WO2002051232A2 - Novel benzazepines and related heterocyclic derivatives - Google Patents

Novel benzazepines and related heterocyclic derivatives Download PDF

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WO2002051232A2
WO2002051232A2 PCT/EP2000/013289 EP0013289W WO02051232A2 WO 2002051232 A2 WO2002051232 A2 WO 2002051232A2 EP 0013289 W EP0013289 W EP 0013289W WO 02051232 A2 WO02051232 A2 WO 02051232A2
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Prior art keywords
dimethoxy
benzyl
benzo
acetamide
tetrahydro
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PCT/EP2000/013289
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French (fr)
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Walter Fischli
Martine Clozel
Thomas Weller
Ralf Koberstein
Hamed Aissaoui
Thierry Sifferlen
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Actelion Pharmaceuticals Ltd.
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Priority to PCT/EP2000/013289 priority Critical patent/WO2002051232A2/en
Priority to ES01988048T priority patent/ES2296825T3/en
Priority to BR0116505-4A priority patent/BR0116505A/en
Priority to AT01988048T priority patent/ATE381560T1/en
Priority to MXPA03004779A priority patent/MXPA03004779A/en
Priority to NZ525613A priority patent/NZ525613A/en
Priority to EP01988048A priority patent/EP1347967B1/en
Priority to JP2002552933A priority patent/JP4219166B2/en
Priority to IL15580601A priority patent/IL155806A0/en
Priority to CA2431982A priority patent/CA2431982C/en
Priority to US10/450,420 priority patent/US7192950B2/en
Priority to CNB018208762A priority patent/CN1261430C/en
Priority to DE60132017T priority patent/DE60132017T2/en
Priority to AU2002240855A priority patent/AU2002240855B2/en
Priority to PCT/EP2001/015074 priority patent/WO2002051838A1/en
Priority to HU0301665A priority patent/HUP0301665A3/en
Priority to KR1020037008764A priority patent/KR100849569B1/en
Publication of WO2002051232A2 publication Critical patent/WO2002051232A2/en
Priority to IL155806A priority patent/IL155806A/en
Priority to ZA200303697A priority patent/ZA200303697B/en
Priority to NO20032905A priority patent/NO326158B1/en

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    • 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
    • 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
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel benzazepines and related heterocyclic derivatives of the general formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
  • the orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and the orexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al, Cell, 1998, 92, 573-585).
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al, Cell, 1998, 92, 573-585).
  • Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic patients (Chemelli R.M. et al, Cell, 1999, 98, 437-451).
  • Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily of G-protein coupled receptor (Sakurai T. et al, Cell, 1998, 92, 573-585).
  • the orexin-1 receptor (OX ⁇ ) is selective for OX-A and the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
  • Orexin receptors are found in the mammalian host and may be responsible for many biological functions such as pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; feeding disorders such as anorexia, bulimia, cachexia and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcus; Froehlich's
  • HIN post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasornnia; jet-lag syndrome; and neurodegerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration epilepsy; seizure disorders and other diseases related to orexin.
  • nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration epilepsy; seizure disorders and other diseases related to orexin.
  • the present invention provides benzazepines and related heterocyclic derivatives which are non-peptide antagonists of human orexin receptors, in particular OXi and OX receptors.
  • these compounds are of potential use in the treatment of obesity and/or sleep disorders. So far not much is known about low molecular weight compounds which have a potential to antagonise either specifically OXi or OX or both receptors at the same time.
  • Recently WO 99/09024, WO 99/58533, WO 00/47577 and WO 00/47580 have been published wherein phenyl urea and phenyl thiourea derivatives are described as being preferably OXi receptor antagonists.
  • novel compounds of the present invention belong to an entirely different class of low molecular weight compounds as compared to all prior art orexin receptor antagonists so far published.
  • the present invention relates to novel benzazepines and related heterocyclic derivatives of the general formula (I).
  • R 1 , R 2 , R 3 , R 4 independently represent cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R n CO-, R 12 R 13 CO-, R 12 R 13 N-, R n OOC-, R n SO 2 NH-, or
  • R 14 -CO- H-, or R 2 and R 3 together as well as R 1 and R 2 together and R 3 and R 4 together may form with the phenyl ring a five, six or seven-membered saturated ring containing one or two oxygen atoms;
  • R 5 , R 6 , R 7 ,R 8 , R 9 , R 10 independently represent hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;
  • R 11 represents lower alkyl, lower alkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
  • R 12 and R 13 independently represent hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
  • R 14 represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R 12 R 13 N-, R u O-;
  • -X-Y- independently represents -CH 2 -CH 2 -, -O-CH 2 -, -S-CH 2 -, -SO 2 -CH 2 - and -NR 15 -CO-;
  • R 15 represents hydrogen, lower alkyl or aralkyl.
  • the compounds of formula (I) can contain one or more asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
  • lower alkyl signifies a straight-chain or branched-chain alkyl group with 1 to 6 carbon atoms, preferably a straight or branched-chain alkyl group with 1-4 carbon atoms.
  • Examples of straight-chain and branched C ⁇ -C 8 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-butyl, tert-butyl and n-pentyl.
  • lower alkenyl signifies a straight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms, preferably allyl and vinyl.
  • lower alkoxy signifies a group of the formula alkyl-O- in which the term “alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert- butoxy, preferably methoxy and ethoxy.
  • Lower alkenyloxy groups are preferably vinyloxy and allyloxy.
  • cycloalkyl alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms.
  • C 3 -C 8 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl, cyclohexyl and particularly cyclohexyl or lower alkyl substituted cycloalkyl which may preferably be substituted with lower alkyl such as methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl, dimethyl-cyclohexyl.
  • aryl signifies a phenyl or naphthyl group which optionally carries one or more substituents, preferably one or two substituents, each independently selected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butoxyphenyl, 4- fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 1 -naphthyl and 2-naphthyl.
  • Preferred are carboxyphenyl, lower alkoxy-phenyl, hydroxyphenyl and particularly phenyl.
  • aralkyl signifies an alkyl or cycloalkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined.
  • Preferred are benzyl and benzyl substituted in the phenyl ring with hydroxy, lower alkyl, lower alkoxy or halogen preferably chlorine. Particularly preferred is benzyl.
  • heterocyclyl and “heterocyclyl-lower alkyl”
  • the heterocyclyl group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated, partially unsaturated or aromatic containing for example 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur which may be the same or different.
  • heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl, pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl.
  • the heterocyclyl group may have up to 5, preferably 1, 2 or 3 optional substituents.
  • suitable substituents include halogen, lower alkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and lower alkyloxy-carbonyls.
  • halogen signifies fluorine, chlorine, bromine or iodine and preferably chlorine and bromine and particularly chlorine.
  • a group of preferred compounds according to the present invention are compounds of formula (II)
  • R' ! and R' 2 independently represent hydrogen, hydroxy, lower alkoxy, lower alkenyloxy or halogen or may form with the phenyl ring a five, six or seven membered-ring containing one or two oxygen atoms;
  • R' 3 , R' 4 , R' 5 independently represent aryl, aralkyl, lower alkyl, lower alkenyl, hydrogen trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;
  • -X-Y- independently represents -CH 2 -CH 2 -, -O-CH 2 -, -S-CH 2 -, -SO 2 -CH 2 - and -NR' 6 -CO-;
  • R' 6 represents hydrogen, lower alkyl or aralkyl.
  • the compounds of formula (II) can contain one or more asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
  • Examples of preferred compounds of formula (II) are: 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- naphthalen- 1 -ylmethyl-acetamide
  • physiologically usable or pharmaceutically acceptable salts of the compounds of formula (I) are salts with physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid; or with organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid
  • organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • the compounds of formula (I) with free carboxy groups can also form salts with physiologically compatible bases.
  • salts examples include alkali metal, alkali earth metal, ammonium and alkylammoniumsalts such as ⁇ a, K, Ca or tetraalkylammonium salt.
  • the compounds of formula (I) can also be present in the form of a zwitterion.
  • Preferred compounds as described above have ICso values below 1000 nM; especially preferred compounds have IC 50 values below 100 nM which have been determinated with the FLIPR (Fluorometric Imaging Plates Reader) method described in the beginning of the experimental section.
  • FLIPR Fluorometric Imaging Plates Reader
  • the compounds of the general formula (I) and their pharmaceutically usable salts can be used for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required such as obesity, diabetes, prolactinoma, narcolepsy, insomriia, sleep apnea, parasomnia, depression, anxiety, addictions, schizophrenia and dementia.
  • the compounds of formula (I) and their pharmaceutically usable salts are particularly useful for the treatment of obesity and sleep disorders.
  • the compounds of formula (I) and their pharmaceutically usable salts can be used as medicament (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula (I) and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, and hard gelatine capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees, and hard gelatine capsules.
  • Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the invention also relates to processes for the preparation of compounds of Formula (I).
  • the compounds of general formula (I) of the present invention are prepared according to the general sequence of reactions outlined in the schemes below, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are as defined in formula (I) above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are as defined in formula (I) above.
