AU700596B2 - 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 PDF

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AU700596B2
AU700596B2 AU69235/96A AU6923596A AU700596B2 AU 700596 B2 AU700596 B2 AU 700596B2 AU 69235/96 A AU69235/96 A AU 69235/96A AU 6923596 A AU6923596 A AU 6923596A AU 700596 B2 AU700596 B2 AU 700596B2
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tetrahydro
dichloro
chloro
crystalline
methyl
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Rolf Emil Amsler
Louis Brammer Hansen
Scott Eugene Mcgraw
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Paion UK Ltd
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—Antidepressants

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

WO 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 (5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2, 3,4, 1H-3-benzazepine-7-ol, their preparation and use as therapeutic agents.
International patent appl. No. WO 93/17012 discloses a class of compounds 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, depression and Parkinson's disease.
In example 3 of International appl. No. WO 93/17012 the preparation of (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl- 2,3,4,5-tetrahydro-lH-3-benzazepine-7-ol of formula I: HO N
C
C1 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.
i i p- I WO 97/10239 PCT/DK96/00383 -2- Further, it has been founu that some acid addition salts of the compound of formula I do form alternate polymorphic forms. This is pharmaceutically undesirable because of the potential that the salt occurs in more than one crystalline form making it very difficult to predict how the 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 pharmaceutically acceptable acid addition salts of the compound of formula I can be obtained in a reproducible crystalline form.
Accordingly, the present invention provides a series of crystalline salts of (+)-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 (+)-8-chloro-5-(5,6-dichloro-2,3dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7ol, hemifumarate; (+)-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; (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, maleate; chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5tetrahydro-1 H-3-benzazepin-7-ol, L(+)-mandelate.
The acid addition salts of the (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-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 i. r iM1iI ''iT Th i nT i ii ^*Xc WO 97/10239 PCT/DK96/00383 -3the 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 comprising crystalline salts of (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol and a pharmaceutically acceptable carrier.
The compositions of this invention are usually adapted for oral administration, 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 containing 0.01 mg 1000 mg for oral dosing. Typical dosage for antiphsychotic 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 inorganic carrier substances suitnhbe for parenteral or oral application which do not deleteriously react with the active compound.
WO 97/10239 PCT/DK96/00383 -4- 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 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, disintegrants, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic 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 suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
For oral administration, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the 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 techniques, contains: Active compound 10 mg Lactosum 67.8 mg Ph.Eur.
Avicel® 31.4 mg Amberlitee IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur. r WO 97/10239 PCT/DK96/00383 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 administering an effective amount of a pharmaceutically acceptable crystalline salt of (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol.
The invention further provides pharmaceutically acceptable crystalline salts of (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3methyl-2,3,4,5-tetrahydro-1H-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 (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol of the invention were synthesized and crystallized from common solvents as described in the following examples.
EXAMPLE 1 (+)-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 25 )-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 g, 20 mmol) was dissolved 99% ethanol at 70 C. Fumaric acid (2.32 g, 20 mmol) was 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. A WO 97/10239 PCT/DK96/00383 -6- Yield: 8.80 g of white crystalline product. M.p. by DSC: 298 0
C.
Elemental Analysis: (C 21
H
20
CI
3
N
1 04, Calculated: C 55.22 H 4.41 Found: C 55.30 H 4.55 Alternate polymorphic forms: None 456.8 g/mol) N 3.07 N 3.94 EXAMPLE 2 (+)-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 formula I.
Yield: 7.75 g of white crystalline product. M.p. by DSC: 276 0
C.
Elemental Analysis: (C 21
H
2 1
C
3
NI
1 0s, Calculated: C 53.24 H 4.47 Found: C 53.21 H 4.55 Alternate polymorphic form: None 473.8 g/mol): N 2.96 N 2.80 EXAMPLE 3 (+)-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 compound of formula I.
~q~41
I,:
I
WO 97/10239 PCT/DK96/00383 -7- Yield: 7.61 g of white crystalline product. M.p. by DSC: 234 0
C.
Elemental Analysis: (C 23
H
22 CIaN, 1 s, Calculated: C 53.66 H 4.31 Found: C 53.79 H 4.37 Alternate polymorphic form: None 514.8 g/mol): N 2.72 N 2.56 EXAMPLE 4 (+)-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 I.
Yield: 10.35 g of white crystalline product. M.p. by DSC: 249 0
C.
Elemental analysis: (C 27
H
26 C1N,0 5 Calculated: C 58.87 H 4.76 Found: C 58.97 H 4.88 Alternate polymorphic form: None 550.9 g/mol): N 2.54 N 2.50

Claims (9)

1. Crystalline salts of (+)-8-chloro-5-(5,6-dichloro-2,3 -dihydro-benzofuran-7- yl)-3-rnethyl-2,3,4, 5-tetrahydro- 1H-3-benzazepine-7-ol, derived from fumaric acid, tartaric acid, maleic acid and L(+)-mandelic acid.
2. A crystalline salt according to claim 1 which is (+)-8-chloro-5-(5,6-dichloro- 2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4, 5-tetrahydro- 1H-3 -benzazepin-7-ol, hemifumarate; (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-r~ethyl- 2,3,4,5 -tetrahydro- 11--3 -benzazepin-7-ol, L(+)-hemitartrate; (+)-8-cloro-5-(5,6- dichloro-2,3 -dihydrobenzofuran-7-yl)-3-methiyl-2,3,4,5-tetrahydro-I--3-benzazepin-7-ol, maleate (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3 tetrahiydro- 11--3 -benzazepin-7-ol, L(+)-mandelate.
3. Crystalline salts of (+)-8-chloro-5 ,6-dichloro-2,3-dihiydro-benzofuran-7- yl)-3-methyl-2,3 ,4,5-tetrahydro- IH-3-benzazepine-7-ol, substantially as hereinbefore j described with reference to any one of the Examples. 6 4. A process for the preparation of crystalline acid addition salts of t 00 chloro-5-(5,6-dichloro-2,3-dihydrobenzo firan-7-yl)-3-methyl-2,3,4,5-tetrahydro-I 1--3- to co benzazepine-7-ol according to claims 1 or 2, which process comprises dissolving the acid of the corresponding addition salt and (+)-8-chloro-5-(5,6-dichiloro-2,3-dihydrobenizofuran-
7-yl)-3-methyl-2,3 5-tetrahydro-l I 1--3-benzazepine-7-ol in a common solvent, and crystallising the resulting salt from the solution. 5. A process for the preparation of crystalline acid addition salts of ,6-dichloro-2,3-dihydrobenzo furan-7-yl)-3-methyl-2,3 ,4,5-tetrahydro- 11-1-3- benzazepine-7-ol, substantially as hereinbefore described with reference to any one of the :~Examples. 6. Crystalline salts of (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-benzofuran-7- yl)-3-methyl-2,3,4,S-tetrahydro-IH-3-benzazepine-7-ol, prepared by the process of claim 4 or 7. A pharmaceutical composition comprising a crystalline salt according to any one "u of claims 1 to 3 or 6 together with a pharmaceutically acceptable carrier or diluent. S. A pharmaceutical composition for use in treating an indication related to dysfunctions of the dopamidne D-1 receptor system comprising an effective amount of a crystalline salt according to any one of claims 1 to 3 or 6 together with a pharmaceutically acceptable carrier or diluent.
9. The pharmaceutical composition according to claim 7 or 8 in the form of an oral dosage unit containing from 0.1-400 mg of the active ingredients. Anmethod of treating an indication related to dysfunctions of the dopamnine D-l receptor system in a mammal comprising administering an effective amount of a crystalline salt according to any one of claims 1 to 3 or 6 or of a composition according to any one of claims 7 to 9- 9
11. A method according to claim 10 wherein the indication is related to psycosis.
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-l receptor system, which process comprises bringing a crystalline salt according to any one of claims 1 to 3 into a galenical dosage form.
13. The use of a crystalline salt according to claims 1 or 2 as a medicament.
14. The use of a salt according to claims 1 or 2 for the preparation of a pharmaceutical composition for treating an indication related to dysfunctions of the dopamine D-1 receptor system. Dated 14 April, 1998 Novo Nordisk A/S 0* 00* *1 o 0 0. 0000 0b 0 00 0 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON op *pd a. prr *1 C I
AU69235/96A 1995-09-15 1996-09-12 Acid addition salts of 2,3,4,5-tetrahydro-1H-3-benzazepine compounds Ceased AU700596B2 (en)

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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

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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) NO981135L (en)
PL (1) PL325514A1 (en)
WO (1) WO1997010239A1 (en)

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NO981135D0 (en) 1998-03-13
KR19990044648A (en) 1999-06-25
AU6923596A (en) 1997-04-01
NO981135L (en) 1998-03-13
HUP9900746A2 (en) 1999-09-28
CZ77898A3 (en) 1998-07-15
EP0850237A1 (en) 1998-07-01
HUP9900746A3 (en) 1999-11-29
CA2231848A1 (en) 1997-03-20
WO1997010239A1 (en) 1997-03-20
PL325514A1 (en) 1998-08-03
IL123602A0 (en) 1998-10-30
MX9802000A (en) 1998-08-30
CN1200121A (en) 1998-11-25
BR9610162A (en) 1999-01-05

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