CA2231848A1 - Acid addition salts of 2,3,4,5-tetrahydro-1h-3-benzazepine compounds - Google Patents
Acid addition salts of 2,3,4,5-tetrahydro-1h-3-benzazepine compounds Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention provides a series of crystalline salts of (S) (+)-8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol, their preparation and use as therapeutic agents.
Description
W O 97/10239 PCT~DK96/00383 Acid Addition Salts of 2,3,4,5-tetrahydro-1H-3-benzazepine Compounds The present invention relates to crystalline salts of tS) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol, their preparation and use as therapeutic agents.
International patent appl. No. W0 93/17012 discloses a class of com-pounds exhibiting strong antidopaminergic effects and thus making them useful in treatment of disorders in the central nervous system related to dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, pain, 15 depression and Parkinson's disease.
In example 3 of International appl. No. W0 93/17012 the preparation of (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yi)-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7-ol of formula l:
C 1~ ~N--CH ( I ) c is described.
Because of its poor solubility, it is preferred that the compound of formula I is used as a therapeutic agent in the form of an acid addition salt.
Further, it has been found that some acid addition salts of the compound of formula I do form alternate polymorphic forms. This is pharmaceuti-cally undesirable because of the potential that the salt occurs in more than one crystalline form making it very difficult to predict how the 5 various parts of the body will react to the different crystalline forms.
In general, for commercial use it is important to have a physiologically acceptable salt with good bioavailability, good handling properties, and reproducible crystalline form.
Surprisingly, it has now been found that a series of new pharmaceuti-cally acceptable acid addition salts of the compound of formula I can be obtained in a reproducible crystalline form.
15 Accordingly, the present invention provides a series of crystalline salts of (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol derived from organic acids such as fumaric, tartaric, maleic and mandelic acids.
Preferred salts of the invention are (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, hemifumarate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofu-ran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( + )-hemi-tartrate; (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol, maleate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( + )-mandelate.
The acid addition salts of the (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihy-drobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol are prepared by dissolving the acid of the corresponding addition salt and the compound of formula I in a common solvent, and crystallizing the resulting salt from the solution.
Examples of the common solvents include lower aliphalic alcohols such as ethanol, methanol, 2-propanol, 2-butanol, 1-hexanol and solvents like isobutylmethylketone and tetrahydrofuran.
The present invention also provides pharmaceutical compositions com-prising crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-benzofuran-7-yl)-3-methyl-2,3,4,~-tetrahydro-1 H-3-benzazepine-7-ol and a pharmaceutically acceptable carrier.
The compositions of this invention are usually adapted for oral admini-stration, but formulations for dissolution for parenteral administration are also within the scope of this invention.
The composition is usually presented as a unit dose composition contain-ing 0.01 mg - 1000 mg for oral dosing. Typical dosage for antiphsy-chotic effect would vary between 0.1 - 400 mg, preferably between 1.0 - 200 mg per day divided in 2 or 3 doses when administered orally.
Preferred unit dosage forms include in solid form, tablets or capsules, in liquid form, solutions, suspensions, emulsions, elixirs or capsules filled with the same, or in form of sterile injectable solutions.
The composition of this invention may be formulated by conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or 30 inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, agar, pectin, acacia, amylose, magnesium stearate, talc, silicic acid, stearic acid, fatty acid 5 monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as binders, lubricants, preservatives, dis-10 integrants, stabilizers, wetting agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are injectable solutions or 15 suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
For oral administration, particularly suitable are tablets, dragees, or cap-sules having talc and/or a carbohydrate carrier or binder or the like, the 20 carrier preferably being lactose and/or corn starch and/or potato starch.
A syrup, elixir or like can be used when a sweetened vehicle can be employed .
A typical tablet, which may be prepared by conventional tabletting tech-25 niques, contains:
Active compound 10 mg !' Lactosum 67.8 mg Ph.Eur.
Avicel~' 31.4 mg AmberliteC' IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.
W O 97/10239 PCT~DK~6/0~3 The invention also provides methods of treatment of certain disorders in the central nerveous system related to dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, depression, pain and Parkinson's disease in mammals including humans which methods comprises admini-5 stering an effective amount of a pharmaceutically acceptable crystallinesalt of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol.
The invention further provides pharmaceutically acceptable crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol for use in the treatment of disorders in the central nerveous system related to dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, depression, pain and Parkinson's disease.
The acid addition salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-benzofuran-7-yl)-3-methyl-2,3,4,5-~etrahydro-1 H-3-benzazepine-7-ol of the invention were synthesized and crystallized from common solvents as described in the following examples.
