GB2355659A - beta-Carboline derivatives for use in treatment of pain, trauma, spasticity and movement disorders - Google Patents
beta-Carboline derivatives for use in treatment of pain, trauma, spasticity and movement disorders Download PDFInfo
- Publication number
- GB2355659A GB2355659A GB0026485A GB0026485A GB2355659A GB 2355659 A GB2355659 A GB 2355659A GB 0026485 A GB0026485 A GB 0026485A GB 0026485 A GB0026485 A GB 0026485A GB 2355659 A GB2355659 A GB 2355659A
- Authority
- GB
- United Kingdom
- Prior art keywords
- formula
- compound
- gat
- alkyl
- gaba
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical compositions comprising a compound of formula (1), wherein n = 2, 3 or 4; Z is an ester group of formula R<SP>3</SP>-O-CO- wherein R<SP>3</SP> is C<SB>1-6</SB> alkyl or C<SB>2-6</SB> alkenyl; <EMI ID=1.1 HE=57 WI=105 LX=532 LY=948 TI=CF> <PC>R<SP>1</SP>, R<SP>2</SP> and R<SP>5</SP> are, independently, halogen, H, OH, CF<SB>3</SB>, OMe, NO<SB>2</SB>; and R<SP>4</SP> = H or C<SB>1-6</SB> alkyl, are useful in the treatment of pain, trauma, spasticity and movement disorder other than that resulting from epilepsy. The compounds may be in free base form or in the form of an acid addition salt, such as the hydrochloride salt. Compounds according to formula (<B>1</B>) are inhibitors of the uptake of GABA (<I>gamma</I>-amino-butyric acid) by the GABA transporter protein GAT-3/4.
Description
2355659 O-CARBOLINE DERIVATIVES
Background of the invention
Field of the invention
The invention relates to the use of 0-carboline derivatives for analgesic and related purposes.
Description of the related art
Nerve impulses pass along the specialised cells known as neurones. Neurones communicate with each other at synapses, mainly by chemical means.
Neurotransmiters are small molecules which pass from vesicles within the neurone to the presynaptic membrane which is distanced from the postsynaptic membrane on a neighbouring neurone or an effector cell such as a muscle cell by the synaptic cleft.
Neurotransmitters transmit a signal across the cleft.
Neurotransmitters can be inhibited by other molecules known as inhibitors, especially by gamma-aminobutyric acid (GABA). The actions of GABA at the synapse are terminated by re-uptake of GABA into the pre-synaptic neurones or into glial cells The inhibition of this GABA uptake results in enhanced availability of this inhibitory neurotransmitter in the synaptic cleft and thus to increased "GABA-ergic" activity. Increased GABA-ergic activity can be useful in the treatment, for example of anxiety, pain and epilepsy, as well as muscular and movement disorders [see, for example, P. Krogsgaard-Larsen et aL, Progress in Medicinal Chemistry, 22, 68-112 (1985)].
A well-known and potent inhibitor of GABA uptake from the synaptic cleft into presynaptic nerve terminals and glial cells is 3piperi'dinecarboxylic acid (nipecotic acid). However, being a relatively polar compound and therefore unable to cross the blood-brain baffier, 3-piperidinecarboxylic acid itself has found no practical utility as a drug.
During the 1990s a new class of proteins have been found, known as GABA transporters. They have been classified as GAT-1, GAT-2, GAT-3 and GAT-4.
- I - These proteins transport GABA fi7om the synaptic cleft back into the neurone. Both GAT-1 and GAT-3/4 (GAT-3 is the rat and human homologue of GAT4 in mice) are located exclusively within the central nervous system (CNS). Whilst GAT-I is widely distributed, GAT-3/4 site expression is regionally specific. There are high levels of GAT-3/4 in the mid-brain, brain stem and spinal cord, key regions involved in pain control. Stimulation of peripheral sensory neurones; known as C- fibres results in release of excitatory neurotransmitters in the spinal cord which result in the transmission and perception of pain. Pre-synaptic GABA receptors (GABA-B receptors) inhibit release of these neurotransmitters and reduce the perception of pain.
