (s, 6 H), 0. 87 (s, 9 Η), 1 • 24 (br, 1 Η), 1. 68~1 98 (m, 4 Η), 2.88 ~ 2.93

(m, 1Η), 3.36 to 3.52 (m, 4Η), 7.1 1 (dd, 2Η, J = 6.4, 2.0Η ζ), 7.26 (dd , 2 Η, J = 6.8, 2.2.4 Η ζ) Reference Example 33: (±) — 6— (tert-butyldimethylcyclohexyl) — 4— (4-chlorophenyl) 1 1-phenyl Lou 1 Preparation of hexene

 To a mixture of oxalyl chloride (1491) and dichloromethane (10 ml), add dimethyl sulfoxide (1541) and dichloromethane (2 m

The mixture of 1) was added, and the mixture was stirred at 168 for 10 minutes. To the reaction mixture was added a mixture of (sat) 15- (tert-butyldimethylcyclohexyl) -3- (4-phenylphenyl) pentan-1-ol (285 mg) and dichloromethane (5 ml). The mixture was stirred at 168 ° C for 1 hour. Triethylamine (8451) was added to the reaction mixture, and the mixture was stirred for 30 minutes under ice cooling. A 1N aqueous solution of ammonium chloride and water were sequentially added to the reaction mixture, and the product was extracted with chloroform. The extract is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (tert-Butyldimethylcyclohexyl) -1- (4-chlorophenyl) pentylnal was obtained as a pale yellow oil.

 To a mixture of benzyltriphenylphosphonium chloride (606 mg) and THF (5 ml) was added n-butyllithium-hexane solution (1.61 M, 8071) under ice-cooling. Was added, and the mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 30 minutes. To the reaction mixture, add a mixture of the crude (Sat) 15- (tert-butyldimethylsiloxy) -13- (4-cyclopentenyl) pentanal and THF (8 ml) obtained earlier with -68. , -68 for 3 hours and then at room temperature for 11 hours. A 1N aqueous solution of ammonium chloride and water were sequentially added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 19: 1), and (Sat) — 6— (tert-butyldimethylsiloxy) -Chlorophenyl) -111-hexene (281 mg) was obtained as a pale yellow oil.

MS: m / z 4 0 1 ((M + H) ⁺ )

 NMR (CD C 1) <5: -0.03 (s, 3H), -0.02 (s, 3H), 0.86 (s.9H), 1.71-1 7 8 (m, 1 H) .1.9 9 2.00 (m, 1 H), 2.45 to 2.7 2 (m, 2 H), 2.85 to 2.92 (m, 1 H), 3.34 to 3.5 4 (m, 2 H), 5.49 (ddd, 38 H, J = l 1.7, 7.3, 6.8 Hz ), 6.03 (ddd, 5/8 H, J = 1 5.6, 8.3, 6.8 Hz)), 6.31 (d, 5Z8 H, J = 1 5.6 Hz) ), 6.38 (d, 3Z8H, J = 11.7 Hz), 7.05-7.33 (m, 9H) Reference example 34: (Sat) 1 3— ( Preparation of 4-chlorophenyl-1 6-phenyl 5-hexen-1-ol

(Earth) 16- (tert-butyldimethyloxy) 1-41- (4-chlorophenyl)-1-Phenyl-1 -hexene (270 mg) and a mixture of THF (5 ml) To this was added a tetra n-butylammonium fluoride THF solution (1 M, 0.8 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, and the resulting residue is subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = Purification by 2: 1) gave (Sat) -13- (4-chlorophenyl) -16-phenyl-5-hexene-1-1-ol (190 mg) as a colorless oil.

MS m / z 2 8 6 (M +)

 NMR (CDC 13) δ 1.16 (br, 1 H), 1.72 to 1.86 (m, 1 Η), 1.94 to 2.07 (m, 1 Η), 2.4 9-2. 7 1 (m, 2 Η),

2.8 6-2. 9 1 (m, 1 Η), 3.42-3.60 (m, 2 Η), 5.50 (ddd, 3/8 Η, J = 1 1.7 , 7.3, 4.4 Η ζ), 6.03 (ddd

, 5/8,, J = 1 5. 6, 8. 3, 7.3 ζ ζ), 6.33 (d, 5/8 Η,

J = 15.6 Η ζ), 6.40 (d, 3/8 Η.J = 11.7 Η ζ), 7.07

~ 7.34 (m, 9 Η)

Reference Example 3 5: (Sat) 1 a l l — r ac— 2— (3,4-dichloro phenyl) 1-4 1 (tetrahydro-2-biranyloxy) butyric acid

 (Earth) 1 a 1 1 1 rac— 2— (3,4-dichlorophenyl) 1-4— (tetrahydro-2-vilanyloxy) butane2tril (10.0 g) and ethanol (12.0 ml) )), A 10 N aqueous sodium hydroxide solution (160 ml) was added, and the mixture was stirred under reflux with heating for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and 1N hydrochloric acid and citric acid were sequentially added to make the liquid acidic. The product was extracted with chloroform and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (a) — a 11 — rac — 2-(3,4-dichlorophenol). 1) 4- (tetrahydro-2-vilanyloxy) butyric acid (10.6 g) was obtained as a brown oil.

 MS: m / z 3 3 3 [(M + H) +]

 NMR (DMS 0- ds) δ: 1.43 to 1.48 (m, 4H), 1.53 to 1.71 (m, 2H), 1.88 to 1.96 (m, 1 H), 2.2 1 to 2.28 (m, 1 H), 3.18 to 3.29 (m, 1 H), 3.39 to 3.75 (m , 3H), 4.45 to 4.50 (m, 1H), 7.29 to 7.33 (m, 1H), 7.56 to 7.6 1 (m, 2 H), 1 2.61 (br, 1 H)

Reference Example 36: Preparation of (sat) 1 al 1 — rac— 1 — (3,4-dichlorophenyl) 13 1 (tetrahydro 2-biranyloxy) propylamine (Earth) 1 al 1-rac-2-(3,4-Dichloromouth phenyl) 1-41 (Tetrahydroxy 2-bilanyloxy) butyric acid (5.00 g). Triethylamine (2.09 ml) and To a mixture of benzene (80 ml) was added difluorophenylazide (3.30 ml), and the mixture was stirred at 50 ° C for 1 hour. To the reaction mixture was added 9-fluorenylmethanol (5.889 g), and the mixture was stirred under reflux with heating for 5 hours. Water was added to the reaction mixture, and the product was extracted with getyl ether. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Jethylamine (50 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 2 days. The reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (eluent; gel form: methanol = 23: 2), and (sat) all-rac— 1- (3,4-Dichlorophenyl) -13- (tetrahydro-2-vilanyloxy) propylamine (2.21 g) was obtained as a brown oil.

MS: m / z 304 ([M + H) +]

 NMR (DMS 0-dβ) 5: 1.43-1.45 (m.4H), 1.56-1.61 (m, 1H), 1.69-1.8 2 (m, 3 H), 1.93 (br, 2 H) .3.2 3 to 3.4 2 (m, 2 H), 3.5 4-3.74 (m, 2 H) , 4.49 (dd, 1 H, J = 1 3.2, 4.4 Hz), 7.2 9 to 7.3 3 (m, 1 H) .7.5 2 (d, 1 H , "J = 8.3 H z), 7.60 (s, 1 H)

Reference Example 3 7: (Sat) I a l l — r ac— 3— Preparation of (1-1 (3,4-dichloropropanyl) — 3— (tetrahydro-1-2-biranyloxy) propylamino) propionanilide

 (Sat) _ al 1 — rac— 1— (3,4-dichlorophenyl) -13- (tetrahydro-2-biranyloxy) propylamine (2.20 g) and toluene (5 m 1) Was added to the mixture, and the mixture was stirred under heating and reflux for 27 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 49: 1) to obtain (sat) all—rac—3— (3, 4-diphenyl phenyl) 1 3—

(Tetrahydro-2-vinylanoxy) propylamino] propionanilide

(2.99 g) was obtained as a brown oil. MS: m / z 4 5 1 ((M + H) +)

 NMR (DMS 0-d) (5: 1.35 to 1.47 (m, 4H), 1.54 to 1.75 (m, 3H), 1.88 to 1.19 3 (m, 1 H), 2.39 (dd, 2 H, J = 6.8, 6.4 Hz), 2.5 1 to 2.5 6 (m, 2 H), 3.2 2-3.37 (m, 2H), 3.5 1-3.72 (m, 3H), 4.42-4.4.66 (m, 2H), 7.01 ( t, 1 H, J = 7.3 H z), 7.26 to 7.34 (m, 3 H), 7.5 5 to 7.60 (m, 4 H), 9.93 (br, 1 H)

Reference Example 3 8: (±) — all — rac— N— [1- (3,4-dichlorophenyl) -13- (tetrahydro-2-vinylanoxy) propyl] 1-N'-phenyl-1,3-propanediamine Preparation

 To a mixture of lithium aluminum hydride (38 O mg) and THF (20 ml) was added ice-cooled (sat) monoal 1-rac-3-[1-(3,4-dichlorophenyl). A mixture of 1-3- (tetrahydro-2-vilanyloxy) propylamino] propionanilide (903 mg) and THF (10 ml) was added, and the mixture was stirred under heating and reflux for 4 hours. An aqueous sodium hydroxide solution was added to the reaction mixture, insolubles in the reaction mixture were removed, and the product was extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then concentrated under reduced pressure to obtain (Sat) 1 a11-rac-1N— [11 (3,4—dichlorophenyl). 1)-(Tetrahydro-12-vinyl-2-propyl) -l-N'-phenyl-1,3-propanediamine (870 mg) was obtained as a pale yellow oil.

MS: m / z 4 3 7 C (M + H) ⁺ )

NMR (DMS 0- d ₆ ) δ: 1.37 to 1.46 (m, 4H), 1.53 to 1.72 (m, 5H), 1.89 to 1.19 4 (m, 1 H), 2.30 to 2.40

(m, 2 H), 2.92 to 3.04 (m, 2 H), 3.29 to 3.39 (m, 2 H), 3.5 to 3.68 (m, 2 H) 3 H), 4.44-4.48 (m, 1 H), 5.4 4 to 5.4.7 (m, 1 H), 6.47 to 6.5 2 (m, 3 H ), 7.03

(dd, 2 H, J = 8.3, 7.3 Hz), 7.2 9 to 7.33 (m, 1 H), 7.5 4 to 7.5 9 (m, 2 H)

Reference Example 3 9: (Sat) 1 all — rac— 1 1 [1 1 (3,4 dichlorophenyl) Preparation of 1-3- (tetrahydro-2-vinylanoxy) propyl] 1-2-oxo-13-phenylhexahydridopyrimidine

 (Earth) 1 all — rac— N— [1— (3,4-dichlorophenol) 1 3— (tetrahydro 2-biranyloxy) propyl] 1 N ′ —Feneru 1,3—Puppandiamin (8 Bis (trichloromethyl) carbonate (23 lmg) was added to a mixture of 53 mg), triethylamine (2.72 ml) and dichloromethane (20 ml) under ice cooling. Stirred under for 1 hour. Dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were sequentially added to the reaction mixture, and the mixture was stirred under ice-cooling for 20 minutes, and then the product was extracted with chloroform. The extract was washed sequentially with a 0.1N aqueous solution of citric acid and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 2: 1), and (Sat) 1 a 1 I—rac — 1— [1-1 (3,4-dichlorophenyl) Enyl) -13- (tetrahydro-2-viranyloxy) propyl] -12-oxo-13-phenylhexahydridopyrimidine (32 Omg) was obtained as a colorless oil.

MS: m / z 4 6 3 [(M + H) ⁺ ]

NMR (DMS 0- d ₆ ) δ 1.50 to 1.58 (m, 4H), 1.7 to 1.83 (m, 2H), 1.90 to 2.08 ( m, 2 H), 2.2 1 -2.2.27 (m, 2 H) .2.94—2.99 (m, 1 H), 3.25—3.3 2 (m, 2 H) 1 H), 3.47 to 3.56 (m, 2 H), 3.6 to 3.67 (m, 2 H), 3.8 2-3.91 (m, 2 H) , 4.58 (d, 1 H, J = 4.4 Hz), 5.87-5.90 (m, 1 H), 7.16 to 7.18 (m, 1 H ), 7.27-7.4.9 (m, 7H)

Reference Example 40: Preparation of (±) — 1— (1— (3,4-dichloromouth phenyl) -13- (hydroxypropyl) -12-oxo-13-phenylhexahydropyrimidine

(Earth) 1 al 1— rac— 1 1 [1 (3,4-dichlorophenyl) 1 3— (tetrahydro 2 _ bilanyloxy) propyl] 1 2 oxo 1 3 phenylhexahydridopyrimidine (32) 0 mg) and methanol (4 ml), 4N hydrochloric acid-dioxane solution (1 ml) was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Was. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 49: 1) to give (Sat)-1-[1-1 (3, 4 —Dichlorophenyl) -1-hydroxypropyl) -12-oxo-13-phenylhexahydropyrimidine (254 mg) was obtained as a colorless oil.