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, hemifumarate (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol (7.97 9, 20 mmol) was dis-solved 99% ethanol at 70~C. Fumaric acid (2.32 g, 20 mmol) was 30 added. The solution was cooled to 0~C, and the resulting suspension was filtered. The filtercake was washed with 99% ethanol (3 x 20 ml) and dried to constant weight.
-W O 97/10239 PCT~DK96/00383 Yield: 8.80 9 (96%) of white crystalline product. M.p. by DSC: 298~C.
Elemental Analysis: (C21H20CI3N,04, 456.8 g/mol) Calculated: C 55.22 H 4.41 N 3.07 %
Found: C 55.30 H 4.55 N 3.94 %
Alternate polymorphic forms: None (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L~ + )-hemitartrate The preparation was carried out analogously to the preparation in Example 1 using L( + )-tartaric acid and 20 mmol of the compound of for-mula 1.
Yield: 7.75 g (82%) of white crystalline product. M.p. by DSC: 276~C.
Elemental Analysis: (C2lH2lCI3NlO5, 473.8 g/mol~:
Calculated: C 53.24 H 4.47 N 2.96 ~/O
Found: C 53.21 H 4.55 N 2.80 ~/0 Alternate polymorphic form: None (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-ol, maleate The preparation of the compound was carried out analogously to the preparation in Example 1 using maleic acid, and 20 mmol of the com-pound of formula 1.
Yield: 7.61 9 ~74%) of white crystalline product. M.p. by DSC: 234OC, Elemental Analysis: (C23H22CI3Nl08, 514.8 g/mol):
Calculated: C 53.66 H 4.31 N 2.72 %
Found: C 53.79 H 4.37 N 2.56 %
Alternate polymorphic form: None (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( ~ )-mandelate The preparation of the compound was carried out analogously to the preparation in Example 1 using L( +)-mandelic acid, and 20 mmol of the compound of formula 1.
Yield: 10.35 9 (94%) of white crystalline product. M.p. by DSC: 249~C.
Elemental analysis: (C27H2~CI3N105, 550.9 g/mol):
Calculated: C 58.87 H 4.76 N 2.54 %
Found: C 58.97 H 4.88 N 2.50 %
Alternate polymorphic form: None
International patent appl. No. W0 93/17012 discloses a class of com-pounds exhibiting strong antidopaminergic effects and thus making them useful in treatment of disorders in the central nervous system related to dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, pain, 15 depression and Parkinson's disease.
In example 3 of International appl. No. W0 93/17012 the preparation of (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yi)-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine-7-ol of formula l:
C 1~ ~N--CH ( I ) c is described.
Because of its poor solubility, it is preferred that the compound of formula I is used as a therapeutic agent in the form of an acid addition salt.
Further, it has been found that some acid addition salts of the compound of formula I do form alternate polymorphic forms. This is pharmaceuti-cally undesirable because of the potential that the salt occurs in more than one crystalline form making it very difficult to predict how the 5 various parts of the body will react to the different crystalline forms.
In general, for commercial use it is important to have a physiologically acceptable salt with good bioavailability, good handling properties, and reproducible crystalline form.
Surprisingly, it has now been found that a series of new pharmaceuti-cally acceptable acid addition salts of the compound of formula I can be obtained in a reproducible crystalline form.
15 Accordingly, the present invention provides a series of crystalline salts of (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol derived from organic acids such as fumaric, tartaric, maleic and mandelic acids.
Preferred salts of the invention are (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, hemifumarate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofu-ran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( + )-hemi-tartrate; (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol, maleate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( + )-mandelate.
The acid addition salts of the (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihy-drobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol are prepared by dissolving the acid of the corresponding addition salt and the compound of formula I in a common solvent, and crystallizing the resulting salt from the solution.
Examples of the common solvents include lower aliphalic alcohols such as ethanol, methanol, 2-propanol, 2-butanol, 1-hexanol and solvents like isobutylmethylketone and tetrahydrofuran.
The present invention also provides pharmaceutical compositions com-prising crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-benzofuran-7-yl)-3-methyl-2,3,4,~-tetrahydro-1 H-3-benzazepine-7-ol and a pharmaceutically acceptable carrier.
The compositions of this invention are usually adapted for oral admini-stration, but formulations for dissolution for parenteral administration are also within the scope of this invention.
The composition is usually presented as a unit dose composition contain-ing 0.01 mg - 1000 mg for oral dosing. Typical dosage for antiphsy-chotic effect would vary between 0.1 - 400 mg, preferably between 1.0 - 200 mg per day divided in 2 or 3 doses when administered orally.