Thus, activation of GABA receptors by GABA released from GABA-ergic neurones in the spinal cord and brainstem leads to a reduced release of neurotransmitters fi7om these fibres and further ascending neurones and so to an analgesic effect.
The antiepileptic drug tiagabine is a selective inhibitor of GAT-I and has analgesic properties, see M. D. Swedberg, J. Pharmacol. Exp. Ther. 269, 1021-1028 (1994). However, tiagabine potentiates GABA-ergic transmission in all regions of the CNS and can therefore have sedative side effects. Compounds capable of increasing GABA function in the spinal cord and brainstem. would therefore have the potential to produce analgesic without sedation.
Certain P-carboline derivatives which are potent inhibitors of GAT-3/4 are disclosed in PCT Patent Application WO 96/34865 (filed by Novo Nordisk A/S and assigned to the present applicant). These are principally compounds of formula (1):
W_(C H2) T, OH R z wherein n is I to 5, RI and R2 independently are principally hydrogen, halogen, hyd roxy, nitro, -WR'O, -SONR"R 12, -COOR", _CONRI4 R", CI-6-alkyl, CI-6-alkoxy, trifluoromethyl or trifluoromethoxy wherein R9, R10, R", R 12, R 13, R 14 and R 15 independently are hydrogen, CI-6-alkyl, C2-6-alkenyl or C2-6 alkynyl; and W is hydrogen or C I -6-alkyl; and R5 and W independently are hydrogen, halogen, hydroxy, nitro, -NR 16 R", 16 -COOR", CI-6-alkyl, CI-6-alkoxy, trifluoromethyl or trifluoromethoxy wherein R, R 17 and R" independently are hydrogen, CI-6-alkyl, C2-6-alkenyl or C2-6- alkynyl; and Z is any of several defined 5-membered ring heterocyclic groups, preferably 3 substituted1,2,4-oxadiazol-5-yl groups; in the form of a free base or a pharmaceutically acceptable salt thereof.
The problem of the present invention is to find further potent GAT-3/4 inhibitors, preferably with a high selectivity for GAT-3/4 inhibition relative to GAT-1 inhibition.
Summary of the invention
It has now been found that compounds of formula (2):
P, OH N--(C H2)_F_ (2) z wherein:
n is 2, 3 or 4; Z is an ester group of formula RI-O-CO- wherein R3 is CI-(' alkyl or C.)- (, alkenyl; and RI, R2 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, nitro, and trifluoromethyl; and R 4 is hydrogen or C1-6 alkyl; in the form of the free base or an acid addition salt thereof are useful for any novel purpose involving the inhibition of GABA uptake via a GAT-3 or GAT-4 subtype carrier, preferably as analgesics, as well as for treatment of trauma, movement disorders (other than resulting from epilepsy) and spasticity.
These compounds are known from US Patent 4,539,407 to have anticonvulsant activity and thus to be useful in the treatment of epilepsy. However, no other effect is disclosed in that patent.
The invention extends to the further medical use of the compounds of formula (2), in any terms permitted by patent law of individual countries or regions. In particular it includes the use of compounds of formula (2) in the preparation of a medicament for the purposes described above and particularly as an analgesic.
The compounds of formula (2) differ from those of WO 96/34865 in that the 3-position substituent in the O-carboline ring system is an ester group instead of a heterocyclic group.
Description of the preferred embodiments
The compounds of formula (2) may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation of suitable salts.
Examples of pharmaceutically acceptable acid addition sal ts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, plithalate, furnarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.
R1 and Ware preferably hydrogen.
R 4 is preferably hydrogen or methyl.
R 5 is preferably hydrogen or a 3- or 4- chloro, bromo or trifluoromethyl substituent.
Within the definition of the ester group, Z, the alkyl and alkenyl groups RI may have straight or branched chains; ethyl and n-propyl are currently pr eferred, but chain branching at the a-carbon atom is specifically included.
A propylene bridge is preferred, i.e. n is preferably 3.
