EP1233965A1 - Isoquinoline and quinazoline derivatives for the treatment of cns disorders - Google Patents

Isoquinoline and quinazoline derivatives for the treatment of cns disorders

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Publication number
EP1233965A1
EP1233965A1 EP00971422A EP00971422A EP1233965A1 EP 1233965 A1 EP1233965 A1 EP 1233965A1 EP 00971422 A EP00971422 A EP 00971422A EP 00971422 A EP00971422 A EP 00971422A EP 1233965 A1 EP1233965 A1 EP 1233965A1
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EP
European Patent Office
Prior art keywords
formula
compound
pharmaceutically acceptable
group
compound according
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.)
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Application number
EP00971422A
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German (de)
French (fr)
Inventor
Laramie Mary GlaxoSmithKline Pharmaceut. GASTER
Thomas Daniel SmithKline Beecham Pharm. HEIGHTMAN
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication of EP1233965A1 publication Critical patent/EP1233965A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • 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
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to novel isoquinoline and quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing them and to their use in the treatment of various disorders.
  • US patent 5,703,072 discloses bicyclic nonane and decane compounds having dopamine receptor affinity which are claimed to be of use in the treatment of schizophrenia.
  • WO 98/50358, WO 98/50346, WO 98/47868, WO 98/47885, WO 98/50543 and WO 99/31086 all disclose a series of novel compounds which are claimed to possess combined 5-HT ⁇ A, 5-HT ⁇ g and 5-HTi rj receptor affinity and which are said to be useful in the treatment of various CNS disorders.
  • WO 97/36867 and WO 98/14433 both disclose a series of lactam derivatives that are claimed to be selective agonist or antagonists of one or both of 5-HT ⁇ A and 5-HT ⁇ pj receptors.
  • the present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • P 1 is phenyl, naphthyl, a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzo fused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
  • R a is halogen, Ci .galkyl, C3_6cycloalkyl, CF3, C1.galkoxy, OCF3, hydroxy, cyano, nitro, hydroxyC ⁇ _6alkyl, COC ⁇ _ 6 alkyl, CO 2 R 5 , SO R 5 , NR 5 R 6 , CONR 5 R 6 , and and R6 are independently hydrogen or Ci .galkyl; n is 0, 1, 2 or 3;
  • R D and R c are independently as defined for R a above; p and q are independently as defined for n above;
  • R3 is hydrogen or together with R ⁇ forms a further group as defined above;
  • X is N or CH.
  • Cj.galkyl groups whether alone or as part of another group may be straight chain or branched.
  • naphthyl is intended, unless otherwise stated, to denote both naphth-1-yl and naphth-2-yl groups.
  • 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • P is a 5 or 6 membered heteroaryl ring suitable examples include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl.
  • P is a benzo fused heteroaryl ring suitable examples include indolyl, benzofuryl, benzothienyl, quinolinyl or isoquinolinyl.
  • the heteroaryl rings can be linked to the remainder of the molecule via any suitable carbon atom or, when present, a nitrogen atom.
  • pi is phenyl, naphthyl, thienyl or pyrazolyl. Most preferably pi is phenyl.
  • R a is preferably halogen (particularly fluorine, chlorine or bromine), a C ⁇ .galkyl group (particularly methyl, ethyl, isopropyl or t-butyl), CF3, cyano, C ⁇ alkoxy group (particularly methoxy or ethoxy) or SO2R ⁇ where R ⁇ is methyl.
  • R a may be the same or different.
  • n is 1 or 2.
  • Suitable P ⁇ and P ⁇ groups include those listed for pi above.
  • a preferred P ⁇ group is phenyl.
  • R D and R c are preferably halogen (particularly fluorine, chlorine or bromine), a
  • Ci .galkyl group (particularly methyl, ethyl, isopropyl or t-butyl), CF3, C1.galkoxy group (particularly methoxy or ethoxy).
  • R D and R c respectively can be the same or different.
  • p is 0 or 1.