  • any compound obtained with one or more optically active carbon atom may be resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates and the meso-forms in a manner known per se.
  • the compounds obtained may also be converted into a pharmaceutically acceptable salt thereof in a manner known per se.
  • the compounds of the general formula (I) may be prepared by standard procedures
  • Benzazepine derivatives wherein X and Y are CH 2 and R 6 is hydrogen might be prepared from the corresponding phenylpropylamine by coupling with the desired carboxyhc acid or acyl chloride followed by treatment with POCl 3 and finally NaBH 4 (Bischler-Napieralski reaction) as shown in Scheme 2a.
  • Benzazepines with variable substituents on position 8 might be prepared by hydrogenolysis of the corresponding 8-benzyloxy-l,3 5 4,5-tetrahydro-benzazepines followed by O-alkylation with the appropriate electrophile (Scheme 2b).
  • the benzylethers can be obtained with the previous procedure (Scheme2d) applied to 3-(4-benzyloxy-phenyl)-propionic acid derivatives.
  • Benzothiazepine and benzoxazepine derivatives wherein X is O or S, Y is CH 2 and R 6 is hydrogen might be prepared from the corresponding arylamine by coupling with the desired carboxyhc acid or acyl chloride followed by treatment with POCl 3 and finally NaBH (Bischler-Napieralski reaction) as shown in Scheme 3.
  • Carboxyhc groups might also be introduced by reaction of a triflate with carbon monoxide, an alcohol and ⁇ alladium(O) (Roth G.P. et al, Tetrahedron Lett., 1992, 33, 1959; Ma D. et al, Bioorg. Med. Chem. Lett., 1998, 8, 18, 2447-2450; Fisher MJ. et al, J. Med. Chem., 1997, 40, 2085-2101; Kraus G.A. et al, Tetrahedron Lett., 1994, 35, 9189-9190). These carboxyhc functions can subsequently be converted into amino functionalties by hydrolysis and Curtius reaction (Scheme 6).
  • Halogen containing 2-benzazepines may be prepared by treatment of halogenated tetralone oximes with POCl 3 /DMF and the resulting l,3,4,5-tetrahydro-l-oxo-2H-2-benzazepine-2- carboxaldehydes can be subsequently deformylated and reduced Majo NJ. et al, Synth. Commun., 1995, 25, 23, 3863-3868) (Scheme 7).
  • Scheme 7 8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine might be prepared by regioselective nitratk of 2,3,4,5-tetrahydro-lH-2-benzazepin-l-one using potassium nitrate and sulfuric ac (Grunewald G.L. et al, J. Heterocyclic Chem., 1994, 31, 1609-1617) (Scheme 8).
  • OXi. and OX 2 receptor antagonist activities of the compounds of formula (I) were determinated in accordance with the following experimental method.
  • Glutamine containing 300 ⁇ g/ml G418, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and
  • FCS foetal calf serum
  • the seeded plates were incubated overnight at 37°C in 5% CO 2 .
  • Human orexin- A as an agonist was prepared as 1 mM stock solution in methanol: water (1:1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
  • BSA bovine serum albumin
  • Antagonists were prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS contaming 0.1 % bovine serum albumin (BSA) and 2 mM HEPES. On the day of the assay, 100 ⁇ l of loading medium (HBSS containing 1% FCS, 2 mM
  • Example 9 Example 3 Example 5 Example 34 Example 35 Example 20 Example 23 Example 25 Example 42
  • the combined organic phases were dried over anhydrous MgSO 4 , filtered and concentrated to give the titled carboxyhc acid (1.14 g, 2.31 mmol, 100%) as a beige solid.
  • LC-MS: rt 3.58 min., 492 (M+l, ES+).

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Abstract

The invention relates to novel benzazepines and related heterocyclic derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.

Description

Novel Benzazepines and related heterocyclic derivatives
The present invention relates to novel benzazepines and related heterocyclic derivatives of the general formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists. The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and the orexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al, Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al, Cell, 1998, 92, 573-585). On the other hand, it was also proposed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic patients (Chemelli R.M. et al, Cell, 1999, 98, 437-451). Two orexin receptors have been cloned and characterized in mammals. They belong to the superfamily of G-protein coupled receptor (Sakurai T. et al, Cell, 1998, 92, 573-585). The orexin-1 receptor (OXι) is selective for OX-A and the orexin-2 receptor (OX2) is capable to bind OX-A as well as OX-B.
Orexin receptors are found in the mammalian host and may be responsible for many biological functions such as pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; feeding disorders such as anorexia, bulimia, cachexia and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcus; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIN, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasornnia; jet-lag syndrome; and neurodegerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration epilepsy; seizure disorders and other diseases related to orexin.
The present invention provides benzazepines and related heterocyclic derivatives which are non-peptide antagonists of human orexin receptors, in particular OXi and OX receptors. In particular, these compounds are of potential use in the treatment of obesity and/or sleep disorders. So far not much is known about low molecular weight compounds which have a potential to antagonise either specifically OXi or OX or both receptors at the same time. Recently WO 99/09024, WO 99/58533, WO 00/47577 and WO 00/47580 have been published wherein phenyl urea and phenyl thiourea derivatives are described as being preferably OXi receptor antagonists. Also quite recently WO 00/47576 described cinnamide derivatives as OXi receptor antagonists. The novel compounds of the present invention belong to an entirely different class of low molecular weight compounds as compared to all prior art orexin receptor antagonists so far published. The present invention relates to novel benzazepines and related heterocyclic derivatives of the general formula (I).
Figure imgf000004_0001
Formula (I)
wherein:
R1, R2, R3, R4 independently represent cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, RnCO-, R12R13CO-, R12R13N-, RnOOC-, RnSO2NH-, or
R14-CO- H-, or R2 and R3 together as well as R1 and R2 together and R3 and R4 together may form with the phenyl ring a five, six or seven-membered saturated ring containing one or two oxygen atoms;
R5, R6, R7,R8, R9, R10 independently represent hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;
R11 represents lower alkyl, lower alkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
R12and R13 independently represent hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
R14 represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R12R13N-, RuO-;
-X-Y- independently represents -CH2-CH2-, -O-CH2-, -S-CH2-, -SO2-CH2- and -NR15-CO-;
R15 represents hydrogen, lower alkyl or aralkyl. The compounds of formula (I) can contain one or more asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixtures of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
In the present description the term "lower alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 6 carbon atoms, preferably a straight or branched-chain alkyl group with 1-4 carbon atoms. Examples of straight-chain and branched Cι-C8 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-butyl, tert-butyl and n-pentyl.
The term "lower alkenyl", alone or in combination, signifies a straight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms, preferably allyl and vinyl.
The term "lower alkoxy", alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert- butoxy, preferably methoxy and ethoxy.
Lower alkenyloxy groups are preferably vinyloxy and allyloxy.
The term "cycloalkyl", alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms.
Examples of C3-C8 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl, cyclohexyl and particularly cyclohexyl or lower alkyl substituted cycloalkyl which may preferably be substituted with lower alkyl such as methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl, dimethyl-cyclohexyl.
The term "aryl", alone or in combination, signifies a phenyl or naphthyl group which optionally carries one or more substituents, preferably one or two substituents, each independently selected from cyano, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butoxyphenyl, 4- fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 1 -naphthyl and 2-naphthyl. Preferred are carboxyphenyl, lower alkoxy-phenyl, hydroxyphenyl and particularly phenyl.
The term "aralkyl", alone or in combination, signifies an alkyl or cycloalkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined. Preferred are benzyl and benzyl substituted in the phenyl ring with hydroxy, lower alkyl, lower alkoxy or halogen preferably chlorine. Particularly preferred is benzyl.
For the term "heterocyclyl" and "heterocyclyl-lower alkyl", the heterocyclyl group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated, partially unsaturated or aromatic containing for example 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur which may be the same or different. Example of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl, pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. The heterocyclyl group may have up to 5, preferably 1, 2 or 3 optional substituents. Examples of suitable substituents include halogen, lower alkyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and lower alkyloxy-carbonyls.
The term "halogen" signifies fluorine, chlorine, bromine or iodine and preferably chlorine and bromine and particularly chlorine.
The term "carboxy", alone or in combination, signifies a -COOH group.
A group of preferred compounds according to the present invention are compounds of formula (II)
Figure imgf000007_0001
General formula (II)
wherein:
R'!and R'2 independently represent hydrogen, hydroxy, lower alkoxy, lower alkenyloxy or halogen or may form with the phenyl ring a five, six or seven membered-ring containing one or two oxygen atoms;
R'3, R'4, R'5 independently represent aryl, aralkyl, lower alkyl, lower alkenyl, hydrogen trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; -X-Y- independently represents -CH2-CH2-, -O-CH2-, -S-CH2-, -SO2-CH2- and -NR'6-CO-; R'6 represents hydrogen, lower alkyl or aralkyl.