MS: m / z 3 7 8 (M ⁺ )

_{NMR (CDC 1 3) 5:} . 1. 9 5~ 2. 0 3 (m, 3 H), 2. 1 2~ 2. 2 0 (m, 1 H), 2. 7 9~2 8 5 ( m, 1 H), 3.0 to 3.07 (m, 1 H), 3.6 to 3.73 (m, 3 H), 3.77 to 3.84 (m, 1 H) ), 4.03 (dd, 1 H, J = 10.3, 3.9 Hz), 5.93 (dd, 1 H, J = 1 2.2, 3.4 Hz), 7. 2 1 7.31 (m, 4H), 7.37 to 7.40 (m, 2H), 7.44 to 7.47 (m, 2H)

Reference Example 4 1: tert-Butyl (Earth) 1 N— [2— (3,4-dichlorophenol) 1 4- (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 1 (2 H), 4'-Piperidin] 1 1'-yl) butyl] -1 Preparation of N-methyl carbamate

To an aqueous solution of 3-oxo-3,4-dihydrospiro [isoquinolin-1- (2H), 4'-piperidine] hydrochloride (5 14 mg) was added aqueous sodium hydroxide solution to improve the liquidity. It was made alkaline and the product was extracted with chloroform. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crude 3-isoquinone-3,4-dihydrospiro [isoquinolin-1- (2H), 4 ' —Piperidine).

tert-butyl (earth) — N— [2- (3,4-dichlorophenyl) 1-41-hydroxybutyl] 1-N-methylcarbamate (454 mg), triethylamine (273 / zl), To a mixture of dichloromethane (5 ml) was added methanesulfonyl chloride (111) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained is combined with the crude 3_oxo—3,4-dihydrospiro (isoquinoline-1 (2Η), 4′-pyridine) and triethylamine (5451) obtained earlier. Add DMF (2 ml) and stir at 70 ° C for 9 hours. Stirred. Brine was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 99: 1) to give tert-butyl (earth) -N- [2- (3,4-dichloromethane). Phenyl) 1-41 (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] 1 1'-yl) butyl] N-methylcarbamate (4 68 mg) as a colorless oil.

MS: m / z 5 4 6 ((M + H) ⁺ )

NMR (CDC 1 _s ) δ: 1.40 (s, 9H), 1.68 to 1.77 (m, 3H), 1.84 to 1.91 (m, 1H) , 2.13 to 2.27 (m, 6 H), 2.64 to 3.03 (m, 6 H), 3.27 to 3.5 2 (m, 2 H), 3 6 3 (s, 2 H), 6.28 (s, 1 H), 7.0 2 to 7.07 (m, 1 H), 7.16 (d, 1 H, J = 5 0 H z), 7.25 to 7.47 (m, 5 H) Reference Example 42: (±) — 1 '— [3- (3,4-dichloromouth phenyl) 1-4M Preparation of [N-butyl] -1,3-oxo-1,3,4-dihydrospiro [isoquinolin-1- (2Η), 4'-piperidine]

 tert-Butyl (earth) 1 N— [2— (3,4-dichlorophenol) 1-41 (3-oxo-1,3,4—dihydrospiro [isoquinoline 1 (2H), 4 ' Tripiloacetic acid (2 ml) was added to a mixture of 1-piperidine] -1'-yl) butyl, 1-N-methylcarbamate (444 mg :) and dichloromethane (5 ml) under ice-cooling. After stirring at ° C for 2 hours and 30 minutes, the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and sodium hydrogen carbonate and 1N aqueous sodium hydroxide solution were added to make the solution alkaline (pH> 9). The product was extracted with chloroform. did. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then concentrated under reduced pressure to give (Sat) -1'-C3- (3,4-dichlorophenyl) -14-methylaminobutyl! Oxo-1,3,4-dihydrospiro [isoquinolin-11 (2H), 4'-piperidine] (333 mg) was obtained as a colorless oil.

MS: m / z 4 4 6 ((M + H)

_{NMR (CDC 1 3) δ:} 1. 7 0 - 1. 7 8 (m, 4 H), 1. 9 Bok 1. 9 7 (m, 1 H), 2.1 2 to 2.3 3 (m, 6 H), 2.40 (s, 3 H), 2.75-2.89 (m, 5 H ), 3.63 (s, 2H), 6.40 (s, 1H), 7.06 to 7.08 (m, 1H), 7.16 (d, 1H, J = 7.5 Hz), 7.28 to 7.40 (m, 5H)

Reference Example 4 3: Preparation of (±) —5 -— (4-chlorophenyl) -1-5- (2-hydroxyxethyl) —2-piperidone

 (Earth) 1 all — rac— 5— (4-chloro phenyl) 1 5— [2- (tetrahydropyran-1-2-yloxy) ethyl] 1-2-piperidone (64 7 mg), methanol ( To a mixture of 13 ml), a 4N hydrochloric acid-dioxane solution (3 ml) was added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with hexane and concentrated under reduced pressure. A saline solution was added to the obtained residue, and the product was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and (Sat) 15- (4-chlorophenyl) -5- (2-hydroxyxetyl) -12-piperidone (3 46 mg) as a pale yellow oil.

MS: m / z 2 5 4 [(M + H)

 NMR (CDC 13) δ 1.86-1.93 (m, 1 H), 1.99 to 2.21 (m, 4 H), 2.33-2.37 (m, 1 H), 3.3 2 to 3.50 (m, 3 Η), 3.8 1 to 3.8.4 (m, 1 Η), 6.49 (br, 1 Η), 7.2 0 to 7.28 (m, 2 Η), 7.33-7.37 (m, 2 Η)

Reference Example 4 4: Preparation of (±) _3— (4-chlorophenyl) -13- (2-hydroxyphenyl) piperidine

(Sat) 5- (4-Chlorophenyl) -5- (2-Hydroxitytyl) 1-2-Piperidone (302 mg) and THF (3ml) in a mixture of borane and THF under ice cooling A complex-THF solution (1.0 M, 3.6 m 1) was added, and the mixture was stirred overnight while heating under reflux. The reaction mixture was concentrated under reduced pressure, and ethanol (10 ml) and a 1N aqueous hydrochloric acid solution (5 ml) were added to the obtained residue, followed by stirring at 80 ° C for 4 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the obtained residue, and the product was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give (Sat) 13- (4-chlorophenyl)- 3- (2-Hydroxityl) piperidine (227 mg) was obtained as colorless crystals. MS: m / z 240 ((M + H)

 NMR (C D C 1) δ 1.50-1.56 (m, 1 H), 1.68-1.

7 1 (m, 1 H), 1.85 to 1.95 (m, 4 H), 2.72 to 2.77 (m, 1 H), 2.86 to 2.91 (m, 1 H), 3.06 (d, 1 H, J = 13 Hz), 3.15 (d, 1 H, J = 13 Hz), 3.40-3. 5 5 (m, 2 H), 7.26 to 7.3.5 (m, 4 H)

Reference Example 4 5: Preparation of (±) — 3-— (4-chlorophenyl) -13- (2-hydroxyl) -111 ((3-isopropoxyphenyl) acetyl] piperidine

 (Sat) 13- (4-chlorophenyl) 1-3- (2-hydroxyxethyl) piperidine (220 mg), 3-isopropoxyphenylacetic acid (374 mg), HOBT (26 To a mixture of 0 mg) and dichloromethane (5 ml) was added 11- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (370 mg) under ice-cooling, followed by stirring at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate, a 1N aqueous solution of hydrochloric acid, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol: = 49: 1), and (Sat) -3- (4-chlorophenyl) 13- (2-hydroxyxethyl) One [(3-isopropoxyphenyl) acetyl] piperidine (336 mg) was obtained as a colorless oil.

MS m / z 4 1 6 ((M + H)

 NMR (CDC 1) (5: 1.30 (d, 6 H, J = 6.4 Hz)), 1.33 to 1.43 (m, 2 H), 1.66-2. 0 1 (m, 5 H) .3.3 to 3.49 (m. 4 H), 3.65 (s, 2 H), 3.70 to 3.79 (m, 4 H) , 4.03 to 4.06 (m, 1H), 4.46 to 4.52 (m, 1H), 6.66 (d, 1H, J = 7.6Hz ), 6.73 to 6.75 (m, 2H), 7.11 7.16 (m, 1H), 7.29 to 7.34 (m, 4H)

Reference Example 46: Preparation of (Sat) -I-N- [2- (3,4-dichlorophenyl) -I-4-hydroxybutyl] _4-Methoxymethoxyethoxy N-methylbenzamide (Earth) 1 N— [2- (3,4-dichlorophenyl) -14-hydroxybutyl) 1-N-methylamine (789 mg), 4-methoxymethoxybenzoic acid 695 mg), HOBT To a mixture of (516 mg) and DMF (3 Oml) was added 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride (731 mg) under ice-cooling, followed by stirring at room temperature overnight. Water was added to the reaction mixture, the product was extracted with ethyl acetate, and the extract was washed successively with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethanol (20 ml) and 1N aqueous sodium hydroxide solution (6.5 ml) were added to the obtained residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, brine was added to the obtained residue, and the product was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and (Sat) —N— [2- (3,4-dichlorophenyl) -14-hydroxoxybutyl] -14 1-Methoxymethoxyl-N-methylbenzamide (87 Omg) was obtained as a pale yellow oil.

MS: m / z 4 1 2 [(M + H) ⁺ ]

 The following compounds were obtained in the same manner as in Reference Example 46.

Reference Example 4 7: (±) — 3— (3,4-dichloromethane) 1—3— (2-hydroxyshetyl) 1— (3—imidazo [1,2—a] pyridylcarbonyl ) Pigeon

 MS: m / z 4 18 ((M + H) +)

 NMR (CDC 1) δ 1.62 to 2.01 (m, 6H), 2.16 to 2.21 (m, 1H), 3.38 to 3.46 (m, 2 Η), 3.7 4 to 3.78 (m, 1 Η), 3.88 (d, 1 Η, J = 1 3.4 Η Η), 3.93 to 3.98 ( m, 1Η), 4.37 (d, 1Η, J = 13.5 5Η), 6.95 (t, 1Η, J = 7.0 0Η), 7.16 ~ 1 9 (m, 1Η), 7.32-7.37 (m, 2Η), 7.47 (s, 1Η), 7.67 (d, 1Η, J = 9.2 Η), 7.8 2 (s, 1 Η), 8.8 1 to 8.8 3 (m, 1 Η)

Reference Example 4 8: Preparation of (±) —3— (3,4-dichloromouth phenyl) -13- (2-hydroxyshetyl) -11- (3,4,5-trimethoxybenzoyl) piperidine (Sat) 1 3— (3,4-dichloromouth phenyl) 1 3— (2—Hydroxyshetil) To a mixture of piperidine (274 mg), triethylamine (340/1) and dichloromethane (5 ml) was added 3,4,5-trimethoxybenzoyl chloride (6 ml) under ice-cooling. (0.6 mg) and stirred at room temperature for 3 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate, a 1N aqueous solution of hydrochloric acid, and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained residue, methanol (5 ml) and a 1N aqueous solution of sodium hydroxide (2 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, brine was added to the obtained residue, and the product was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 49: 1) to give (Sat) 13- (3,4-dichloromouth phenyl) 13- (2- (Hydroxitytyl) 111 (3,4,5-trimethoxybenzoyl) piperidine (32 mg) was obtained as a colorless oil.

