WO2008152097A1 - Cinnamic acid derivatives as modulators of the ep2 receptor - Google Patents

Cinnamic acid derivatives as modulators of the ep2 receptor Download PDF

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WO2008152097A1
WO2008152097A1 PCT/EP2008/057394 EP2008057394W WO2008152097A1 WO 2008152097 A1 WO2008152097 A1 WO 2008152097A1 EP 2008057394 W EP2008057394 W EP 2008057394W WO 2008152097 A1 WO2008152097 A1 WO 2008152097A1
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alkyl
crc
substituted
hydroxy
cyano
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PCT/EP2008/057394
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French (fr)
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Bernd Buchmann
Nico BRÄUER
Marcus Koppitz
Olaf Peters
Knut Eis
Antonius Ter Laak
Bernhard Lindenthal
Gernot Langer
Tim Wintermantel
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Bayer Schering Pharma Aktiengesellschaft
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

  • Cinnamic acid derivatives as modulators of the EP 2 receptor are Cinnamic acid derivatives as modulators of the EP 2 receptor
  • the present invention relates to cinnamic acid derivatives as EP 2 receptor modulators, processes for their preparation, and their use as medicaments.
  • prostaglandins are key molecules in the processes of female reproductive biology such as, for example, control of ovulation, of fertilization, of nidation, of decidualization (e.g. placenta formation) and of menstruation.
  • Prostaglandins likewise play an important part in the pathological changes in the reproductive tract, including menorrhagia, dysmenorrhea, endometriosis and cancer.
  • the mechanism by which prostaglandins bring about these changes has not yet been completely elucidated.
  • Recent results indicate that prostaglandins, their receptors and signal transduction pathways thereof are involved in processes such as angiogenesis, apoptosis, proliferation, and in inflammatory/antiinflammatory and immunological processes.
  • Prostaglandin E 2 (PGE 2 ) is of particular interest, having a wide variety of cellular effects through binding to functionally different receptor subtypes, namely the EPi, EP 2 , EP 3 and EP 4 receptors.
  • the receptor subtypes to which prostaglandin E 2 binds appear to be of particular interest for the receptor-mediated effects which are involved in the control of fertility. It has thus been possible to show that the reproductive functions in EP 2 knockout mice (EP 2 " ' " ), i.e.
  • mice no longer having a functional PGE 2 receptor of the EP 2 subtype are impaired, and that these animals have a smaller "litter size" (Matsumoto et al., 2001 , Biology of Reproduction 64, 1557-1565). It was likewise possible to show that these EP 2 knockout mice (Hizaki et al. Proc Natl Acad Sci U. S. A. 1999 Aug 31 ; 96(18):10501 -10506) show distinctly reduced cumulus expansion and severe subfertility, which is to be regarded as causally connected with diminished reproductive processes such as ovulation and fertilization.
  • the EP 2 receptor accordingly represents an important target for developing medicaments for controlling female fertility.
  • the existence of the 4 subclasses of the PGE 2 receptor opens up the possibility of targeted development of selectively active compounds.
  • scarcely any selective EP 2 receptor ligands which bind to the EP 2 subtypes of the PGE 2 receptor are known, since most known compounds also bind to the other PGE 2 receptor subtypes such as, for example, to the EP 4 receptor.
  • EP 2 receptor antagonists are described, for example in the application US2005059742 (Jabbour, Medical Research Concil). A method in which an EP 2 and/or an EP 4 antagonist can be employed for the treatment of menorrhagia and dysmenorrhea is claimed. AH6809 is disclosed as antagonist of the EP 2 or EP 4 receptor, but no other specific antagonists and no new compounds are disclosed.
  • EP 2 or EP 4 antagonists are claimed for the treatment of pathological conditions such as, for example, allergic disorders, Alzheimer's disease, pain, abortion, painful menstruation, menorrhagia and dysmenorrhea, endometriosis, bone disorders, ischemia etc.
  • pathological conditions such as, for example, allergic disorders, Alzheimer's disease, pain, abortion, painful menstruation, menorrhagia and dysmenorrhea, endometriosis, bone disorders, ischemia etc.
  • the described compounds are, however, distinguished by a particularly high affinity for the EP 3 receptor.
  • a further application (WO04/032964) describes novel compounds which are likewise distinguished by a particularly high affinity for the EP 3 receptor, but also have EP 2 -antagonistic effects and which are used for the treatment and prophylaxis of allergic disorders.
  • EP 4 antagonists ( ⁇ -lactams) are claimed in the application WO03/103604 (Applied Research Systems). The compounds bind approximately 60-fold better to the EP 4 than to the EP 2 receptor and are claimed inter alia for the treatment of premature labor, dysmenorrhea, asthma, infertility or fertility impairments.
  • the compounds bind to the EP 4 - and to the EP 2 receptor subtypes.
  • the application WO03/037433 claims ⁇ - cycloalkyl, 17 heteroaryl prostaglandin derivatives as EP 2 receptor antagonists, in particular for the treatment of elevated intraocular pressure.
  • Tani et al. claim in the application US2005124577 8-azaprostaglandin derivatives for the treatment of immunological disorders, allergic disorders, premature labor, abortion, etc.
  • the compounds bind to the EP 2 and to the EP 4 receptor.
  • European patent application EP 1306087 describes EP 2 receptor agonists which are used for the treatment of erectile dysfunction (Ono Pharmaceuticals). The same class of structures is described in European patent EP 860430 (Ono Pharmaceuticals), and their use for the manufacture of a medicament for the treatment of immunological disorders, asthma and abortion is claimed.
  • WO04/009117 describes EP 2 and EP 4 receptor agonists for the treatment of disorders caused by uterine contraction, for example painful menstruation (Ono Pharmaceuticals).
  • Agonists of the EP 2 and of the EP 4 receptors are frequently described in connection with the treatment of osteoporosis (WO99/19300 (Pfizer), US2003/0166631 (Dumont Francis), WO03/77910 (Pfizer), WO03/45371 (Pfizer), WO03/74483 and WO03/09872 (Ono Pharmaceuticals)) and for glaucoma treatment (WO04/37813, WO04/37786, WO04/19938, WO03/103772, WO03/103664, WO03/40123, WO03/47513, WO03/47417 (Merck Frosst Canada)) and US6410591 and US6747037 (Allergan).
  • A is a C5-C12 heteroaryl radical which may optionally be substituted one or more times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-,
  • -S-CO-O- CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -0-(CH 2 )m-0- > -0-C-(CHs) 2 -O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, hydroxy, R 4 or by R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical R 4 and which is substituted at least once or else more than once, identically or differently, by R', where
  • R' is an -S(O) p -Ci-C 6 -alkyl group or -S(O) p -C 3 -C 6 -cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , CF 3 , COOH, C r C 6 -acyl or NH-CO- Ci-C ⁇ -alkyl radical, cyano, -CONH 2, a CrC 6 -alkoxy group which is substituted by cyano, hydroxy,
  • Cs-Ce-cycloalkyl COOH, CONH 2 , CO 2 -(C r C 6 -alkyl), CO-NH(CrC 6 -alkyl), CO-N(Ci-C 6 -alkyl) 2> N-(Ci-C 6 -alkyl) 2 or NH-CO-d-Ce-alkyl, a Ci-C 6 -alkyl group which is substituted by cyano, hydroxy, C 3 -C 6 - cycloalkyl, COOH, CONH 2 , CO 2 -(Ci-C 6 -alkyl), CO-NH(C r C 6 -alkyl),
  • Ci-C 6 -acyl Ci-C 6 -alkoxy, hydroxy, cyano, CO 2 -(Ci -Ce-alkyl), N-(C r C 6 -alkyl) 2 , CO-NH(C r C 6 -alkyl) or CO-N(Ci-C 6 -alkyl) 2 , or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 6 -alkyl, hydroxy, cyano, CO 2 -(Ci-C 6 -alkyl), Ci-C 6 -alkyl, Ci-C 6 -acyl, N-(Ci-C 6 -alkyl) 2j CO-NH(Ci-C 6 -alkyl), CO-N(Ci-C 6 -alkyl) 2 or d-C 6 - alkoxy
  • R 1 is a hydrogen, a Ci-C 6 -alkyl radical which may optionally be substituted,
  • R 2 is a hydrogen, halogen, cyano, -S(O)q-CH 3 , where q is 0-2, a
  • Ci-C 4 -alkoxy radical or Ci-C 6 -alkyl radical where this radical may be substituted in any way
  • R 3 is a hydrogen, halogen, amino, an -S(O) p -Ci-C 6 -alkyl group or -S(O)p-C 3 -C 6 -cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , COOH, CO-NH 2 , NH-CO-NH 2 , C r C 6 - acyl-, NH-(CrC 6 -alkyl), N-(Ci-C 6 -alkyl) 2 or NH-CO-C r C 6 -alkyl radical, a Ci-C ⁇ -alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C 6 -acyl, Ci-C 6 -alkoxy, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), N-(Ci-C 6 -alkyl) 2 , COOH, CO- NH 2
  • N-(Ci-C 6 -alkyl) 2 COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or CO-N(Ci-C 6 -alkyl) 2 , or a C 3 -C 6 -cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 6 -alkyl, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), CrC 6 -alkyl, CrC 6 -acyl,
  • N-(Ci-C 6 -alkyl) 2 COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl), CO-N(Ci-C 6 -alkyl) 2 or Ci-C 6 -alkoxy,
  • Ci-C 6 -acyl is a hydrogen, halogen, amino, -S(O) p -Ci-C 6 -alkyl or -S(O) P -C 3 -C 6 - cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , COOH, CO-NH 2 , NH-CO-NH 2 , C r C 6 - acyl, NH-(CrC 6 -alkyl), N-(Ci-C 6 -alkyl) 2 or NH-CO-C r C 6 -alkyl or a Ci-C ⁇ -alkyl group which may optionally be substituted one or more times, identically or differently, by Ci-C 6 -acyl, Ci-C6-alkoxy, hydroxy, cyano, CO 2 -(C r C 6 -alkyl), N-(d-C 6 -alkyl) 2 , COOH,
  • N-(Ci-C 6 -alkyl) 2 COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or CO-N(Ci-C 6 -alkyl) 2 , a C 3 -C 6 -cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C ⁇ -alkyl, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), CrC 6 -acyl, N-(Ci-C 6 -alkyl) 2 , COOH,
  • R 3 and R 4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH 2 -CO-O-, -0-CO-CH 2 -, -CH 2 -CO-NH-, -NH-CO-CH 2 -,
  • Y is a-(CH 2 ) n - group, where n is 2 or 3,
  • the compounds of the invention have an antagonistic effect on the EP 2 receptor and thus serve to control female fertility.
  • Ci-C ⁇ -alkyl means in each case a straight-chain or branched alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl and hexyl which may be substituted as desired one or more times, identically or differently, for example by halogen.
  • alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl and hexyl which may be substituted as desired one or more times, identically or differently, for example by halogen.
  • Ci-C ⁇ -alkoxy means in each case a straight-chain or branched alkoxy radical such as, for example, methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, sec-butoxy-, isobutoxy-, tert-butyloxy-, pentoxy-, isopentoxy- and hexoxy which may optionally be substituted one or more times, identically or differently, for example by halogen.
  • alkoxy radical such as, for example, methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, sec-butoxy-, isobutoxy-, tert-butyloxy-, pentoxy-, isopentoxy- and hexoxy which may optionally be substituted one or more times, identically or differently, for example by halogen.