The compounds of formula (II) can contain one or more asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
Examples of preferred compounds of formula (II) are: 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- naphthalen- 1 -ylmethyl-acetamide
N-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-acetamide
2-[ 1 -(3 ,4-Dimethoxy-benzyl)-J,8-dimethoxy- 1 ,3 ,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan-2-yl-acetamide
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[fj[l,4]oxazepin-4-yl]- N-indan-2-yl-acetamide
2-[5-(3,4-Dimethoxy-beι zyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazeρin-4-yl]- N-indan- 1 -yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan- 1 -yl-acetamide
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimemoxy-5,5-dioxo-5,6,7,9-tefrahydro-5λ-thia-8-aza- benzocyclohepten-8-yl]-N-indan-2-yl-acetamide
2-[9-(3,4-Dimemoxy-benzyl)-2,3-dimemoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ-thia-8-aza- benzocyclohepten-8-yl]-N-indan-l-yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan- 1 -yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan-2-yl-2-phenyl-acetamide 2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6J-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-naphthalen-l-ylmethyl-acetamide
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6J-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-(2-ethoxy-benzyl)-acetamide
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-indan-l-yl-acetamide
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[fJ[l,4]oxazepin-4-yl]- N-(l,2,3,4-tetrahydro-naphthalen-l-yl)-acetamide
N-Benzyl-2-[9-(3,4-dimemoxy-benzyl)-2,3-dimethoxy-6,7-dmydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-acetamide
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepin-4-yl]- N-indan- 1 -yl-acetamide
N-Butyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-2-phenyl-acetamide
2-[ 1 -(3,4-Dimethoxy-benzyl)-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan- 1 -yl-2-phenyl-acetamide
N-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide
N-Cyclopentyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-2-phenyl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- furan-2-ylmethyl-2-phenyl-acetamide {2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-acetic acid ethyl ester
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-N-pyridin-4-ylmethyl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-N-pyridin-3-ylmethyl-acetamide
N-Cyclopropyl-2-[ 1 -(3 ,4-dimethoxy-benzyl)-7, 8-dimethoxy- 1 ,3 ,4,5 -tetrahydro- benzo [c] azepin-2-yl] -2-phenyl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(2- oxo-tetrahydro-furan-3-yl)-2-phenyl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4- methoxy-indan- 1 -yl)-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(3- ρhenyl-indan-l-yl)-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-(4- methyl-indan- 1 -yl)-acetamide
2-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-3-hydroxy-propionic acid methyl ester
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- ethylcarbamoylmethyl-2-phenyl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- [(ethyl-memyl-carbamoyl)-methyl]-2-phenyl-acetamide 2-[l-(3,4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl] -N-indan- 1 -yl-acetamide
2-[8-Benzyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2 yl] -N-indan- 1 -yl-acetamide
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahyclro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-propionic acid methyl ester
N-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy- l,3,4,5-tetrahydro-benzo[c]azeρin-2-yl]-2-phenyl-acetamide
N-(lH-Benzoimidazol-2-ylmethyl)-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide
2-[8-Allyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-indan-l-yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl] -N-indan- 1 -yl-acetamide
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-N,N-dimethyl-propionamide
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-N-ethyl-N-methyl-propionamide
2-[l-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl]-N-indan- 1 -yl-acetamide
2-[8-(2,2-Difluoro-ethbxy)-l-(3,4^αmιethoxy-berιzyl)-7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepm-2-yl]-N-indan-l-yl-a'cetamide Examples of particularly preferred compounds of formula (II) are:
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan-2-yl-acetamide
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepin-4-yl]- N-indan- 1 -yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan- 1 -yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan- 1 -yl-acetamide
2- [ 1 -(3 ,4-Dimethoxy-benzyl)-7, 8-dimethoxy- 1 ,3 ,4,5 -tetrahydro-benzo [c] azepin-2-yl] -N- indan-2-yl-2-phenyl-acetamide
N-Butyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-2-phenyl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- indan- 1 -yl-2-phenyl-acetamide
N-Benzo[l,3]dioxol-5-yhτιemyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide
N-Cyclopentyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-2-phenyl-acetamide
2-[l-(3,4-Dimemoxy-berιzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N- furan-2-ylmethyl-2-phenyl-acetamide
{2-[l-(3,4-Dimethoxy-benzyl)-7,8-α4methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino} -acetic acid ethyl ester 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-N-pyridin-3-ylmethyl-acetamide
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetτahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-propionic acid methyl ester
N-(lH-Benzoimidazol-2-ylmethyl)-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide
2-[8-Allyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl] -N-indan- 1 -yl-acetamide
2-[l-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl] -N-indan- 1 -yl-acetamide
2-[ 1 -(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy- 1 ,3,4,5-tetrahydro-benzo[c]azepin- 2-yl] -N-indan- 1 -yl-acetamide
2-[8-(2,2-Difluoro-ethoxy)-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-N-indan-l-yl-acetamide
Examples of physiologically usable or pharmaceutically acceptable salts of the compounds of formula (I) are salts with physiologically compatible mineral acids such as hydrochloric acid, sulphuric or phosphoric acid; or with organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula (I) with free carboxy groups can also form salts with physiologically compatible bases.
Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammoniumsalts such as Νa, K, Ca or tetraalkylammonium salt. The compounds of formula (I) can also be present in the form of a zwitterion.
Preferred compounds as described above have ICso values below 1000 nM; especially preferred compounds have IC50 values below 100 nM which have been determinated with the FLIPR (Fluorometric Imaging Plates Reader) method described in the beginning of the experimental section.
The compounds of the general formula (I) and their pharmaceutically usable salts can be used for the treatment of diseases or disorders where an antagonist of a human orexin receptor is required such as obesity, diabetes, prolactinoma, narcolepsy, insomriia, sleep apnea, parasomnia, depression, anxiety, addictions, schizophrenia and dementia.
The compounds of formula (I) and their pharmaceutically usable salts are particularly useful for the treatment of obesity and sleep disorders.
The compounds of formula (I) and their pharmaceutically usable salts can be used as medicament (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
The compounds of formula (I) and their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees, and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees, and hard gelatine capsules.
Suitable adjuvants for soft gelatine capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The invention also relates to processes for the preparation of compounds of Formula (I).
The compounds of general formula (I) of the present invention are prepared according to the general sequence of reactions outlined in the schemes below, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are as defined in formula (I) above. As the case may be any compound obtained with one or more optically active carbon atom may be resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates and the meso-forms in a manner known per se.
The compounds obtained may also be converted into a pharmaceutically acceptable salt thereof in a manner known per se.
The compounds of the general formula (I) may be prepared by standard procedures
(procedure A wherein R7 and R8 are hydrogen) and {procedure B wherein R7 and R8 are other than hydrogen) shown in Scheme 1 using synthesized benzazepine and related heterocyclic derivatives.
B
Figure imgf000016_0001
Figure imgf000016_0002
Scheme 1
Benzazepine derivatives wherein X and Y are CH2 and R6 is hydrogen might be prepared from the corresponding phenylpropylamine by coupling with the desired carboxyhc acid or acyl chloride followed by treatment with POCl3 and finally NaBH4 (Bischler-Napieralski reaction) as shown in Scheme 2a.
Figure imgf000017_0001
Bischler-Napieralski
2) NH4OH 25% reaction
3) LiAIH4
Figure imgf000017_0002
Scheme 2α
Benzazepines with variable substituents on position 8 might be prepared by hydrogenolysis of the corresponding 8-benzyloxy-l,354,5-tetrahydro-benzazepines followed by O-alkylation with the appropriate electrophile (Scheme 2b). The benzylethers can be obtained with the previous procedure (Scheme2d) applied to 3-(4-benzyloxy-phenyl)-propionic acid derivatives. B
Figure imgf000018_0001
Scheme 2b
Benzothiazepine and benzoxazepine derivatives wherein X is O or S, Y is CH2 and R6 is hydrogen might be prepared from the corresponding arylamine by coupling with the desired carboxyhc acid or acyl chloride followed by treatment with POCl3 and finally NaBH (Bischler-Napieralski reaction) as shown in Scheme 3.
Figure imgf000019_0001
i) cr N Bischler-Napieralski reaction
2) UAIH4
Figure imgf000019_0002
Scheme 3
l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-one derivatives wherein X is NR15, Y is CO < R6 is hydrogen might be prepared by Friedel-Crafts acylation of the correspond acetamido-aniline with the respective acyl chloride (Stembach L.Η. et αl., J. Org. Che 1962, 27, 3781-3788), followed by N-deprotection, cyclisation by treatment with met esters of α-amino acids (Stembach L.Η. et αl., J. Org. Chem., 1962, 27, 3788-3796) 1 finally hydrogenolysis of the dihydro compound (Fryer R.I. et αl., J. Med. Chem., 19 386-389) (Scheme 4).