MS m / z 4 6 8 ((Μ + Η) ⁺ )

 NMR (CD C 13) (5: 1.42 to 1.75 (m, 2H), 1.81 to 2.08 (m, 3H), 2.09 to 2.1 8 (m, 1 H), 3.30 to 3.5 5 (m, 4 H), 3.7 1 -3.95 (m, 1 1 H), 4.10 0 to 4.29 (m, 1 H), 6.48 (s, 2 H), 7.2 u 7.40 (m, 1 H), 7.40-7.5.58 (m, 2 H)

Reference Example 49 9: Preparation of ethyl 4-hydroxy 2- [2_ (2_mercaptoethyl) phenyl] piperidine-1 1-caprolepoxylate

To a mixture of 2-bromophenylthiol (1.45 g), THF (10 ml), and ethyl ether (20 ml), add n-butyllithium hexane at 100 ° C or lower. The solution (1.66M, 8.5 ml) was added and stirred at —100 ° C. for 1 hour. To the reaction mixture was added 1-ethoxycarbonyl 4-piperidone (1.71 g) at −90 ° C. or lower, and the mixture was stirred at 100 ° C. for 3 hours. After treatment and purification, ethyl 4-hydroxy41- [2- (2-mercaptoethyl) phenyl] piperidine-11-carboxylate (505 mg) was obtained as a colorless oil. MS: m / z 3 10 [(M + H) ⁺ ] Reference Example 50: Ethyl 3,4-dihydrospiro [1H-2-benzothiopyran

Preparation of 1,4'-piperidine] 1 1'-carboxylate

 Ethyl 4-hydroxy 4- [2- (2-mercaptoethyl) phenyl] piperidine-111-carboxylate (488 mg) and dichloromethane (5 ml) were added to a mixture of trifluoroacetic acid under ice-cooling. (2 ml) was added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into ice, neutralized with sodium bicarbonate, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give ethyl 3,4-dihydrospiro.

(1H-2-benzothiopyran-1,4'-piperidine) 1'-carboxylate (414 mg) was obtained as a colorless oil.

MS: m / z 29 2 [(M + H) +]

 NMR (CDC 13) δ: 1.29 (t, 3 H, J = 7.3 Hz), 1.90 (d, 2 H, J = 13.5 Hz), 2.18 (dt, 2 H, J = 1 3.5, 4.3 Hz), 2.82 (t, 2 H, J = 6.0 Hz), 3.13 (t, 2 H, J =

6.0 Hz), 3.32 to 3.38 (m, 2H), 4.10 to 4.19 (m, 4H), 7.11 to 7.17 (m , 2 H), 7.2 2 (t. 1 H, J = 6.7 Hz),

7.3.4 (d, 1 H, J = 8.0 Hz)

 The following compounds were obtained in the same manner as in Reference Example 46.

Reference Example 51 1: (±) — 1— [3,5-bis (trifluoromethylphenyl) acetyl] 13— (3,4-dichloromethylphenyl) 13— (2—h Droxitytil) piperizine

 MS: m / z 5 2 8 [(M + H) +]

 NMR (CDC 13) 5: 1.40 to 2.40 (m, 6 H), 3.37 to 3.56 (m, 5 H), 3.80 (d, 1 H, J = 15.3 Hz), 3.83 (d, 1 H, J = 15.3 Hz), 4.31 (d, 1 H, J = 14.5 Hz), 7 20-7.44 (m, 3H), 7.64 (s, 2H), 7.77 (s, 1H)

 The compounds of Reference Examples 51 to 54 were obtained in the same manner as in Reference Example 24.

Reference Example 5 2: (Sat) 1 N— [2- (4-chlorophenyl) 1-4 Hydroxypuchi 1] N-methylbenzamide

MS: / z 3 1 7 (M ⁺ )

 NMR (CDC 1) (5: 1.80-2.03 (m, 2H), 2.68.3.02 (both s, 3H in total), 3.29-3. 3 8 (m, 1 H), 3.45 to 3.6 (m, 2 H), 3.64 to 3.73 (m, 1 H), 3.93 to 4.0 1 (m, 1 H), 7.07 to 7.39 (m, 9 H)

Reference Example 5 3: (Sat) 1 N- [4-hydroxy-2-((4-trifluoromethylphenyl) butyl]] 1 N-methylbenzamide

MS: m / z 35 1 (M ⁺ )

 NMR (CD C 1) (5: 1.77 to 2.06 (m, 2H), 2.69, 3.05 (both s, 3H in total), 3.12 to 3 7.6 (m, 4 H), 3.94 to 4.04 (m, 1 H), 6.98-7.67 (m, 9 H)

Reference Example 5 4: (Sat) 1 N— [4-hydroxy 2 _ (2-naphthyl) butyl] 1 N-methylbenzamide

MS: m / z 3 3 3 (M +)

 NMR (CDC 1) δ 1.77 to 2.13 (m, 2H), 2.63, 3.04 (both s, 3H in total), 3.19 to 3.40 (m, 1 H) .3.4 5-3, 75 (m, 1 H), 4.12 to 4.20 (m, 1 H), 6.95 to 7.8.8 (m , 1 2 H)

Example 1: (Sat) 1 1'- 2-[1-Benzyl-3_ (3, 4-dichloromethyl) 1-3-pyrrolidinyl] ethyl] spiro [isobenzofuran 1 (3H),

Preparation of 4'-piperidine] hydrochloride

(Sat) 1- 1-benzoyl-3- (3,4-dichlorophenyl) _3- (2-hydroxyxethyl) pyrrolidine (555 mg), triethylamine (3201) and dichloromethane (1 0 ml) was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Spiro [isobenzofuran-1- (3H), 4'-piperidine] (347 mg :), triethylamido (640 ml) and DMF (2 ml) were added, and the mixture was stirred at 70 ° C for 6 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: black form: methanol: methanol water = 490: 0: 10: 1), 4N dioxane hydrochloride solution was added, and ether was added. After solidification, (Sat) 1 1 '-[2- (1-benzoyl-3- (3-, 4-dichlorophenyl) -13-pyrrolidinyl] ethyl] spiro [isobenzofuran-1 (3H;), 4′-Piperidine] hydrochloride (317 mg) was obtained as a pale red amorphous solid.

MS: m / z 5 3 5 [(M + H) ⁺ ]

_{NMR (DMS O - d e)} 6:. 1. 7 5 - 1. 8 2 (m, 2 H), 2. 1 6~ 2 4 4 (m, 6 H), 2. 6 7 ~ 3. 1 2 (m, 3 H), 3.35 to 3.5 1 (m, 5 H), 3.7 to 3.77 (m, 2 H), 5.0 1 (d, 1 H, J = 8.8 Hz), 7.13 ~ 6.68 (m, 12 H), 10.6.6, 10.0.88 (both br and 1 H in total)

 The compounds of Examples 2 to 8 were obtained in the same manner as in Example 1. Example 2: (±) —1 ′ — [2— [3— (3,4-dichlorophenyl) 111] ((3-isopropoxyphenyl) acetyl] -13-piperidyl) ethyl] Nzofuran 1 (3H), 4-piperidine] oxalate hydrate MS: m / z 6 2 1 [(M + H) +]

Elemental analysis value (as C ₃₈ H ₄₄ N ₂ Οτ C 12 H ₂₀ ) ():

Theoretical value: C = 6 2.55, H = 6.35 N = 3.84, C 1 = 9.7 2 Experimental value: C = 6 2.47, H = 6.25 N = 3.76, C1 = 9.89 Example 3: (±)-1 '1 [2-[3-(3,4-dichloromouth phenyl) 1 1 1 [(3-isopropoxyphenyl ) Acetyl] —3-Piperidyl] ethyl] 1-3,4—Dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] dihydrochloride Melting point: 220 ° C (decomposition)

Elemental analysis (as _{C 37 H 47 N 3 0 2} C 1 4)

Theoretical value: C = 6 2.80. H = 6.69, N = 5.94, C1 = 20.0.04 Experimental value: C = 6 2.61, H = 6.65, N = 5.89, C1 = 1.9.98 Example 4: (±) — 1 '— (2— [3— (3,4—Dichlorophenyl) 1 1 1 (3—imidazo (1,2—a) pyridylcarbonyl) 1—3-pyridyl] ethyl] -3,4-Dihydrospiro [isoquinolinyl 1 (2 H), 4'-Piridine] 2 fumarate 0.5 pentahydrate

Melting point: 15 3 to 15 8 ° C

Elemental analysis (as _{C 42 H 45 N 6 0 9} C 1 2 · 0. 5 Η 2 0) (%):

Theoretical value: C = 59.7, H = 5.50, N = 8.30, C1 = 8.40 Experimental value: C = 59.93, H = 5.78 N = 8.09, C1 = 8.445 Example 5: (±) —1 ′ — [2— [1 — ([3,5-bis (trifluoromethyl) phenyl] acetyl] 13— ( 3,4-dichlorophenyl-1-3-piperidyl) ethyl] 1,3,4-dihydrospiro [isoquinolin-1- (2H), 4'-piperidine] difumarate 0.5 pentahydrate

Melting point: 14 3 ~ 1 45 ° C

Elemental analysis _{(C 44 H 45 N 3 0} 9 F 6 C 1 2 - as _{0. 5 H 2 0) (%} ):. Theoretical: C = 55. 4 1, H = 4 8 6, N = 4 4 1, F = 11.95, Cl = 7.43 Experimental value: C = 55.32, H = 4.64, N = 4.40, F = 12.03, Cl = 7.22 Example 6: (±) -1 '-[2_ [3- (3,4-dichlorophenyl)-1-] [(3-isopropoxyphenyl) acetyl] _3-hyperidyl] Ethyl] Spigot [Benzo [c] thiophene 1 (3H), 4'-piperidine] 2-

 MS: m / z 65 3 [(M + H) +]

NMR (DMS O-de) δ: 1.03 to 1.07 (m, 1H), 1.19 to 1.25 (m, 6Η), 1.36 to 1.74 (m, 5Η), 2.00-2.20 (m, 7Η), 2.6 to 3.26 (m, 5Η), 3.54-3.77 (m, 4Η) 3.93 (d, 1 Η, J = 17.2 Η ζ), 4.4 4 to 4.5 7 (m, 2 Η), 6.60 to 6.83 (m, 5 ), 7.06, 7.19 (both t, 1 Η, J = 8.0 Η ζ), 7.33 to 了. 37 (m, 4 Η), 7.42 to 7. 64 (m, 3 3) Example 7 _: (±) — 1 '— [2— [3— (3,4 dichlorophenyl) —1— (3,4,5—trimethoxybenzoyl) 1-3-piperidyl] ethyl] 1,3,4 — Dihydrospiro [isoquinoline 1 (2Η), 4'-piperidine] fumarate Melting point: 194-—195 ° C

Elemental analysis (as _{C S6 H 43 N 3 0 4} C 1 2)

Theoretical value: C = 6 2.50.H = 6.16, N = 5.47, C1 = 9.22 Experimental value: C = 62.21, H = 6.11, = 5.46, C 1 = 9.20 Example 8: (±) — 1 '— [2— [3— (4-chlorophenyl) -1 1 — [(3-isopropoxyphenyl) acetyl] 1 3-Piperidyl] ethyl] 1,3,4-dihydrospiro [1H-2-benzobenzopyran-1,4'-piperidin] fumarate MS: m / z 601, ((M + H)

NMR (DMS 0- d ₆ ) 5: 1.2 1 (d, 6 H, J = 6.OH z), 1.45-1.84 (m, 6 H), 1.97 to 2 0 0 (m, 3H), 2.1-4-2. 21 (m, 1 H), 2.37-2.46 (m, 2 H), 2.71 to 2.80 (m, 4H), 3.06 to 3.46 (m.4H), 3.66—4.16 (m, 6H), 4.46 to 4.52 (m , 1 H), 6.59 (s, 2 H), 6.60 to 6.82 (m, 3 H), 7.07 to 7.2 0 (m, 5 H), 7. 3 3 ~ 7.4.8 (m, 4 H) ―

Example 9: (±) —1 ′ 1 [2— [3— (3,4-dichlorophenyl) 1 1! : (3-Isopropoxyphenyl) acetyl] 1-3-piperidyl] ethyl] 1 '(a)-Methyl-3,4 dihydrospiro [isoquinolin-1 1 (2H), 4'-piperidinium] iodide Preparation of salt

(±) — 1 '— [2— (3— (3,4 diphenyl phenyl)) 1 1— ((3—sopropoxyphenyl) acetyl: Γ1 3—piperidyl] ethyl] 1 3, 4— To a mixture of dihydrospiro [isoquinolin-l 1 (2H), 4'-piperidine] (234 mg) and acetonitrile (2 ml) was added methyl chloride (231). The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; eluent: medium: 24: 1) to give (±) — 1 '_ [2— [3— (3,4-dichloromouth phenyl) 1 1 1 1 ((3 -Isopropoxyphenyl) acetyl-1-3-piperidyl] ethyl] 1-1 '(a) -methyl-1.3.4-dihydrospiro (isoquinolin-1 1 (2H), 4'-pyridinium) The iodide salt (12 Omg) was obtained as a pale yellow oil.