  • Ci-C ⁇ -acyl means in each case a straight-chain or branched radical such as, for example, formyl, acetyl, propionyl, butyryl, isobutyroyl, valeryl and benzoyl which may optionally be substituted one or more times, identically or differently, for example by halogen.
  • C3-C6-Cycloalkyl means monocyclic 3-6-membered alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the C3-C6-cycloalkyl radicals may, instead of the carbon atoms, comprise one or more heteroatoms such as oxygen, sulfur and/or nitrogen.
  • Preferred heterocycloalkyls are those having 3 to 6 ring atoms.
  • Ring systems in which optionally one or more possible double bonds may be contained in the ring are for example cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, with the connection possibly taking place either at the double bond or at the single bonds.
  • Halogen means in each case fluorine, chlorine, bromine or iodine.
  • the C6-Ci2-aryl radical includes in each case 6-12 carbon atoms and may for example be benzo-fused. Examples which may be mentioned are: phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, fluorenyl, anthracenyl etc.
  • the C 5 -Ci6-heteroaryl radical comprises in each case 5-16 ring atoms and may, instead of the carbon, comprise one or more, identical or different, heteroatoms such as oxygen, sulfur or nitrogen in the ring, and may be mono-, bi- or tricyclic and may additionally in each case be benzo-fused. Examples which may be mentioned are: thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.
  • quinolinyl isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.
  • the heteroaryl radical may in each case be benzo-fused.
  • 5- membered heteroaromatic rings which may be mentioned are: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof, and of 6- membered heteroaromatic rings pyridine, pyrimidine, thazine, quinoline, isoquinoline and benzo derivatives.
  • Heteroatoms mean oxygen, nitrogen or sulfur atoms.
  • suitable salts are the physiologically tolerated salts of organic and inorganic bases, such as, for example, the readily soluble alkali metal and alkaline earth metal salts, and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1 ,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, ths-hydroxymethylaminomethane, aminopropanediol, Sovak base, 1 -amino-2,3,4-butanethol.
  • organic and inorganic bases such as, for example, the readily soluble alkali metal and alkaline earth metal salts, and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1 ,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, ths-hydroxymethylaminomethane, aminopropan
  • physiologically tolerated salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid inter alia.
  • the present invention likewise relates to compounds of the general formula (I) where
  • A is a C 5 -Ci 2 heteroaryl radical which may optionally be substituted one or more times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-,
  • R 4 which is substituted at least once or else more than once, identically or differently, by R', where
  • R' is an -S(O) p -Ci-C 6 -alkyl group or -S(O) p -C 3 -C 6 -cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , CF 3 , COOH, C r C 6 -acyl or NH-CO-
  • R 1 is a hydrogen, a Ci-C 6 -alkyl radical which may be substituted one or more times by halogen
  • R 2 is a hydrogen, halogen, cyano, -S(O) q -CH 3 , where q is 0-2, a
  • Ci-C 4 -alkoxy radical or Ci-C 6 -alkyl radical which may be substituted one or more times by halogen
  • R 3 is a hydrogen, halogen, amino, an -S(O) p -Ci-C 6 -alkyl group or
  • CO-N(Ci-C 6 -alkyl) 2 a C6-Ci 2 -aryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC 6 -alkyl, C 3 -C 6 - cycloalkyl, CrC 6 -acyl, CrC 6 -alkoxy, hydroxy, cyano, CO 2 -(Ci -C 6 - alkyl), N-(C r C 6 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(C r C 6 -alkyl) or CO-N(Ci-C 6 -alkyl) 2 , a C 5 -Ci 2 -heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC 6 -alkyl, Ci-C 6 -acyl, CrC 6 -alkoxy, hydroxy, cyano, CO 2 -
  • N-(Ci-C 6 -alkyl) 2 COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or CO-N(CrC 6 -alkyl) 2> or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 6 -alkyl, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), Ci-C 6 -alkyl, Ci-C 6 -acyl, N-(Ci-C 6 -alkyl) 2> COOH, CO-NH 2 , CO-NH(d-C 6 -alkyl), CO-N(Ci-C 6 -alkyl) 2 or Ci-C 6 -alkoxy,
  • p is a hydrogen, halogen, amino, -S(O) p -Ci-C 6 -alkyl or -S(O) P -C 3 -C 6 - cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , COOH, CO-NH 2 , NH-CO-NH 2 , Ci-C 6 - acyl, NH-(Ci-C 6 -alkyl), N-(Ci-C 6 -alkyl) 2 or NH-CO-d-C 6 -alkyl or a Ci-C6-alkyl which may optionally be substituted one or more times, identically or differently, by d-C 6 -acyl, d-C 6 -alkoxy, hydroxy, cyano, CO 2 -(d-C 6 -alkyl), N-(Ci-C 6 -alkyl) 2 , COOH, CO-NH 2 ,
  • N-(Ci-C 6 -alkyl) 2 COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or CO-N(Ci-C 6 -alkyl) 2 , a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C ⁇ -alkyl, hydroxy, cyano, CO 2 -(Ci-C 6 -alkyl), CrC 6 -acyl, N-(Ci-C 6 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl), CO-N(Ci-C 6 -alkyl) 2 or Ci-C 6 -alkoxy,
  • R 3 and R 4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH 2 -CO-O-, -0-CO-CH 2 -, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -O-(CH 2 ) m -O-, -0-C-(CHs) 2 -O-, where m is 1 -3,
  • Y is a -(CH 2 )n- group, where n is 2 or 3,
  • A is a C 5 -Ci 2 heteroaryl radical which may optionally be substituted one or more times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -0-(CH 2 )m-0- > -0-C-(CHs) 2 -O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once,
  • R 4 which is substituted at least once or else more than once, identically or differently, by R', where
  • R' is an -S(O) p -Ci-C 6 -alkyl group or -S(O) p -C 3 -C 6 -cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , CF 3 , COOH, C r C 6 -acyl or NH-CO-
  • Ci-C ⁇ -alkyl radical a d-C ⁇ -alkoxy group which is substituted by cyano, hydroxy
  • NH-CO-d-Ce-alkyl a d-Ce-alkyl group which is substituted by cyano, hydroxy, C 3 -C 6 - cycloalkyl, COOH, CONH 2 , CO 2 -(d-C 6 -alkyl), CO-NH(Ci-C 6 -alkyl),
  • CO-N(Ci-C 6 -alkyl) 2 or a C 3 -C 6 -cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C ⁇ -alkyl, hydroxy, cyano, CO 2 -(Ci-C 6 -alkyl), d-C ⁇ -alkyl, d-C ⁇ -acyl,
  • R 1 is a hydrogen, a Ci-C ⁇ -alkyl radical which may be substituted one or more times by halogen
  • R 2 is a hydrogen, halogen, cyano, -S(O) q -CH 3 , where q is 0-2, a
  • Ci-C 4 -alkoxy radical or CrC 6 -alkyl radical which may be substituted one or more times by halogen
  • R 3 is a hydrogen, halogen, amino, an SCF 3 , -S(O) P -CH 3 or
  • Ci-C 6 -acyl NH-(CrC 6 -alkyl), N-(d-C 6 -alkyl) 2 or NH-CO-C r C 6 -alkyl radical, a Ci-C ⁇ -alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C 6 -acyl, Ci-C6-alkoxy, hydroxy, cyano, CO 2 -(C r C 6 -alkyl), N-(d-C 6 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or by CO-N(Ci-C 6 -alkyl) 2> a Ci-
  • CO-N(Ci-C 6 -alkyl) 2 a C6-Ci 2 -aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 6 -alkyl, C 3 -C 6 - cycloalkyl, Ci-C 6 -acyl, Ci-C 6 -alkoxy, hydroxy, cyano, CO 2 -(Ci-C 6 - alkyl), N-(C r C 6 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(C r C 6 -alkyl) or
  • CO-N(Ci-C 6 -alkyl) 2 a C 5 -Ci 2 -heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 6 -alkyl, Ci-C 6 -acyl, CrC 6 -alkoxy, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), N-(Ci-C 6 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or
  • CO-N(Ci-C 6 -alkyl) 2 or a C 3 -C 6 -cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 6 -alkyl, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), CrC 6 -alkyl, CrC 6 -acyl, N-(Ci-C 6 -alkyl) 2> COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl), CO-N(Ci-C6-alkyl) 2 or Ci-C 6 -alkoxy,
  • Ci-C 6 -acyl- NH-(Ci-C 6 -alkyl), N-(CrC 6 - alkyl) 2 or NH-CO-d-Ce-alkyl- or a Ci-C 6 -alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C 6 -acyl, Ci-C6-alkoxy, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), N-(Ci-C 6 -alkyl) 2 , COOH, CO-
  • Ci-C 6 -alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO 2 -(CrC 6 - alkyl), N-(Ci-C 6 -alkyl) 2> NH-C 3 -C 6 -cycloalkyl, COOH, CO-NH 2 , CO-NH(Ci-C 6 -alkyl) or by CO-N(Ci-C 6 -alkyl) 2> an O-C 6 -Ci 2 -aryl, CH 2 -O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, hydroxy, cyano, CO 2 -(CrC 6 -alkyl), O-CO-(Ci-C 6 -alkyl), N-
  • R 3 and R 4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-,
  • Y is a -(CH 2 )n- group, where n is 2 or 3,
  • A is a C 5 -Ci 2 heteroaryl radical which may optionally be substituted once, twice, three or four times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-,
  • m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R 4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R 4 , and which is substituted at least once or else more than once, identically or differently, by R', where
  • R' is an -S(O) p -Ci-C 4 -alkyl group or -S(O) p -C 3 -C 6 -cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , CF 3 , COOH, C r C 4 -acyl or
  • Cs-Ce-cycloalkyl COOH, CONH 2 , CO 2 -( C r C 4 -alkyl), CO-NH(CrC 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , N-(Ci-C 4 -alkyl) 2 or
  • NH-CO-CrC 4 -alkyl a CrC 4 -alkyl group which is substituted by cyano, hydroxy, C 3 -C 6 - cycloalkyl, COOH, CONH 2 , CO 2 -(Ci-C 4 -alkyl), CO-NH(C r C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , N-(C r C 4 -alkyl) 2 or N H-CO-Ci -C 4 -alkyl, an O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, CO 2 -(C r C 2 -alkyl),
  • CO-N(CrC 4 -alkyl) 2 or a C 3 -C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 4 -alkyl, hydroxy, cyano, CO 2 -(C r C 4 -alkyl), C r C 4 -alkyl, C r C 4 -acyl, N-(Ci-C 4 -alkyl) 2 , CO-NH(Ci-C 4 -alkyl), CO-N(C r C 4 -alkyl) 2 or
  • R 1 is a hydrogen, a Ci-C 4 -alkyl radical which may be substituted one or more times by halogen,
  • R 2 is a hydrogen, halogen, cyano, -S(O) q -CH 3 , where q is 0-2, a Ci-C 4 alkoxy radical or Ci-C 4 -alkyl radical which may be substituted one or more times by halogen, is a hydrogen, halogen, amino, an SCF 3 , -S(O) P -CH 3 or
  • CO-N(Ci-C 4 -alkyl) 2 a C6-Ci 2 -aryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C 4 - alkyl, Cs-C ⁇ -cycloalkyl, Ci-C 4 -acyl, CrC 4 -alkoxy, hydroxy, cyano, CO 2 -(CrC 4 -alkyl), N-(Ci-C 4 -alkyl) 2 , COOH, CO-NH 2 ,