Figure imgf000020_0001
Figure imgf000020_0002
Scheme 4
For the preparation of benzazepine derivatives with electron- withdrawing substituents on the phenyl ring, the previous procedures based on the Bischler-Napieralski reaction are incompatible. Therefore cyano groups might be introduced by reaction of a triflate with cyanide ions and palladium(0) (Austin N.E. et al, Bioorg. Med. Chem. Lett., 2000, 10, 2553-2555; Ritter K. et al, Synthesis, 1993,735; Selnick H.G. et al, Synth. Commun. 1995, 25, 20, 3255-3262) (Scheme 5).
Figure imgf000020_0003
Scheme 5 Carboxyhc groups might also be introduced by reaction of a triflate with carbon monoxide, an alcohol and ρalladium(O) (Roth G.P. et al, Tetrahedron Lett., 1992, 33, 1959; Ma D. et al, Bioorg. Med. Chem. Lett., 1998, 8, 18, 2447-2450; Fisher MJ. et al, J. Med. Chem., 1997, 40, 2085-2101; Kraus G.A. et al, Tetrahedron Lett., 1994, 35, 9189-9190). These carboxyhc functions can subsequently be converted into amino functionalties by hydrolysis and Curtius reaction (Scheme 6).
Figure imgf000021_0001
1) hydrolysis
2) Curtius reaction
Figure imgf000021_0002
Scheme 6
Halogen containing 2-benzazepines may be prepared by treatment of halogenated tetralone oximes with POCl3/DMF and the resulting l,3,4,5-tetrahydro-l-oxo-2H-2-benzazepine-2- carboxaldehydes can be subsequently deformylated and reduced Majo NJ. et al, Synth. Commun., 1995, 25, 23, 3863-3868) (Scheme 7).
Figure imgf000021_0003
Scheme 7 8-nitro-2,3,4,5-tetrahydro-lH-2-benzazepine might be prepared by regioselective nitratk of 2,3,4,5-tetrahydro-lH-2-benzazepin-l-one using potassium nitrate and sulfuric ac (Grunewald G.L. et al, J. Heterocyclic Chem., 1994, 31, 1609-1617) (Scheme 8).
Schmidt reaction KN03/H2S04
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
Scheme 8
Experimental Section
I. Biology
Determination of OXi and OX2 receptor antagonist activities
The OXi. and OX2 receptor antagonist activities of the compounds of formula (I) were determinated in accordance with the following experimental method.
Experimental method: Intracellular calcium measurements
Chinese hamster ovary (CHO) cells expressing the human orexin- 1 receptor and the human orexin-2 receptor, respectively, were grown in culture medium (Ham F-12 with L-
Glutamine) containing 300 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and
10 % inactivated foetal calf serum (FCS). The cells were seeded at 80O00 cells / well into 96- well black clear bottom sterile plates
(Costar) which had been precoated with 1% gelatine in Hanks' Balanced Salt Solution
(HBSS). All reagents were from Gibco BRL.
The seeded plates were incubated overnight at 37°C in 5% CO2.
Human orexin- A as an agonist was prepared as 1 mM stock solution in methanol: water (1:1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
Antagonists were prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS contaming 0.1 % bovine serum albumin (BSA) and 2 mM HEPES. On the day of the assay, 100 μl of loading medium (HBSS containing 1% FCS, 2 mM
HEPES, 5 mM probenecid (Sigma) and 3 μM of the fluorescent calcium indicator fluo-3
AM (1 mM stock solution in DMSO with 10% pluronic acid) (Molecular Probes) was added to each well.
The 96-well plates were incubated for 60 min at 37° C in 5% CO2. The loading solution was then aspirated and cells were washed 3 times with 200 μl HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 μl of that same buffer was left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), antagonists were added to the plate in a volume of 50 μl, incubated for 20 min and finally 100 μl of agonist was added. Fluorescence was measured for each well at 1 second intervals, and the height of each fluorescence peak was compared to the height of the fluorescence peak induced by 10 nM orexin- A with buffer in place of antagonist. For each antagonist, IC50 values (the concentration of compound needed to inhibit 50 % of the agonistic response) were determined. Selected compounds are displayed in Table 1
IC50 (nM)
Example 9 Example 3 Example 5 Example 34 Example 35 Example 20 Example 23 Example 25 Example 42
Example 43
Figure imgf000024_0001
Table 1
II. Chemistry
The following examples illustrate the preparation of pharmacologically active compounds of the invention but do not at all limit the scope thereof. All compounds were prepared in racemic form. All temperatures are stated in °C.
All hydrochloride salts were prepared by dissolving the free-base in dichloromethane and treating with an excess of HC1 in propanol-2 (5-6M).
A. Starting materials: Synthesis of tetrahydrobenzazepine and related heterocyclic derivatives:
3-(3,4-Dimethoxy-phenyl)-propionamide
To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid (10.0 g, 47.56 mmol) in dry THF (175 ml), under nitrogen, was added TEA (7.3 ml, 52.44 mmol), and the resulting mixture was cooled to -10°C before ethyl chloroformate (5 ml, 52.47 mmol) was added dropwise. After stirring at -10°C (20 min), ammonium hydroxide (25% in water, 105 ml) in THF (105 ml) was added and the mixture was stirred at -15°C for 30 min and then at RT for 1.5h. The reaction mixture was concentrated in vacuo, extracted three times with CH2C12 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to give the titled compound (9.73 g, 46.50 mmol, 97%) as a colorless solid. No further purification of the crude amide was necessary. LC-MS: rt = 2.94 min., 210 (M+l, ES+).
3-(3,4-Dimethoxy-phenyl)-propylamine
A solution of 3-(3,4-dimethoxy-phenyl)-propionamide (11.09 g, 53.00 mmol) in anhydrous THF (400 ml) was slowly added to a stirred, ice-cooled suspension of LiALH4 (4.02 g, 106.00 mmol) in anhydrous THF (170 ml). Upon completion of the addition, the mixture was stirred at reflux for 2h. After cooling to 0°C, H2O (5 ml) and NaOH IN (5 ml) were added dropwise to decompose the excess of hydride. The suspension was then filtered and the residue after evaporation was partitioned between H O (40 ml) and CH2C12 (100 ml). The organic layer was washed with NaHCO3 and brine, dried over anhydrous MgSO , and concentrated under reduced pressure to give the crude amine (7.00 g, 35.84 mmol, 68%) as a yellow oil.
1H-NMR (300 MHz, CDC13) δ: 6.9-6.6 (3H, m), 3.9-3.8 (6H, d), 2.9-2.7 (2H, m), 2.65- 2.55 (2H, m), 1.9-1.75 (2H, m).
2-(3,4-Dimethoxy-phenyl)-iV-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide
A solution of 3-(3,4-dimethoxy-phenyl)-propylamine (12.51 g, 64.06 mmol) and TEA (10 ml, 71.84 mmol) in anhydrous THF (70 ml) was cooled to 0°C and (3,4-dimethoxy- phenyl)-acetyl chloride (13.75 g, 64.07 mmol) in THF (28 ml) was added dropwise. After stirring at RT for 13h under nitrogen, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the titled compound (12.81 g, 34.30 mmol, 53%) as a beige solid.
LC-MS: rt = 4.00 min., 374 (M+l, ES+).
l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine
A mixture of 2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide (6.16 g, 16.49 mmol) and POCl3 (4.95 ml, 54.07 mmol) in anhydrous acetonitrile (185 ml) was stirred at reflux for 4h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (125 ml). The solution was cooled to 0°C and ΝaBH4 (4.31 g, 113.93 mmol) was added portionwise. After stirring at 0°C for 2h under nitrogen, the reaction mixture was poured into H2O and extracted three times with CH2C12. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the titled compound as a racemic mixture (2.29 g, 6.40 mmol, 39%, yellow oil). LC-MS: rt = 3.02 min., 358 (M+l, ES+).
[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]- phenyl-acetic acid methyl ester A mixture of l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH- benzo[c]azeρine (1J0 g, 3.08 mmol), TEA (1.3 ml, 9.33 mmol), methyl α- bromophenylacetate (487 μl, 3.09 mmol) in anhydrous toluene (13 ml) was stirred at reflux for 17h under nitrogen. After cooling, the reaction mixture was dissolved in CΗ2C12 (40 ml), washed with H O (15 ml) and the aqueous phase was extracted two times with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/hexane: 1/1) gave the titled compound as a mixture of stereoisomers (1.34 g, 2.65 mmol, 86%, yellow oil). LC-MS: rt = 3.99 min. and rt = 4.24 min., 506 (M+l, ES+).
[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]- phenyl-acetic acid
To a solution of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid methyl ester (1.17 g, 2.31 mmol), in MeOH (9 ml) and dioxane (12 ml), was added dropwise aqueous NaOH 2N (11 ml, 22 mmol). The resulting yellow homogeneous mixture was then stirred at 45 °C for 8h. The reaction mixture was then concentrated in vacuo and washed with Et2O (5 ml). The aqueous phase was acidified (pH = 1) with HC12N and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled carboxyhc acid (1.14 g, 2.31 mmol, 100%) as a beige solid. LC-MS: rt = 3.58 min., 492 (M+l, ES+).