MS: m / z 6 4 8 [(M-I) ⁺ ]

NMR (CDC 1) δ 1.27 (dd, 6 H. J = 6.0, 1.5 H z), 1.55-1.61 (m, 4 H), 1.79- 1.85 (m, 3 H), 2.0 4-2.10 (m, 1 H), 2.27 to 2.42 (m, 4 H), 2.73 (t, 2 H, J = 1 2 H z), 2.94-3.05 (m, 3 H), 3.17 to 3.5 2 (m, 9 H), 3.74 (d, 1 H, J = 15 Hz), 3.86 (d, 2 H, J = 15 Hz), 4.42 (d, 1 H, J = 13 Hz), 4.4 9 to 4.54 (m, 1H), 6.74-6.80 (m, 3H), 7.08 (d, 1H, J = 7.0Hz), 7. . 1 6-7 2 2 (m, 4 H), 7. 3 6 - 7. 5 0 (m, 3 H), 3 C -NMR (CDC 1 3) (5: 4 4. 5 8 (N + - to obtain a CH ₃ (ax)) follows in the same manner as in example 9 compound.

Example 10 0: (±) — 1 ′ —benzyl-1 ′ — [2— [3— (3,4-dichlorophenyl) 1-1 — [(3-isopropoxyphenyl) acetyl] -13-piberidyl 1) 3,4-Dihydrospiro [isoquinolin-1 (2H), 4'-piperidinium] bromide hydrate

MS: m / z 7 2 4 C (M-B r) ⁺ ]

Elemental analysis (as _{C 44 H 52 N 3 0 2} B r C 1 · Η 2 0) (%)

Theoretical value: C = 64. 1 6. H = 6.61, N = 5.10, Br = 9.70. Cl = 8.61 Experimental value: C = 63.97, Η = 6.8 2, Ν = 5.0 6, Br = 9.8 1, Cl = 8.5 8 Example 1 1

Compound A: (Sat) — 1 '— (2— [3— (3,4-dichlorophenyl) —1 — [(3-isopropoxyphenyl) acetyl] -1-3-pyridyl] Etil] ichi 1

'(a) —Methyl-3-oxo-1,3,4-dihydrospiro [isoquinolin-1 1 (2H), 4'-pipidine diadium] Preparation of iodide salt hydrate

After performing the same reaction as in Example 9, the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; chloroform: methanol). = 24: 1) and purified by (Sat) 1 1 '1 [2-[3-(3,4-dichlorophenyl) 1 1 1 [(3-isopropoxyphenyl) acetyl] 1 3 —Piperidyl] ethyl] 1 1 '(a) —Methyl-3-oxo-1,3,4-dihydrospiro [isoquinolin 1 (2H), 4'-piberidinium] iodide salt hydrate (1 19 mg) as a pale yellow solid.

MS: m / z 662 [(M-I) ⁺ ]

Elemental analysis (as _{C 38 H 4e N 3 O s} C 1 I · Η 2 0) ()

Theoretical values: C = 56.4 4, H = 5.9 8, N = 5.2 0, CI = 8.7 7, 1 = 15.6 9 Experimental values: C = 56.58, H = 5.8 1, N = 5.17 , CI = 8.6 3, 1 = 15.6 9 ¹⁸ C-NMR (CDC 1) δ: 4 4.48 [N ⁺ -CH ₃ (ax)]

Compound B: (±) — 1 '1 [2-[3-(3.4-dichloromethyl) phenyl] 1-1 ((3-isopropoxyphenyl) acetyl] 1-3-piperidyl] ethyl] 1 1' (e) -Methyl-3-oxo-1,3,4-dihydrospiro [isoquinolin-1- (2H), 4'-piperidinim] iodide salt 1.Preparation of pentahydrate

 After Compound A was eluted, change the eluate of the silica gel column chromatography to chromatoform: methanol = 23: 2 and (Sat) 1 1 '1 [2— [3— (3,4 Phenyl) 1 1-[(3-isopropoxyphenyl) acetyl] 13 -piperidyl] ethyl] 1 1 '(e)-methyl-3 -oxo 1 3, 4-dihydrospiro [isoquinoline 1 ( 2H), 4'-Piperidinium] Iodide salt 1.5 hydrate (171 mg) was obtained as a pale yellow solid.

MS: m / z 66 2 [(M-I) ⁺ ]

Elemental analysis (as _{C 38 H 4S N 3 Os C} 1 2 I · 1. 5 H 2 0) (%)

Theoretical value: C = 55.82, H = 6.04, N = 5.14, Cl = 8.67, I = 15.52 Experimental value: C = 55.76, H-5.8 4, N = 5. 1 6, Cl = 8.7 7, I = 15. 8 1, 3 C-NMR (CDC 1) δ: 5 2. 8 7 (N + - CH 3 (eq) ]

Example 12: (±) —1′-one [2- [3- (3,4-dichlorophenyl) 1-111] [2- (3-isopropoxyphenyl) ethyl] -13-piperidyl Preparation of 1,3-dihydrospiro [isoquinolin-1- (2H) .4'-piperidine] fumarate (Sat) _ 1 '1 [2-[3-(3,4-dichlorophenyl) 1-1 [(3-sopropoxyphenyl) acetyl] 1-3-piperidyl] ethyl] 1 3. To a mixture of 4-dihydrospiro (isoquinolin-1- (2H), 4'-piperidine) (106 mg) in THF (1 ml) was added a borane-THF complex-THF solution (1.OM, lml) and stirred for 2 hours 30 minutes at 60 ° C. After concentrating the reaction mixture under reduced pressure, ethanol (5 ml) and a 1N aqueous hydrochloric acid solution (2.5 ml) were added. Water was added to the reaction mixture, and the mixture was adjusted to PHI 2 with a 1N aqueous sodium hydroxide solution and extracted with chloroform.The extract was washed with saturated saline, and the organic layer was sulfuric anhydride. After drying over magnesium, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; : Methanol: Ammonia water = 98: 2: 0.0 1) After purification, fumaric acid (17 mg) and methanol (1ml) were added, and the mixture was concentrated under reduced pressure. After addition of 5 ml), the mixture was concentrated under reduced pressure, and (Sat) 1 1 '1 [2-[3-(3,4-dichlorophenyl) 1 1 1 [2-(3-isopropoxy) Nyl) ethyl] -13-piridyl] ethyl] 13,4-dihydrospiro [isoquinolin_1 (2H) .4'-piperidine] fumarate (74 mg) was obtained as a colorless solid. MS: m / z 620 C (M + H) ⁺ ]

NMR (DMS 0- d ₆ ) δ 1.04 (d, 3 H, J = 5.9 Hz), 1.23 (d, 6 H, J = 6.4 Hz), 1.28 Up to 1.36 (m, 1 H), 1.55 to 1.74 (m, 4 H), 1.84 to 1.92 (m, 2 H), 2.06 to 2.12 (m , 3 H), 2.30 ~ 2.47 (m, 4 H), 2.55 ~ 2.59 (m, 2 H), 2.69 ~ 2.8 1 (m, 5 H), 2. 90 ~ 2.92 (m, 4 H), 4.52 ~ 4.58 (m, 1 H), 6.58 (s, 2 H), 6.72 ~ 6.79

(m, 3 H), 7.04 to 7.2 1 (m, 5 H), 7.38 (dd, 1 H, J = 8.8, 2.0 Hz), 7.50 (d, 1 H, J = 8.3 Hz), 7.63 (d, 1 H, J = 2.0 Hz)

 The structural formulas of the compounds of Examples 1 to 12 are shown in Tables 1 (1) to (3).

Example 13 3: (Sat) 1 N— [2- (3,4-dichlorophenyl) 1-4-spiro

(Isobenzofuran-1 (3H), 4'-piperidine) -1'-yl) butyl Preparation of —N-methylbenzamide

 (Earth) 1 N— [2- (3,4-dichlorophenyl) -4-hydroxybutyl] —N-methylbenzamide (233 mg), tridimethylamine (1381), and dichloromethane ( Methanesulfonyl chloride under ice-cooling.

(64.01) was added, and the mixture was stirred at room temperature for 50 minutes. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Spiro [isobenzofuran 1 (3H), 4'-piperidine] (138 mg), triethylamine (27761) and DMF were added to the obtained residue.

(5 ml) was added and the mixture was stirred at 70 for 4 hours. Ethyl acetate was added to the reaction mixture, which was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (eluent: chloroform: methanol: aqueous ammonia = 490: 0: 10: 1) to give (Sat) —N— (2— (3,4 1- (Spiro [isobenzofuran — 1 (3H), 4'-piperidine] 1'-yl) butyl] 1 N-methylbenzamide (156 mg) as pale yellow oil Obtained as a product.

MS m / z 5 2 3 ((M + H) +)

 NMR (CDC 13) (5: 1.74-1.95 (m, 6H), 2.15 to 2.34 (m, 4H), 2.65 to 2.8 1 (m, 4 H), 3.0 2 to 3.89 (m, 4 H), 5.05 (s, 2 H), 7.1 4 to 7.4 2 (m, 12 H)

 The compounds of Examples 14 to 16 were obtained in the same manner as in Example 13.

Example 14: (Sat) 1N— (2- (4-chlorophenyl) -14_ (spiro [isobenzofuran-1 (3H), 4′-piperidine) -11′-yl) butyl] 1N — Methylbenzamide hydrochloride

MS: m / z 4 8 9 (M ⁺ )

NMR (DMS 0- d ₆ ) <5: 1.73-2.45 (m, 6H), 2.57-3.78 (m, 12H), 5.03 (s , 2 H), 6.93 to 7.5 5 (m, 13 H)

Example 15: (Sat) 1 N-methyl-1 N- (4-1 (spiro [isobenzofuran-1 (3H), 4'-piperidine) -11'-1yl) 1-2- (4-trifur Oromethyl Phenyl) butyl] benzamido fumarate

Melting point: 1 7 9

Elemental analysis (as _{C S6 H 37 N 2 0 6} F 3) ():

Theoretical value: C = 6 5.82, H = 5.84, N = 4.39, F = 8.92 2 Experimental value: C = 6 5.76, H = 5.87, N = 4.38, F = 8.72 Example 16: (Sat) -N-methyl-N- (2- (2-naphthyl) -14- (spiro [isobenzofuran-1 (3H) , 4'-piperidine] 1 1'-yl) butyl] benzamido fumarate

Melting point: 16 4 to 16 5 ° C

Elemental analysis (as _{C 38 H 40 N 2 0 6} ) (%):

Theoretical value: C = 73.5 3. H = 6.50, N = 4.51

Experimental values: C = 7 3.3 1, H = 6.6 2, N = 4.44

Example 17: (Sat) 1 N— [2— (3,4 diphenyl phenyl) 1-41 (spiro (isobenzofuran 1 (3H), 4′-piperidine) 1 1′—yl) [Putyl] mono-N-methylpicolinin amide dihydrochloride

 (Sat) 1-1 — [3 — (3,4-dichlorophenyl) -14-methylaminobutyl) spiro [isobenzofuran-1 (3H), 4'-piperidine] (160 mg) To a mixture of triethylamine (1861-1) and dichloromethane (5 ml) was added picolinoyl chloride hydrochloride (102 mg) under ice-cooling, followed by stirring at room temperature for 2 hours. Brine was added to the reaction mixture, and the product was extracted with black hole form. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: chloroform: methanol = 24: 1), and thereto is added a 4N hydrochloric acid-dioxane solution, and the mixture is solidified from ethyl ether to give (Sat.) — N— [2— (3,4-dichlorophenyl) -14- (spiro [isobenzofuran-1 (3H), 4'-piperidine] 1 1'-yl) butyl] -1-N-methylpicolinamide The dihydrochloride (13 O mg) was obtained as a colorless amorphous solid.