  • CO-N(Ci-C 4 -alkyl) 2 a C3-C6-cycloalkyl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by CrC 4 - alkyl, hydroxy, cyano, CO 2 -(CrC 4 -alkyl), CrC 4 -acyl, N-(Ci-C 4 - alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 4 -alkyl), CO-N(C r C 4 -alkyl) 2 or Ci-C 4 -alkoxy, R 3 and R 4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH 2 -CO-O-, -0-CO-CH 2 -, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -O-
  • Y is a -(CH 2 ) n group, where n is 2 or 3,
  • A is a C 5 -Ci 2 heteroaryl radical which may optionally be substituted once, twice or three times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, metaposition, or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -0-(CH 2 )m-0- > -0-C-(CHs) 2 -O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice
  • Ci-C 4 -alkyl a Ci-C 4 -alkyl group which is substituted by cyano, hydroxy, C 3 -Ce- cycloalkyl, COOH, CONH 2 , CO 2 -(Ci-C 4 -alkyl), CO-NH(C r C 4 -alkyl),
  • CO-N(Ci-C 4 -alkyl) 2 or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C 4 -alkyl, hydroxy, cyano, CO 2 -(CrC 4 -alkyl), CrC 4 -alkyl, CrC 4 -acyl,
  • R 1 is a hydrogen, a Ci-C 4 -alkyl radical which may be substituted once, twice or three times by halogen,
  • R 2 is a hydrogen, halogen, cyano, -S(O) q -CH 3 , where q is 0-2, a
  • Ci-C 4 -alkoxy radical or Ci-C 4 -alkyl radical which may be substituted once, twice or three times by halogen,
  • R 3 is a hydrogen, halogen, amino, an SCF 3 , -S(O) P -CH 3 or
  • p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , COOH, CO-NH 2 , NH-CO-NH 2 , Ci-C 4 - acyl, NH-(CrC 4 -alkyl), N-(Ci-C 4 -alkyl) 2 or NH-CO-C r C 4 -alkyl radical, a Ci-C 4 -alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C 4 -acyl, Ci-C 4 -alkoxy, hydroxy, cyano, CO 2 -(d-C 4 -alkyl), N-(Ci-C 4 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2 ,
  • CO-NH 2 CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2 , an O-C 6 -Ci 2 -aryl, CH 2 -O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, hydroxy, cyano, CO 2 -(C r C 4 -alkyl), O-CO-(Ci-C 4 -alkyl), N-(C r C 4 -alkyl) 2 , NH-(Ci-C 4 -alkyl), CO-NH(C 5 -Ci 2 -heteroaryl), CO-NH(Ci-C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , a C 6 -Ci 2 -aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C
  • CO-NH 2 CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2> an O-C 6 -Ci 2 -aryl, CH 2 -O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, hydroxy, cyano, CO 2 -(C r C 4 -alkyl), O-CO-(Ci-C 4 -alkyl), N-(C r C 4 -alkyl) 2 , NH-(Ci-C 4 -alkyl), CO-NH(C 5 -Ci 2 -heteroaryl), CO-NH(Ci-C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2> a C 6 -Ci 2 -aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C 4 -
  • R 3 and R 4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, -0-CO-CH 2 -, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -O-(CH 2 ) m -O-, -O-C-(CH 3 ) 2 -O-, where m is 1 -3,
  • Y is a -(CH 2 )n- group, where n is 2 or 3,
  • A is a C 5 -Ci 2 heteroaryl radical which may optionally be substituted once, twice or three times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -
  • R' is an -S(O) p -Ci-C 4 -alkyl group or -S(O)p-C 3 -C 6 -cycloalkyl group, where p is 0-2, an SO 2 NH 2 , SO 2 NH-CH 3 , CF 3 , COOH, C r C 4 -acyl- or NH- CO-CrC 4 -alkyl radical, a Ci-C 4 -alkoxy group which is substituted by cyano, hydroxy, C 3 -C 6 -cycloalkyl, COOH, CONH 2 , CO 2 -( C r C 4 -alkyl), CO- NH(Ci-C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , N-(Ci-C 4 -alkyl) 2 or NH-CO-
  • Ci-C 4 -alkyl a Ci-C 4 -alkyl group which is substituted by cyano, hydroxy, C 3 -C 6 - cycloalkyl, COOH, CONH 2 , CO 2 -(Ci-C 4 -alkyl), CO-NH(C r C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , N-(C r C 4 -alkyl) 2 or N H-CO-Ci -C 4 -alkyl, an O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, CO 2 -(Ci-C 2 -alkyl), CO-
  • R 1 is a hydrogen, a Ci-C 4 -alkyl radical which may be substituted once, twice or three times by halogen,
  • R 2 is a hydrogen, halogen, cyano, -S(O) q -CH 3 , where q is 0-2, a
  • Ci-C 4 -alkoxy radical or Ci-C 4 -alkyl radical which may be substituted once, twice or three times by halogen,
  • R 3 is a hydrogen, halogen, amino, an SCF 3 , -S(O) P -CH 3 or
  • Ci-C 4 -acyl an SO 2 NH 2 , SO 2 NH-CH 3 , COOH, CO-NH 2 , NH-CO-NH 2 , Ci-C 4 - acyl, NH-(CrC 4 -alkyl), N-(Ci-C 4 -alkyl) 2 or NH-CO-C r C 4 -alkyl radical, a Ci-C 4 -alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C 4 -acyl, Ci-C 4 -alkoxy, hydroxy, cyano, CO 2 -(d-C 4 -alkyl), N-(Ci-C 4 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2
  • CO-NH 2 CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2 , an O-C 6 -Ci 2 -aryl, CH 2 -O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, hydroxy, cyano, CO 2 -(C r C 4 -alkyl), O-CO-(Ci-C 4 -alkyl), N-(C r C 4 -alkyl) 2 , NH-(Ci-C 4 -alkyl), CO-NH(C 5 -Ci 2 -heteroaryl), CO-NH(Ci-C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , a C 6 -Ci 2 -aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C
  • CO-NH 2 CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2> an O-C 6 -Ci 2 -aryl, CH 2 -O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, hydroxy, cyano, CO 2 -(C r C 4 -alkyl), O-CO-(Ci-C 4 -alkyl), N-(C r C 4 -alkyl) 2 , NH-(Ci-C 4 -alkyl), CO-NH(C 5 -Ci 2 -heteroaryl), CO-NH(Ci-C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2> a C 6 -Ci 2 -aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C 4 -
  • R 3 and R 4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH 2 -CO-O-, -0-CO-CH 2 -, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -O-(CH 2 ) m -O-, -O-C-(CH 3 ) 2 -O-, where m is 1 -3,
  • Y is a -(CH 2 )n- group, where n is 2 or 3,
  • A is a C 5 -Ci 2 heteroaryl radical which may optionally be substituted once, twice or three times by R 4 and/or R 3 , or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, 0-CO-CH 2 -, -O-CO-NH-, -NH-CO-O-, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-,
  • R 1 is a hydrogen, a Ci-C 4 -alkyl radical which may be substituted once, twice or three times by halogen,
  • R 2 is a hydrogen, halogen, cyano, -S(O) q -CH 3 , where q is 0-2, a Ci-C 4 -alkoxy radical or Ci-C 4 -alkyl radical which may be substituted once, twice or three times by halogen,
  • R 3 is a hydrogen, halogen, amino, an SCF 3 , -S(O) P -CH 3 or
  • Ci-C 4 -alkyl group which may optionally be substituted once, twice or three times, identically or differently, by Ci-C 4 -acyl, CrC 4 - alkoxy, hydroxy, cyano, CO 2 -(CrC 4 -alkyl), N-(Ci-C 4 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2 , a Ci-C 4 -alkoxy which may optionally be substituted once, twice or three times, identically or differently, by Ci-C 4 -acyl, CrC 4 - alkoxy, hydroxy, cyano, CO 2 -(CrC 4 -alkyl), N-(Ci-C 4 -alkyl) 2 , COOH, CO-NH 2 , CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4
  • CO-NH 2 CO-NH(Ci-C 4 -alkyl) or by CO-N(Ci-C 4 -alkyl) 2 , an O-C 6 -Ci 2 -aryl, CH 2 -O-C 6 -Ci 2 -aryl, O-C 5 -Ci 6 -heteroaryl, hydroxy, cyano, CO 2 -(C r C 4 -alkyl), O-CO-(Ci-C 4 -alkyl), N-(C r C 4 -alkyl) 2 , NH-(Ci-C 4 -alkyl), CO-NH(C 5 -Ci 2 -heteroaryl), CO-NH(Ci-C 4 -alkyl), CO-N(Ci-C 4 -alkyl) 2 , a C6-Ci 2 -aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C 4
  • R 3 and R 4 are either in ortho, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH 2 -CO-O-, -0-CO-CH 2 -, -CH 2 -CO-NH-, -NH-CO-CH 2 -, -O-CO- NH-, -NH-CO-O-, -CO-CH 2 -(CH 2 ) m -, -CH 2 -(CH 2 ) m -CO-, -O-(CH 2 ) m -
  • Y is a -(CH 2 )2- group
  • the present invention likewise relates to medicaments which comprise the compounds of the invention with suitable formulating substances and carriers.
  • novel EP 2 agonists and antagonists are distinguished by greater selectivity and stability.
  • the present invention relates to medicaments for the treatment and prophylaxis of disorders which include fertility impairments, infectious disorders, cancer, viral infections, cardiovascular disorders, elevated intraocular pressure, glaucoma, skeletal system disorders, angiogenetic disorders, uterine contraction impairments, pain, neuroinflammatory disorders, immunomodulatory infections and nephrological disorders.
  • Fertility impairments mean the disorders which lead to no ovulation taking place, that no nidation of a fertilized oocyte occurs and no decidualization takes place
  • infectious disorders mean disorders caused by unicellular parasites
  • cancer means solid tumors and leukemia
  • viral infections mean for example cytomegalievirus infections
  • immunomodulatory infections mean for example avian influenza
  • cardiovascular disorders mean ischemic reperfusion disorder, stenoses, arterioscleroses and restenoses
  • angiogenetic disorders mean for example endometriosis and fibrosis
  • elevated intraocular pressure means glaucoma
  • uterine contraction impairments mean for example painful menstruation
  • skeletal system disorders mean osteoporosis
  • neuroinflammatory disorders mean multiple sclerosis, Alzheimer's disease, pain and nephrological disorders mean glomerulonephritis.
  • the present invention likewise relates to medicaments for the treatment and prophylaxis of the disorders detailed above, which comprise at least one compound of the general formula I, and medicaments with suitable formulating substances and carriers.
  • a pharmaceutical product which, besides the active ingredient, comprises inert organic or inorganic pharmaceutical carrier materials which are suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
  • the pharmaceutical products may be in solid form, for example as tablets, coated tablets, suppositories, capsules, in semisolid form, for example as ointments, creams, gels, suppositiories, emulsions or in liquid form, for example as solutions, suspensions or emulsions.
  • excipients which are intended to act for example as fillers, binders, disintegrants, lubricants, solvents, solubilizers, masking flavors, colorant, emulsifiers.
  • excipients for the purpose of the invention are saccharides (mono-, di-, tri-, oligo-, and/or polysaccharides), fats, waxes, oils, hydrocarbons, anionic, nonionic, cationic natural, synthetic or semisynthetic surfactants.
  • excipients such as preservatives, stabilizers, wetting agents or emulsifiers; salts to modify the osmotic pressure or buffers.
  • the present invention likewise relates to these pharmaceutical products.
