Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to Dopamine Dl receptor agonist compounds, to methods for preparing such compounds and to their use.
• GB 1 599 705 discloses 1-thienyl and l-furyl-2,3,4,5-tetrahydro-lH-3-benzazepines having utility as cardiovascular agents.
• Some benzazepines as Dopamine Dl receptor agonists have been described.
• l-phenyl-3 -benzazepines are disclosed in EP 0 230 755-A and carbamates of6-chloro-7,8-dihydroxy-l (4'-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3- benzazepine are disclosed in EP 0 380 355-A.
• the present invention provides compounds which are potent and selective ligands for the Dopamine Dl receptor.
• Such compounds can be used in the treatment of neurodegenerative diseases especially, but not limited to, Parkinson's disease.
• Parkinson's disease is a progressive neurodegenerative disorder characterized by the progressive death of presynaptic dopamine nuerones in the substantia nigra that innervate postsynaptic striatal neurones and the resultant loss of striatal dopamine.
• the primary therapy for Parkinson's disease focuses upon compensation for this loss of dopamine in the striatum.
• the current main-stay for this replacement in the administrattion of the metabolic precursor of dopamine, namely, L-DOPA which is converted into dopmaine in the central nervous system.
• L-DOPA can cause severe adverse effects such as nausea, vomiting, cardiac arrythmias and hypotension. Additionally, long-term use of L- DOPA is associated with the development of abnormal involuntary movements (dyskinesias) and psychosis. Furthermore, the positive benefits associated with chronic L-DOPA therapy experienced by suffers is lessened, typically several years after treatment was first initiated. Therapeutic agents that selectively interact positively with postsynaptic dopamine Dl receptors in the striatum, directly or in-directly (hereafter termed dopamine Dl agonists) are particularly valuable as anti-Parkinsonian agents.
• R 1 is hydrogen, halogen, C ⁇ -C 4 alkyl, or CF 3 ;
• R 2 is hydrogen, methyl, or lower alkenyl of 3-5 carbon atoms
• R 3 and R 4 together form a furan, dihydrofuran, thiophene, dihydrothiophene, cyclopentane or cyclohexane ring and R 5 is hydrogen or R 4 and R 5 together form a furan, dihydrofuran, thiophene, dihydrothiophene, cyclopentane or cyclohexane ring and R 3 is hydrogen;
• R 6 is hydrogen, halogen, CF 3 , CN, NO 2 orNH ;
• R 7 is hydrogen, halogen, CF 3 , CN, NO 2 orNH 2 .
• the compounds of formula I may be presented as a mixture of enantiomers, which may be resolved into the individual pure enantiomers. This resolution may conveniently be performed by fractional crystallisation, from various solvents, of the salts of compounds of the formula I with optically active acids or by other methods known from the literature e.g. chiral column chromatography. Therefore, this invention includes all isomers, whether resolved or mixtures thereof.
• Particularly valuable embodiments of this invention are non-toxic, pharmaceutically acceptable acid addition salts of benzazepines of formula I.
• Such salts include those derived from inorganic and organic acids such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, acetic, lactic, maleic, phthalic and tartaric acids.
• the compounds of the invention are useful because of their pharmacological activity.
• the compounds of the invention are potent (high affinity) and selective ligands for the central dopamine Dl receptor (Table 1) as measured by competitive radio-ligand displacement assays using rat striatal tissue homogenates as per the method described in Psychoph rmacology 117:275-286 (1995).
• the benzazepine compounds of Formula I possess anti-Parkinsonian activity due to central dopaminergic activity as demonstrated by employing the standard pharmacological test procedure as reported by Ungerstedt et al., in Brain Research 24:485-493 (1970). This procedure is based on the drug-induced rotation (circling) of rats having extensive unilateral dopaminergic lesions of the substantia nigra. Briefly, the test comprises the quantitative recording of rotational behaviour in rats in which 6-hydroxydopamine lesions of the nigrostriatal dopamine system have been produced. Unilateral brain lesioning of the substantia nigra in one hemisphere results in the dopamine receptor system in that region to become hypersensitive following the degeneration of the nigral cell bodies.
• Activation of these super-sensitive dopamine receptors by drugs induce asymmetrical movement of the animal, contralateral rotation (with respect to the lesioned side of the brain).
• the rate and duration of contralateral rotation induced upon drug administration is an index of central dopaminergic activity of the agent.
• Compounds which are known to be clinically effective in controlling Parkinsonism, e.g. L-DOPA and apomorphine, are also effective in this rat circling model.
• the compound l-indan-5-yl-6-chloro-3-methyl-2,3,4,5- tetrahydro-lH-3-benzazepine-7,8-diol produces robust circling in the unilateral lesioned 6- hydroxy dopamine rat model in a dose-related fashion from 0.438 to 5.79 micromoles/kg when administered by subcutaneous injection.
• l-Indan-5-yl-6-chloro-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine (1.03 g, 2.77 mmol) was dissolved in anhydrous dichloromethane (15 ml), which was cooled to -78°C. To this solution was added dropwise BBr 3 (1.0 M solution in dichloromethane, 13.8 ml, 13.8 mmol) over 25 min. The reaction mixture was stirred at -78°C for 1 h, at 0°C for 3 h and at r.t for further 1 h.
• the crude amine was taken up in methanol (40ml) and aqueous formaldehyde (2.8ml, 37% wt, 37 mmol) was added followed by sodium cyanoborohydride (lJ5g, 21mmol) and the resulting solution stirred for 18 hours.
• the solvents were removed in vacuo, and the residue taken up in hydrochloric acid (100ml, IM).
• the solution was washed with diethyl ether (2x 100ml) and basified with concentrated aqueous ammonia (100ml, 0.880), the mixture was extracted with dichloromethane (2x 100ml).
• the reaction mixture was maintained at -78°C for 1 hour, allowed to warm to 0°C and stirred for 2 hours.
• the reaction mixture was subsequently cooled to -78°C, methanol (10ml) added slowly and stirred for 1 hour, and for 18 hours at ambient temperature.
• the solvents were removed in vacuo to afford the crude product. Purification by column chromatography on silica using dichloromethane/ methanol (9:1) as eluant and re-crystallisation from propan-2-ol diethyl ether afforded the title compound as a buff solid (lOOmg, 17%). Anal.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
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• 1999
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• 2000
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• 2001
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