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  • 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
  • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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• • A—HUMAN NECESSITIES
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  • 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
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
  • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • C07D405/12—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 linked by a chain containing hetero atoms as chain links
• • 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
  • C07D409/12—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 linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention relates to novel sulfonamide compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
• WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WO 01/32646 disclose a series of aryl sulphonamide and sulphoxide compounds that are said to be 5-HT 6 receptor antagonists and which are claimed to be useful in the treatment of various CNS disorders.
• a structurally novel class of compounds has now been found which possess affinity for the 5- HT 6 receptor.
• the present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
• R 1 represents hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C ⁇ _ 6 alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, . 6 alkoxy, arylCi -6 alkoxy, C ⁇ -6 alkylthio, C ⁇ .6 alkoxyC ⁇ -6 alkyl, C 3 . 7 cycloalkylC ⁇ alkoxy, C ⁇ -6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, C ⁇ .
• 6 alkyl arylcarboxamidoCi_ 6 alkyl, aroyl, aroylC ⁇ _6 alkyl, arylC ⁇ _ 6 alkanoyl, or a group CONR 3 R 4 or SO 2 NR 3 R 4 , wherein R 3 and R 4 independently represent hydrogen or C ⁇ . 6 alkyl or together may be fused to form a 5- to 7- membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom; R 2 represents hydrogen or C]. 6 alkyl; m represents an integer from 1 to 3; n represents an integer from 1 to 4;
• A represents phenyl, naphthyl or a monocyclic or bicyclic heteroaryl group each of which may be optionally substituted by one or more substituents which may be the same or different, and which are selected from those defined for R 1 ; or solvates thereof.
• Alkyl groups may be straight chain or branched and the groups alkoxy and alkanoyl shall be inte ⁇ reted similarly.
• Alkyl moieties are more preferably C 1-4 alkyl, eg. methyl or ethyl.
• the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
• aryl includes phenyl and naphthyl.
• heteroaryl is intended to mean a 5 or 6 membered monocyclic aromatic or a fused 8- 10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur.
• monocyclic aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.
• fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzirnidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
• Heteroaryl groups, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where otherwise indicated above.
• aryl or heteroaryl groups have more than one substituent
• said substituents may be linked to form a ring, for example a carboxyl and amine group may be linked to form an amide group.
• A is substituted by 0 to 3 substituents, more preferably 0, 1 or 2 substituents.
• A represents phenyl or a monocyclic heteroaryl group (such as thienyl) optionally substituted by one or more halogen (such as chlorine or bromine, eg. 3 -chlorophenyl, 4- chlorophenyl, 4-bromophenyl, 5-bromophenyl, 2,3-dichlorophenyl or 3,5-dichlorophenyl), C ⁇ _ 6 alkyl (such as methyl, eg. 4-methyl or ethyl, eg. 2-ethyl), C ⁇ -6 alkoxy (such as methoxy, eg. 2- methoxy), trifluoromethoxy (such as 2-trifluoromethoxy) or trifluoromethyl (such as 3- trifluoromethyl) groups.
• halogen such as chlorine or bromine, eg. 3 -chlorophenyl, 4- chlorophenyl, 4-bromophenyl, 5-bromophenyl, 2,3-dichloropheny
• A represents unsubstituted phenyl or phenyl substituted by 3 -trifluoromethyl, halogen (eg. 4-chloro and 4-bromo) and/or 2-trifluoromethoxy.
• A represents phenyl di-substituted by halogen (especially 4-chloro or 4-bromo) and 2-trifluoromethoxy.
• m is 0 or 1, most preferably 0.
• R 1 is preferably halogen (eg. 6-chlorine, 9-chlorine or 9-bromine) or C 1-6 alkoxy (such as methoxy, eg. 8-methoxy).
• halogen eg. 6-chlorine, 9-chlorine or 9-bromine
• C 1-6 alkoxy such as methoxy, eg. 8-methoxy
• n is 0.
• Preferred compounds according to the invention include examples El -El 7 as shown 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 present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
• the compound of formula (I) forms an acid addition salt with hydrochloric acid.
• the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate.
• This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. 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 fo ⁇ nula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
• R 1 , R 2 , m and n are hereinbefore defined and P 1 is a suitable protecting group such as acetyl, trifluoroacetyl, -butyloxycarbonyl, 2',2',2'-trichloroethoxycarbonyl, benzyl or methyl, with a compound of formula (III)
• A is a ⁇ hereinbefore defined and L is a suitable leaving group, such as a halogen atom (eg. fluorine or chlorine) and thereafter deprotecting the resultant compound; or
• Process (a) typically comprises the use of a suitable base such as pyridine or triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran.
• a suitable base such as pyridine or triethylamine
• an inert solvent such as dichloromethane or tetrahydrofuran.
• Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g.
• Suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
• Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation. Examples of process (c) include interconversions of the groups R 1 , R 2 and A.
• compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
• Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for the 5-HT 6 receptor and are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, cognitive memory disorders (e.g. Alzheimers disease, age related cognitive decline and mild cognitive impairment), Parkinsons Disease, ADHD (Attention Deficit Disorder/Hyperactivity Syndrome), sleep disorders (including disturbances of Circadian rhythm), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
• Compounds of the invention are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome).
• Compounds of the invention are also expected to be of use in the treatment of obesity.
• the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
• the invention provides for a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of depression, anxiety, obesity and cognitive memory disorders
• the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• the invention provides 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 or prophylaxis of the above disorders.
• 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.
• 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 infusable 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 colourants.
• 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 sterilization 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 0.05 to 200 mg, for example 20 to 40 mg; and such unit doses will preferably be administered once a day, although administration more than once a day may be required; and such therapy may extend for a number of weeks or months.
• the title compound (D4) was prepared in 72% yield as described in Description 3, by treatment of 7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-lH-benzo[rf]azepine (D2) with phenyl sulfonyl chloride.
• a second crop of the product (D9) (7.4g, total yield 31.4g, 60.7mmol, 62%) was isolated from the filtrate by concentrating the filtrate and re-chromatographing the residue over silicagel (acetone/toluene gradient) followed by crystallisation from diethyl ether / hexane.
• the mixture was poured into ice/water (1 litre) and dichloromethane (2 litres) added.
• the organic phase was separated and neutralised to pH6 by addition of saturated sodium bicarbonate solution.
• the organic phase was separated, dried (MgSO 4 ) and purified by cliromatography
• Examples E3-E5 were prepared by a two step process, using the appropriate aryl sulfonyl chloride with 7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-lH-benzo[d]azepine (D2) in a similar manner to that described in Description 3, followed by a deprotection step in a similar manner to that described in Example 1.
• Examples E7-E9 were prepared by a two step process, using the appropriate aryl sulfonyl chloride with 7-amino-3-t-butyloxycarbonyl-2,3,4,5-tetrahydro-lH-benzo[c ]azepine (D2) in a similar manner to that described in Description 3, followed by a deprotection step in a similar manner to that described in Example 1.
• Examples 13-15 E13-E15
• Examples E13-E15 were prepared by treatment of the appropriate trifluoroacetyl protected aminobenzoft ] azepine derivative (D16 for E13 and E14 and D17 for E15) with the required arylsulfonyl chloride in an analogous manner to the process described in D8, followed by treatment of the product with aqueous ammonia (2M), and subsequent purified by recrystallisation of their respective hydrochlorides.

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