  • Suitable for oral use are in particular tablets, coated tablets or capsules with talc and/or hydrocarbon carriers or binders, such as, for example, lactose, corn starch or potato starch. Use can also take place in liquid form, such as, for example, as solution to which, where appropriate, a sweetener is added.
  • Clathrates are likewise also suitable for oral use of such compounds, examples of clathrates which may be mentioned being those with alpha-, beta-, gamma- cyclodextrin or else beta-hydroxypropylcyclodextrin.
  • Sterile, injectable, aqueous or oily solutions are used for parenteral administration.
  • Particularly suitable are injection solutions or suspensions, especially aqueous solutions of active compounds in polyethoxylated castor oil.
  • vaginal administration examples include pessaries, tampons or intrauterine device.
  • Appropriately prepared crystal suspensions can be used for intraarticular injection. It is possible to use for intramuscular injection aqueous and oily injection solutions or suspensions and appropriate depot preparations.
  • the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments both for systemic and for local therapy.
  • novel compounds can be used in the form of aerosols and inhalations for pulmonary administration.
  • novel compounds can be used as drops, ointments and tinctures in appropriate pharmaceutical preparations.
  • Formulations possible for topical application are gels, ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures.
  • the dosage of the compounds of the general formula I should in these preparations be 0.01 % - 20% in order to achieve an adequate pharmacological effect.
  • the dosage of the active ingredients may vary depending on the route of administration, age and weight of the patient, nature and severity of the disorder to be treated and similar factors. Treatment can take place by single dosages or by a large number of dosages over a prolonged period.
  • the daily dose is 0.5 - 1000 mg, preferably 50 - 200 mg, it being possible to give the dose as a single dose to be administered once or divided into 2 or more daily doses.
  • Carrier systems which can be used are also surface-active excipients such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof, and liposomes or constituents thereof.
  • the present invention likewise relates to the formulations and dosage forms described above.
  • Administration of the compounds of the invention can take place by any conventional method, including oral and parenteral, e.g. by subcutaneous or intramuscular injections.
  • the present invention likewise relates to enteral, parenteral, vaginal and oral administrations.
  • the compounds of the invention of the general formula I bind to the EP 2 receptor and have agonistic or antagonistic effect. It is possible to determine whether an agonistic or an antagonistic effect is present by an agonism test (see Example 1.2.1. of the Biological Examples) or by an antagonism test (see Example 1.2.2. of the Biological Examples).
  • Antagonists mean molecules which bind to their corresponding receptors and which inhibit the initiation of the signal transduction pathway(s) coupled to the receptor by the naturally occurring ligand(s).
  • the antagonists normally compete with the naturally occurring ligand of the receptor for binding to the receptor.
  • other modifications of the receptor are also possible by molecules which prevent the signal transduction pathways coupled to the receptor being activated by the naturally occurring ligand(s) (e.g. non-competitive, steric modifications of the receptor).
  • Receptor antagonists typically bind selectively to their particular receptor and not to other receptors. They normally have a higher binding affinity than the natural ligand. Although antagonists which have a higher affinity for the receptor than the natural ligand are preferred, it is likewise possible to employ antagonists having a lower affinity.
  • the antagonists preferably bind reversibly to their corresponding receptors.
  • the EP 2 receptor antagonist has a preferred affinity for the EP 2 receptor compared with any other EP receptor.
  • the antagonism is measured in the presence of the natural agonist (PGE 2 ).
  • Agonists mean molecules which bind to their corresponding receptors and normally compete with the naturally occurring ligand of the receptor for binding to the receptor, and which stimulate the initiation of the signal transduction pathway coupled to the receptor. Agonists may also assist the binding of the natural ligand.
  • Receptor agonists typically bind selectively to their particular receptor and not to other receptors. They normally have a higher binding affinity than the natural ligand. Although agonists which have a higher affinity for the receptor than the natural ligand are preferred, it is likewise possible to employ agonists having a lower affinity. The agonists preferably bind reversibly to their corresponding receptors.
  • the EP 2 receptor agonist has a preferred affinity for the EP 2 receptor compared with any other EP receptor.
  • Agonists are tested via the initiation of the signal transduction and/or physiological effect mediated by the corresponding receptor.
  • ligands The compounds or low molecular weight substances which bind to a receptor are referred to as ligands. Their binding is normally reversible. Binding of a ligand to the corresponding receptor activates or inactivates the signal transduction pathway coupled to the receptor. The ligand mediates its intracellular effect in this manner. Ligands mean agonists and antagonists of a receptor.
  • the present invention likewise relates to the use of the substances of the invention as EP 2 receptor antagonists for the treatment of disorders which are caused by disturbances in the signal transduction chain in which the EP 2 receptor is involved, such as, for example, pain and fertility impairments, and which are likewise suitable for controlling fertility.
  • the oocyte is surrounded in the preovulatory antral follicle by cumulus cells which form a dense ring of cells around the oocyte.
  • cumulus cells After the lutenizing hormone peak (LH peak), a series of processes is activated and leads to a large morphological change in this ring of cells composed of cumulus cells.
  • the cumulus cells form an extracellular matrix which leads to so-called cumulus expansion (Vanderhyden et al. Dev Biol. 1990 Aug;140(2):307-317). This cumulus expansion is an important constituent of the ovulatory process and of the subsequent possibility of fertilization.
  • Prostaglandins and here prostaglandin E 2 , whose synthesis is induced by the LH peak, are of crucial importance in cumulus expansion.
  • Prostanoid EP 2 knockout mice Hizaki et al.. Proc Natl Acad Sci U S A. 1999 Aug.
  • the substances of the invention have inhibitory effects in cumulus expansion tests.
  • the present invention relates to the use of the substances of the invention for controlling fertility.
  • the EP 2 receptor antagonist AH 6809 inhibits cumulus expansion by about only 30% and not until the concentration is 100 - 200 ⁇ M
  • a 61 % inhibition of cumulus expansion can be achieved in the presence of the substance of Example 1 at a concentration which is 10 times lower.
  • the test substances compete with the natural EP 2 receptor agonist PGE 2 .
  • the present invention relates to the use of the substances of the invention for inhibiting cumulus expansion and thus ovulation and fertilization for contraception.
  • Prostaglandins play an important part in angiogenesis (Sales, Jabbour, 2003, Reproduction 126, 559 - 567; Kuwano et al., 2004, FASEB J. 18, 300-310; Kamiyama et al., 2006, Oncogene 25, 7019-7028; Chang et al. 2005, Prostaglandins & other Lipid Mediators 76, 48-58).
  • Endometriosis is a chronic disorder caused by impairments of blood vessels. About 10% of women regularly suffer from heavy bleeding during menstruation, caused by changes in the blood vessels of the endometrium. In addition, structural differences in the blood vessels have been observed, such as, for example, incomplete formation of the smooth muscle cell layer (Abberton et al., 1999, Hum. Reprod. 14, 1072-1079). Since the blood loss during menstruation is partly controlled by constriction of the blood vessels, it is obvious that the defects in the smooth muscles make a substantial contribution to the bleeding.
  • the present invention relates to the use of the substances of the general formula I for treating endometriosis.
  • Prostaglandins play an important part in uterine contraction, and excessively strong contractions are responsible for painful menstruation (Sales, Jabbour, 2003, Reproduction 126, 559 - 567).
  • the present invention relates to the use of the substances of the general formula I for the treatment of painful menstruation.
  • the present invention relates to the use of the substances of the general formula I for the treatment and prevention of cancers.
  • Prostaglandins also play an important part in processes counteracting osteoporosis.
  • the present invention therefore relates to the use of the substances of the invention for the treatment of osteoporosis.
  • the present invention relates to the use of the substances of the invention for the treatment of inflammatory hyperalgesia.
  • the salts are prepared in a conventional way by mixing a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is in solution where appropriate, and separating off the precipitate or working up the solution in a conventional way.
  • the invention thus also relates to medicaments based on compounds of the general formula I and usual excipients or carriers.
  • the invention additionally relates to a process for preparing the compounds of the invention of the general formula I, which comprises reacting a compound of the formula Il
  • R 5 may be a hydroxy group, a chlorine or bromine atom or a CrC ⁇ -alkyl radical, with preference for hydrogen, chlorine, the methyl or ethyl radical, by methods known to the skilled worker, and subsequently eliminating protective groups required where appropriate.
  • the reaction can initially take place by activating the acid function, and in this case for example the carboxylic acid of the formula III is initially converted in the presence of a tertiary amine such as, for example, triethylamine with isobutyl chloroformate into the mixed anhydride.
  • a tertiary amine such as, for example, triethylamine with isobutyl chloroformate
  • Reaction of the mixed anhydride with the alkali metal salt of the appropriate amine takes place in an inert solvent or solvent mixture such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures between -30 0 C and + 60 0 C, preferably at 0°C to 30 0 C.
  • an inert solvent or solvent mixture such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures between -30 0 C and + 60 0 C, preferably at 0°C to 30 0 C.
  • a further possibility is to activate the carboxylic acid by reagents such as, for example, HOBt or HATU.
  • Reaction of the acid takes place for example with HATU in an inert solvent such as, for example, DMF in the presence of the appropriate amine of the general formula III and a tertiary amine such as, for example, ethyldiisopropylamine at temperatures between -50 and +60 0 C, preferably at 0 0 C to 30 0 C.
  • an inert solvent such as, for example, DMF
  • a tertiary amine such as, for example, ethyldiisopropylamine
  • R 5 is d-C ⁇ -alkyl
  • R 5 it is also possible for example to carry out a direct amidolysis of the ester with the appropriate amine, possibly with the assistance of thalkylaluminum reagents, preferably thmethylaluminum.
  • R 5 is a chlorine or bromine atom
  • R 5 is a chlorine or bromine atom
  • an inert solvent e.g. tetrahydrofuran, methylene chloride, methanol or else ethyl acetate
  • the compounds of the general formula Il which serve as starting materials are either known or can be prepared for example by reacting in a manner known per se the known hydrazines IV, where appropriate prepared from the corresponding known anilines by nitrosation followed by a reduction,
  • R 1 has the meaning indicated above
  • R 6 is a CrC 6 -alkyl radical, in a Fischer indole cyclization, and subsequently reducing the resulting ester by methods known to the skilled worker such as, for example, diisobutylaluminum hydride in an inert solvent at temperatures between -50 and 25°C, preferably between -30 and 0 0 C, to the corresponding alcohol which is in turn converted into the amino function by conversion into a leaving group such as tosylate, mesylate, trifluoromesylate, chloride, bromide or iodide and subsequent reaction with, for example, sodium azide, followed by a hydrolysis with PPh 3 /H 2 O in tetrahydrofuran.
  • the invention additionally relates to an alternative process for preparing the compounds of the invention of the general formula I, which comprises firstly reacting a compound of the formula Il
  • an inert solvent e.g. tetrahydrofuran, methylene chloride, methanol or else ethyl acetate
  • the invention additionally relates to a further alternative process for preparing the compounds of the invention of the general formula I, which comprises firstly reacting a compound of the formula Il
  • the compounds of the general formula X are then reacted in a Sonogashira reaction known to the skilled worker, with uses of palladium catalysts such as, for example, Pd(OAc) 2 , Pd 2 (dba) 3 , PdCI 2 (PPhIs) 2 , PdCI 2 or PdCI 2 (PhCN) 2 in the presence of a Cu salt such as, for example, CuI, with compounds of the general formula IX
  • an inert solvent e.g. tetrahydrofuran, methylene chloride, methanol or else ethyl acetate
  • Antagonism assay (data for each well of a 384-well plate): The substance solutions (0.75 ⁇ l) introduced into an assay plate and 30% DMSO are dissolved in 16 ⁇ l of a KRSB+IBMX stimulation solution (1 X Krebs- Ringer Bicarbonate Buffer; Sigma-Aldrich # K-4002; including 750 ⁇ M 3-isobutyl- 1 -methylxanthine Sigma-Aldrich # 1-7018), and then 15 ⁇ l thereof are transferred into a media-free cell culture plate which has been washed with KRSB shortly beforehand.