It has been demonstrated that the novel compounds of formula (2) which selectively inhibit the uptake of GABA, via the GAT-3/4 subtype carrier, from the synaptic cleft, possess useful pharmacological properties in the central nervous system, in that they cause a selective enhancement of GABA-ergic activity. They are primarily useful to treat pain.
The compounds of formula (2) may be prepared as follows:
Method A:
R R4 OH H + X-(CH2)rFN RS RZ (3) (4) A compound of formula (3) wherein R1, RI and Z are as defined above, may be reacted with an azaheterocyclic compound of formula (4) wherein n, W and R5 are defined above and X is a suitable leaving group such as halogen, p- toluene sulphonate or mesylate. This alkylation reaction may be carried out in a suitable solvent such as acetone, dibutylether, 2-butanone, tetrahydrofuran, methylisobutylketone, methylisopropylketone, toluene, benzene or DMF in the presence of a base e.g.
potassium carbonate, sodium hydride or potassium tert.-butoxide at a temperature up to reflux for the solvent used, for e.g. I to 200 h.
Method B:
R I R 4 014 IN-(CH2)C)X< + H (2) A compound of formula (5) wherein RI, R2, n, Z and X are as defined above may be reacted with an azaheterocyclic compound of formula (6) wherein R4 and R5 are as defined above. This reaction may be carried out in a suitable solvent as defined above in the presence of a base as defined above and possibly a catalyst, e.g. an alkali metal iodide, at a temperature up to reflux for the solvent used, for e.g. I to 200 h.
Method C:
R 4111-0 + Y W R N - (CH Z) 1 Z 1 9NM (7) An azaheterocyclic ketone of formula (7) wherein RI, R2, n, R and Z are as defined above may be reacted with a Grignard reagent of formula (8) wherein R' is as defined above and Y is chloro, bromo or iodo. This reaction may b e. carried out in a suitable solvent such as diethyl ether, THF, toluene or benzene at a suitable temperature up to reflux temperature for the solvent used, for e.g. 1 to 5 h.
Phannacological Dat 3 H-GABA uptake was measured by a modification of the method of Fjalland et al., (1978). A crude membrane preparation was prepared from selected brain areas of male Wistar rats. To test for GAT-I inhibition, whole forebrain was used. To test for GAT-4 inhibition the fresh inferior colliculus was used, this being an area of the brain associated with GAT-4 activity. The tissue was homogenised in 20 ml of ice cold 0.32 M sucrose with a hand driven teflon/glass Potter-Elvehjem homogeniser.
The homogenate was centrifuged at 4'C for 10 min. at 1,000 x g, and the pellet was discarded. The supernatant was recentrifuged at 4'C for 20 min. at 10,000 x g. The pellet was then homogenised in 50 volumes 0.32 M sucrose. To 300 gl (GAT- 1) or gl (GAT-4) of uptake-buffer (200 nM NaCl, 15.3 mM KC1, 6.67 MM MgS04, 3.83 mM CaC12,16.67 mM glucose, 66.67 mM Tris, pH 7.5 at 30'C) was added 100 d test substance and 50 [tl tissue suspension. In the GAT4 inhibition test 100 gl of 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5,6-tetrahydro-3pyridinecarb oxylic acid (I nM final concentration) was also added. The samples were mixed and incubated at 30'C for 8 min. Then 3 H-GABA (0.9 nM final concentration) and unlabelled GABA (25 nM final concentration) was added, and the incubation was continued for an additional 8 min. The reaction was terminated by rapid filtration through Whatman GF/F glass fiber filters under vacuum. The filters were then washed twice in 10 ml of ice-cold isotonic (0.9%) saline, and the tritium trapped on the filters was quantified by conventional scintillation spectroscopy. Non-specific binding was determined in duplicate using nipecotic acid (500 ILM final concentration). Total binding minus non-specific binding gives the specific binding.