MS: m / z 5 2 4 C (M + H) ⁺ ]

NMR (DMS 0-d) 6: 1.77-1.84 (m, 2 H), 1.99-2 3 7 (m, 4 H), 2.7 3 to 3.18 (m, 7 H), 3.29 to 3.76 (m, 5 H), 5.0 2, 5.0 9 (both s, 2H in total), 6.98 to 7.94 (m, 10H), 8.54-8.58 (m, 1H), 10.0.78 1 0.82 (both br, 1 H in total)

 The compounds of Examples 18 to 27 were obtained in the same manner as in Example 17.

Example 18: (±) —4-chloro-1-N— [2- (3,4-dichlorophenyl) 1-41- (spiro (isobenzofuran-1- (3H), 4′—piperidine) 1'-yl) butyl] 1-N-methylbenzamide hydrochloride

MS: m / z 5 5 6 (M ⁺ )

NMR (DMS 0- d ₆ ) 6: 1.80 to 2.37 (m, 6 H), 2.7 1 -2.75 (m, 2 H), 2.86-3.2 6 (m, 6 H), 3.45-3.68 (m, 4 H), 5.03 (s, 2 H), 6.99 to 7.95 (m, 1 1 H ), 10.84 (br, 1H)

Example 19: (N) -N- [2- (3,4-dichlorophenyl) -141 (spiro [isobenzofuran-1-1 (3H), 4'-piperidine] 1-1'-II 1) N-dimethylbenzamide hydrochloride

MS: m / z 5 3 7 [(M + H) +]

 NMR (DMS 0-d 6) (5: 1.76 to 2.44 (m, 9H), 2.54 to 3.21 (m, 7H), 3.29 to 3. 5 7 (m, 5 H), 5.01, 5.04 (both s, 2H in total), 7.08 to 7.70 (m, 1 1H), 10.0.82 (br, 1 H)

Example 20: (Sat) 1 N— [2— (3,4-dichlorophenyl) 1-141 (spiro [isobenzofuran-1 (3H) .4′—piperidine) 1 1′1 Le) butyl] mono-N-methylpropionamide fumarate

Melting point: 16 7 ~ 16 8 'C

Elemental analysis (as _{C 30 H 36 N 2 0 6} C 1 2) (%):

Theoretical value: C = 6 0.91, H = 6.13, N = 4.74

Experimental value: C = 6 0.92, H = 6.12, N = 4.73

Example 21: (Sat) 1 N— [2— (3,4-dichloromouth phenyl) 1-41 (spiro [Isobenzofuran-1-1 (3H), 4'-piperidin] -1-1'-yl) butyl-N-methylcyclohexanecarboxamide hydrochloride

MS: m / z 5 2 9 [(M + H) +]

 NMR (DMS 0-d 6) (5: 1.07 to 1.39 (m, 6H), 1.51 to 1.67 (m, 4H), 1.79 to 1. 8 3 (m, 2 H), 2.0 5 to 2.4 1 (m, 5 H), 2.76 to 2.80 (m, 4 H), 3.10 0 to 3.17 (m, 4H), 3.48-3.58 (m, 4H), 5.03, 5.04 (both s, 2H in total), 7.14 to 7.7 1 (m, 7 Η), 1 0.6.9.10.8.9 (both br and 1 て in total)

Example 22: (Sat) I -— (2- (3,4-dichlorophenyl) —4 -— (spiro [isobenzofuran-1- (3Η), 4′—pyrididine] 1 1—— Le) butyl] 1-methyl-2-naphthalenecarboxamido fumarate

Melting point: 202-203

Elemental analysis (as _{C 38 H 38 N 2 0 6} C 1 2) (%):

Theoretical value: C = 6 6.18, H = 5.5, N = 4.06

Experimental values: C = 6 6.34, H = 5.59, N = 4.06

Example 23: (Sat) 1 N— [2— (3,4-dichloromouth phenyl) 1-4— (spiro (isobenzofuran-1 (3H), 4′-piperidine) 1 1′-yl 1) N-methyl-3-thiophenecarboxamide hydrochloride

MS: m / z 5 2 9 [(M + H) ⁺ ]

NMR (DMS 0- d ₆ ) 5: 1.80-1.83 (m, 2 H), 1.99 to 2.39 (m, 4 H) .2.80 to 2.9 2 (m, 4 H), 2.94 to 3.25 (m, 4 H), 3.42 to 3.45 (m, 2 H), 3.6 to 3.67 (m , 2 H), 5.03 (s, 2 H), 6.85 to 7.67 (m, 10 H), 10.6.8 (br, 1 H)

 The structural formulas of the compounds of Examples 13 to 23 are shown in Tables 2 (1) and (2).

Example 24: 1- (all) rac-N- [2- (3,4-dichlorophenyl) -1 4 _ (spiro [isobenzofuran-1 (3H), 4'-piperidine] 1 1'-yl) butyl] 1-N-methyl-2-phenylphenylpropionamide fumarate MS: m / z 55 1 [(M + H) ⁺ ]

NMR (DMS 0-d _δ ) 5: 0.96-1.33 (m, 3H), 1.60-1.62 (m, 2H), 1.72-1.9 2 (m, 4 H), 2.20-2.45 (m, 4 H), 2.65 to 3.03 (m, 6 H), 3.18 to 4.0 4 ( m, 3 H), 4.96 (s, 2 H), 6.60 (s, 2 H), 6.85-7.65 (m, 12 H)

Example 25: Phenyl (earth) 1 N— [2— (3,4-dichlorophenyl) —4— (spiro [isobenzofuran 1 (3H), 4′-piperidine) 1 1′-yl) Butyl] —N-methylcarbamate fumarate

Melting point: 158 ~ 160

Elemental analysis (as _{C 34 H 3e N 2 0 7} C 1 2) (%):

Theoretical value: C = 6 2.29, H = 5.53, N = 4.27

Experimental value: C = 6 2. 1 6. H = 5.54, N = 4.23

Example 26: (Sat) 1 N— [2— (3,4-dichlorophenyl) 1-41 (spiro [isobenzofuran-1 (3H), 4′-piperidine) 1 1′-yl) butyl ] N-methylbenzenesulfonamide hydrochloride

MS: m / z 55 9 [(M + H) ⁺ ]

NMR (DMS 0- d ₆ ) δ 1.80-1.84 (m, 2 H), 2.08-2.32 (m, 4 H), 2.60-2.6 3 (m, 3 H), 2.8 u 2.84 (m, 1 H), 3.0 6 to 3.18 (m, 6 H), 3.40 to 3.49 (m, 3 H) 2H), 5.03 (s, 2H), 7.15-7.16 (m, 1H), 7.33 to 7.75 (m, 11H), 10 . 4 0 (br, 1 H)

 Table 3 (1) shows the structural formulas of the compounds of Examples 24 to 26.

Example 27: N- (2- (3,4-dichloromouth phenyl)) 1-41 (spiro [isobenzofuran-1 (3H), 4'-piperidine) 1-1 ' -Yl) butyl] — 3,4,5-10 Limethoxy N-methylbenzamido fumarate

Melting point: 18 3 ~ 18 5 ° C

Elemental analysis (as _{C 37 H 42 N 2 0 9} C 1 2) (%):

Theoretical value: C = 6 0.91, H = 5.80, N = 3.84, C1 = 9.72 Experimental value: C = 6 0.6, H = 5.70, N = 3.84, C1 = 9.82 Example 28: (Sat) one N— [2— (3, 4 —Dichloro mouth phenyl) 1 4 1 (spiro

Preparation of (isobenzofuran-1 (3H), 4'-piperidine) -1'-yl) butyl- 1-N-methyl-2-benzofurancarboxamide dofumarate

 (Sat) 1-11 [3- (3,4-dichlorophenyl) -14-methylaminobutyl] spiro [isobenzofuran 1 (3H), 4'-piperidine] hydrochloride (190 mg), HOBT (78 mg), 2-benzofurancarboxylic acid (75 mg), and DMF (5 ml) were added to a mixture of 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride (89 mg) under ice-cooling. ) And triethylamine (17 2

1) was added sequentially, and the mixture was stirred at room temperature for 4 hours. Brine was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 49: 1), fumaric acid (36 mg) was added, and 2-propanol and getyl were added. Crystallized from a mixture of ethers. The obtained crude crystals were recrystallized from a mixture of methanol and acetonitrile to give (±) —N— [2- (3,4-dichloromouth phenyl) 1-41 (spiro (isobenzofuran-1 (3H) , 4'-Piperidine] -l'-yl) butyl-l-N-methyl-2-benzofurancarboxamide dofumarate (132 mg) was obtained as colorless crystals.

Melting point: 19 1 ~ 19 2

Elemental analysis (as _{C 36 H 3e N 2 0 7} C 12) (%):

Theoretical value: C = 6 3.63, H = 5.34, N = 4.12

Experimental value: C = 6 3. 6 2. H = 5. 37, N = 4. 11

 The compounds of Examples 29 to 32 were obtained in the same manner as in Example 28.

Example 29: (Sat) —N— [2_ (3,4-dichloromouth phenyl) -14- (spiro [isobenzofuran-1 (3H), 4'-piperidine] 1-1'-1 1) N-methyl-1H-Benzimidazole 5-carboxamide

MS: m / z 56 3 [(M + H) ⁺ ]

NMR (DMS 0- d ₆ ) 5: 1.55-1.58 (m, 2H), 1.78-1 . 8 8 (m, 3 H), 2.0 5 to 2.40 (m, 5 H), 2.60 to 3.15 (m, 6 H), 3.6 2 to 3.8 2 (m, 2 H), 4.94 (s, 2 H), 6.9 l to 7.63 (m, 10 H), 8.30 (d, 1 H, J = 1 4 2 H z), 1 2 • 5 7 (br, 1 H)

Example 30: (Sat) 1 N— [2- (3,4-dichlorophenyl) 1-4- (spiro (isobenzofuran-1 (3H), 4'-piperidine) 1-yl) butyl] 1 N —Methyl-2-quinolinecarboxamido fumarate

Melting point: 16 2 to 16 3

Elemental analysis (as _{C S7 H 37 N S Ο β} C 1 2) (%):

Theoretical value: C = 6 4.35, H = 5.40, N = 6.008

Experimental value: C = 6 4.42, H = 5.4, N = 6.04

Example 31: (Sat) 1 N— [2— (3,4-dichlorophenyl) -14- (spiro [isobenzofuran 1 (3H), 4′-piperidine] 1 1′-yl) Butyl) 1-hydroxydroxy-1-N-methylbenzamide

MS: mZz 5 3 9 [(M + H) +]

NMR (DMS 0-d _e ) δ 1.54 to 1.57 (m, 2Η), 1.79 to 1.84 (m, 4.). 2.10 to 2.25 (m, 4Η), 2.58-2.79 (m, 5Η), 3.10 0 to 3 .-- 16 (m, 1Η), 3.55 to 3.70 ( m, 2Η), 4.94 (s, 2Η), 6.72, 6.74 (both s, 2 2 in total), 6.96 to 6.98 (m, 2Η) ), 7.22-7.28 (m, 5 Η), 7.52 to 7.54 (m, 2 Η), 9.76 (br, 1 Η)

Example 3 2: (P)-(2- (3,4-dichlorophenyl) -141- (spiro [isobenzofuran-1-1 (3Η), 4'-piperidine) -1-1'- )

-2-(Imidazo [1.2-a] £. Lysine-1-yl) N-methylacetamide 1.5 fumarate

Melting point: 1 87-190 ° C

Elemental analysis (as _{C 38 H 40 N 4 0 8} C 1 2) (%):

Theoretical value: C = 60.7, H = 5.36, N = 7.45C1 943 3 Experimental value: C = 60.81, H = 5.33, N = 7 . 5 7 C 1 9 5 1 The structural formulas of the compounds of Examples 27 to 32 are shown in Tables 2 (2) and (3).

Example 33: (Sat) 1-1'-1 [4- (N-benzyl N-methylamino) 1-3- (3.4-dichrophenyl) butyl] Spiro [isobenzofuran-1 (3H) , 4'-piperidine]

 A mixture of lithium aluminum hydride (54 mg) and THF (5 ml) was added to a mixture of (sat) 1 N— [2- (3.4. Dichloromouth phenyl) 14 1 (spiro [isobenzofuran 1] under ice cooling. 11- (3H), 4'-piperidine-1'-yl]) butyl]-A mixture of N-methylbenzamide (25 Omg) and THF (5 ml) was added, and the mixture was stirred under ice cooling for 4 hours. did. Sodium sulfate and brine were sequentially added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: black form: methanol = 49: 1), and (Sat) 1-1 ′-[4-1 (N-benzyl-1-N-methylamido) (D) 1-3- (3,4-dichlorophenyl) butyl] spiro [isobenzofuran-1-1 (3H), 4'-piperidine] (111 mg) was obtained as a colorless oil.