  • KRSB+IBMX stimulation solution (1 X Krebs- Ringer Bicarbonate Buffer; Sigma-Aldrich # K-4002; including 750 ⁇ M 3-isobutyl- 1 -methylxanthine Sigma-Aldrich # 1-7018
  • the substance solutions (0.75 ⁇ l) introduced into an assay plate and 30% DMSO are dissolved in 16 ⁇ l of a KRSB+IBMX stimulation solution (1 X Krebs- Ringer Bicarbonate Buffer; Sigma-Aldrich # K-4002; including 750 ⁇ M 3-isobutyl- 1 -methylxanthine Sigma-Aldrich # 1-7018), and then 15 ⁇ l thereof are transferred into a media-free cell culture plate which has been washed with KRSB shortly beforehand.
  • a KRSB+IBMX stimulation solution (1 X Krebs- Ringer Bicarbonate Buffer; Sigma-Aldrich # K-4002; including 750 ⁇ M 3-isobutyl- 1 -methylxanthine Sigma-Aldrich # 1-7018
  • the oocyte In the preovulatory antral follicle, the oocyte is surrounded by cumulus cells which form a dense ring of cells around the oocyte. After the LH peak (lutenizing hormone), a series of processes is activated and leads to a large morphological change in this ring of cells composed of cumulus cells. In this case, the cumulus cells form an extracellular matrix which leads to so-called cumulus expansion
  • Prostaglandins and here prostaglandin E 2 , whose synthesis is induced by the LH peak, are of crucial importance in cumulus expansion.
  • Prostanoid EP 2 knockout mice show a markedly reduced cumulus expansion and severe subfertility, demonstrating the importance of the prostanoid EP 2 receptor for this process.
  • the cumulus-oocyte complexes are then incubated with prostaglandin E2 (PGE2) (0.3 ⁇ M), vehicle control (ethanol) or test substances for 20-24 hours.
  • PGE2 prostaglandin E2
  • Medium alpha-MEM medium with 0.1 mM IBMX, pyruvates (0.23 mM) glutamines (2 mM), pen/strep 100 IU/ml pen. and 100 ⁇ g/ml strep.) and HSA (8 mg/ml)).
  • Cumulus expansion is then established through the division into four stages (according to Vanderhyden et al. Dev Biol. 1990 Aug;140(2):307-317).
  • Table 1 Example of the biological activity of the compounds of the invention (measured by the cAMP antagonism assay):

Abstract

The present invention relates to cinnamic acid derivatives of the general formula (I), process for their preparat ion, and the use thereof for the manufacture of pharmaceutical compositions for the tr eatment of disorders and indications connected with the EP2 receptor.

Description

Cinnamic acid derivatives as modulators of the EP2 receptor
The present invention relates to cinnamic acid derivatives as EP2 receptor modulators, processes for their preparation, and their use as medicaments.
It has long been known that prostaglandins are key molecules in the processes of female reproductive biology such as, for example, control of ovulation, of fertilization, of nidation, of decidualization (e.g. placenta formation) and of menstruation. Prostaglandins likewise play an important part in the pathological changes in the reproductive tract, including menorrhagia, dysmenorrhea, endometriosis and cancer. The mechanism by which prostaglandins bring about these changes has not yet been completely elucidated. Recent results indicate that prostaglandins, their receptors and signal transduction pathways thereof are involved in processes such as angiogenesis, apoptosis, proliferation, and in inflammatory/antiinflammatory and immunological processes.
The effects of prostaglandins are mediated by their G protein-coupled receptors which are located on the cell surface. Prostaglandin E2 (PGE2) is of particular interest, having a wide variety of cellular effects through binding to functionally different receptor subtypes, namely the EPi, EP2, EP3 and EP4 receptors. The receptor subtypes to which prostaglandin E2 binds appear to be of particular interest for the receptor-mediated effects which are involved in the control of fertility. It has thus been possible to show that the reproductive functions in EP2 knockout mice (EP2 "'"), i.e. in mice no longer having a functional PGE2 receptor of the EP2 subtype, are impaired, and that these animals have a smaller "litter size" (Matsumoto et al., 2001 , Biology of Reproduction 64, 1557-1565). It was likewise possible to show that these EP2 knockout mice (Hizaki et al. Proc Natl Acad Sci U. S. A. 1999 Aug 31 ; 96(18):10501 -10506) show distinctly reduced cumulus expansion and severe subfertility, which is to be regarded as causally connected with diminished reproductive processes such as ovulation and fertilization.
The EP2 receptor accordingly represents an important target for developing medicaments for controlling female fertility. The existence of the 4 subclasses of the PGE2 receptor opens up the possibility of targeted development of selectively active compounds. However, to date, scarcely any selective EP2 receptor ligands which bind to the EP2 subtypes of the PGE2 receptor are known, since most known compounds also bind to the other PGE2 receptor subtypes such as, for example, to the EP4 receptor.
EP2 receptor antagonists are described, for example in the application US2005059742 (Jabbour, Medical Research Concil). A method in which an EP2 and/or an EP4 antagonist can be employed for the treatment of menorrhagia and dysmenorrhea is claimed. AH6809 is disclosed as antagonist of the EP2 or EP4 receptor, but no other specific antagonists and no new compounds are disclosed.
In an earlier application of the same group (EP1467738), EP2 or EP4 antagonists are claimed for the treatment of pathological conditions such as, for example, allergic disorders, Alzheimer's disease, pain, abortion, painful menstruation, menorrhagia and dysmenorrhea, endometriosis, bone disorders, ischemia etc. The described compounds are, however, distinguished by a particularly high affinity for the EP3 receptor. A further application (WO04/032964) describes novel compounds which are likewise distinguished by a particularly high affinity for the EP3 receptor, but also have EP2-antagonistic effects and which are used for the treatment and prophylaxis of allergic disorders.
Ono Pharmaceutical claims in the application WO03/016254 the preparation of benzene or saturated carboxylic acid derivatives which are substituted by aryl or heterocycles, inter alia as PGE2 receptor antagonists. The disclosed compounds are claimed for the treatment of a large number of disorders, including allergic disorders, Alzheimer's disease, pain, abortion, painful menstruation, menorrhagia and dysmenorrhea, endometriosis, bone disorders, ischemia etc. The described compounds are, however, distinguished by a particularly high affinity for the EP3 receptor. A further application (WO04/032964) describes novel compounds which are likewise distinguished by a particularly high affinity for the EP3 receptor, but also have EP2-antagonistic effects and which are used for the treatment and prophylaxis of allergic disorders.
The application WO04/39807 of Merck Frosst, Canada, discloses the preparation of pyridopyrrolizines and pyridoindolizines. However, these compounds are distinguished by good binding to the PGD2 receptor, and this receptor represents a different subtype of the prostaglandin receptor. Naphthalene derivatives as EP4 receptor ligands are disclosed in application US2004102508 of SmithKline Beecham Corperation. The claimed compounds are used for the treatment or prophylaxis of pain, allergic reactions and neurodegenerative disorders.
EP4 antagonists (γ-lactams) are claimed in the application WO03/103604 (Applied Research Systems). The compounds bind approximately 60-fold better to the EP4 than to the EP2 receptor and are claimed inter alia for the treatment of premature labor, dysmenorrhea, asthma, infertility or fertility impairments. The same company claims in the applications WO03/053923 (substituted pyrrolidines) or WO03/035064 (substituted pyrazolidinones) compounds for the treatment of disorders associated with prostaglandins, such as, for example, infertility, hypertension and osteoporosis. The compounds bind to the EP4- and to the EP2 receptor subtypes. The application WO03/037433 claims ω- cycloalkyl, 17 heteroaryl prostaglandin derivatives as EP2 receptor antagonists, in particular for the treatment of elevated intraocular pressure.
The application WO03/064391 (Pfizer Products) describes metabolites of [3-[[N- (4-tert-butylbenzyl)(pyridin-3-ylsulfonyl)amino]methyl]acetic acid which inhibit the binding of [3H] prostaglandin E2 to the EP2 receptor. The use of these metabolites for the treatment of osteoporosis is disclosed.
Tani et al. claim in the application US2005124577 8-azaprostaglandin derivatives for the treatment of immunological disorders, allergic disorders, premature labor, abortion, etc. The compounds bind to the EP2 and to the EP4 receptor.
European patent application EP 1306087 describes EP2 receptor agonists which are used for the treatment of erectile dysfunction (Ono Pharmaceuticals). The same class of structures is described in European patent EP 860430 (Ono Pharmaceuticals), and their use for the manufacture of a medicament for the treatment of immunological disorders, asthma and abortion is claimed. WO04/009117 describes EP2 and EP4 receptor agonists for the treatment of disorders caused by uterine contraction, for example painful menstruation (Ono Pharmaceuticals).
The applications WO03/74483 and WO03/09872 describe agonists which bind equally to the EP2 and to the EP4 receptor (Ono Pharmaceuticals). - A -
Agonists of the EP2 and of the EP4 receptors are frequently described in connection with the treatment of osteoporosis (WO99/19300 (Pfizer), US2003/0166631 (Dumont Francis), WO03/77910 (Pfizer), WO03/45371 (Pfizer), WO03/74483 and WO03/09872 (Ono Pharmaceuticals)) and for glaucoma treatment (WO04/37813, WO04/37786, WO04/19938, WO03/103772, WO03/103664, WO03/40123, WO03/47513, WO03/47417 (Merck Frosst Canada)) and US6410591 and US6747037 (Allergan).
The patent application WO04/12656 (Applied Research Systems) claims EP2 receptor agonists in connection with inflammation.
The patent application WO03/77919 (Merck & Co. Inc.) claims EP4 receptor agonists for the treatment of fertility.
Various prior art applications (WO 95/27712, CEMAF; WO 00/72815, Neurim Pharmaceuticals) or European Patent EP 1226138 (Affinium Pharmaceuticals) disclose indole derivatives. These compounds are Fab I inhibitors with antibacterial effect or are used as skin protectives or cosmetics, but they have no effect on the EP2 receptor.
However, to date, no selective EP2 receptor agonists and antagonists which control the processes which are ultimately responsible for ovulation, fertilization, nidation and decidualization and thus contribute to promoting or inhibiting fertility are known.
It is therefore an object of the present invention to provide stable EP2 receptor antagonists.