Values for non-GABA uptake carrier-mediated uptake Of3 H-GABA for some representative compounds of the present invention, along with the best results from the compound of PCT Application WO 96/34865, are shown below. Comparing the compound of present Example I with the best compounds of WO 96/34865, which are those of Examples 4 and 7 thereof, it will be seen that the compound of the invention shows greater GAT-4 inhibition. Substitution of the rings is generally less favourable, although the 3-chloro substituent in the right-hand benzene ring gave a particularly good result. Replacement of the ester group Z by a -COOH group was unfavourable, as shown by the comparison included ("Comp"). In several instances the compounds of the invention display high ratios of IC50, GAT-I:GAT4. Thus, for the compound of Example I of the present invention, the ratio is about 41 compared with 14 for the best compound (in that respect) of WO 96/34865, the compound of Example 28.
R OH gQN-(CH2)T PCT Application WO 96/34865 Z = oxadiazolyl Ex. of IC50 rIM z k7 RI R 5 4. 7 C2H5 H H 6700 890 R AV 7. it A H H 3700 890 10. it Ph H H not done 1440 26. CH3 H H 12200 1640 28. ZI CH3 H H 17000 1240 N Present invention Z = ester group (carboxylic acid group for comparison) Ex. of this z RI R 5 IC50 (nM) specification GAT-1 GAT-4
I n-C3H700C H H 8900 430 2 C2H500C H H 18400 450 3 C2H5OOC 6-NO2 H >3000 960 4 C2H500C H 4-F 6100 1130 Comp. HOOC H 4-Cl not done 11280 iSO -C3H700C H 4-Cl 7200 1500 6 C2H500C H 4-Br 10800 1860 7 C2H500C H 4-CF3 15000 2170 8 C2H500C H 4-OCH3 21200 1760 9 C2H500C H 3-Cl 12700 690 C2H500C H 3-CF3 14400 1380 The compounds of formula (2) are preferably formulated with a pharmaceutical carrier or diluent. The compositions containing the compounds of formula (2) may be prepared by conventional techniques and in conventional forms, for example capsules, tablets, solutions or suspensions.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.
Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier for oral administration is used, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely, but will usually be from about 25 mg to about I g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
Generally, the compounds of formula (2) are dispended in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
The dosage of the compounds of formula (2) is 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
A typical tablet, which may be prepared by conventional tabletting techniques contains:
Core:
Active compound (as free compound or salt thereof) 100 mg Colloidal silicon dioxide ("Aerosil", TM) 1.5 mg Cellulose, microcryst. ("Avicel", TM) 70 mg Modified cellulose gum ("Ac-Di-Sol", TM) 7.5 mg Magnesium stearate Coatin HPMC Approx. 9 mg Mywacett, TM 9-40 T Approx. 0.9 mg Acylated monoglycenide used as plasticizer for film coating.
The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intraurethral, intramuscular, topical, intransal, ophthalmic solution or an ointment, the oral route being preferred.
The following Examples illustrate the preparation of the compounds used in the invention.
Preparative Examples Example I
Propyl 9-(3-(4-Phenyl-4-hydroxypiperidino)propyl)-p -carboline-3carboxylate.
Propyl-9H-pyrido[3,4-b]lndolecarboxylate 2.5g (10 mmol) was dissolved in N,N-dimethylformamide (125 mL) and 0.55g (14 mmol) NaH was added under nitrogen, the mixture was stirred lh at room temperature. 4.72 g (30 mmol) 2-bromo 1-chloropropane was added and the reaction mixture was stirred for 20 h. at room temperature. The mixture was evaporated in vacuo and redissolved in CH202 (125ml). 2N HCI (100 mL) was added and the mixture was filtered. The organic phase was washed with 5% NaHC03(aq) (100 mL) and NaCI (brine) (25 mL). It was then dried with MgS04, filtered and evaporated in vacuo to give the crude propyl (9H-I-(3-chlorolbromopropyl)pyrido[3,4-b]indolecarboxylate. Recrystallisation from 2-propanol gave 3.19g (98% in yield).
This compound was a bromo/chloro mixture and was used below without any further purification.