MS: m / z 5 09 [(M + H) ⁺ ]

_{NMR (DMS 0- d e) 5} :.. 1. 5 4 - 1. 6 2 (m, 3 H), 1. 7 7 ~ 1 9 6 (m, 3 H), 2. 0 7~2 2 3 (m, 7 H), 2.46 to 2.69 (m, 4 H), 2.97-3.05 (m, 1 H), 3.38.3.5 1 ( Both d,

1 H, J = 1 3.4 Hz), 4.93 (s, 2 H) .7.1 1 7.28 (m,

10 0 H), 7.4 6 to 7.5 4 (m, 2 H)

Example 34: (Sat) 1 N— [2— (3,4 dichlorophenyl) 1-41 (3,4—dihydrospiro [isoquinolin-1 1 (2H), 4′-piperidine) 1 1'-yl) butyl] —Preparation of N-methylbenzamide dihydrochloride

To an aqueous solution of 3,4-dihydrospiro [isoquinolin-1- (2H), 4'-piperidine] dihydrochloride (254 mg) was added aqueous sodium hydroxide solution to improve the liquidity. The product was made alkaline and the product was extracted with black form. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crude 3,4-dihydrospiro [isoquinoline-1-1 (2H), 4'-pi Resin). (Earth) 1 N— [2- (3,4-dichlorophenyl) 1-4-hydroxybutyl] 1-N-methylbenzamide (195 mg :), triethylamine (931) and dichloromethane (5 ml) ) Was added to the mixture under ice-cooling, and the mixture was stirred at 4 ° C for 3 hours. After ethyl acetate was added to the reaction mixture, the mixture was washed with water and saturated saline in this order, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was mixed with the crude 3,4-dihydro (isoquinolin-1- (2H), 4'-piperidine), triethylamine (230 (1)) and DMF (1 ml) obtained earlier. Was added and the mixture was stirred at 70 for 4 hours.Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 97: 3), 4N hydrochloric acid-dioxane solution (4151) was added, and a mixture of 2-propanol and ethyl acetate was added. The obtained crude crystals were recrystallized from methanol to give (Sat) 1-N-C2- (3,4-dichloromouth phenyl) 1-4- (3,4-dihydrospiro [isoquinoline _ 1 (2H), 4'-piperidine] 1 1 ' ] 1-N-methylbenzamide dihydrochloride (157 mg) (Compound A) was obtained as colorless crystals.

Melting point: 2 25 ° C (decomposition)

Elemental analysis (as _{C S 1 H 37 N 3 0} C 1 4) (%):

Theoretical value: C = 6 1.09, H = 6.12, N = 6.89, C1 = 2 3.27 Experimental value: C = 6 0.87, H = 6.09 , N = 6.87, C 1 = 2 3.02 Compound B: (-) 1 N— [2— (3,4-dichlorophenyl) 1-41 (3,4-dihydrospiro [isoquinol 1 (2H), 4'-piperidine] 1 '-(yl) butyl] -N-methylbenzamide dihydrochloride

 (Earth) 1 N— [2— (3,4-Dichloromouth phenyl) 1-4-Hydroxybutyl] 1N—Methylbenzamide Instead of (1) 1 N— [2— (3,4—Dichlorophenyl) ) [1-Hydroxybutyl]-N-methylbenzamide was obtained in the same manner as for compound A.

Melting point: 229 ° C (decomposition)

Elemental analysis (as _{C 31 H 37 N 3 OC 1} 4) (): Theoretical value: C = 6 1.0 9. H = 6.1 2. N = 6.89, C1 = 2 3.27 Experimental value: C = 60.6.9 = H = 6.10 , N = 6. 8 3, C 1 = 2 2. 9 9 rotation: [ "] ^{_{D 25 - 2 6. 3 ° (}} C = 0. 5, CH 3 OH)

Example 35: 1 (Sat) N— [2— (3,4 diphenyl phenyl) 1-41 (3,4-dihydrospiro [1H—2—Venzopyran-1 1,4′-piperidine) 1 1'-yl) butyl] —Preparation of N-methylbenzamidofumarate

 (Sat) —N— [2— (3,4-dichlorophenyl) 1-4— (3,4 dihydrospiro (1H—2-benzopyran-1 1,4 ′) obtained in the same manner as in Example 34. -Piperidin] 1 1'-yl) butyl] 1 N-methylbenzamide (358 mg), fumaric acid (77 mg), and crystallization from a mixture of 2-propanol and getyl ether The obtained crude crystals were recrystallized from acetonitrile to give (Sat) 1 N— (2— (3,4-dichlorophenyl) 1 4 1 (3,4—dihydrospiro [1H—2— Benzopyran (1,4'-piperidine) -11'-yl) butyl- 1-N-methylpentazamide dofumarate (207 mg) was obtained as colorless crystals.

Melting point: 199 ~ 201 ° C

Elemental analysis (as _{C 36 H 38 N 2 Ο β} C 1 2) (%):

Theoretical value: C = 6 4.32, H = 5.86, N = 4.29, Cl = 1.0.85 Experimental value: C = 64.31, H = 5.80 , N = 4.30, C1 = 10.57 The compounds of Examples 36 to 38 were obtained in the same manner as in Example 35.

Example 36: (Sat) 1 N— [2— (3,4—dichloromouth phenyl) 1-4 1 (3-oxo_ 3, 4—dihydrospiro (1 H—2—benzobenzoyl) 1,4 '-Piperidine] 1 1' yl) butyl] 1-N-methylbenzamide 0.5 fumaric acid 0.1 hydrate

Melting point: 198 ~ 200 ° C

Elemental analysis (as _{C 33 H 34 N 2 0 5} C 1 2 · 0. 1 Η 2 0) (%): theory: C = 6 4. 8 3, H = 5. 6 4, N = 4. 5 8, C 1 = 1 1.60 Experimental values: C = 6 4.44, H = 5.54, N = 4.67, C 1 = 1 1.68 Example 3 7: ( ±) — a I l — rac— N— [2- (3,4-dichlorophenyl) — 4- (3-methylspiro [isobenzofuran-1- (3H), 4'-piperidine 1 1'-yl) butyl] 1-N-methylbenzamide dofumarate Melting point: 147-149

Elemental analysis (as _{C 35 H 38 N 2 0 6} C 1 2) (%):

Theoretical value: C = 6 4. 3 2. H = 5.86, N = 4.29, C1 = 1.0.85 Experimental value: C = 64.24, H = 5.86, N = 4.26, C1 = 10.8.1 Example 3 8: (±) —1-1 [1— (3,4-dichlorophenyl) 1-3— (spiro (isobenzofuran-1- (3H ), 4'-Piperidin] 1 1'-yl) propyl]-2-oxo-3- 3-phenylhexahydridopyrimidine fumarate

Melting point: 218-220

Elemental analysis (as _{C 36 H 37 N 3 O e} C 1 2) (%):

Theoretical value: C = 63.06, H = 5.59, N = 6.30, C1 = 10.6.4 Experimental value: C = 63.0 7. H = 5.62 , N = 6.34, C1 = 10.64 Example 39: (Sat) 1 1 '1 [4- (N-benzoyl-1N-methylamino) 1 3 1 (3,4-dichloro) Mouth phenyl) butyl] spiro [benzo [c] thiophene 1

Preparation of (3H), 4'-piperidine] 2-oxide

 1 '1 t rt -butoxycarbonylspiro [benzo [c] thiophene 1

(3H), 4'-piperidine) To a mixture of 2-x-oxide (950 mg) and dichloromethanone (25 ml) was added trifluoroacetic acid (10 ml) under ice-cooling. For 30 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and sodium bicarbonate and a 1N aqueous solution of sodium hydroxide were added to make the liquid alkaline. The product was extracted with black-mouthed form, and the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crude spiro.

[Benzo [c] thiophene-1 (3H), 4'-piperidine) 2-year-old oxide was obtained as a pale yellow oil.

 (Earth) 1 N— [2- (3,4-dichlorophenyl) -14-hydroxybutyl] —N-methylbenzamide (345 mg), triethylamine (2051) and dichloromethane Methanesulfonyl chloride under ice-cooling

(83/1) was added and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. Concentrated under reduced pressure. The obtained residue was added to the crude spiro [benzo [c] thiophene-1 (3H), 4'-piperidine) 2-oxide, triethylamine (4101) and DMF (2 ml). ) Was added and the mixture was stirred at 70 ° C. for 5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: black form: methanol = 49: 1) to give (S) 1 1 '1 [41 (N-benzoyl-N-methylamino) I 3-((3.4 dichloromouth phenyl) butyl) spiro (benzo (c) thiophene 1 (3H), 4'-piperidine) 2-year-old oxide (429 mg) was obtained as a colorless oil. MS: m / z 5 5 5 ((M + H) ⁺ )

 NMR (CDC 13) δ 1.57 to 1.63 (m, 3H), 1.85 to 2.4.44 (m, 8H), 2.70 to 3.27 (m, 5 Η), 3.5 4 ~ 3.9 1 (m, 2 Η), 4.00 (d, 1 Η, J = 1 2 Η ζ), 4.32 (d, 1 Η, J = 16 Hz), 6.8 0-7.19 (m, 3 Η), 7.30-7.42 (m, 9) Example 40: (Sat) _Ν— [2— (3.4 dichlorophenyl) 1 4 _ (2-methyl-1,3,4-dihydrospiro [isoquinoline 1 (2Η), 4'-piperidine) 1 1'-yl ] -Ν-methylbenzamide hydrochloride hydrate

(Sat) 1 1 '1 [3- (3,4-dichloromouth phenyl) 14-methylaminobutyro] 1-2-Methyl-1,3,4-dihydrospiro [isoquinoline 1 (2Η), 4' To a mixture of piperidine (435 mg), triethylamine (2701), and dicopenmetan (10 ml), add benzoylcopenlide (1701) under ice-cooling. The mixture was stirred at room temperature for 8 hours. After ethyl acetate was added to the reaction mixture, the mixture was washed successively with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: chloroform: methanol: ammonia water = 97: 3: 0.01), and then 4N hydrochloric acid-dioxane solution (5001) was purified. ) And crystallized from a mixture of methanol and ethyl acetate. The obtained crude crystals were recrystallized from a mixture of methanol and acetonitrile to give (Sat) 1 N— [2- (3,4-dichloromouth phenyl) 14 _ (2 Dihydrospiro [isoquinoline 1 (2H), 4'-piperidine] 1 1'- L) butyl] 1 N-methylbenzamide hydrochloride hydrate (117 mg) was obtained as colorless crystals.