3-(4-Benzyloxy-3-methoxy-phenyI)-propionic acid benzyl ester
A mixture of 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid (5J g, 25.99 mmol), anhydrous K2CO3 (25 g, 180.88 mmol) and benzyl bromide (7.5 ml, 63.14 mmol) in anhydrous acetone (100 ml) was stirred at reflux for 7.5h under nitrogen. After cooling, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (CH2C12) gave the titled compound (8.83 g, 23.45 mmol, 90%). LC-MS: rt = 5.65 min., 377 (M+l, ES+). 3-(4-Benzyloxy-3-methoxy-phenyl)-propionic cid
To a solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionic acid benzyl ester (11.03 g, 29.30 mmol), in MeOH (110 ml) and dioxane (145 ml), was added dropwise aqueous NaOH 2N (139 ml, 278 mmol). The resulting yellow homogeneous mixture was then stirred at 50°C for 17h. The reaction mixture was then concentrated in vacuo and washed with Et2O (100 ml). The aqueous phase was acidified (pH = 1) with HCl 2N and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgSO , filtered and concentrated to give the titled carboxyhc acid (8.4 g, 29.30 mmol, 100%) as a colorless solid. LC-MS: rt = 4.53 min., 285 (M-l, ES-).
3-(4-Benzyloxy-3-methoxy-phenyl)-propionamide
To a stirred solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionic acid (8.38 g, 29.30 mmol) in dry THF (110 ml), under nitrogen, was added TEA (4.5 ml, 32.33 mmol), and the resulting mixture was cooled to -10°C before ethyl chloroformate (3.1 ml, 32.53 mmol) was added dropwise. After stirring at -10°C (20 min), ammomum hydroxide (25% in water, 65 ml) in THF (65 ml) was added and the mixture was stirred at -15°C for 30 min and then at RT for 1.5h. The reaction mixture was concentrated in vacuo, extracted three times with CH2C12 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to give the titled compound (8.40 g, 29.30 mmol, 100%) as a colorless solid. No further purification of the crude amide was necessary. LC-MS: rt = 4.08 min., 286 (M+l, ES+).
3-(4-BenzyIoxy-3-methoxy-phenyl)-propylamine
A solution of 3-(4-benzyloxy-3-methoxy-ρhenyl)-propionamide (7.85 g, 27.53 mmol) in anhydrous THF (210 ml) was slowly added to a stirred-ice-cooled suspension of LiAlH
(2.09 g, 55.07 mmol) in anhydrous THF (90 ml). Upon completion of the addition, the mixture was stirred at reflux for lh. After cooling to 0°C, H2O (15 ml) was added dropwise to decompose the excess of hydride and the suspension was then filtered. The residue after evaporation was partitioned between H2O (50 ml) and CH2C12 (100 ml). The organic layer was washed with NaHCO3 and brine, dried over anhydrous MgSO , and concentrated under reduced pressure to give the crude amine (6.03 g, 22.22 mmol, 81 %) as a yellow oil. LC-MS: rt = 3.20 min., 272 (M+l, ES+).
iV-[3-(4-Benzyloxy-3-methoxy-phenyl)-propyI]-2-(3,4-dimethoxy-phenyl)-acetamide
A solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propylamine (6.06 g, 22.36 mmol) and TEA (3.5 ml, 25.14 mmol) in anhydrous THF (25 ml) was cooled to 0°C and (3,4- dimethoxy-phenyl)-acetyl chloride (4.80 g, 22.36 mmol) in THF (10 ml) was added dropwise. After stirring at RT for 28h under nitrogen, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the titled compound (6.57 g, 14.61 mmol, 65%) as a beige solid. LC-MS: rt = 4.90 min., 450 (M+l, ES+).
8-Benzyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-2,3,4,5-tetrahydro-lH- benzo[c]azepine
A mixture of N-[3-(4-benzyloxy-3-methoxy-phenyl)-propyl]-2-(3,4-dimethoxy-phenyl)- acetamide (6.04 g, 13.43 mmol) and POCl3 (4.1 ml, 44.78 mmol) in anhydrous acetonitrile (350 ml) was stirred at reflux for 5h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (120 ml). The solution was cooled to 0°C and ΝaBH4 (3.50 g, 92.70 mmol) was added portionwise. After stirring at 0°C for 2h under nitrogen, the reaction mixture was poured into H2O and extracted three times with CH2C12. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the titled compound as a racemic mixture (2.44 g, 5.62 mmol, 42%, yellow oil). LC-MS: rt = 3.52 min., 434 (M+l, ES+). (3,4-Dimethoxy-phenoxy)-acetonitrile
To a solution of 3,4-dimethoxyphenol (5.0 g, 0.0324 mol) in dry acetone (160 ml), were added chloroacetonitrile (2.05 ml, 0.0324 mol) and anhydrous K2CO3 (6.72 g, 0.0486 mol). The reaction mixture was stirred at reflux for 20h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H2O, extracted with CH2C12, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/ hexane: 3/7) gave the titled product (4,5 g, 68%)
1H-NMR (300MHz, CDC13) δ: 6.8 (lH,d), 6.6 (lH,d), 6.5 (lH,dd), 4.75 (2H,s), 3.85 (6H, d).
2-(3,4-Dimethoxy-phenoxy)-ethyIamine
To a cold (0°C) suspension of L1AIH4 (1.73 g, 0.0456 mol) in anhydrous THF (72 ml), was added dropwise a solution of (3,4-dimethoxy-phenoxy)-acetonitrile (5.88 g, 0.0304 mol) in anhydrous THF (42 ml). The resulting mixture was allowed to warm-up and stirred at RT for 20h under nitrogen. The mixture was combined with a mixture of H O/2N NaOH(aq) (4/1) to destroy the excess of LiALH-μ The white suspension was filtered and the solid was washed with CH C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/ MeOH: 9/1) gave the titled product (4,65 g, 77%) 1H-NMR (300MHz, CDC13) δ: 6.78 (lH,d), 6.55 (lH,d), 6.4 (lH,dd), 3.95 (2H,t), 3.80 (6H, d), 3.05 (2H, t), 1.92 (2H, br.s.).
N-[2-(3,4-Dimethoxy-phenoxy)-ethyl]-2-(3,4-dimethoxy-phenyi)-acetamide
To a cold (0°C) solution of 2-(3,4-dimethoxy-phenoxy)-ethylamine (2.3 g, 0.0118 mol) in anhydrous THF (21 ml), were added TEA (1.4 ml, 0.0192 mol) and portionwise 3,4- dimethoxyphenylacetylchloride (2.49 g, 0.0116 mol). The resulting mixture was stirred al RT for 20h under nitrogen.The mixture was combined with H O and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude solid. Recrystallisation over diethylether gave the titled product (3.59 g, 80%) as a white solid.
1H-NMR (300MHz, CDC13) δ: 6.8 (3H,m), 6.4 (lH,d), 6.35 (lH,dd), 5.95 (lH,br.s) 3.95 (2H,t), 3.80 (12H,q), 3.6 (2H,m), 3.55 (2H,s). LC-MS: rt = 3.84 min., 376 (M+l, ES+).
5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[fJ[l,4]oxazepine
To a stirred solution of N-[2-(3,4-dimethoxy-phenoxy)-ethyl]-2-(3,4-dimethoxy-phenyl)- acetamide (3.6 g, 9.56 mmol) in dry CH3CΝ (20 ml), was added POCl3 (2.62 ml, 0.0286 mol). The resulting mixture was stirred at reflux for 3h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (80 ml). The solution was cooled to 0°C and NaBH4 (2.53 g, 0.067 mol) was added portionwise. The resulting pale yellow suspension was stirred at RT for 16h under nitrogen. The reaction mixture was poured into H2O and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/ MeOH: 9/1) gave the titled product (1.14 g, 33%) as a viscous brown oil.
1H-NMR (300MHz, CDC13) δ: 6.8-6.6 (5H,m), 6.45 (lH,s), 4.15 (lH,m), 3.80 (12H,q), 3.55-2.95 (6H,m).
LC-MS: rt = 2.99 min., 360 (M+l, ES+).
(3,4-Dimethoxy-phenylsulfanyl)-acetonitrile
To a solution of 3,4-dimethoxythiophenol (5.0 g, 0.0294 mol) in dry DMF (150 ml), were added chloroacetonitrile (1.85ml, 0.0294 mol), anhydrous K2CO3 (6.09 g, 0.0441 mol) and DMAP (358 mg, 2.9 mmol). The reaction mixture was stirred at 80°C for 20h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H2O, extracted with CH2C12, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt) gave the titled product (5.16 g, 84%).