2.Og (6 mmol) of propyl 9H-I-(3-chloroibromopropyl)pyrido[3,4b]indolecarboxylate prepared above was dissolved in NN-dimethylformamide (100 mL). 4-Phenyl-4-hydroxypiperidine 1.07g (6 mmol) and triethylamine (1 mL) were added. The reaction mixture was stirred under nitrogen at 60'C for 12 h. The reaction mixture was evaporated in vacuo and redissolved in CH202 (100 mL), washed with 5% NaHC03 (aq) (50 mL) and NaCI (brine) (50 mL) and then dried with magnesium sulfate. Evaporation in vacuo gave the crude product as an brown oil.
Further purification was performed on a silica gel column (150g; CH2CI2/EtOH/ NH40H(25%aq); 185:14:1 as eluant). 2.48g was isolated as the free amine. To 700mg of the free amine was added HCI (2.3M in ethanol), the solvent was evaporated and the product (as. hydrochloride salt) recrystallised from ethanol and diethyl ether, yield 752 mg. For physical data, see list after Examples 3- 10.
- I I - Example 2
Ethyl 9-(3-(4-Phenyl-4-hydroxypiperidino)-propyl)-p-carboline-3carboxylate.
Ethyl 9H-I-(3-chloro/bromopropyl)pyrido[3,4-6]lndole carboxylate was synthesised in the same manner as in Example I The title compound (hydrochloride salt) was then synthesised in the same manner as in Example 1, to give 1 g white crystals, yield 54%.
Examples 3-10
The other compounds of the Table shown above were synthesised in the same manner as Example I Physical data Compound 1: Hydrochloride.
Mp: 168-170'C.
Sample for NMR contains ethanol and 2HCl, Mp: I 79-180'C.
IH-NMR: (D6-DMSO 20OMHz) 1.05(d,t;3H); 1.7(d;2H); 1.8(q;IH); 2.4(m;2H); 2.55(d,d;IH); 3.2(m;4H); 4.4(t;2H); 4.35(t;2H); 5.4(broad s; 3H); 7.25(t;IH); 7.35(t;2H); 7.45(d,t;2H); 7.8(t;IH); 8.1(d,M); 8.6(d;lH); 9. 2(s;IH); 9.6(s;IH); 11.5(s;IH).
Compound 2: Hydrochloride.
Mp: amorphous, about 113'C.
Contains ethanol.
IH-NMR: (CDC13;200MHz) 1.25(t;3H); 1.5(t;3H); 1.65(s;lH); 2.05 2.2(m;4H); 3.45(d,t;4H); 3.7(d;2H); 3.75(q;1,5H); 4.6(m;4H); 7.3(d;1,5H); 7.4(d,t;2,5H); 1.5(d;2H); 7.65(d,d;2H); 8.2(d;IH); 8.9(s;lH); 9.05(s;lH).
Compound 3: Hydrochloride.
3HCI salt, Mp: 182-185'C.
FAB MS 502.2 (M+ + 1). The sample crystallised was reckoned to contain 0.38 mole H20 as water of crystallisation.
Sample for NMR contains ethanol.
IH-NMR: (CD30D; 20OMHz) 1.5(t;3H); 1.9(d;2H); 2.4-2.7(m;4H); 3.6(m;6H); 4.65(q;2H); 5.0(t;2H); 7.2-7.4(m;3H); 7.5(d,2H); 8.3(d,IH); 8. 7(d;IH); 9.5(d;2H); 9.9(s;IH).
Compound 4:
Liquid chromatography mass spectrometry (LC-MS): M+1=475; Retention time (Rt)=3.00 min; area; 82%.
Compound 5: Hydrochloride.
Contains ethanol.
Mp: 201-205'C.
IH-NMR: (D6-DMSO 20OMHZ) 1.3(t;3H); 1.6(d;2H); 2.0-2.4(m;4H); 2.6 3.2(broad m;6H); 4.4(q;2H); 4.7(m;2H); 5.5(broad s; IH); 7.3(d;IH); 7.4(t; 4H); 7.6(t;IH); 7.8(d;IH); 8.4(d;IH); 8.9(s;lH); 9.2(S;IH).