This object is achieved by the compounds of the general formula I
Figure imgf000005_0001
where A is a C5-C12 heteroaryl radical which may optionally be substituted one or more times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-,
-S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, hydroxy, R4 or by R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical R4 and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC6-acyl or NH-CO- Ci-Cβ-alkyl radical, cyano, -CONH2, a CrC6-alkoxy group which is substituted by cyano, hydroxy,
Cs-Ce-cycloalkyl, COOH, CONH2, CO2-(CrC6-alkyl), CO-NH(CrC6-alkyl), CO-N(Ci-C6-alkyl)2> N-(Ci-C6-alkyl)2 or NH-CO-d-Ce-alkyl, a Ci-C6-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C6-alkyl), CO-NH(CrC6-alkyl),
CO-N(Ci-C6-alkyl)2, N-(CrC6-alkyl)2 or NH-CO-Ci-C6-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(CrC6-alkyl), CO-NH(CrC6-alkyl), CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino,
CONH2, d-Ce-alkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci -Ce-alkyl), N-(CrC6-alkyl)2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2j CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or d-C6- alkoxy,
R1 is a hydrogen, a Ci-C6-alkyl radical which may optionally be substituted,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or Ci-C6-alkyl radical, where this radical may be substituted in any way,
R3 is a hydrogen, halogen, amino, an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl-, NH-(CrC6-alkyl), N-(Ci-C6-alkyl)2 or NH-CO-CrC6-alkyl radical, a Ci-Cβ-alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO- NH2, CO-NH(CrC6-alkyl) or by CO-N(Ci-C6-alkyl)2, a Ci-Cβ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(Ci-C6-alkyl)2, NH-C3-C6-cycloalkyl, COOH, CO-NH2,
CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(d-C6-alkyl), N-(d-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, d-Ce-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl),
N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), CrC6-alkyl, CrC6-acyl,
N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
is a hydrogen, halogen, amino, -S(O)p-Ci-C6-alkyl or -S(O)P-C3-C6- cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl, NH-(CrC6-alkyl), N-(Ci-C6-alkyl)2 or NH-CO-CrC6-alkyl or a Ci-Cβ-alkyl group which may optionally be substituted one or more times, identically or differently, by Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(d-C6-alkyl)2, COOH,
CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2, a Ci-Cβ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(CrC6-alkyl)2, NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(d-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, d-Ce-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl),
N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-Cβ-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), CrC6-acyl, N-(Ci-C6-alkyl)2, COOH,
CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(CrC6-alkyl)2 or Ci-C6-alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-,
-O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a-(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates, for the manufacture of a medicament for fertility control, which overcome the known disadvantages and have improved properties, i.e. a good activity, good solubility and stability.
The compounds of the invention have an antagonistic effect on the EP2 receptor and thus serve to control female fertility.
Ci-Cβ-alkyl means in each case a straight-chain or branched alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl and hexyl which may be substituted as desired one or more times, identically or differently, for example by halogen. Ci-Cβ-alkoxy means in each case a straight-chain or branched alkoxy radical such as, for example, methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, sec-butoxy-, isobutoxy-, tert-butyloxy-, pentoxy-, isopentoxy- and hexoxy which may optionally be substituted one or more times, identically or differently, for example by halogen.
Ci-Cβ-acyl means in each case a straight-chain or branched radical such as, for example, formyl, acetyl, propionyl, butyryl, isobutyroyl, valeryl and benzoyl which may optionally be substituted one or more times, identically or differently, for example by halogen.
C3-C6-Cycloalkyl means monocyclic 3-6-membered alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The C3-C6-cycloalkyl radicals may, instead of the carbon atoms, comprise one or more heteroatoms such as oxygen, sulfur and/or nitrogen. Preferred heterocycloalkyls are those having 3 to 6 ring atoms. Ring systems in which optionally one or more possible double bonds may be contained in the ring are for example cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, with the connection possibly taking place either at the double bond or at the single bonds.
Halogen means in each case fluorine, chlorine, bromine or iodine.
The C6-Ci2-aryl radical includes in each case 6-12 carbon atoms and may for example be benzo-fused. Examples which may be mentioned are: phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, fluorenyl, anthracenyl etc.
The C5-Ci6-heteroaryl radical comprises in each case 5-16 ring atoms and may, instead of the carbon, comprise one or more, identical or different, heteroatoms such as oxygen, sulfur or nitrogen in the ring, and may be mono-, bi- or tricyclic and may additionally in each case be benzo-fused. Examples which may be mentioned are: thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzooxazolyl, benzimdazolyl, benzothiazolyl, indazolyl, indolyl, isoindolyl, etc; or pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof such as, for example, quinolyl, isoquinolyl, etc; or azocinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.
The heteroaryl radical may in each case be benzo-fused. Examples of 5- membered heteroaromatic rings which may be mentioned are: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof, and of 6- membered heteroaromatic rings pyridine, pyrimidine, thazine, quinoline, isoquinoline and benzo derivatives.
Heteroatoms mean oxygen, nitrogen or sulfur atoms.
If an acidic function is present, suitable salts are the physiologically tolerated salts of organic and inorganic bases, such as, for example, the readily soluble alkali metal and alkaline earth metal salts, and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1 ,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, ths-hydroxymethylaminomethane, aminopropanediol, Sovak base, 1 -amino-2,3,4-butanethol.
If a basic function is present, the physiologically tolerated salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid inter alia.
The present invention likewise relates to compounds of the general formula (I) where
A is a C5-Ci2 heteroaryl radical which may optionally be substituted one or more times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-,
-0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical
R4 and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC6-acyl or NH-CO-
Ci-Cβ-alkyl radical, a CrC6-alkoxy group which is substituted by cyano, hydroxy, Cs-Ce-cycloalkyl, COOH, CONH2, CO2-(CrC6-alkyl), CO-NH(CrC6-alkyl), CO-N(Ci-C6-alkyl)2, N-(Ci-C6-alkyl)2 or NH-CO-d-Ce-alkyl, a Ci-C6-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C6-alkyl), CO-NH(CrC6-alkyl), CO-N(Ci-C6-alkyl)2, N-(CrC6-alkyl)2 or N H-CO-Ci -C6-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(CrC6-alkyl), CO-NH(CrC6-alkyl), CO-N(d-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, d-Ce-alkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci -Ce-alkyl), N-(CrC6-alkyl)2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-Cβ-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), CrC6-alkyl, CrC6-acyl, N-(Ci-C6-alkyl)2, CO-NH(Ci-C6-alkyl), CO-N(CrC6-alkyl)2or CrC6- alkoxy,
R1 is a hydrogen, a Ci-C6-alkyl radical which may be substituted one or more times by halogen, R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or Ci-C6-alkyl radical which may be substituted one or more times by halogen,
R3 is a hydrogen, halogen, amino, an -S(O)p-Ci-C6-alkyl group or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl-, NH-(CrC6-alkyl), N-(CrC6-alkyl)2 or NH-CO-CrC6-alkyl radical, a d-Cβ-alkyl which may optionally be substituted one or more times, identically or differently, by CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO- NH2, CO-NH(CrC6-alkyl) or by CO-N(CrC6-alkyl)2> a d-Cβ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci -C6- alkyl), N-(CrC6-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(CrC6-alkyl) or by CO-N(CrC6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(d-C6-alkyl), N-(CrC6-alkyl)2,
NH-(CrC6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl),
CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC6-alkyl, C3-C6- cycloalkyl, CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(Ci -C6- alkyl), N-(CrC6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC6-alkyl, Ci-C6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl),
N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(CrC6-alkyl)2> or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(d-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
is a hydrogen, halogen, amino, -S(O)p-Ci-C6-alkyl or -S(O)P-C3-C6- cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, Ci-C6- acyl, NH-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2 or NH-CO-d-C6-alkyl or a Ci-C6-alkyl which may optionally be substituted one or more times, identically or differently, by d-C6-acyl, d-C6-alkoxy, hydroxy, cyano, CO2-(d-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2> a Ci-C6-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(Ci-C6-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(d-C6-alkyl), O-CO-(d-C6-alkyl), N-(d-C6-alkyl)2,
NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl),
CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(CrC6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl),
N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-Cβ-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), CrC6-acyl, N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -0-C-(CHs)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodexthn clathrates.
Particular preference is given to those compounds of the general formula (I) where
A is a C5-Ci2 heteroaryl radical which may optionally be substituted one or more times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical
R4 and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC6-acyl or NH-CO-
Ci-Cβ-alkyl radical, a d-Cβ-alkoxy group which is substituted by cyano, hydroxy,
Cs-Ce-cycloalkyl, COOH, CONH2, CO2-(CrC6-alkyl),
CO-NH(CrC6-alkyl), CO-N(d-C6-alkyl)2, N-(d-C6-alkyl)2 or
NH-CO-d-Ce-alkyl, a d-Ce-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(d-C6-alkyl), CO-NH(Ci-C6-alkyl),
CO-N(Ci-C6-alkyl)2, N-(d-C6-alkyl)2 or N H-CO-Ci -C6-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(d-C6-alkyl),
CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino,
CONH2, d-Ce-alkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano,
CO2-(Ci -Ce-alkyl), N-(Ci-C6-alkyl)2, CO-NH(CrC6-alkyl) or
CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-Cβ-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), d-Cβ-alkyl, d-Cβ-acyl,
N-(Ci-C6-alkyl)2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2or CrC6- alkoxy,
R1 is a hydrogen, a Ci-Cβ-alkyl radical which may be substituted one or more times by halogen, R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or CrC6-alkyl radical which may be substituted one or more times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, Ci-C6- acyl, NH-(CrC6-alkyl), N-(d-C6-alkyl)2 or NH-CO-CrC6-alkyl radical, a Ci-Cβ-alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(d-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2> a Ci-Cβ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(CrC6-alkyl)2, NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(d-C6-alkyl),
CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(CrC6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or
CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, Ci-C6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or
CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), CrC6-alkyl, CrC6-acyl, N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, Ci-C6-acyl-, NH-(Ci-C6-alkyl), N-(CrC6- alkyl)2 or NH-CO-d-Ce-alkyl- or a Ci-C6-alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-
NH2, CO-NH(CrC6-alkyl) or by CO-N(Ci-C6-alkyl)2> a Ci-C6-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(CrC6- alkyl), N-(Ci-C6-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 , a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6- alkyl), N-(CrC6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(Ci-C6-alkyl)2> a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), CrC6-acyl, N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-,
-S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
Particular preference is given to those compounds of the general formula (I) where
A is a C5-Ci2 heteroaryl radical which may optionally be substituted once, twice, three or four times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-,
-CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4, and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC4-acyl or
N H-CO-Ci -C4-alkyl radical, a CrC4-alkoxy group which is substituted by cyano, hydroxy,
Cs-Ce-cycloalkyl, COOH, CONH2, CO2-( CrC4-alkyl), CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, N-(Ci-C4-alkyl)2 or
NH-CO-CrC4-alkyl, a CrC4-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, N-(CrC4-alkyl)2 or N H-CO-Ci -C4-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(CrC2-alkyl),
CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, CrC4-alkyl, CrC4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(CrC4-alkyl)2, CO-NH(CrC4-alkyl) or
CO-N(CrC4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), CrC4-alkyl, CrC4-acyl, N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(CrC4-alkyl)2or
CrC4-alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted one or more times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a Ci-C4 alkoxy radical or Ci-C4-alkyl radical which may be substituted one or more times by halogen, is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC4-acyl-, NH-(Ci-C4-alkyl), N-(CrC4-alkyl)2 or NH-CO-Ci-C4- alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice, three or four times, identically or differently, by CrC4-acyl, CrC4- alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice, three or four times, identically or differently, by hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2> a C5-Ci2-heteroaryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by