  • q is 0, 1 or 2.
  • R and R ⁇ are preferably hydrogen.
  • R ⁇ is hydrogen.
  • X is N.
  • m is 1.
  • Particularly preferred compound according to the invention are:-
  • the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid
  • organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the present invention also provides a process for the preparation of a compound of formula (I) which comprises coupling a compound of formula (II) or a protected derivative thereof:
  • Suitable activated carboxylic acid groups include acyl chlorides or acyl bromides.
  • Activated compounds of formula (II) can also be prepared by reaction of the corresponding carboxylic acid with a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylphosphorylazide.
  • a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylphosphorylazide.
  • Compounds of formulae (II) and (III) are typically reacted together in an inert solvent such as dichloromethane or dimethylformamide at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • Standard protection and deprotection techniques such as those described in Greene T.W. 'Protective groups in organic synthesis', New York, Wiley (1981), can be used.
  • primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives.
  • Carboxylic acid groups can be protected as esters.
  • Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures well known in the art.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • Serotonin (5-hydroxytryptamine; 5-HT) receptors have been implicated in a number of pharmacological effects including mood disorders including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of Circadian rhythm), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • mood disorders including depression, seasonal affective disorder and dysthymia
  • anxiety disorders including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder
  • memory disorders including dementia, amnesic disorders and
  • Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia.
  • WO 95/31988 refers to the use of a 5-HTJD receptor antagonist in conjunction with a 5-HT] A receptor antagonist to treat CNS, endocrine and GI disorders
  • K. Rasmussen Annual Reports in Medicinal Chemistry, (1995) 30, 1) describes the utility of 5-HT ⁇ ⁇ receptor agonists and partial agonists in the treatment of various CNS disorders
  • P. Trouillas Progress in Brain Research, C.I. de Zeeuw, P. Stara and J. Voogd, Eds. 1997, 144, 589)
  • G. Maura J. Neurochemistry, 1996, 66, 202 propose that administration of agonist ligands selective for the 5-HT ⁇ A receptor or for both 5-HT ⁇ A and 5-HTID receptors should provide effective treatment for human cerebellar ataxias.
  • the present invention also provides for a compound of formula (I) or a pharmaceutically acceptable salt for use in the treatment of the aforementioned disorders.
  • the invention provides for a compound of formula (I) or a pharmaceutically acceptable salt for use in the treatment or prophylaxis of depression.
  • the present invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of disorders (particularly the aforementioned disorders) in which a ligand with affinity for 5-HTj receptors is beneficial.
  • the invention provides a method of treating disorders (particularly the aforementioned disorders) in which a ligand with affinity for 5-HTj receptors is beneficial which comprises administering a safe and therapeutically effective amount to a patient in need thereof of compound of formula (I) or a pharmaceutically acceptable salt.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, a selective serotonin reuptake inhibitor (SSRI) antidepressant.
  • SSRI selective serotonin reuptake inhibitor
  • the affinities of the compounds of this invention for the 5-HT ⁇ A, 5-HTJB and 5-HTi j) receptors can be determined by the following radioligand binding assay.
  • HEK 293 cells expressing 5-HT ⁇ A receptors (4 x lONml) are homogenised in Tris buffer and stored in 1 ml aliquots.
  • CHO cells expressing 5-HTi g receptors (4 x 10 ⁇ cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots.
  • CHO cells expressing 5-HT ⁇ rj receptors (0.563 x 10 ⁇ /ml) are homogenised in Tris buffer and stored in 1 ml aliquots.
  • pKi values are calculated from the IC50 generated by an iterative least squares curve fitting programme. All examples were tested in accordance with this radioligand binding assay and were found to have a pKi of greater than 7.5 at 5-HT ⁇ A, 5-HTJB and 5-HTi rj receptors.
  • the intrinsic activity of the compounds of this invention can be determined according to the following procedure.