Comparative compound (acid): Hydrochloride.
MP>2500C.
IH-NMR: (D6-DMSO 20OMHz) 1.7(d;2H); 2.35(m;4H); 3.1-3.5(m; 7H); 4.7(t;2H); 5.6(s;IH); 7.4(m;5H); 7.7(t;lH); 7.9 (d;IH); 8.5(d;IH); 9.0(s; IH); 9.3(s;IH); 10.6(s;lH).
Compound 6: Hydrochloride. Mp: amorphous.
Contains ethanol.
IH-NMR: (D6-DMSO 20OMHz) 1.4(d;6H); 1.7(d;2H); 2.45(m;2H); 3.1 3.3(m;4H); 3.45(d;2H); 4.7(t;2H); 5.2(h;IH); 7.35(d;2H); 7.45(t;3H); 7. 8(t;IH); 8.05(d;IH); 8.6(d;lH); 9.2(s;IH); 9.5(s;IH); 11.3(s;lH).
Compound 7: Free amine.
Mp: amorphous.
LC-MS: M+1=538; Rt=2.88 min; area 96%.
Compound 8: Hydrochloride.
Mp: amorphous.
LC-MS: M+1=526; Rt=3.50 min; area 97%.
Compound 9: Free amine.
LC-MS: M+1=488; Rt=2.92 min; area: 72%.
Compound 10: Free amine. Mp: amorphous. LC-MS: M+1=493; Rt=3.33 min; area: 100%. Compound 11: Free amine. Mp: amorphous. LC-MS: M+1=526; Rt=3. 50 min; area: 99%.
Claims (8)
1. A method of treating a patient suffering from pain, trauma, a movement disorder, other than resulting from epilepsy, or spasticity, which comprises administering to said patient an effective amount of a compound of formula (2):
R I+ T&OH (2) (C tid R z wherein:
n is 2, 3 or 4; Z is an ester group of formula R3-0-CO- wherein R3 is CI-6 alkyl or C26 alkenyl; and RI, R2 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, nitro, and trifluoromethyl; and W is hydrogen or C 1 -6 alkyl; in the form of the free base or an acid addition salt thereof.
2. The method of Claim 1, wherein RI and R2 are both hydrogen atoms.
3. The method of Claim 2, wherein n is 3.
4. The method of Claim 3, wherein R 3 is ethyl or n-propyl.
5. The method of Claim 1, wherein Z is C2H5-0-CO- or n-C.3H7-0-CO-, n is 3 and RI and R2 are both hydrogen atoms.
6. The method of Claim 5, wherein W and R 5 are hydrogen atoms.
7. Use of a compound of formula (2):
OH 5 N-(c H 2) R, (2) z 5 wherein:
n is 2, 3 or 4; Z is an ester group of formula R3-0-CO- wherein R3 is CI-6 alkyl or C2- 6 alkenyl; and RI, R2 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, nitro, and trifluoromethyl; and Wis hydrogen or C 1 -6 alkyl; in the preparation of a formulation for treating a patient suffering from pain, trauma, a movement disorder, other than resulting from epilepsy, or spasticity.