Ci-C4-alkyl, CrC4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4- alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4-alkyl) or CO-N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), CrC4-alkyl, CrC4-acyl, N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy, is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, CrC4-acyl-, NH-(Ci-C4-alkyl), N-(CrC4- alkyl)2 or NH-CO-d-C^alkyl-, a Ci-C4-alkyl group which may optionally be substituted once, twice, three or four times, identically or differently, by CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice, three or four times, identically or differently, by hydroxy, cyano,
CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, Cs-Cβ-cycloalkyl, Ci-C4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2,
CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by CrC4-alkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci -C4- alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4-alkyl) or
CO-N(Ci-C4-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by CrC4- alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), CrC4-acyl, N-(Ci-C4- alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(CrC4-alkyl)2 or Ci-C4-alkoxy, R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
Preference is likewise given to those compounds of the general formula (I) where
A is a C5-Ci2 heteroaryl radical which may optionally be substituted once, twice or three times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, metaposition, or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice or three times, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4 and which is substituted at least once or else twice or three times, identically or differently, by R', where R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC4-acyl or NH-CO-Ci-C4 alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy,
Cs-Ce-cycloalkyl, COOH, CONH2, CO2-( CrC4-alkyl), CO-
NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, N-(Ci-C4-alkyl)2 or NH-CO-
Ci-C4-alkyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, C3-Ce- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(CrC4-alkyl),
CO-N(Ci-C4-alkyl)2, N-(CrC4-alkyl)2 or NH-CO-Ci-C4-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(CrC2-alkyl), CO-
NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino,
CONH2, Ci-C4-alkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano,
CO2-(Ci -C4-alkyl), N-(CrC4-alkyl)2, CO-NH(CrC4-alkyl) or
CO-N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), CrC4-alkyl, CrC4-acyl,
N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(CrC4-alkyl)2or CrC4- alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, Ci-C4- acyl, NH-(CrC4-alkyl), N-(Ci-C4-alkyl)2 or NH-CO-CrC4-alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(d-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, NH-C3-C6-cycloalkyl, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy, R4 is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, Ci-C4-SCyI-, NH-(Ci-C4-alkyl), N-(CrC4- alkyl)2 or NH-CO-CrC4-alkyl- or a Ci-C4-alkyl group which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, CrC4- alkoxy, hydroxy, cyano, CO2-(d-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-C3-C6-cycloalkyl, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2> a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4-alkyl), CO-N(CrC4-alkyl)2 or CrC4- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
Preference is likewise given to those compounds of the general formula (I) where A is a C5-Ci2 heteroaryl radical which may optionally be substituted once, twice or three times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -
CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice or three times, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4, and which is substituted at least once or else twice or three times, identically or differently, by R', where
R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC4-acyl- or NH- CO-CrC4-alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy, C3-C6-cycloalkyl, COOH, CONH2, CO2-( CrC4-alkyl), CO- NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, N-(Ci-C4-alkyl)2 or NH-CO-
Ci-C4-alkyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, N-(CrC4-alkyl)2 or N H-CO-Ci -C4-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C2-alkyl), CO-
NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(CrC4-alkyl)2, CO-NH(CrC4-alkyl) or CO-
N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(CrC4-alkyl)2or CrC4- alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, Ci-C4- acyl, NH-(CrC4-alkyl), N-(Ci-C4-alkyl)2 or NH-CO-CrC4-alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(d-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, NH-C3-C6-cycloalkyl, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy, R4 is a hydrogen, halogen, amino, SO2NH2-, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, Ci-C4-SCyI-, NH-(Ci-C4-alkyl), N-(CrC4- alkyl)2 or NH-CO-CrC4-alkyl- or a Ci-C4-alkyl group which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, CrC4- alkoxy, hydroxy, cyano, CO2-(d-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2> a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4-alkyl), CO-N(CrC4-alkyl)2 or CrC4- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
Preference is likewise given to those compounds of the general formula (I), where
A is a C5-Ci2 heteroaryl radical which may optionally be substituted once, twice or three times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-,
-0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice or three times, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be additionally substituted one or more times, identically or differently, by the radical R4, and which is substituted at least once or else twice or three times, identically or differently, by R', where R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, CrC4-acyl or NH- CO-Ci -C4-alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy, Cs-Ce-cycloalkyl, COOH, CONH2, CO2-( d-C4-alkyl), CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, N-(Ci-C4-alkyl)2 or NH- CO-Ci-C4-alkyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, Cs-Ce- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, N-(CrC4-alkyl)2 or N H-CO-Ci -C4-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(CrC2-alkyl), CO-NH(CrC4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(CrC4-alkyl)2, CO-NH(CrC4-alkyl) or CO-N(CrC4-alkyl)2or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), CrC4-alkyl, CrC4-acyl, N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(CrC4-alkyl)2or CrC4- alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a Ci-C4-alkoxy radical or Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC4- acyl, NH-(CrC4-alkyl), N-(Ci-C4-alkyl)2 or NH-CO-CrC4-alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2,
NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-
(Ci-C4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl),
N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), Ci-C4-alkyl, CrC4-acyl, N-
(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(CrC4-alkyl), CO-N(CrC4- alkyl)2 or Ci-C4-alkoxy,
is a hydrogen, halogen, amino, SO2NH2-, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC4-acyl-, NH-(Ci-C4-alkyl), N-(CrC4- alkyl)2 or NH-CO-CrC4-alkyl-, a Ci-C4-alkyl group which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, CrC4- alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, NH-C3-C6-cycloalkyl, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), O-CO-(Ci-C4-alkyl), N-(CrC4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4-alkyl, hydroxy, cyano, CO2-(CrC4-alkyl), CrC4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(CrC4-alkyl)2 or CrC4- alkoxy,
R3 and R4 are either in ortho, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO- NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-
O-, -0-C-(CHs)2-O-, where m is 1 -3,
X is a -CH=CH- group, and Y is a -(CH2)2- group,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodexthn clathrates.
The following compounds corresponding to the present invention are very particularly preferred:
1. (E)-3-Benzo[1 ,3]dioxol-5-yl-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
2. (E/Z)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyhdin-4-yl- acrylamide
3. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-phenoxyphenyl)- acrylamide
4. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyridin-2-ylacrylamide
5. (E)-3-(4-Acetylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
6. (E)-3-(6-Amino-5-methylpyridin-3-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol- 3-yl)ethyl]acrylamide
7. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-thiophen-2-yl- acrylamide
8. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(2-oxo-2,3-dihydro-1 H- indol-5-yl)acrylamide 9. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(5-methylpyhdin-2-yl)- acrylamide 10.5-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- nicotinamide
11. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(2-ethoxycarbonyl- phenyl)acrylamide
12. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-thiophen-3-yl- acrylamide
13. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyridin-3-ylacrylamide 14. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-trifluoromethyl- phenyl)acrylamide
15. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-methoxycarbonyl- phenyl)acrylamide 16. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(5-methoxycarbonyl)- pyridin-3-ylacrylannide
17. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(6-hydroxynaphthalin- 2-yl)acrylamide
18. (E)-3-[4-(2-Dimethylaminoethoxy)phenyl]-N-[2-(7-fluoro-2,4-dimethyl-1 H- indol-3-yl)ethyl]acrylamide
19.5-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}-N- methylnicotinannide 20.3-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzoic acid 21. (E)-3-(2-Aminopyrimidin-5-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide 22. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(1 H-indol-5-yl)- acrylamide
23. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-methylpyridin-2-yl)- acrylamide
24. (E)-3-(4-Cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide 25. (E)-3-(3-Cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide 26. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(3-trifluoromethyl- phenyl)acrylamide 27. (E)-3-(3-Cyanomethylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
28. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyrimidin-5-yl- acrylamide
29. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(2-trifluoromethyl- phenyl)acrylamide 30. (E)-3-(2-Cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide 31. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-naphthalin-2-yl- acrylamide 32. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-naphthalin-1 -yl- acrylamide 33. (E)-3-(4-Cyanomethylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
34. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-sulfamoylphenyl)- acrylamide
35. (E)-3-(4-Acetylamino-3-fluorophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-
3-yl)ethyl]acrylamide Se. CEJ-N-^^-Fluoro^^-dimethyl-I H-indol-S-yOethyll-S-CS-sulfamoylphenyl)- acrylamide 37. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(2-hydroxyethyl)- phenyl]acrylamide 38. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-methanesulfonyl- phenyl)acrylamide
39. (E)-3-(2-Aminobenzothiazol-6-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
40.5-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzofuran-2-carboxylic acid 41. (E)-3-[4-(2-Aminothiazol-4-yl)phenyl]-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-
3-yl)ethyl]acrylamide 42. (EJ-S-CS-Chloro^-cyanophenyO-N-^^-fluoro^^-dimethyl-i H-indol-3-yl)- ethyl]acrylamide 43. (E)-3-(3-Acetylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
44. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(2-pyrrolidin-1 -yl- ethoxy)phenyl]acrylamide
45. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(morpholine-
4-sulfonyl)phenyl]acrylamide 46. (E)-3-(2-Acetylbenzofuran-5-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide 47. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-isoquinolin-4-yl- acrylamide 48. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(1 H-indol-6-yl)- acrylamide 49. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-isopropylamino- quinazolin-6-yl)acrylamide
50. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-hydroxy-3-hydroxy- methylphenyl)acrylannide
51. (E)-3-(3,5-Difluoro-4-hydroxymethylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H- indol-3-yl)ethyl]acrylamide 52. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-hydroxy-3-isoxazol-
5-ylphenyl)acrylamide 53. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-piperazin-1 -yl- phenyl)acrylamide
54. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(3-piperazin-1 -ylmethyl- phenyl)acrylamide
55. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(1 H-pyrazol-3-yl)- phenyl]acrylamide
56.4-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzamide 57.4-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}-
3-methylbenzannide 58. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[3-(1 H-tetrazol-5-yl)- phenyl]acrylamide 59. (E)-3-[4-(2-Aminothiazol-4-yl)phenyl]-N-[2-(4,7-difluoro-2-methyl-1 H-indol-
3-yl)ethyl]acrylamide
60.5-{(E)-2-[2-(4,7-Difluoro-2-methyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzofuran-2-carboxylic acid
61. (E)-3-(2-Aminobenzothiazol-6-yl)-N-[2-(4,7-difluoro-2-methyl-1 H-indol-3-yl)- ethyl]acrylamide The present invention relates to the use of the compounds of the invention for manufacturing medicaments which comprise at least one of the compounds of formula I.
The present invention likewise relates to medicaments which comprise the compounds of the invention with suitable formulating substances and carriers.
Compared with known prostaglandin E2 ligands, the novel EP2 agonists and antagonists are distinguished by greater selectivity and stability.
The present invention relates to medicaments for the treatment and prophylaxis of disorders which include fertility impairments, infectious disorders, cancer, viral infections, cardiovascular disorders, elevated intraocular pressure, glaucoma, skeletal system disorders, angiogenetic disorders, uterine contraction impairments, pain, neuroinflammatory disorders, immunomodulatory infections and nephrological disorders.
Fertility impairments mean the disorders which lead to no ovulation taking place, that no nidation of a fertilized oocyte occurs and no decidualization takes place, infectious disorders mean disorders caused by unicellular parasites, cancer means solid tumors and leukemia, viral infections mean for example cytomegalievirus infections, hepatitis, hepatitis B and C and HIV disorders, immunomodulatory infections mean for example avian influenza, cardiovascular disorders mean ischemic reperfusion disorder, stenoses, arterioscleroses and restenoses, angiogenetic disorders mean for example endometriosis and fibrosis, elevated intraocular pressure means glaucoma, uterine contraction impairments mean for example painful menstruation, skeletal system disorders mean osteoporosis, neuroinflammatory disorders mean multiple sclerosis, Alzheimer's disease, pain and nephrological disorders mean glomerulonephritis.