  • HEK293 cell membranes stably expressing human 5-HTi A receptors and CHO cell membranes stably expressing human 5-HTj ⁇ receptors are homogenised in HEPES/EDTA buffer and stored in 1 ml aliquots, and [35s]GTP ⁇ S binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications.
  • Membranes from ⁇ cells are pre- incubated at 30°C for 30 min in 20 mM HEPES buffer (pH 7.4) in the presence of MgC_2 (3 mM), NaCl (100 mM), GDP (10 ⁇ M) and ascorbate (0.2 mM), with or without compounds.
  • the reaction is started by the addition of 10 ⁇ l of [ ⁇ SJGTP ⁇ S (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C.
  • Non-specific binding was determined using non-radiolabelled GTP ⁇ S (20 ⁇ M) added prior to the membranes.
  • the reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5 x 1 ml washes with ice cold HEPES (20 mM) /MgCl2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [ ⁇ SJGTP ⁇ S functional assay.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
  • Examples E4 - E7 were prepared using a similar procedure to that described for Example 3.

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Abstract

The invention relates to novel isoquinoline and quinazoline derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.

Description

ISOQUINOLINE AND QUINAZOLINE DERIVATIVES FOR THE TREATMENT OF CNS DISORDERS
The present invention relates to novel isoquinoline and quinazoline derivatives, processes for their preparation, pharmaceutical compositions containing them and to their use in the treatment of various disorders.
US patent 5,703,072 discloses bicyclic nonane and decane compounds having dopamine receptor affinity which are claimed to be of use in the treatment of schizophrenia. WO 98/50358, WO 98/50346, WO 98/47868, WO 98/47885, WO 98/50543 and WO 99/31086 all disclose a series of novel compounds which are claimed to possess combined 5-HTι A, 5-HTιg and 5-HTi rj receptor affinity and which are said to be useful in the treatment of various CNS disorders. WO 97/36867 and WO 98/14433 both disclose a series of lactam derivatives that are claimed to be selective agonist or antagonists of one or both of 5-HTι A and 5-HTιpj receptors.
A structurally distinct class of compounds have now been found that also exhibit combined 5-HTi A, 5-HTi β and 5-HTi ) receptor affinity. It is expected that such compounds will be useful for the treatment and prophylaxis of various disorders. In a first aspect, the present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
(I) in which R.1 is selected from a group of formula (i) or (ii)
Group of formula (ϊ)
(i) where P 1 is phenyl, naphthyl, a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzo fused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
Ra is halogen, Ci .galkyl, C3_6cycloalkyl, CF3, C1.galkoxy, OCF3, hydroxy, cyano, nitro, hydroxyCι_6alkyl, COCι_6alkyl, CO2R5, SO R5, NR5R6, CONR5R6, and and R6 are independently hydrogen or Ci .galkyl; n is 0, 1, 2 or 3;
Group of formula (ii)
(ii) in which P^ and P-> are independently as defined for pi above;
RD and Rc are independently as defined for Ra above; p and q are independently as defined for n above;
R2 is hydrogen or together with the group R^ forms a further group -CH = CH- or
(CR7R8)2- where R^ and R& are independently hydrogen or C1.galkyl;
R3 is hydrogen or together with R^ forms a further group as defined above;
Y is N or CH; m is 1 or 2;
X is N or CH.
Cj.galkyl groups whether alone or as part of another group may be straight chain or branched. Where used herein the term naphthyl is intended, unless otherwise stated, to denote both naphth-1-yl and naphth-2-yl groups. The term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
Within the definition of R! formula (i) When P is a 5 or 6 membered heteroaryl ring suitable examples include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. When P is a benzo fused heteroaryl ring suitable examples include indolyl, benzofuryl, benzothienyl, quinolinyl or isoquinolinyl. The heteroaryl rings can be linked to the remainder of the molecule via any suitable carbon atom or, when present, a nitrogen atom. Preferably pi is phenyl, naphthyl, thienyl or pyrazolyl. Most preferably pi is phenyl. When n is not 0, Ra is preferably halogen (particularly fluorine, chlorine or bromine), a C^.galkyl group (particularly methyl, ethyl, isopropyl or t-butyl), CF3, cyano, C^alkoxy group (particularly methoxy or ethoxy) or SO2R^ where R^ is methyl. When n is 2 or 3 the groups Ra may be the same or different. Preferably n is 1 or 2.