1H-NMR (300MHz, CDC13) δ: 7.2 (lH,d), 7.15 (lH,d), 6.9 (lH,d), 3.85 (6H, d), 3.5 (2H, s). 2-(3,4-Dimethoxy-phenylsuIfanyl)-ethylamine
To a cold (0°C) solution of (3,4-dimethoxy-phenoxy)-acetonitrile (7.53 g, 0.036 mol) in anhydrous THF (41 ml), was added portionwise NaBH (1.22 g, 0.032 mol) and dropwise a solution of BF3.OEt2 (5.37 ml, 0.02 mol) in anhydrous THF (13.4 ml) over 30 min.. The resulting rnixture was stirred at RT for 3h under nitrogen. The mixture was concentrated in vacuo, the residue was dissolved in CH2C12 and washed with HCl 37%. The aqueous phase was neutralized with NaOH 30% and extracted with CH2Cl2.The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/ MeOH: 9/1) gave the titled product (3.6 g, 46%). 1H-NMR (300MHz, CDC13) δ: 7.05 (2H,m), 6.85 (lH,d), 3.80 (6H, d), 2.95 (2H,m), 1.7 (2H, br.s.).
2-(3,4-Dimethoxy-phenyl)-iV-[2-(3,4-dimethoxy-phenylsulfanyl)-ethyl]-acetamide
To a cold (0°C) solution of 2-(3,4-dimemoxy-ρhenylsulfanyl)-ethylamine (3.97g, 0.0186 mol) in anhydrous THF (49 ml), were added TEA (3.11 ml, 0.0186 mol) and portionwise 3,4-dimethoxyphenylacetylchloride (4.0 g, 0.0186 mol). The resulting mixture was stirred at RT for 20h under nitrogen. The mixture was combined with H2O and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgSO , filtered and concentrated to give a crude solid. Flash chromatography (AcOEt) gave the titled product (7.08 g, 97%). 1H-NMR (300MHz, CDC13) δ: 6.95-6.7 (6H,m), 5.95 (lH.br.s), 3.95 (12H,q), 3.5 (2H,s), 3.55 (2H,q), 2.95 (2H,t).
LC-MS: rt = 3.87 min., 392 (M+l, ES+).
9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptene
To a stirred solution of 2-(3,4-dimethoxy-phenyl)-N-[2-(3,4-dimethoxy-phenylsulfanyl)- ethyl]-acetamide (4.0 g, O.Olmol) in dry CH3CN (21 ml), was added POCl3 (2.80 ml, 0.03 mol). The resulting mixture was stirred at reflux for 3h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (85ml). The solution was cooled to 0°C and NaBRt (2.7 g, 0.069 mol) was added portionwise, the resulting pale yellow suspension was stirred at RT for 16h under nitrogen. The reaction mixture was poured into H2O and extracted three times with CH2C12. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/ MeOH: 9/1) gave the titled product (1J4 g, 27%) as a viscous brown oil.
1H-NMR (300MHz, CDC13) δ: 7.1 (1H, s), 6.8 (4H,s), 4.6 (lH,m), 4.15, 3.80 (12H,q), 3.45-2.75 (6H,m). LC-MS: rt = 4.39 min., 376 (M+l, ES+).
9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzycloheptene-8-carboxylic acid tert-butyl ester
To a cold (0°C) stirred solution of 9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9- tefrahydro-5-thia-8-aza-bencycloheptene (417 mg, 1.11 mmol) in 5 ml of dry CH2C12, were added TEA (168 μL, 1.2 mmol) and di-tert.-butyl-dicarbonate (262 mg, 1.2 mmol). The resulting mixture was allowed to warm-up and stirred at RT for 20h under nitrogen. The reaction mixture was combined with water, extracted twice with CH2C12, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude yellow oil. Flash chromatography (AcOEt) gave the title compound as a pale yellow oil (486 mg, 91%). 1H-NMR (300 MHz, CDC13) δ: 7.15 (1H, d); 6.6-6.8 (4H, m); 5.05 (1H, m); 3.85 (12H, d); 3.65 (2H, m); 3.45 (2H, m); 2.75 (2H, m); 1.45 (9H, d).
9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ6 -thia-8- aza-benzycloheptene-8-carboxylic acid tert-butyl ester
To a cold (0°C) stirred solution of 9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6J-dihydro- 9H-5-thia-8-aza-benzocycloheptene-8-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) in 1 ml of dry CΗ2C1 , was added 3-chloroperbenzoic acid (106 mg, 0.614 mmol). The resulting mixture was stirred at 0°C for 2h and allowed to warm-up and stirred at RT overnight. The reaction mixture was combined with water, extracted twice with CH2C12, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/ hexane: 1/1) gave the title compound as a pale yellow solid (76 mg, 71%). 1H-NMR (300 MHz, CDC13) δ: 7.15 (1H, d); 6.6-6.8 (4H, m); 5.25 (1H, m); 3.85 (12H, d); 3.65 (2H, m); 3.35 (2H, m); 2.75 (2H, m); 1.35 (9H, d).
9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza- benzycloheptene 5,5-dioxide.
To a stirred solution of 9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9- tetrahydro-5λ6 -thia-8-aza-benzycloheptene-8-carboxylic acid tert-butyl ester (310 mg, 0.61 mmol) in 3 ml of dry CH2C12, was added trifluoroacetic acid (372 μL, 4.86 mmol). The resulting mixture was stirred at RT for 20h under nitrogen. The reaction mixture combined with water/ NaOH 2N, extracted twice with CH2C12, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2C12/ MeOH: 1/1) gave the title compound as a pale yellow oil (118 mg, 47%).
1H-NMR (300 MHz, CDC13) δ: 7.6 (1H, d); 6.85 (4H, m); 4.95 (1H, m); 3.95-3.81 (12H, m); 3.45 (4H, m); 3.25 (2H, m).
B. General procedure A:
At -15°C a solution of the respective amine (1 equivalent) in THF (0.40 M) was added dropwise to a solution of 2-bromoacetyl bromide (1 equivalent) in THF (0.20 M). The reaction mixture was treated dropwise with a solution of diisopropylethylamine (4 equivalents) in THF (2.0 M), allowed to warm up slowly to RT and stirred at RT for 30 min. A solution of the respective benzazepine (1 equivalent) in THF (0.20 M) was added and the mixture was heated to 75°C for 15h. After cooling, AcOEt and H2O were added, and the aqueous phase was extracted two times with AcOEt. The combined organic phases were washed with brine, dried over anhydrous MgSO , filtered and concentrated in vacuo. Flash chromatography gave the benzazepine derivative. Example 1
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV- naphthalen-1-ylmethyl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 1-naphtalenemethylamine and l-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt = 3.95 min, 555 (M+l, ES+).
Example 2
iV-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,354,5- tetrahydro-benzo [c] azepin-2-yl] -acetamide :
prepared by reaction of 2-bromoacetyl bromide with piperonylamine and l-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine.
LC-MS: rt = 3.67 min, 549 (M+l, ES+).
Example 3
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV- indan-2-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt = 3.83 min, 531 (M+l, ES+).
Example 4:
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5Η-benzo[f][l,4]oxazepin-4- yl]-iV-indan-2-yl-acetamide: prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and
5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro- benzo[f] [1 ,4]oxazepine. LC-MS: rt = 4.34 min, 533 (M+l, ES+).
Example 5
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[fJ[l,4]oxazepin-4- yl] -N-indan-1-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 1-aminoindane and 5 -(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][l,4]oxazepine. LC-MS: rt = 4.62 min, 533 (M+l, ES+).
Example 6
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Λ indan-1-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 1-aminoindane and l-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt = 3.90 min, 531 (M+l, ES+).
Example 7
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ6-thia-8- aza-benzocyclohepten-8-yl]-iV-indan-2-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 2-aminoindane hydrochloride and 9- (3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptene-5,5-dioxide. LC-MS: rt = 3.81 min, 581 (M+l, ES+). Example 8
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-5λ6-thia-8- aza-benzocyclohepten-8-yl]--V-indan-l-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 1-aminoindane and 9-(3,4- dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tefrahydro-5-thia-8-aza-benzocycloheptene- 5,5-dioxide LC-MS: rt = 4.49 min, 581 (M+l, ES+).
Example 9
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV indan-1-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with S(+)- 1-aminoindane and l-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine.
LC-MS: rt = 3.80 min, 531 (M+l, ES+).
Example 10
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5Η-benzo[f][l,4]oxazepin-4- yI]-iV-naphthalen-l-ylmethyl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 1-naphtalenemethylamine and 5-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tefrahydro-benzo[f][l,4]oxazepine. LC-MS: rt = 4.39 min, 557 (M+l, ES+).
Example 11
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepin-4- yl]-iV-(2-ethoxy-benzyl)-acetamide: prepared by reaction of 2-bromoacetyl bromide with 2-ethoxy-benzylamine and 5-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[fl[l,4]oxazepine. LC-MS: rt = 4.34 min, 551 (M+l, ES+).
Example 12
2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepin-4- yl]-7V-indan-l-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with S(+)- 1-aminoindane and 5-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tefrahydro-benzo[f][l,4]oxazepine. LC-MS: rt = 4.32 min, 533 (M+l, ES+).
Example 13
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-S-ylJr/V^l^^^-tetrahydro-naphthalen-l-y^-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-naphthalen-l- ylamine and 9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetrahydro-5-thia-8-aza- benzocycloheptene.. LC-MS: rt = 5.01 min, 563 (M+l, ES+).
