EP0850237A1 - 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

Info

Publication number
EP0850237A1
EP0850237A1 EP96930028A EP96930028A EP0850237A1 EP 0850237 A1 EP0850237 A1 EP 0850237A1 EP 96930028 A EP96930028 A EP 96930028A EP 96930028 A EP96930028 A EP 96930028A EP 0850237 A1 EP0850237 A1 EP 0850237A1
Authority
EP
European Patent Office
Prior art keywords
tetrahydro
dichloro
chloro
methyl
dihydrobenzofuran
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Withdrawn
Application number
EP96930028A
Other languages
German (de)
English (en)
French (fr)
Inventor
Louis Brammer Hansen
Rolf Emil Amsler
Scott Eugene Mcgraw
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Paion UK Ltd
Original Assignee
Novo Nordisk AS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0850237A1 publication Critical patent/EP0850237A1/en
Withdrawn legal-status Critical Current

Links

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 .

Landscapes

  • 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)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP96930028A 1995-09-15 1996-09-12 Acid addition salts of 2,3,4,5-tetrahydro-1h-3-benzazepine compounds Withdrawn EP0850237A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK103095 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
EP0850237A1 true EP0850237A1 (en) 1998-07-01

Family

ID=8100205

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96930028A Withdrawn EP0850237A1 (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 (cs)
JP (1) JPH11512403A (cs)
KR (1) KR19990044648A (cs)
CN (1) CN1200121A (cs)
AU (1) AU700596B2 (cs)
BR (1) BR9610162A (cs)
CA (1) CA2231848A1 (cs)
CZ (1) CZ77898A3 (cs)
HU (1) HUP9900746A3 (cs)
IL (1) IL123602A0 (cs)
NO (1) NO981135D0 (cs)
PL (1) PL325514A1 (cs)
WO (1) WO1997010239A1 (cs)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK23392D0 (da) * 1992-02-24 1992-02-24 Novo Nordisk As Heterocykliske forbindelser, deres anvendelse og fremstilling

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9710239A1 *

Also Published As

Publication number Publication date
BR9610162A (pt) 1999-01-05
AU700596B2 (en) 1999-01-07
HUP9900746A2 (hu) 1999-09-28
KR19990044648A (ko) 1999-06-25
CA2231848A1 (en) 1997-03-20
NO981135L (no) 1998-03-13
NO981135D0 (no) 1998-03-13
JPH11512403A (ja) 1999-10-26
CN1200121A (zh) 1998-11-25
AU6923596A (en) 1997-04-01
PL325514A1 (en) 1998-08-03
IL123602A0 (en) 1998-10-30
CZ77898A3 (cs) 1998-07-15
MX9802000A (es) 1998-08-30
WO1997010239A1 (en) 1997-03-20
HUP9900746A3 (en) 1999-11-29

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