Within the definition of R! formula (ii)
Suitable P^ and P^ groups include those listed for pi above. A preferred P^ group is phenyl. RD and Rc are preferably halogen (particularly fluorine, chlorine or bromine), a
Ci .galkyl group (particularly methyl, ethyl, isopropyl or t-butyl), CF3, C1.galkoxy group (particularly methoxy or ethoxy). When p and or q are 2 or 3 the groups RD and Rc respectively can be the same or different. Preferably p is 0 or 1. Preferably q is 0, 1 or 2.
When R^ together with a group R^ forms a group -(CR^R^)2- both of the groups
R and R^ are preferably hydrogen. Preferably R^ is hydrogen. Preferably X is N. Preferably m is 1.
Particularly preferred compound according to the invention are:-
(S)-(-)-(4-Chlorobenzamido)- 1 -(octahydropyrrolo[l ,2-α]pyrazin-2-yl)isoquinoline, (S)-(-)-(3,4-Dichlorobenzamido)- 1 -(octahydropyrrolo[ 1 ,2-α]pyrazin-2-yl)isoquinoline, (S)-(-)-(2-Chlorobenzamido)-4-(octahydropyrrolo[l,2- ]pyrazin-2-yl)quinazoline or a pharmaceutically acceptable salt thereof. Other preferred compounds of this invention include Examples E4 - E7, as tabulated below, or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water. Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
In a further aspect, the present invention also provides a process for the preparation of a compound of formula (I) which comprises coupling a compound of formula (II) or a protected derivative thereof:
R -
(II) in which R! is as defined in formula (I) and L is an activated carboxylic acid group with a compound of formula (III) or a protected derivative thereof
(III) in which X, Y, m, R^ and R^ are as defined in formula (I) and optionally thereafter:
• removing any protecting groups;
• forming a pharmaceutically acceptable salt.
Suitable activated carboxylic acid groups include acyl chlorides or acyl bromides. Activated compounds of formula (II) can also be prepared by reaction of the corresponding carboxylic acid with a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylphosphorylazide. Compounds of formulae (II) and (III) are typically reacted together in an inert solvent such as dichloromethane or dimethylformamide at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
It will be appreciated by those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques, such as those described in Greene T.W. 'Protective groups in organic synthesis', New York, Wiley (1981), can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures well known in the art.
Intermediate compounds of formula (II) and (III) are commercially available, can be prepared using methods described herein or by analogous methods thereto or using standard procedures known in the art.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
The involvement of serotonin receptors in a number of pharmacological effects has been reviewed by R. A. Glennon in "Serotonin Receptors: Clinical Implications", Neuroscience and Behavioural Reviews, 1990, 14, 35 and by L.O.Wilkinson and C.T. Dourish in "Serotonin Receptor Subtypes : Basic and Clinical Aspects" S. Peroutka Ed., John Wiley and Sons, New York, 1991 p.147.
Serotonin (5-hydroxytryptamine; 5-HT) receptors have been implicated in a number of pharmacological effects including mood disorders including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of Circadian rhythm), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders. Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia.
Ligands with high affinity for the 5-HTj receptors are well recognised as having therapeutic utility for the treatment of the above conditions. For example: WO 95/31988 refers to the use of a 5-HTJD receptor antagonist in conjunction with a 5-HT] A receptor antagonist to treat CNS, endocrine and GI disorders; K. Rasmussen (Annual Reports in Medicinal Chemistry, (1995) 30, 1) describes the utility of 5-HTι ^ receptor agonists and partial agonists in the treatment of various CNS disorders; P. Trouillas (Progress in Brain Research, C.I. de Zeeuw, P. Stara and J. Voogd, Eds. 1997, 144, 589) and G. Maura (J. Neurochemistry, 1996, 66, 202) propose that administration of agonist ligands selective for the 5-HTι A receptor or for both 5-HT^A and 5-HTID receptors should provide effective treatment for human cerebellar ataxias.