Sublimation point:> 1 at 80

Elemental analysis (as _{C 32 H 38 N 3 0 C} 1 3 · Η 2 0) (%):

Theoretical value: C = 63.52, H = 6.66, N = 6.94, Cl = 1.7.58 Experimental value: C = 63.2, H = 6.66 , N = 6.96, C 1 = 1 7.85 Example 4 1: (Sat) 1 N— [4— (2-Acetyl—3,4-dihydrospiro [isoquinoline 1 1 (2 H), 4'-Piperidine] 1 1'-yl) 1 2- (3,4-dichlorophenyl) butyl] 1 N-Methylbenzamidofumarate 0.1 monohydrate (Earth) 1 N 2- (3,4-dichlorophenyl) 1-4-1 (3,4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] 1-1'-yl) butyl] 1-N- Acetic anhydride (781) was added to a mixture of methylbenzamide dihydrochloride (25 O mg), triethylamine (2401) and dichloromethane (5 ml) under ice-cooling, and the mixture was added at room temperature. Stirred for hours. Triethylamine (1141) and acetic anhydride (781) were added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 days. Triethylamine (1141) and acetic anhydride (78/1) were added to the reaction mixture under ice cooling, and the mixture was further stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, washed sequentially with water and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: black form: methanol = 49: 1), fumaric acid (38 mg) was added, and 2-propanol and getyl ether were added. Crystallized from the mixture. The obtained crude crystals were recrystallized from a mixture of acetonitrile and ethyl acetate, and (Sat) 1 N— [4— (2-acetyl-3,4—dihydrospiro [isoquinolin-1 1 (2H ), 4'-piperidine] 1 1'-yl) 1 2-(3, 4-dichloromethyl phenyl) butyl) 1 N-methylpentazamido fumarate 0.1 monohydrate (11 O mg) Obtained as colorless crystals. Melting point: 177-178 ° C

Elemental analysis (as _{C 37 H 41 N 3 0 6} C 1 2 0. 1 H 2 0) (%):

Theoretical value: C = 6 3.81, H = 5.96, N = 6.03, C1 = 10.18 Experimental value: C = 63.51, H = 5.82 , N = 6. 0 5.C 1 = 1 0. 1 5 Example 4 2: (Earth) 1 al 1 — rac—N— [2— (3,4-dichlorophenyl) 1-4 — (2-hydroxy-1,3,4-dihydrospiro [naphthalene 1 1 (2 H), Preparation of 4'-piperidine) 1 1'-yl) butyl) 1-N-methylbenzamide dofumarate 0.6 hexahydrate

 (Sat) —N— [2— (3,4-dichlorophenyl) 1-41 (2-oxo-1,3,4-dihydrospiro) synthesized in the same manner as in Example 13 (naphthalene-1 (2H), To a mixture of 4'-piperidine] -1'-yl) butyl and 1-N-methylbenzamide (63 mg) and methanol (2 ml) was added sodium hydride (15 mg) at room temperature. For 10 minutes. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, and the product was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1), fumaric acid (6.0 mg) was added, and 2-propanol and getyl ether were added. Crystallized from the mixture, (±) — all— rac—N— (21- (3,4-dichloromouth phenyl) 1-4- (2-hydroxy-3,4-dihydrospiro [naphthalene-1 (2H ), 4'-Piperidine] 1 '-(yl) butyl) 1-N-methylbenzamidofumarate 0.6 hexahydrate (1 Omg) was obtained.

Melting point: 15.5 ° C

Elemental analysis (as _{C S6 H 40 N 2 0 6} C 1 2 · 0. 6 Η 2 0) (%): theory: C = 6 3. 7 3, H = 6. 1 2, N = 4. 13

Experimental values: C = 6 3.5 1, H = 5.88, N = 4.14

Example 43: (Sat) 1 N— [2- (3,4-dichlorophenyl) -14- (spiro (isobenzofuran-1 (3H), 4′-piperidine) 1-1′-yl) Butyl] 1 N-Methylthiobenzamide fumarate

(Sat) 1-1'-1 [3- (3,4-dichlorophenyl) -14-methylaminobutyrol] spiro [Isobenzofuran-1 (3H), 4'-piperidine] (20 Omg) triethylamine (6 To a mixture of 71) and pyridine (5 ml) was added S- (thiobenzoyl) thioglycolic acid (11 mg), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, brine was added to the resulting residue, and the product was added to ethyl acetate. Extracted. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 49: 1), fumaric acid (14 mg) was added, and the residue was crystallized from 2-propanol and purified (Sat. 1) N- [2- (3,4-dichlorophenyl) 1-41 (spiro [isobenzofuran-1 (3H), 4'-piperidine] 1 1'-yl) butyl] 1 N-methylthiobenzami Dofumarate (50 mg) was obtained as colorless crystals.

Melting point: 93-194

Elemental analysis (as _{C 34 H 3e N 2 0 5} C 1 2 S) ():

Theoretical value: C = 6 2.29, H = 5.53, N = 4.27, C1 = 1.0.81, S

= 4.89

Experimental value: C = 6 2.12, H = 5.5, N = 4.28, C1 = 1.0.90, S = 5.0.00

Example 44: (Sat) — N— [2— (3,4-dichloromouth phenyl) 1-4 — (3-year-old oxo 3.4. 4-dihydrospiro (isoquinoline-1 1 (2H), 4) '—Piperidin]-1' 1-yl-butyl) 1-4-Methoxymethoxy N-methylbenzamide

 (Sat) 1 N— [2— (3,4-dichlorophenyl) -14-hydroxybutyl) -14-methoxymethoxy-1-N-methylbenzamide (860 mg), triethylamine (4 To a mixture of 361) and dichloromethane (10 ml) was added methanesulfonyl chloride (178-1) under ice cooling, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Methanesulfonyl chloride (15 × 1) was added to the reaction mixture under ice-cooling, and the mixture was stirred at 4 overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (E) -N- [2- (3,4-dichloromethane). Methyl phenyl-14-mesyloxybutyl) -14-methoxymethoxy-N-methylbenzamide (960 mg) was obtained as a colorless oil.

To the aqueous solution of 3-hydroxy-1,3 dihydrospiro [isoquinolin-1- (2H), 4'-piperidine] hydrochloride (433 mg), add sodium hydroxide aqueous solution, Was made alkaline and the product was extracted with chloroform. Extracts were washed with saturated saline After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The obtained residue was added to the previously obtained (Sat) —N— [2- (3,4-dichloromouth phenyl) -14-mesyloxybutyl] -14-methoxymethoxyl-N-methylbenzamide (466 mg ) Triethylamine (425-1) and DMF (2 ml) were added, and the mixture was stirred at 0 ° C for 5 hours. After adding ethyl acetate to the reaction mixture, the mixture was washed with water and saturated saline in this order, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: black form: methanol = 49: 1) to give (Sat) -1 N- [2- (3,4-dichlorophenyl) -1 4- (3-oxo-3,4-dihydrospiro [isoquinoline 1 (2H), 4'-pyridin] 1 1'-yl) butyl] 1-4-methoxymethoxy N-methylbenzami Do (

316 mg) as a colorless oil.

MS: m / z 6 10 0 ((M + H)

 NMR (CDC13) 5: 1.77 to 1.97 (m, 4H), 2.17 to 2.30 (m, 6H), 2.69 to 3.24 (m , 6Η), 3.48 to 3.57 (m, 4Η), 3.63 (s, 2Η), 3.86-3.93 (m, 1Η), 5. 1 9 (s, 2 Η), 6.30 (s, 1 Η), 6.8 4-7.16 (m, Τ Η), 7.28-7.40 (m, 4 Η )

Example 45: (Sat) — Ν— (2- (3,4-dichlorophenol) 1-41 (3-oxo3,4-dihydrospiro [isoquinolin-1 (2) .4 ′) —Piperidin] — 1 '—yl) butyl! —Preparation of Ν-methylbenzamidofumarate

Example 4 (Sat) 1- (2- (3,4-dichloromouth phenol) 1-41 (3-oxo-1,3,4-dihydrospiro obtained in the same manner as 4) 1 (2Η), 4 'monopiperidine]-1' yl) butyl] -Ν-methylbenzamide (210mg), fumaric acid (44mg), 2-propanol and getyl ether Crystallized from the mixture. The obtained crude crystals were recrystallized from a mixture of methanol, acetonitril and ethyl acetate to give (Sat) 1 N— [2- (3,4-dichlorophenyl) 1-4 1 (3-oxo-1 3, 4-Dihydrospiro (isoquinolin-1 (2H), 4'-piperidine) 1'-yl) butyl] 1-N-methylbenzamide dofumarate (128 mg) was obtained as colorless crystals. Melting point: 209 ° C (decomposition)

Elemental analysis (as _{C 35 H S7 N 3 O s} C 1 2)

Theoretical value: C = 63.06, H = 5.59, N = 6.30, C1 = 11.0.64 Experimental value: C = 63.1, H = 5.49 , N = 6.31, C1 = 10.5.5 Example 46: (Sat) 1 N— [2— (3,4-dichlorophenyl) 1 4 1 (3—3 years old) , 4-Dihydrospiro [isoquinolin-1- (2H), 4'-piperidine] 1'-yl) butyl] -1,3,4,5-trimethoxy N-methylbenzamido fumarate Preparation of pentahydrate

 (Sat) 1-N— [2- (3,4-dichlorophenyl) -14-hydroxybutyl) -1,3,4,5-trimethoxy N-methylbenzamide (828 mg), triethylamido Methanesulfonyl chloride (159 // 1) was added to a mixture of methane (39 1〃1) and dichloromethane (10 ml) under ice cooling, followed by stirring at room temperature for 1 hour. Mensulfonyl chloride (141) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain (Sat) 1 N— [2— (3,4— [Dichlorophenyl) -141-mesyloxybutyl] -1,3,4,5-trimethoxy-1-N-methylbenzamide (9555 mg) was obtained as a colorless oil.

To an aqueous solution of 3-oxo-3,4-dihydrospiro [isoquinolin-1- (2H), 4'-piperidine] hydrochloride (457 mg) was added aqueous sodium hydroxide solution, Was made alkaline and the product was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was combined with the previously obtained (Sat) 1-N- [2- (3,4-dichlorophenyl) -14-mesyloxyptyl] -1,3,4,5-trimethoxy N-methylbenzamide (61) Triethylamine (504 wl) and DMF (4 ml) were added, and the mixture was stirred at 70 for 5 hours and 30 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated saline in that order, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 49: 1), fumaric acid (116 mg) was added, and 2-propanol and getyl ether were added. Crystallized from the mixture of (Sat) — N— [2— (3, 4- Dichlorophenyl) -4-1 (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 (2H), 4'-piperidine] 1'-yl) butyl]-3, 4. 5-Trimethoxy N-methylbenzamidofumarate 0.5 hydrate (599 mg) was obtained as colorless crystals.

Melting point: 1 3 8—1 4 2

Elemental analysis (as _{C 38 H 43 N s OaC 1} 2 · 0. 5 H 2 0)

Theoretical value: C = 59.61, H = 5.79, N = 5.49, C1 = 9.26 Experimental value: C = 59.56, H = 5.62, N = 5.47, C1 = 9.06

 The compounds of Examples 47 and 48 were obtained in the same manner as in Example 46.

Example 47: (Sat) one N— [2- (3,4-dichlorophenyl) -4-1 (5-methylspiro [isobenzofuran-1 (3H), 4′—piperidine] 1-1 ′ ”— Yl) butyl] —N-methylbenzamido fumarate

Melting point: 18 4 to 18 6 ° C

Elemental analysis (as _{C S5 H 38 N 2 0 6} C 1 2) (%)

Theoretical value: C = 64.32, H = 5.86, N = 4.29, C1 = 1.0.85 Experimental value: C = 64.29, H = 5.85 , N = 4.30, C1 = 10.6.4 Example 48: (Sat) -1'-1 [41- (N-benzoyl-N-methylamino) -3-1 (3,4 [Phenyl] butyl] 1,3,4-dihydrospiro [1H—2—benzothiopyran-1,4'-piperidine] 2-oxodofumarate 0.4 hydrate

Melting point: 16 1 ~ 16 3 ^e C

Elemental analysis value (as C ₃₅ H ₃₈ N ₂ O ₆ Cl ₂ S * 0.4 H ₂₀ ) (%)

Theoretical value: C = 60.67, H = 5.64, N = 4.04, Cl = 10.23, S = 4.63 Experimental value: C = 60.73, H = 5 59, N = 4.00, Cl = 1.07, S = 4.52 The structural formulas of the compounds of Examples 33 to 48 are shown in Tables 3 (1) to (4).

Example 4 9:

 Thickened aqueous solution containing the compound of the present invention for spraying in the recruitment

 w / v%

7 g of the compound of the present invention 0.9 g of sodium chloride

 Potassium dihydrogen phosphate 0.60 g

 Sodium hydroxide 0.0 56 g

 Methyl p-oxybenzoate 0.080 g

 Propyl n-oxybenzoate 0.020 g

 0.5 000 g of hydroxypropyl methylcellulose

 Glycerin 10 g

 Propylene glycol 20 g

 The amount required to make the pure water 100 m1

 Sodium chloride, sodium dihydrogen phosphate, sodium hydroxide and hydroxypropyl methylcellulose were dissolved in water in this order.

 The compound of the present invention and methyl p-hydroxybenzoate and propyl p-hydroxybenzoate were dissolved in propylene glycol and glycerin, and after the dissolution was completed, this solution was added to the above aqueous solution.

 Put this in a nasal drop container and spray about 0.1 ml once.

Example 50:

 Powder containing the compound of the present invention for intranasal administration

 Compound of the present invention 2.5 g

 H P C -M 2.5 g

 0.5 g of mannitol

 90 g of ethanol

 Pure water 10 g

 The compound of the present invention, HPC-1M, and mannitol were dissolved in a mixture of ethanol and pure water, and a dried product was obtained by spray drying.