Preferred unit dosage forms include in solid form, tablets or capsules, in liquid form, solutions, suspensions, emulsions, elixirs or capsules filled with the same, or in form of sterile injectable solutions.
The composition of this invention may be formulated by conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or 30 inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, agar, pectin, acacia, amylose, magnesium stearate, talc, silicic acid, stearic acid, fatty acid 5 monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as binders, lubricants, preservatives, dis-10 integrants, stabilizers, wetting agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are injectable solutions or 15 suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
For oral administration, particularly suitable are tablets, dragees, or cap-sules having talc and/or a carbohydrate carrier or binder or the like, the 20 carrier preferably being lactose and/or corn starch and/or potato starch.
A syrup, elixir or like can be used when a sweetened vehicle can be employed .
A typical tablet, which may be prepared by conventional tabletting tech-25 niques, contains:
Active compound 10 mg !' Lactosum 67.8 mg Ph.Eur.
Avicel~' 31.4 mg AmberliteC' IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.
W O 97/10239 PCT~DK~6/0~3 The invention also provides methods of treatment of certain disorders in the central nerveous system related to dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, depression, pain and Parkinson's disease in mammals including humans which methods comprises admini-5 stering an effective amount of a pharmaceutically acceptable crystallinesalt of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol.
The invention further provides pharmaceutically acceptable crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol for use in the treatment of disorders in the central nerveous system related to dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, depression, pain and Parkinson's disease.
The acid addition salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-benzofuran-7-yl)-3-methyl-2,3,4,5-~etrahydro-1 H-3-benzazepine-7-ol of the invention were synthesized and crystallized from common solvents as described in the following examples.
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, hemifumarate (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol (7.97 9, 20 mmol) was dis-solved 99% ethanol at 70~C. Fumaric acid (2.32 g, 20 mmol) was 30 added. The solution was cooled to 0~C, and the resulting suspension was filtered. The filtercake was washed with 99% ethanol (3 x 20 ml) and dried to constant weight.
-W O 97/10239 PCT~DK96/00383 Yield: 8.80 9 (96%) of white crystalline product. M.p. by DSC: 298~C.
Elemental Analysis: (C21H20CI3N,04, 456.8 g/mol) Calculated: C 55.22 H 4.41 N 3.07 %
Found: C 55.30 H 4.55 N 3.94 %
Alternate polymorphic forms: None (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L~ + )-hemitartrate The preparation was carried out analogously to the preparation in Example 1 using L( + )-tartaric acid and 20 mmol of the compound of for-mula 1.
Yield: 7.75 g (82%) of white crystalline product. M.p. by DSC: 276~C.
Elemental Analysis: (C2lH2lCI3NlO5, 473.8 g/mol~:
Calculated: C 53.24 H 4.47 N 2.96 ~/O
Found: C 53.21 H 4.55 N 2.80 ~/0 Alternate polymorphic form: None (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-ol, maleate The preparation of the compound was carried out analogously to the preparation in Example 1 using maleic acid, and 20 mmol of the com-pound of formula 1.
Yield: 7.61 9 ~74%) of white crystalline product. M.p. by DSC: 234OC, Elemental Analysis: (C23H22CI3Nl08, 514.8 g/mol):
Calculated: C 53.66 H 4.31 N 2.72 %
Found: C 53.79 H 4.37 N 2.56 %
Alternate polymorphic form: None (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( ~ )-mandelate The preparation of the compound was carried out analogously to the preparation in Example 1 using L( +)-mandelic acid, and 20 mmol of the compound of formula 1.
Yield: 10.35 9 (94%) of white crystalline product. M.p. by DSC: 249~C.
Elemental analysis: (C27H2~CI3N105, 550.9 g/mol):
Calculated: C 58.87 H 4.76 N 2.54 %
Found: C 58.97 H 4.88 N 2.50 %
Alternate polymorphic form: None
Claims (12)
1. Crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-benzofuran-7-yl)-3-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepine-7-ol, derived from fumaric acid, L(+)-tartaric acid, maleic acid and L(+)-mandelic acid.
2. A crystalline salt according to claim 1 which is (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol, hemifumarate; (S)(+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-ben-zazepin-7-ol, L(+)-hemitartrate, (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepin-7-ol, maleate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol, L(+)-mandelate.
3, The use of a crystalline salt according to claims 1 or 2 as a medicament.
4. The use of a salt according to claims 1 or 2 for the preparation of a pharmaceutical compusition for treating an indication related to dysfunctions of the dopamine D-1 receptor system.
5. A pharmaceutical composition comprising a crystalline salt according to claim 1 or 2 together with a pharmaceutically acceptable carrier or diluent.