Example 14
N-Benzyl-2-[5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H- benzo[fj[l,4]oxazepin-4-yl]-acetamide:
prepared by reaction of 2-bromoacetyl bromide with benzylamine and 5-(3,4-dimethoxy- benzyl)-7,8-dimethoxy-2,3 ,4,5-tetrahydro-benzo [f] [ 1 ,4]oxazepine. LC-MS: rt = 4.05 min, 507 (M+l, ES+). Example 15
2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-iV-indan-l-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with S(+)- 1-aminoindane and 9-(3,4- dimethoxy-benzyl)-2,3-dimethoxy-6,7,8,9-tetiahydro-5-thia-8-aza-benzocycloheptene. LC-MS: rt = 4.85 min, 549 (M+l, ES+).
Example 16
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Λ (4-methoxy-indan-l-yl)-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 4-methoxy-indan-l-ylamine and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt = 3.83 min, 561 (M+l, ES+).
Example 17
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-Λ (3-phenyl-indan-l-yl)-acetamide:
prepared by reaction of 2-bromoacetyl bromide with 3-phenyl-indan-l-ylamine and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt = 4.42 min, 607 (M+l, ES+).
Example 18
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-i\ (4-methyl-indan-l-yl)-acetamide: prepared by reaction of 2-bromoacetyl bromide with 4-methyl-indan-l-ylamine and 1- (3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt - 4.02 min, 545(M+1, ES+).
Example 19
2-[8-Benzyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-_V-indan-l-yl-acetamide:
prepared by reaction of 2-bromoacetyl bromide with S(+)- 1-aminoindane and l-(3,4- dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-benzo[c]azepine. LC-MS: rt = 4.39 min, 607 (M+l, ES+).
C. General procedure B:
To a solution of the respective [l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid (1 equivalent) in anhydrous DMF (0.04 M) was added PyBOP (1.1 equivalents), the respective amine (1 equivalent) and N-diisopropylethylamine (2.3 equivalents). The resulting mixture was stirred at RT for 15h under nitrogen. After reaction, AcOEt was added, and the organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography provided the benzazepine derivative.
Example 20
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV- indan-2-yl-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-aminoindane hydrochloride. LC-MS: rt = 4.26 min, 607 (M+l, ES+).
Example 21 N-Butyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl] -2-phenyl-acetamide: prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with n-butylamine. LC-MS: rt = 3.91 min, 547 (M+l, ES+).
Example 22
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV- indan-l-yl-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with S(+)-l-aminoindane. LC-MS: rt = 4.09 min and rt = 4.39 min (diastereoisomers), 607 (M+l, ES+).
Example 23
N-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo [c] azepin-2-y 1] -2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with piperonylamine.
LC-MS: rt = 3.88 min and rt = 3.98 min (diastereoisomers), 625 (M+l, ES+).
Example 24
iV-CyclopentyI-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with cyclopentylamine.
LC-MS: rt = 3J9 min and rt = 3.92 min (diastereoisomers), 559 (M+l, ES+). Example 25
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-7V- furan-2-ylmethyl-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with furfurylamine. LC-MS: rt = 3.72 min and rt = 3.85 min (diastereoisomers), 571 (M+l, ES+).
Example 26
{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-acetylamino}-acetic acid ethyl ester:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with glycine ethyl ester hydrochloride. LC-MS: rt = 3.72 min, 577 (M+l, ES+).
Example 27
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyI-iV-pyridin-4-ylmethyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 4-picolylamine. LC-MS: rt = 3.09 min, 582 (M+l, ES+).
Example 28
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2- phenyl-iV-pyridin-3-ylmethyl-acetamide: prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-picolylamine. LC-MS: rt = 3.20 min, 582 (M+l, ES+).
Example 29
iV-Cyclopropyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-2-phenyI-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with cyclopropylamine. LC-MS: rt = 3.59 min, 531 (M+l, ES+).
Example 30
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-iV- (2-oxo-tetrahydro-furan-3-yI)-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dim lέettlhoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-4-butyrolactone hydrobromide. LC-MS: rt = 3.46 min, 575 (M+l, ES+).
Example 31
2- {2- [1 -(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l ,3,4,5-tetrahy dro-benzo [c] azepin-2-yl] - 2-phenyI-acetylamino}-3-hydroxy-propionic acid methyl ester:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with L-serine methyl ester hydrochloride. LC-MS: rt = 3.40 min, 593 (M+l, ES+).
Example 32 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-7V ethyIcarbamoyϊmethyI-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-acetamide. LC-MS: rt = 3.37 min, 576 (M+l, ES+).
Example 33
2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]--V [(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-N-ethyl-N-methyl-acetamide. LC-MS: rt = 3.42 min, 590 (M+l, ES+).
Example 34
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl] 2-phenyl-acetylamino}-propionic acid methyl ester:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azeρin-2-yl]-phenyl-acetic acid with 3-amino-propionic acid methyl ester. LC-MS: rt = 3.52 min, 577 (M+l, ES+).
Example 35
iV-(lH-Benzoimidazol-2-ylmethyl)-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-2-phenyI-acetamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-aminomethyl-benzimidazole dihydrochloride hydrate. LC-MS: rt = 3.36 min, 621 (M+l, ES+).
Example 36
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]- 2-phenyl-acetylamino}-iVyV-dimethyl-propionamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-N,N-dimethyl-propionamide. LC-MS: rt = 3.42 min, 590 (M+l, ES+).
Example 37
3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]- 2-phenyl-acetylamino}-.V-ethyl-iV-methyl-propionamide:
prepared by reaction of [l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-N-ethyl-N-methyl-propionamide. LC-MS: rt = 3.40 min, 604 (M+l, ES+).
D. Variation of substituents on position 8:
General procedure:
To a solution of the respective 8-benzyloxy-l,3,4,5-tetrahydro-benzazepine in methanol (0.07 M) was added palladium (10 wt. % on activated carbon; 10 % of the benzylether weight) and the resulting heterogeneous mixture was vigorously stirred under an hydrogen atmosphere at RT until disappearance of benzylether (TLC). After reaction the mixture was filtered through celite and concentrated in vacuo. Flash chromatography yielded the pure phenol derivative. To a solution of this phenol derivative (1 equivalent) in anhydrous DMF (0.04 M) was added successively anhydrous potassium carbonate (5 equivalents) and the respective electrophile (1.2 equivalents). The resulting heterogeneous mixture was stirred at 50°C for 15h. After reaction the mixture was dissolved in AcOEt and washed with a saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over anhydrous MgSO , filtered and concentrated in vacuo. Flash chromatography provided the pure benzazepine derivative.
Example 38
2-[l-(3,4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl]-iV-indan-l -yl-acetamide:
prepared by hydrogenolysis of 2-[8-benzyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy- l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-l-yl-acetamide.
LC-MS: rt = 3.64 min, 517 (M+l, ES+).
Example 39
iV-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy- l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide:
prepared by hydrogenolysis of N-benzo[l,3]dioxol-5-ylmethyl-2-[8-benzyloxy-l-(3,4- dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide. LC-MS: rt = 3.77 min, 611 (M+l, ES+).
Example 40
2-[8-AUyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl] -iV-indan-1-yl-acetamide:
prepared by reaction of 2-[l-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-N-indan-l -yl-acetamide with allylbromide. LC-MS: rt = 4.05 min, 557 (M+l, ES+).
Example 41 2-[l-(3,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl]-iV-indan-l-yl-acetamide:
prepared by reaction of 2-[l-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5- tetrahydro-berιzo[c]azepin-2-yl]-N-indan-l-yl-acetamide with 1-bromopropane. LC-MS: rt = 4.13 min, 559 (M+l, ES+).
Example 42
2-[l-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-l,3,4,5-tetrahydro- benzo [c] azepin-2-yl]-iV-indan-l-yl-acetamide:
prepared by reaction of 2-[l-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl]-N-indan-l-yl-acetamide with 2-bromopropane. LC-MS: rt = 4.07 min, 559 (M+l, ES+).