The obtained dried product was pulverized to obtain a powder having a particle diameter of about 250 μm. 30 mg of this was filled into No. 4 gelatin capsules. At the time of administration, set the capsule in a special spraying tool with a needle for piercing the capsule and a rubber ball for sending air, pierce both ends of the capsule, and press the rubber ball to empty. Inhale the powder into the nasal cavity from the tip.

EC

 o

 o o

 o

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Table 1-1 (3)

Table 2 (1)

0 ΐ

 (Ζ)-Halla

68E8Z / S6 ΟΛ \ Table 2 — (3)

Table 3 (1)

L 0 ΐ

) One ella

€ IL00 / S6df / XDJ 68 £ 8 S6 OAV 8 0 ΐ

 (Β)-ε ¾

£ OO / S6df / I3d 68 £ 8Z / S6 OAV Table 3 — (4)

 The following table shows, in addition to the compounds of the above-described examples, typical compounds of the present invention and specific physical property values.

These compounds were synthesized using the methods of preparation described above and the synthetic methods described in the Examples, and modifications thereof, which are known to those of ordinary skill in the art. Y (CH

0

. Re

Compound R q R ² X ¹ n X ² Properties

 CI

86 '1 CH ₃ C = 0 0 NH Fumarate

CI

 mp:

87 ′ 1 CH ₃ 10 fumarate 177-178. C

CI

 88 0 -CH = CH-0 Fumarate

CI

MS: m / z +

89 '1 CH ₃ C = NH 0 522 [(M + H)]

 O O C

P

Compound R ⁸ R ⁹ RR ² Physical properties

 CI

90 = 0 CH ₃ fumarate mp 186 ~ 187 ° C

Cl

91-CH (CH ₃ ) ₂ H CH ₃

Cl

92-C2H5 H CH ₃ Fumarate mp 130 ~ 132 ° C

Compound RR ² n Physical properties

 Cl

93 CH ₃ 1 fumarate mp: 154 ~ 156 ° C

Br

94 CH ₃ 0 fumarate mp: 18 door 184. C -R ⁵

-R ⁵

0.5

₂ ) _n -R ⁵

Claims

The scope of the claims

1. A spiro compound represented by the general formula (I), a salt thereof, a hydrate thereof, or a solvate thereof.

„-X ² -R ⁵ (I)

[The symbols in the formula represent the following meanings.

N ^A : a nitrogen atom which may form a quaternary ammonium salt with a lower alkyl group or an aralkyl group, or which may be oxidized

Z-C (R ⁸ R ⁹ )-Z ¹ -or CH ₂ C (R ¹⁰ R) -Z

 Z oxygen atom or S (0).

ZZ ¹ , NR ¹² , or C (R ¹³ R ¹⁴ )

 s: 0, 1 or 2

 R: aryl group which may be substituted

 n: 0 or an integer from 1 to 5

P and Q: identical or different, 0 or 1 (but not 0 at the same time p and Q) X ^1: over C (= 0) -, one C (= S) one, one S (= 0) One, — S 0 _2- , One C (= NR ⁶ )-,-CH _2- , or — CH = CH — (where X ^{1 is} CH = CH

In the case of —, n and Q are both 0 and X ² is a single bond. X ² : an oxygen atom, a sulfur atom, one NR ⁷ -or a single bond (provided that X ^{1 is} -C (= N

R ⁶ ) when it is one and n is 0, X ² is a sulfur atom, one NR ⁷ — or a single bond)

R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ : 1) The same or different, and a hydrogen atom or a lower alkyl group (when n is an integer of 2 to 5, a plurality of R ³ and R ⁴ can be the same or different, respectively), 2) R ¹ and R ² together form a lower alkylene group having 1 to 4 carbon atoms when is 1. It is possible, Is 0, a lower alkylene group having 2 to 5 carbon atoms can be formed, or 3) n is 0 and X ^{1 is} -C (= 0) one, — C (= S ) —, One S (= 0) one, -S 0 ₂ one or one C (= NR ⁶ ) —, R ² and R ⁷ are combined to form a lower group having 2 to 4 carbon atoms. Can form an alkylene group

R ⁵ : a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, an aryl group which may be substituted, a cycloalkyl group which may be substituted, Or a substituted or unsubstituted heterocyclic group

R ⁸ , R ⁹ , R ^1D , R ¹¹ : 1) The same or different, a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a hydroxy lower alkyl group, a mercapto group, a lower alkylthio group, or a mercapto lower alkyl Or 2) R ⁸ and R ⁹ or R ^1D and R ¹¹ are combined to form an oxo group

R ¹² : a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group, a lower alkanol group, a cycloalkylcarbonyl group, an optionally substituted arylcarbonyl group, or Optionally substituted aryloxycarbonyl group

R ¹³ and R ¹⁴ : 1) identical or different, substituted by a hydrogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group or a lower alkylthio group, 2) a hydroxyl group, a lower alkoxy group, a mercapto group or a lower alkylthio group Or a lower alkyl group, or 3) an oxo group in which R ¹³ and R ¹⁴ are

 B z: 1) unsubstituted benzene ring, or 2) benzene ring substituted with the same or different 1 to 4 substituents below

 Substituents: i) Halogen atom, hydroxyl group, lower alkoxy group, mercapto group, lower alkylthio group, carboxy group, lower alkanol group, lower alkoxycarbonyl group, nitro group, amino group, lower alkylamino group Or lower alkoxycarbonylamino group, il) lower alkyl group or lower alkenyl group which may be substituted by the substituent of the above i), or iii) two adjacent substituents are taken together. Methylenedioxy or ethylenedioxy

2. In the general formula (I) according to claim 1, p and q are 1, and R ^{1 2.} The compound or a salt thereof according to claim 1, wherein R ² and R ² together form a lower alkylene group having 1 to 4 carbon atoms.

3. The compound or a salt thereof according to claim 1, wherein p and q are 1, and R ¹ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group.

 4. In the compound represented by the general formula (I) according to claim 1,

(In the formula, R ⁸ and R ⁹ are the same or different and are each a hydrogen atom or a lower alkyl group, or an oxo group,

R ^{1 Q} and R ¹¹ are a hydrogen atom or an integral oxo group,

R ¹² is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a lower alkyl group or a benzoyl group;

R ¹³ is a hydroxyl group, a mercapto group or a hydroxy lower alkyl group,

R ¹⁴ is a hydrogen atom or an oxo group together with R ¹³ )

4. The compound according to claim 2 or 3, or a salt thereof.

5. In the compound represented by the general formula (I) according to claim 1, formula

5. The compound according to claim 4, which is a group represented by: or a salt thereof.

 6. In the compound represented by the general formula (I) according to claim 1, the R force is 1) an unsubstituted phenyl group or an unsubstituted naphthyl group, or 2) the same or different substituents 1 to A phenyl group substituted by 4 groups, wherein the substituent is i) a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, a carboxy group, a lower alkanol group, or a lower alkoxy group; Carbonyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, sorbamoyl group, cyano group, nitro group, amino group, mono-lower alkylamino group, di-lower alkylamino group or lower alkanoylamino group, ii) a lower alkyl group, a lower alkenyl group or a lower alkynyl group which may be substituted by the substituent of the above i) Or iii) the compound or a salt thereof according to claim 1, wherein two adjacent substituents are taken together to form an alkylene group having 3 to 4 carbon atoms, a methylenedioxy group or an ethylenedioxy group.

 7. is 1) unsubstituted phenyl group, unsubstituted naphthyl group, or 2) phenyl group substituted by halogen atom, trifluoromethyl group, lower alkoxy group, cyano group, lower alkyl group, or methylenedioxy group. 7. The compound according to claim 6, or a salt thereof.

 8. 1 '— [2— [3— (3,4-dichlorophenyl) 1-111 ((3-isopropoxyphenyl) acetyl] -13-piperidyl] ethyl] 1 1 (a) 1-methyl-1 3, 4-Dihydrospiro [isoquinolin-1- (2H), 4'-piperidinium] salt.

 9.1 '-[2- [3- (3,4-dichlorophenyl) 1-1] [(3-isopropoxyphenyl) acetyl] -13-piperidyl] ethyl] 1 (a) monomethyl

— 3-oxo-1,3,4-dihydrospiro [isoquinoline 1 (2 H), 4 ' Salt).

 1 0. N— [2- (3,4-dichlorophenyl) 4-1- (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 (2H), 4-piperidine] -1 1'— Butyl) 1-N-methylbenzamide or a salt thereof.

 1 1. N— [2— (3,4-dichloromouth phenyl) 4-1- (3-oxo-1,3,4-dihydrospiro [isoquinolin-1 1 (2H), 4-piperidine] 1 1'— Yl) butyl] 1,3,4,5-trimethoxy N-methylbenzamide or a salt thereof.

1 2.1 '1 [4-1 (N-benzoyl N-methylamino) 1 3- (3,4-dichlorophenyl) butyl] Spiro [benzo [c] thiophene 1 (3H), 4'-piperidine] 2—Aged oxide or salt thereof.

 1 3. A spiro compound represented by the general formula (A) or a salt thereof.

[The symbols in the formula represent the following meanings.

X: — 0—, one NH— or one S 0 ₂ -Z ³ : —CH ₂ — or one C (= 0) —

t: 0 or 1 (however, when t is 0, X is 1 S 0 _2— , and when Z ³ is 1 C (= 0) —, X is 1 0— Shall be)]

 1 4. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

 1 5. A tachykinin receptor antagonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

 16. The antagonist according to claim 15, wherein the tachykinin receptor is a substance P receptor and a Z or neurokinin A receptor.

1 7. Central nervous system diseases including tachykinin-mediated anxiety, depression, psychiatric disorders and schizophrenia; dementia in AIDS, senile dementia of Alzheimer type, Alzheimer's disease Disease, Down syndrome, demyelinating disease, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy, and neurodegenerative diseases including neuralgia; chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma Respiratory diseases including; inflammatory bowel disease (IBD), inflammatory diseases including psoriasis, connective tissue inflammation, osteoarthritis, and rheumatoid arthritis; allergic diseases including eczema and rhinitis; hypersensitivity diseases including sensitivity to vines Ophthalmologic diseases, including conjunctivitis, spring conjunctivitis, destruction of the blood-aqueous-water-aqueous barrier associated with various inflammatory eye diseases, increased intraocular pressure and miosis; contact dermatitis, red-topy dermatitis, juniper rash Rot disease including eczema-like dermatitis of the skin; debilitating disease including alcoholism; somatic disease due to stress; reflex sympathetic dystrophy including shoulder-hand syndrome; mood swings; including graft rejection Diseases associated with unfavorable immune response and immune enhancement, including systemic lupus erythematosus, or immune suppression; diseases due to abnormalities in the nerves regulating the internal organs; gastrointestinal disorders, including ulcerative colitis, Crohn's disease; X Irradiation, chemotherapeutic agents, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, reduced intracranial pressure or side effects associated with administration of various drugs Vomiting, including vomiting induced; bladder dysfunction including urinary incontinence; eosinophilia due to collagen disease, scleroderma, fascioliasis infection; vasodilation, including angina, migraine, and Reino's disease. 16. The antagonist according to claim 15, which is an agent for preventing or treating a tachykinin-mediated disease comprising: a disease caused by abnormal blood flow due to contraction; pain nociceptive pain including migraine;

 18. The antagonist according to claim 17, which is an agent for preventing or treating respiratory diseases including chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, and asthma.

 19. The antagonist according to claim 17, which is an agent for preventing or treating allergic diseases including eczema and rhinitis.

 20. The antagonist according to claim 17, which is an agent for the prevention or treatment of ophthalmologic diseases including conjunctivitis, spring conjunctivitis, destruction of the blood-aqueous-humidity barrier, increased intraocular pressure and miosis associated with various inflammatory eye diseases. .

 21. The antagonist according to claim 17, which is an agent for preventing or treating a central nervous system disease including anxiety, depression, psychiatry or schizophrenia.

22. The antagonist according to claim 17, which is an agent for preventing or treating pain of nociceptive pain including migraine.

2 3. X-ray irradiation, chemotherapeutic agents, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure, or administration of various drugs 16. The antagonist according to claim 17, which is a prophylactic or therapeutic agent for vomiting, including vomiting induced by a side effect associated with.