6. A pharmaceutical composition for use in treating an indication related to dysfunctions of the dopamine D-1 receptor system comprising an effective amount of a crystalline salt according to claim 1 or 2, together with a pharmaceutically acceptable carrier or diluent.
7. The pharmaceutical composition according to claim 5 or 6 in the form of an oral dosage unit containing from 0.1-400 mg of the active ingredients.
8. A process for the preparation of crystalline acid addition salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol according to claims 1 or 2, which process comprises dissolving the acid of the corresponding addition salt and (S)(+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol in a common solvent, and crystallising the resulting salt from the solution.
9. A method of treating an indication related to dysfunctions of the dopamine D-1 receptor system in a mammal comprising administering an effective amount of a crystalline salt according to claim 1 or 2.
10. A method according to claim 9 wherein the indication is related to psycosis.
11. A method of treating an indication related to dysfunctions of the dopamine D-1 receptor system in a mammal comprising administering a pharmaceutical composition according to claim 5.
12. A process for the manufacture of a pharmaceutical composition to be used in the treatment of an indication related to dysfunctions of the dopamine D-1 receptor system, which process comprises bringing a crystalline salt according to claim 1 or 2 into a galenical dosage form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1030/95 | 1995-09-15 | ||
| DK103095 | 1995-09-15 | ||
| PCT/DK1996/000383 WO1997010239A1 (en) | 1995-09-15 | 1996-09-12 | Acid addition salts of 2,3,4,5-tetrahydro-1h-3-benzazepine compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2231848A1 true CA2231848A1 (en) | 1997-03-20 |
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ID=8100205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002231848A Abandoned CA2231848A1 (en) | 1995-09-15 | 1996-09-12 | Acid addition salts of 2,3,4,5-tetrahydro-1h-3-benzazepine compounds |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0850237A1 (en) |
| JP (1) | JPH11512403A (en) |
| KR (1) | KR19990044648A (en) |
| CN (1) | CN1200121A (en) |
| AU (1) | AU700596B2 (en) |
| BR (1) | BR9610162A (en) |
| CA (1) | CA2231848A1 (en) |
| CZ (1) | CZ77898A3 (en) |
| HU (1) | HUP9900746A3 (en) |
| IL (1) | IL123602A0 (en) |
| NO (1) | NO981135D0 (en) |
| PL (1) | PL325514A1 (en) |
| WO (1) | WO1997010239A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK23392D0 (en) * | 1992-02-24 | 1992-02-24 | Novo Nordisk As | Heterocyclic Compounds, Their Uses and Preparation |
-
1996
- 1996-09-12 BR BR9610162A patent/BR9610162A/en unknown
- 1996-09-12 AU AU69235/96A patent/AU700596B2/en not_active Ceased
- 1996-09-12 IL IL12360296A patent/IL123602A0/en unknown
- 1996-09-12 JP JP9511574A patent/JPH11512403A/en active Pending
- 1996-09-12 CN CN96197660A patent/CN1200121A/en active Pending
- 1996-09-12 PL PL96325514A patent/PL325514A1/en unknown
- 1996-09-12 CZ CZ98778A patent/CZ77898A3/en unknown
- 1996-09-12 HU HU9900746A patent/HUP9900746A3/en unknown
- 1996-09-12 EP EP96930028A patent/EP0850237A1/en not_active Withdrawn
- 1996-09-12 WO PCT/DK1996/000383 patent/WO1997010239A1/en not_active Application Discontinuation
- 1996-09-12 CA CA002231848A patent/CA2231848A1/en not_active Abandoned
- 1996-09-12 KR KR1019980701902A patent/KR19990044648A/en not_active Application Discontinuation
-
1998
- 1998-03-13 NO NO981135A patent/NO981135D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL325514A1 (en) | 1998-08-03 |
| CN1200121A (en) | 1998-11-25 |
| HUP9900746A3 (en) | 1999-11-29 |
| EP0850237A1 (en) | 1998-07-01 |
| AU700596B2 (en) | 1999-01-07 |
| WO1997010239A1 (en) | 1997-03-20 |
| AU6923596A (en) | 1997-04-01 |
| NO981135L (en) | 1998-03-13 |
| BR9610162A (en) | 1999-01-05 |
| HUP9900746A2 (en) | 1999-09-28 |
| KR19990044648A (en) | 1999-06-25 |
| NO981135D0 (en) | 1998-03-13 |
| MX9802000A (en) | 1998-08-30 |
| CZ77898A3 (en) | 1998-07-15 |
| JPH11512403A (en) | 1999-10-26 |
| IL123602A0 (en) | 1998-10-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20010912 |