8. Use according to Claim 7, wherein the compound of formula (2) is as ftirther defined in any one of Claims 2 to 6.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9925880.8A GB9925880D0 (en) | 1999-11-01 | 1999-11-01 | B-Carboline derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
GB0026485D0 GB0026485D0 (en) | 2000-12-13 |
GB2355659A true GB2355659A (en) | 2001-05-02 |
Family
ID=10863779
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB9925880.8A Ceased GB9925880D0 (en) | 1999-11-01 | 1999-11-01 | B-Carboline derivatives |
GB0026485A Withdrawn GB2355659A (en) | 1999-11-01 | 2000-10-30 | beta-Carboline derivatives for use in treatment of pain, trauma, spasticity and movement disorders |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB9925880.8A Ceased GB9925880D0 (en) | 1999-11-01 | 1999-11-01 | B-Carboline derivatives |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU1044501A (en) |
GB (2) | GB9925880D0 (en) |
WO (1) | WO2001032176A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010081115A1 (en) * | 2009-01-09 | 2010-07-15 | University Of Texas Southwestern Medical Center | Pro-neurogenic compounds |
US8362277B2 (en) | 2009-01-09 | 2013-01-29 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US8735440B2 (en) | 2009-01-09 | 2014-05-27 | Board Of Regents Of The University Of Texas System | Methods for treating amyotrophic lateral sclerosis using pro-neurogenic compounds |
US9095572B2 (en) | 2009-01-09 | 2015-08-04 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9243281B2 (en) | 2013-11-11 | 2016-01-26 | Board Of Regents Of The University Of Texas System | Neuroprotective chemicals and methods for identifying and using same |
US9616048B2 (en) | 2009-01-09 | 2017-04-11 | Board Of Regents Of The University Of Texas System | Anti-depression compounds |
US9701676B2 (en) | 2012-08-24 | 2017-07-11 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9902713B2 (en) | 2013-11-11 | 2018-02-27 | Board Of Regents Of The University Of Texas System | Neuroprotective compounds and use thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT2802320T (en) | 2011-11-15 | 2019-06-17 | Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd | Tricyclic compounds, compositions comprising them and uses thereof |
WO2016203468A1 (en) | 2015-06-15 | 2016-12-22 | Raziel Therapeutics Ltd. | Carbazole derivatives for the treatment of fibrotic diseases and related symptoms, and conditions thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4539407A (en) * | 1983-12-13 | 1985-09-03 | American Home Products Corporation | β-Carboline anticonvulsants |
WO1996034863A1 (en) * | 1995-05-05 | 1996-11-07 | Novo Nordisk A/S | Novel heterocyclic chemistry |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996034865A1 (en) * | 1995-05-05 | 1996-11-07 | Novo Nordisk A/S | Novel heterocyclic chemistry |
-
1999
- 1999-11-01 GB GBGB9925880.8A patent/GB9925880D0/en not_active Ceased
-
2000
- 2000-10-30 GB GB0026485A patent/GB2355659A/en not_active Withdrawn
- 2000-10-30 WO PCT/GB2000/004163 patent/WO2001032176A1/en active Application Filing
- 2000-10-30 AU AU10445/01A patent/AU1044501A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4539407A (en) * | 1983-12-13 | 1985-09-03 | American Home Products Corporation | β-Carboline anticonvulsants |
WO1996034863A1 (en) * | 1995-05-05 | 1996-11-07 | Novo Nordisk A/S | Novel heterocyclic chemistry |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2010203356B2 (en) * | 2009-01-09 | 2015-11-26 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US10183011B2 (en) | 2009-01-09 | 2019-01-22 | Board Of Regents Of The University Of Texas System | Anti-depression compounds |
WO2010081115A1 (en) * | 2009-01-09 | 2010-07-15 | University Of Texas Southwestern Medical Center | Pro-neurogenic compounds |
US8735440B2 (en) | 2009-01-09 | 2014-05-27 | Board Of Regents Of The University Of Texas System | Methods for treating amyotrophic lateral sclerosis using pro-neurogenic compounds |
US8748473B2 (en) | 2009-01-09 | 2014-06-10 | Board Of The Regents Of The University Of Texas System | Methods of treating post-traumatic stress disorder using pro-neurogenic compounds |
US8791149B2 (en) | 2009-01-09 | 2014-07-29 | Board Of Regents Of The University Of Texas System | Methods of treating traumatic brain injury using pro-neurogenic compounds |
US8877797B2 (en) | 2009-01-09 | 2014-11-04 | Board Of Regents Of The University Of Texas System | Methods for treating Parkinson's disease using pro-neurogenic compounds |