Example 43
2-[8-(2,2-Difluoro-ethoxy)-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-iV-indan-l-yl-acetamide:
prepared by reaction of 2-[l-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5- tefrahydro-benzo[c]azepin-2-yl]-N-indan- 1 -yl-acetamide with 2-bromo- 1 , 1 -difluoroethane. LC-MS: rt = 4.14 min, 581 (M+l, ES+). Abbreviations:
AcOEt Ethyl acetate
BSA Bovine serum albumine
CHO Chinese hamster ovary
DMF Dimethylformamide
DMSO Dimethylsulfoxide
ES Electron spray
FCS Foetal calf serum
FLIPR Fluorescent imaging plate reader
HBSS Hank's balanced salt solution
HEPES 4-(2-Hydroxyethyl)-piperazine- 1 -ethanesulfonic acid
MeOH Methanol
MS Mass spectroscopy
LC Liquid chromatography
PyBOP Benzotriazole- 1 -yl-oxy-tris-pyrrolidino-
Phosphoniumhexafluorophosphate
Rf Retention front
Rt retention time
RT Room temperature
TEA Triethylamine
Tf CF3SO2-
THF Tetrahydrofuran
TLC Thin layer chromatography

Claims

Claims 1. Compounds of the general formula (I)
Figure imgf000049_0001
Formula (I)
wherein:
R1, R2, R3, R4 independently represent cyano, nitro, halogen, hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, RπCO-, NR12R13CO-, R12R13N-, RnOOC-, RπSO2NH- or
R14-CO-NH- or R2 and R3 together as well as R1 and R2 together and R3 and R4 together may form with the phenyl ring a five, six or seven-membered ring containing one or two oxygen atoms;
R5, R6, R7,R8, R9, R10 independently represent hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;
R11 represents lower alkyl, lower alkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
R12and R13 independently represent hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;
R14 represents lower alkyl, aryl, cycloalkyl, heterocyclyl, R12R13N- or RπO-;
-X-Y- independently represents -CH2-CH2-, -O-CH2-, -S-CH2-, -SO2-CH2- and -NR15-CO-;
R15 represents hydrogen, lower alkyl or aralkyl. and optically pure enantiomers, mixtures of enantiomers racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
2. Compounds of the general formula (II)
Figure imgf000050_0001
Formula (II) wherein:
R^and R'2 independently represent hydrogen, hydroxy, lower alkoxy, lower alkenyloxy or halogen or may form with the phenyl ring a five, six or seven membered-ring containing one or two oxygen atoms;
R'3, R'4, R'5 independently represent aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; -X-Y- independently represents -CH2-CH2-, -O-CH2-, -S-CH2-, -SO2-CH2- and -NR'6-CO-; R'δ represents hydrogen, lower alkyl or aralkyl. and optically pure enantiomers, mixtures of enantiomers racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, mixture of diastereoisomeric racemates, or meso forms and pharmaceutically acceptable salts thereof.
3. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepiii-2- yl]-N-naphthalen- 1 -yhnethyl-acetamide
4. N-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy- l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-acetamide
5. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tefrahydro-benzo[c]azepin-2- yl]-N-indan-2-yl-acetamide
6. 2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepin- 4-yl]-N-indan-2-yl-acetamide
7. 2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepin- 4-yl] -N-indan- 1 -yl-acetamide
8. 2-[l-(3,4-Dimemoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-indan-l -yl-acetamide
9. 2-[9-(3,4-Dimemoxy-benzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tefrahydro-516-thia- 8-aza-benzocyclohepten-8-yl]-N-indan-2-yl-acetamide
10. 2-[9-(3,4-Dimethoxy-berLzyl)-2,3-dimethoxy-5,5-dioxo-5,6,7,9-tetrahydro-516-thia- 8-aza-benzocyclohepten-8-yl]-N-indan-l-yl-acetamide
11. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl] -N-indan- 1 -yl-acetamide
12. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-indan-2-yl-2-phenyl-acetamide
13. 2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-naphthalen- 1 -ylmethyl-acetamide
14. 2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-(2-ethoxy-benzyl)-acetamide
15. 2-[9-(3,4-Dimethoxy-benzyl)-2,3-dimethoxy-6,7-dihydro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-N-indan- 1 -yl-acetamide
16. 2-[5 -(3 ,4-Dimethoxy-benzyl)-7, 8-dimethoxy-2,3 -dihydro-5H-benzo [f] [ 1 ,4]oxazepin- 4-yl]-N-(l ,2,3 ,4-tetrahydro-naphthalen- 1 -yl)-acetamide
17. N-Benzyl-2-[9-(3,4-dimethoxy-benzyl)-2,3-dimethoxy-6,7-d dro-9H-5-thia-8-aza- benzocyclohepten-8-yl]-acetamide
18. 2-[5-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3-dihydro-5H-benzo[f][l,4]oxazepi 4-yl] -N-indan- 1 -yl-acetamide
19. N-Butyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-2-phenyl-acetamide
20. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-indan- 1 -yl-2-phenyl-acetamide
21. N-Benzo[l,3]dioxol-5-ylmethyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy- l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide
22. N-Cycloρentyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo [c] azepin-2-yl] -2-phenyl-acetamide
23. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tefrahydro-benzo[c]azepin-2- yl]-N-furan-2-ylmethyl-2-phenyl-acetamide
24. {2-[l-(3,4-Dimethoxy-berizyl)-7,8-mmethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2 yl]-2-phenyl-acetylamino} -acetic acid ethyl ester
25. 2-[ 1 -(3,4-Dimethoxy-benzyl)-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-2-phenyl-N-pyridin-4-ylmethyl-acetamide
26. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tefrahydro-benzo[c]azepin-2- yl]-2-phenyl-N-pyridin-3-ylmethyl-acetamide
27. N-Cyclopropyl-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro- benzo[c]azepm-2-yl]-2-phenyl-acetamide
28. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-(2-oxo-tetiahydro-luran-3-yl)-2-phenyl-acetamide
29. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-(4-methoxy-indan- 1 -yl)-acetamide
30. 2-[l-(3 ,4-Dimethoxy-benzyl)-7, 8-dimethoxy- 1 ,3 ,4,5 -tetrahydro-benzo [c] azepin-2- yl] -N-(3 -phenyl-indan- 1 -yl)-acetamide
31. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl] -N-(4-methyl-indan- 1 -yl)-acetamide
32. 2-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tefrahyάro-benzo[c]azepin- 2-yl]-2-phenyl-acetylamino}-3-hydroxy-propionic acid methyl ester
33. 2-[l-(3,4-Dimethoxy-berιzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin-2- yl]-N-ethylcarbamoylmethyl-2-phenyl-acetamide
34. 2-[l-(3,4-Dimethoxy-benzyl)-7,8-mmethoxy-l,3,4,5-tefrahydro-benzo[c]azepin-2- yl]-N-[(ethyl-methyl-carbamoyl)-methyl]-2-phenyl-acetamide
35. 2-[l-(3,4-Dimethoxy-benzyl)-8-hydroxy-7-methoxy-l,3,4,5-tetrahydro- benzo[c]azepin-2-yl]-N-indan-l-yl-acetamide
36. 2-[8-Ben2yloxy-l-(3,4-mmethoxy-benzyl)-7-methoxy-l,3,4,5-tetiahydro- benzo[c]azepin-2-yl]-N-indan-l-yl-acetamide
37. 3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-drmethoxy-l,3,4,5-tetiahydro-benzo[c]azepin- 2-yl]-2-phenyl-acetylamino}-propionic acid methyl ester
38. N-Benzo[l ,3]dioxόl-5-ylmethyl-2-[ 1 -(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy- 1 ,3 ,4,5 -tetrahydro-benzo [c] azepin-2-yl] -2-phenyl-acetamide
39. N-(lH-Benzoimidazol-2-yhnethyl)-2-[l-(3,4-dimethoxy-benzyl)-7,8-dimethoxy- l,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide
40. 2-[8-Allyloxy-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5-tetrahydro- benzo [c] azepin-2-yl] -N-indan- 1 -yl-acetamide
41. 2-[ 1 -(3 ,4-Dimethoxy-benzyl)-7-methoxy-8-propoxy- 1 ,3 ,4,5-tetrahydro- benzo[c]azepin-2-yl]-N-indan-l-yl-acetamide
42. 3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl]-2-phenyl-acetylamino}-NrN-dimethyl-propionamide
43. 3-{2-[l-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-l,3,4,5-tetrahydro-benzo[c]azepin- 2-yl]-2-phenyl-acetylamino}-N-ethyl-N-methyl-propionamide
44. 2-[l-(3,4-Dimethoxy-benzyl)-8-isopropoxy-7-methoxy-l,3,4,5-tetrahydro- benzo [c] azepin-2-yl] -N-indan- 1 -yl-acetamide
45. 2-[8-(2,2-Difluoro-ethoxy)-l-(3,4-dimethoxy-benzyl)-7-methoxy-l,3,4,5- tetrahydrobenzo [c] azepin-2-yl] -N-indan- 1 -yl-acetamide
46. Pharmaceutical compositions for the treatment of disorders which are associated with the role of orexin, especially disorders such as obesity and sleep disorders, comprising containing a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, and usual carrier materials and adjuvants.
47. The compounds of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, for use as medicaments for the treatment of disorders which are associated with a role of orexin, especially obesity and sleep disorders.
48. A method of treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound as claimed in any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof.
49. A process for the manufacture of pharmaceutical compositions for the treatment of disorders associated with the role of orexin, especially obesity and sleep disorders, containing one or more compounds as claimed in any one of claims 1 to 15, or a pharmaceutically acceptable salt or salts thereof, as active ingredients which process comprises mixing one or more active ingredient or ingredients with pharmaceutically acceptable excipients and adjuvants in a manner known per se.
50. A compound as described as end-product in any one of examples 1 to 43.
51. The invention as hereinbefore described.
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