The present invention also provides for a compound of formula (I) or a pharmaceutically acceptable salt for use in the treatment of the aforementioned disorders. In particular, the invention provides for a compound of formula (I) or a pharmaceutically acceptable salt for use in the treatment or prophylaxis of depression.
In a further aspect the present invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of disorders (particularly the aforementioned disorders) in which a ligand with affinity for 5-HTj receptors is beneficial.
In a further aspect the invention provides a method of treating disorders (particularly the aforementioned disorders) in which a ligand with affinity for 5-HTj receptors is beneficial which comprises administering a safe and therapeutically effective amount to a patient in need thereof of compound of formula (I) or a pharmaceutically acceptable salt.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, a selective serotonin reuptake inhibitor (SSRI) antidepressant.
The affinities of the compounds of this invention for the 5-HTι A, 5-HTJB and 5-HTi j) receptors can be determined by the following radioligand binding assay. HEK 293 cells expressing 5-HTι A receptors (4 x lONml) are homogenised in Tris buffer and stored in 1 ml aliquots. CHO cells expressing 5-HTi g receptors (4 x 10^ cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots. CHO cells expressing 5-HTι rj receptors (0.563 x 10^/ml) are homogenised in Tris buffer and stored in 1 ml aliquots. 0.4 ml of a cell suspension is incubated with [3H]-5-HT (4 nM) for 5-HTι g/ι j) receptors and [3H]-8-OH DP AT (1 nM) for 5-HT1A receptors in Tris Mg HC1 buffer (pH 7.7) and test drug, at 37°C for 45 minutes. Each test drug is tested at 10 concentrations (0.01 mM to 0.3 nM final concentration), with non-specific binding defined using 0.01 mM 5-HT. The total assay volume is 0.5 ml. Incubation is stopped by rapid filtration using a Packard Filtermate (filters pre-soaked in 0.3% polyethylenimine) and radioactivity measured by Topcount scintillation counting. pKi values are calculated from the IC50 generated by an iterative least squares curve fitting programme. All examples were tested in accordance with this radioligand binding assay and were found to have a pKi of greater than 7.5 at 5-HTι A, 5-HTJB and 5-HTi rj receptors.
The intrinsic activity of the compounds of this invention can be determined according to the following procedure. HEK293 cell membranes stably expressing human 5-HTi A receptors and CHO cell membranes stably expressing human 5-HTjβ receptors are homogenised in HEPES/EDTA buffer and stored in 1 ml aliquots, and [35s]GTPγS binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications. Membranes from \ cells are pre- incubated at 30°C for 30 min in 20 mM HEPES buffer (pH 7.4) in the presence of MgC_2 (3 mM), NaCl (100 mM), GDP (10 μM) and ascorbate (0.2 mM), with or without compounds. The reaction is started by the addition of 10 μl of [^^SJGTPγS (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C. Non-specific binding was determined using non-radiolabelled GTPγS (20 μM) added prior to the membranes. The reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5 x 1 ml washes with ice cold HEPES (20 mM) /MgCl2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [^^SJGTPγS functional assay.
It has been found, using the [35s]GTPγS functional assay, that certain compounds of formula (I) show varying levels of intrinsic efficacy, which is defined by a scale ranging from 1.0 to 0 (1 defines the maximum response elicited by the agonist 5-HT, 0 defines zero intrinsic efficacy). The difficulties in describing intrinsic activity of drugs acting at G protein coupled receptors is recognised in the art (Hoyer and Boddeke, Trends in Pharmacological Sciences, July 1993, [Vol. 14], page 270-275). Compounds of formula (I) which have low intrinsic activity in the [35s]GTPγS functional assay are more likely to be antagonists in vivo. As disclosed in WO 95/31988, the simultaneous antagonism of pre-synaptic 5-HT^ A/ IB/ ID receptors will result in increased release of 5-HT in vivo and this should improve 5-HT neurotransmission. Accordingly, we believe that the compounds of this invention will be useful in the treatment of CNS disorders and that they will act as antidepressants in vivo.
In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following Descriptions and Examples illustrate the preparation of compounds of the invention.
Description 1
5-Nitro-l-chIoroisoquinoline and 7-Nitro-l-chloroisoquinoline (Dl) A stirred solution of a mixture of 5- and 7-nitroisoquinolin-l-ols (Chem. Pharm. Bull. 1968, 16, 715; 3.8 g, 20 mmole) in POCI3 (15 ml) under argon was heated under reflux for 3 h. After cooling the POCI3 was removed in vacuo and the residue partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO/j, filtered and concentrated to dryness in vacuo giving the title compounds as a pale yellow solid (3.7 g, 89%). MS: m z (MH) - 209/211.
Description 2
(S)-(-)-5-Nitro-l-(octahydropyrrolo[l,2-α]pyrazin-2-yl)isoquinoline and (S)-(-)-7- Nitro-l-(octahydropyrrolo[l,2- ]pyrazin-2-yl)isoquinoline (D2)
A stirred solution of l-chloro-5/7-nitroisoquinolines (Dl, 1.8 g, 8.6 mmole) in DMF (20 ml) was treated with (S)-(-)-octahydropyrrolo[l,2-a]pyrazine (J. Med. Chem., 1993, 36, 2311; 1.2 g, 9.5 mmole) and E.3N (1.3 ml, 9.5 mmole) and heated at 100° for 3 h. After cooling, the solvent was removed in vacuo and the residue partitioned between water and EtOAc. The organic layer was dried over MgSOzj., filtered and concentrated to dryness in vacuo. The residue was passed through a silica gel column eluting with DCM/MeOH/NH4OH 19: 1:0.1 giving the title compounds as a red oil (336 mg, 13%). MS: m/z (MH) = 299.
Description 3
(S)-(-)-7-Amino-l-(octahydropyrrolo[l,2-α]pyrazin-2-yl)isoquinoline (D3)
A solution of (S)-(-)-5-nitro-l-(octahydropyrrolo[l,2- ]pyrazin-2-yl)isoquinoline and (S)-(-)-7-nitro-l-(octahydropyrrolo[l,2- ]pyrazin-2-yl)isoquinoline (D2, 240 mg, 0.81 mmole) in EtOH (20 ml) was treated with 10% Pd/C and hydrogenated at 1 bar for 5 h. After filtration through kieselguhr and concentrated in vacuo, the residue was purified by silica gel chromatography eluting with DCM/MeOH/NH4OH 19:2:0.1 to give the title compound as a yellow glass (51 mg, 23%).
MS: m/z (MH) = 269. 1H-NMR (250 MHz, CDC13): δ (ppm): 7.96 (d, IH), 7.58 (d, IH), 7.22 (d, IH), 7.13 (d, IH), 7.06 (d, IH), 3.97 (br. s, 2H), 3.90-3.70 (m, 2H), 3.20-3.05 (m, 3H), 2.85 (dd, IH), 2.65-2.50 (m, IH), 2.40-2.20 (m, 2H), 1.95-1.70 (m, 3H), 1.60-1.45 (m, IH).
Description 4 (S)-(-)-6-Nitro-4-(octahydropyrrolo[l,2-α]pyrazin-2-yl)quinazoline (D4) A stirred solution of 4-chloro-6-nitroquinazoline (J. Chem. Soc. 1948, 360; 1.0 g, 4.8 mmole) in dry DCM under Ar was treated with (S)-(-)-octahydropyrrolo[l,2-α]pyrazine (1.21 ml, 9.6 mmole). After 18 h the solution was evaporated to dryness in vacuo and the residue partitioned between DCM and water. The organic phase was dried over MgSO-j, filtered and concentrated to dryness in vacuo to give an orange gum (0.93 g, 65%). MS: m z (MH) - 300.
Description 5 (S)-(-)-6-Amino-4-(octahydropyrrolo[l,2-α]pyrazin-2-yϊ)quinazoline (D5) A solution of (S)-(-)-6-nitro-4-(octahydropyrrolo [ 1 ,2-α]pyrazin-2-yl)quinazoline (D4, 740 mg, 2.5 mmole) in EtOH (70 ml) was treated with 10% Pd C and hydrogenated at 1 bar for 15 h. The suspension was filtered and the solvent removed in vacuo to give a yellow solid (667 mg, quant.).
MS: m/z (MH) = 270.1H-NMR (250 MHz, CDC13): δ (ppm): 8.54 (s, IH), 7.64 (d, IH), 7.32 (d, IH), 7.06 (s, IH), 4.21 (br. s, 2H), 3.92-3.74 (m, 2H), 3.21-3.08 (m, 3H), 2.88 (dd, IH), 2.67-2.52 (m, IH), 2.44-2.21 (m, 2H), 1.94-1.72 (m, 3H), 1.62-1.44 (m, IH).
Example 1 (S)-(-)-(4-Chlorobenzamido)-l-(octahydropyrrolo[l,2-α]pyrazin-2-yI)isoquinoIine (El)
A stirred solution of 4-chlorobenzoic acid (44 mg, 0.28 mmole), HOBt (Hydroxybenztriazole).H2θ (38 mg, 0.28 mmole) and (S)-(-)-7-amino-l- (octahydropyrrolo[l,2- ]pyrazin-2-yl)isoquinoline (D3, 51 mg, 0.19 mmole) in DMF (3 ml) was treated with polystyrylmethyl cyclohexyl carbodiimide (250 mg resin, 0.38 mmole) and heated at 60° for 15 h. After filtration the solution was concentrated to dryness and purified by preparative thin layer chromatography eluting with DCM/MeOH/NH4OH 19:1:0.1 to give the title compound as an off white foam (53 mg, 68%).
MS: m z (MH) = 407/409. IH NMR (250 MHz, CDC13): δ (ppm): 8.56 (s, IH), 8.21 (br. s, IH), 8.11 (d, IH), 7.85 (d, 2H), 7.75-7.65 (m, 2H), 7.45 (d, 2H), 7.20 (d, IH), 3.95- 3.80 (m, 2H), 3.25-3.10 (m, 3H), 2.90 (t, IH), 2.75-2.60 (m, IH), 2.50-2.20 (m, 2H), 1.95-1.70 (m, 3H), 1.60-1.45 (m, IH).
Example 2
(S)-(-)-(3,4-Dichlorobenzamido)-l-(octahydropyrrolo[l,2-α]pyrazin-2- yl)isoquinoline (E2) The title compound was prepared from 3,4-dichlorobenzoic acid and (S)-(-)-7-amino-l- (octahydropyrrolo[l,2-α]pyrazin-2-yl)isoquinoline (D3, 82 mg, 0.3 mmole) according to the procedure for Example 1, giving a brown glass (78 mg, 58%). MS: m/z (MH) = 415/417. IH NMR (250 MHz, CDC13): δ (ppm): 8.52 (br. s, IH), 8.52 (s, IH), 8.07 (d, IH), 8.02 (d, IH), 7.80-7.60 (m, 3H), 7.47 (d, IH), 7.17 (d, IH), 3.90- 3.70 (m, 2H), 3.25-3.10 (m, 3H), 3.00-2.85 (m, IH), 2.80-2.20 (m, 3H), 2.00-1.70 (m, 3H), 1.60-1.40 (m, lH).