US9095572B2 (en) | 2009-01-09 | 2015-08-04 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9095571B2 (en) | 2009-01-09 | 2015-08-04 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9278923B2 (en) | 2009-01-09 | 2016-03-08 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US8604074B2 (en) | 2009-01-09 | 2013-12-10 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US8362277B2 (en) | 2009-01-09 | 2013-01-29 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9156787B2 (en) | 2009-01-09 | 2015-10-13 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9446042B2 (en) | 2009-01-09 | 2016-09-20 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9446022B2 (en) | 2009-01-09 | 2016-09-20 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9616048B2 (en) | 2009-01-09 | 2017-04-11 | Board Of Regents Of The University Of Texas System | Anti-depression compounds |
US10172827B2 (en) | 2009-01-09 | 2019-01-08 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9962368B2 (en) | 2009-01-09 | 2018-05-08 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9884820B2 (en) | 2009-01-09 | 2018-02-06 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9701676B2 (en) | 2012-08-24 | 2017-07-11 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
US9902713B2 (en) | 2013-11-11 | 2018-02-27 | Board Of Regents Of The University Of Texas System | Neuroprotective compounds and use thereof |
US9645139B2 (en) | 2013-11-11 | 2017-05-09 | Board Of Regents Of The University Of Texas System | Neuroprotective chemicals and methods for identifying and using same |
US9243281B2 (en) | 2013-11-11 | 2016-01-26 | Board Of Regents Of The University Of Texas System | Neuroprotective chemicals and methods for identifying and using same |
Also Published As
Publication number | Publication date |
---|---|
GB9925880D0 (en) | 1999-12-29 |
GB0026485D0 (en) | 2000-12-13 |
WO2001032176A1 (en) | 2001-05-10 |
AU1044501A (en) | 2001-05-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10273214B2 (en) | Subunit selective NMDA receptor potentiators for the treatment of neurological conditions | |
US20080255149A1 (en) | Carboxyamine Compounds and Methods of Use Thereof | |
IL278053B1 (en) | Peptide macrocycles against acinetobacter baumannii | |
JPH03148221A (en) | D-cycloserine and d-alanine containing composition for treating the disorder of memory and learning for treating the disorder of memory and learning rate or the disorder of recognition or mind | |
IL103214A (en) | Pharmaceutical compositions containing tachykinin antagonists for the treatment of emesis | |
KR20060076317A (en) | Triaza-spiropiperidine derivatives for use as glyt-1 inhibitors in the treatment of neurological and neuropsychiatric disorders | |
JPH05320162A (en) | Peptidic quinuclidine | |
MX2011012712A (en) | Aryl substituted carboxamide derivatives as calcium or sodium channel blockers. | |
TW200950779A (en) | Novel glucagon receptor antagonists, compositions, and methods for their use | |
CN109952301B (en) | 5-HT2C receptor agonists and compositions and methods of use | |
PL180209B1 (en) | Novel heterocyclic compounds | |
WO2015095783A1 (en) | Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment | |
CZ657890A3 (en) | Chroman derivative, process of its preparation and pharmaceutical composition containing thereof | |
WO2015200619A1 (en) | Inhibitors of histone deacetylase | |
GB2355659A (en) | beta-Carboline derivatives for use in treatment of pain, trauma, spasticity and movement disorders | |
EP2681209B1 (en) | Compounds and methods for the treatment of pain and other disorders | |
TWI360538B (en) | N-(1h-indolyl)-1h-indole-2-carboxamide derivatives | |
JP4762250B2 (en) | Phenyl-piperazine methanone derivatives | |
JP2022513030A (en) | A pharmaceutical composition comprising a histone deacetylase 6 inhibitor | |
AU2004262970B2 (en) | Treatment for Alzheimer's disease and related conditions | |
JP2002507600A (en) | Piperidinyl and N-amidinopiperidinyl derivatives | |
US7728022B2 (en) | (4, 5, 6, 7-tetrahydro-1-H-indol-7-yl) acetic acid derivatives for treatment of Alzheimer's disease | |
TW201000480A (en) | Imidazo pyridine derivatives | |
JP2008526795A (en) | Sulfanyl-substituted phenylmethanone as a glycine transporter 1 (GLYT-1) inhibitor for treating neurological disorders and neuropsychiatric disorders | |
CN115850270B (en) | Alpha-carboline compound or pharmaceutical composition thereof, and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |