Classifications

• • 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

Definitions

• the present invention relates to 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, their preparation and use as therapeutic agents.
• 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 various parts of the body will react to the different crystalline forms.
• the present invention provides a series of crystalline salts of
• 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-1 H-3-benzazepin-7-ol, maleate; (S) ( + )-8- chloro-5-(5, 6-dichloro-2,3-di
• 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-benzazepi ⁇ e-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.
• 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-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol and a pharmaceutically acceptable carrier.
• 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.
• 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.
• composition of this invention may be formulated by conventional methods of galenic pharmacy.
• Conventional excipients are such pharmaceutically acceptable organic or 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 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- integrants, 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.
• auxiliary agents such as binders, lubricants, preservatives, dis- integrants, 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.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• tablets, dragees, or cap ⁇ sules 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 tech- niques, contains:
• 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- stering an effective amount of a pharmaceutically acceptable crystalline salt 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 preparation was carried out analogously to the preparation in Example 1 using L( + )-tartaric acid and 20 mmol of the compound of for ⁇ mula I .

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

Priority Applications (8)

Applications Claiming Priority (2)

Publications (1)

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ID=8100205

Family Applications (1)

Country Status (13)

Citations (1)

• 1996
  • 1996-09-12 CA CA002231848A patent/CA2231848A1/en not_active Abandoned
  • 1996-09-12 AU AU69235/96A patent/AU700596B2/en not_active Ceased
  • 1996-09-12 BR BR9610162A patent/BR9610162A/pt unknown
  • 1996-09-12 HU HU9900746A patent/HUP9900746A3/hu unknown
  • 1996-09-12 CN CN96197660A patent/CN1200121A/zh active Pending
  • 1996-09-12 EP EP96930028A patent/EP0850237A1/en not_active Withdrawn
  • 1996-09-12 JP JP9511574A patent/JPH11512403A/ja active Pending
  • 1996-09-12 CZ CZ98778A patent/CZ77898A3/cs unknown
  • 1996-09-12 PL PL96325514A patent/PL325514A1/xx unknown
  • 1996-09-12 WO PCT/DK1996/000383 patent/WO1997010239A1/en not_active Ceased
  • 1996-09-12 IL IL12360296A patent/IL123602A0/xx unknown
  • 1996-09-12 KR KR1019980701902A patent/KR19990044648A/ko not_active Withdrawn
• 1998
  • 1998-03-13 NO NO981135A patent/NO981135L/no unknown

Patent Citations (1)

Non-Patent Citations (1)

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