Example 3 (S)-(-)-(2-chIorobenzamido)-4-(octahydropyrrolo[l,2-α]pyrazin-2-yl)quinazoline (E3)
A stirred solution of 2-chlorobenzoic acid (78 mg, 0.50 mmole), HOBt.H2θ (67 mg, 0.50 mmole) and (S)-(-)-6-amino-l-(octahydropyrrolo[l,2-<3]pyrazin-2-yl)quinazoline (D5, 90 mg, 0.33 mmole) in DMF (8 ml) was treated with polystyrylmethyl cyclohexyl carbodiimide (440 mg resin, 0.66 mmole) and heated at 60° for 18 h. After filtration the solution was concentrated to dryness and purified by flash chromatography eluting with DCM/MeOH 9:1 to give the title compound as an off white glass (45 mg, 33%). MS: m/z (MH) = 408/410. IH NMR (250 MHz, CDC13): δ (ppm): 8.77 (d, IH), 8.68 (s, IH), 8.30 (s, IH), 7.86 (d, IH), 7.79 (dd, IH), 7.56 (dd, IH), 7.49-7.36 (m, 3H), 4.51 (m, 2H), 3.39 (m, IH), 3.09 (m, 2H), 2.56 (m, IH), 2.26 (m, 2H), 1.85 (m, 4H), 1.52 (m, IH).
Examples E4 - E7 were prepared using a similar procedure to that described for Example 3.
Example R MS I Example R MS

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
(I) in which R^ is selected from a group of formula (i) or (ii)
Group of formula (i)
(i) where p is phenyl, naphthyl, a 5 or 6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a benzo fused heteroaryl ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur; Ra is halogen, C^.^alkyl, C3_6cycloalkyl, CF3, C1.galkoxy, OCF3, hydroxy, cyano, nitro, hydroxyCι_6alkyl, COCι_6alkyl, CO2R5, SO2R5, NR5R6, CONR5R6, and SO2NR5R6 where R^ and R^ are independently hydrogen or Ci .galkyl; n is 0, 1, 2 or 3;
Group of formula (ii)
(ϋ) in which P^ and P3 are independently as defined for P above; Rb and Rc are independently as defined for Ra above; p and q are independently as defined for n above; R2 is hydrogen or together with the group R3 forms a further group CH = CH or (CR R°)2 where R^ and R^ are independently hydrogen or Ci .galkyl; R3 is hydrogen or together with R^ forms a further group as defined above; X is N or CH m is 1 or 2; Y is N or CH.
2. A compound according to claim 1 in which I is a group of formula (i) wherein p is phenyl.
3. A compound according to claim 1 or 2 in which R^ is hydrogen.
4. A compound according to any the preceding claims in which X is N and m is l.
5. A compound according to claim 1 which is: (S)-(-)-(4-Chlorobenzamido)- 1 -(octahydropyrrolo[ 1 ,2-α]pyrazin-2-yl)isoquinoline, (S)-(-)-(3,4-Dichlorobenzamido)- 1 -(octahydropyrrolo[ 1 ,2-α]pyrazin-2-yl)isoquinoline, (S)-(-)-(2-Chlorobenzamido)-4-(octahydropyrrolo [ 1 ,2-α]pyrazin-2-yl)quinazoline, a compound E4, E5, E6 or E7 or a pharmaceutically acceptable salt thereof.
6. A process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof which comprises coupling a compound of formula (II):
(II) in which R is as defined in formula (I) and L is an activated carboxylic acid group with a compound of formula (III):
(IH) in which X, Y, m, R^ and R3 are as defined in formula (I) and optionally thereafter: • removing any protecting groups;
• forming a pharmaceutically acceptable salt.
7. A compound according to any of claims 1 to 5 for use in therapy.
8. A compound according to any of claims 1 to 5 for use in the treatment of depression.
9. A pharmaceutical composition which comprises a compound according to any of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
10. The use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of disorders in which a ligand with affinity for 5-HTj receptors is beneficial.
EP00971422A 1999-11-05 2000-11-03 Isoquinoline and quinazoline derivatives for the treatment of cns disorders Withdrawn EP1233965A1 (en)

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