The present invention likewise relates to medicaments for the treatment and prophylaxis of the disorders detailed above, which comprise at least one compound of the general formula I, and medicaments with suitable formulating substances and carriers.
For the compounds of the invention to be used as medicaments they are brought into the form of a pharmaceutical product which, besides the active ingredient, comprises inert organic or inorganic pharmaceutical carrier materials which are suitable for enteral or parenteral administration, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. The pharmaceutical products may be in solid form, for example as tablets, coated tablets, suppositories, capsules, in semisolid form, for example as ointments, creams, gels, suppositiories, emulsions or in liquid form, for example as solutions, suspensions or emulsions.
They comprise where appropriate excipients which are intended to act for example as fillers, binders, disintegrants, lubricants, solvents, solubilizers, masking flavors, colorant, emulsifiers. Examples of types of excipients for the purpose of the invention are saccharides (mono-, di-, tri-, oligo-, and/or polysaccharides), fats, waxes, oils, hydrocarbons, anionic, nonionic, cationic natural, synthetic or semisynthetic surfactants. They additionally comprise where appropriate excipients such as preservatives, stabilizers, wetting agents or emulsifiers; salts to modify the osmotic pressure or buffers.
The present invention likewise relates to these pharmaceutical products.
It is expedient to produce aerosol solutions for inhalation.
Suitable for oral use are in particular tablets, coated tablets or capsules with talc and/or hydrocarbon carriers or binders, such as, for example, lactose, corn starch or potato starch. Use can also take place in liquid form, such as, for example, as solution to which, where appropriate, a sweetener is added. Clathrates are likewise also suitable for oral use of such compounds, examples of clathrates which may be mentioned being those with alpha-, beta-, gamma- cyclodextrin or else beta-hydroxypropylcyclodextrin.
Sterile, injectable, aqueous or oily solutions are used for parenteral administration. Particularly suitable are injection solutions or suspensions, especially aqueous solutions of active compounds in polyethoxylated castor oil.
Examples suitable and customary for vaginal administration are pessaries, tampons or intrauterine device.
Appropriately prepared crystal suspensions can be used for intraarticular injection. It is possible to use for intramuscular injection aqueous and oily injection solutions or suspensions and appropriate depot preparations.
For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments both for systemic and for local therapy.
The novel compounds can be used in the form of aerosols and inhalations for pulmonary administration.
For local use on the eyes, external auditory canal, middle ear, nasal cavity and paranasal sinuses, the novel compounds can be used as drops, ointments and tinctures in appropriate pharmaceutical preparations.
Formulations possible for topical application are gels, ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures. The dosage of the compounds of the general formula I should in these preparations be 0.01 % - 20% in order to achieve an adequate pharmacological effect.
The dosage of the active ingredients may vary depending on the route of administration, age and weight of the patient, nature and severity of the disorder to be treated and similar factors. Treatment can take place by single dosages or by a large number of dosages over a prolonged period. The daily dose is 0.5 - 1000 mg, preferably 50 - 200 mg, it being possible to give the dose as a single dose to be administered once or divided into 2 or more daily doses.
Carrier systems which can be used are also surface-active excipients such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof, and liposomes or constituents thereof.
The present invention likewise relates to the formulations and dosage forms described above.
Administration of the compounds of the invention can take place by any conventional method, including oral and parenteral, e.g. by subcutaneous or intramuscular injections. The present invention likewise relates to enteral, parenteral, vaginal and oral administrations. The compounds of the invention of the general formula I bind to the EP2 receptor and have agonistic or antagonistic effect. It is possible to determine whether an agonistic or an antagonistic effect is present by an agonism test (see Example 1.2.1. of the Biological Examples) or by an antagonism test (see Example 1.2.2. of the Biological Examples).
Antagonists mean molecules which bind to their corresponding receptors and which inhibit the initiation of the signal transduction pathway(s) coupled to the receptor by the naturally occurring ligand(s). The antagonists normally compete with the naturally occurring ligand of the receptor for binding to the receptor. However, other modifications of the receptor are also possible by molecules which prevent the signal transduction pathways coupled to the receptor being activated by the naturally occurring ligand(s) (e.g. non-competitive, steric modifications of the receptor).
Receptor antagonists typically bind selectively to their particular receptor and not to other receptors. They normally have a higher binding affinity than the natural ligand. Although antagonists which have a higher affinity for the receptor than the natural ligand are preferred, it is likewise possible to employ antagonists having a lower affinity.
The antagonists preferably bind reversibly to their corresponding receptors.
The EP2 receptor antagonist has a preferred affinity for the EP2 receptor compared with any other EP receptor. The antagonism is measured in the presence of the natural agonist (PGE2).
Agonists mean molecules which bind to their corresponding receptors and normally compete with the naturally occurring ligand of the receptor for binding to the receptor, and which stimulate the initiation of the signal transduction pathway coupled to the receptor. Agonists may also assist the binding of the natural ligand.
Receptor agonists typically bind selectively to their particular receptor and not to other receptors. They normally have a higher binding affinity than the natural ligand. Although agonists which have a higher affinity for the receptor than the natural ligand are preferred, it is likewise possible to employ agonists having a lower affinity. The agonists preferably bind reversibly to their corresponding receptors.
The EP2 receptor agonist has a preferred affinity for the EP2 receptor compared with any other EP receptor.
Agonists are tested via the initiation of the signal transduction and/or physiological effect mediated by the corresponding receptor.
The compounds or low molecular weight substances which bind to a receptor are referred to as ligands. Their binding is normally reversible. Binding of a ligand to the corresponding receptor activates or inactivates the signal transduction pathway coupled to the receptor. The ligand mediates its intracellular effect in this manner. Ligands mean agonists and antagonists of a receptor.
The substance of Example 36 shows no inhibition in the cellular agonism test but a good activity (IC5O = 1 x 10 E-6 M) in the antagonism test.
The present invention likewise relates to the use of the substances of the invention as EP2 receptor antagonists for the treatment of disorders which are caused by disturbances in the signal transduction chain in which the EP2 receptor is involved, such as, for example, pain and fertility impairments, and which are likewise suitable for controlling fertility.
The oocyte is surrounded in the preovulatory antral follicle by cumulus cells which form a dense ring of cells around the oocyte. After the lutenizing hormone peak (LH peak), a series of processes is activated and leads to a large morphological change in this ring of cells composed of cumulus cells. In this case, the cumulus cells form an extracellular matrix which leads to so-called cumulus expansion (Vanderhyden et al. Dev Biol. 1990 Aug;140(2):307-317). This cumulus expansion is an important constituent of the ovulatory process and of the subsequent possibility of fertilization.
Prostaglandins, and here prostaglandin E2, whose synthesis is induced by the LH peak, are of crucial importance in cumulus expansion. Prostanoid EP2 knockout mice (Hizaki et al.. Proc Natl Acad Sci U S A. 1999 Aug
31 ;96(18):10501 -6.) show a distinctly reduced cumulus expansion and severe subfertility, demonstrating the importance of the prostanoid EP2 receptor for this process.
The substances of the invention have inhibitory effects in cumulus expansion tests.
The present invention relates to the use of the substances of the invention for controlling fertility.
Whereas the EP2 receptor antagonist AH 6809 inhibits cumulus expansion by about only 30% and not until the concentration is 100 - 200 μM, a 61 % inhibition of cumulus expansion can be achieved in the presence of the substance of Example 1 at a concentration which is 10 times lower. In these experiments, the test substances compete with the natural EP2 receptor agonist PGE2.
The present invention relates to the use of the substances of the invention for inhibiting cumulus expansion and thus ovulation and fertilization for contraception.
Prostaglandins play an important part in angiogenesis (Sales, Jabbour, 2003, Reproduction 126, 559 - 567; Kuwano et al., 2004, FASEB J. 18, 300-310; Kamiyama et al., 2006, Oncogene 25, 7019-7028; Chang et al. 2005, Prostaglandins & other Lipid Mediators 76, 48-58).
Endometriosis is a chronic disorder caused by impairments of blood vessels. About 10% of women regularly suffer from heavy bleeding during menstruation, caused by changes in the blood vessels of the endometrium. In addition, structural differences in the blood vessels have been observed, such as, for example, incomplete formation of the smooth muscle cell layer (Abberton et al., 1999, Hum. Reprod. 14, 1072-1079). Since the blood loss during menstruation is partly controlled by constriction of the blood vessels, it is obvious that the defects in the smooth muscles make a substantial contribution to the bleeding. The present invention relates to the use of the substances of the general formula I for treating endometriosis.
Prostaglandins play an important part in uterine contraction, and excessively strong contractions are responsible for painful menstruation (Sales, Jabbour, 2003, Reproduction 126, 559 - 567). The present invention relates to the use of the substances of the general formula I for the treatment of painful menstruation.
Increasing research results also demonstrate the importance of EP receptors, and especially of the EP2 receptor, in a large number of types of cancer (e.g. breast cancer, colon carcinoma, lung cancer, prostate cancer, leukemia, skin cancer), suggesting future possibilities of employing modulators (antagonists or agonists) of the EP2 receptor for the therapy and prevention (prophylactic and/or adjuvant) of cancer (Fulton et al. Cancer Res 2006; 66(20): 9794-7; Castellone et al. Science VOL 310 2005, 1504-1510; Chang et al. Cancer Res 2005; 65(11 ): 4496-9); Hull et al. MoI Cancer Ther 2004;3(8):1031-9; Richards et al. J Clin Endocrinol Metab 88: 2810-2816, 2003; Sinha et al. 2007, Cancer Res; 67(9):4507-13; Wang et al. 2004, Seminars in Oncology, VoI 31 , No 1 , Suppl 3: pp 64-73), Jain et al. Cancer Res 2006; 66(13): 6638-48).
The present invention relates to the use of the substances of the general formula I for the treatment and prevention of cancers.
Prostaglandins also play an important part in processes counteracting osteoporosis. The present invention therefore relates to the use of the substances of the invention for the treatment of osteoporosis.
Reinold et al. (J. Clin. Invest. 115, 673-679 (2005)) describes PGE2 receptors of the EP2 subtype as the key signaling elements in inflammatory hyperalgesia. Mice no longer having this receptor (EP2 "'") do not experience spinal inflammatory pain. There is evidence that an inflammatory, increased pain sensitivity can be treated by targeted modulation of EP2 receptors.
The present invention relates to the use of the substances of the invention for the treatment of inflammatory hyperalgesia.
Where the preparation of the starting compounds is not described, they are known or can be prepared in analogy to known compounds or processes described herein. It is likewise possible to carry out all the reactions described herein in parallel reactors or using combinatorial techniques.
The salts are prepared in a conventional way by mixing a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is in solution where appropriate, and separating off the precipitate or working up the solution in a conventional way.
The invention thus also relates to medicaments based on compounds of the general formula I and usual excipients or carriers.
The invention additionally relates to a process for preparing the compounds of the invention of the general formula I, which comprises reacting a compound of the formula Il
Figure imgf000046_0001
in which R1, R2 and Y have the meanings indicated above, with a carboxylic acid derivative of the general formula III
Figure imgf000046_0002
in which A, R3, R4 and X have the meanings indicated above, and R5 may be a hydroxy group, a chlorine or bromine atom or a CrCβ-alkyl radical, with preference for hydrogen, chlorine, the methyl or ethyl radical, by methods known to the skilled worker, and subsequently eliminating protective groups required where appropriate.
In the case where R5 is a hydroxy group, the reaction can initially take place by activating the acid function, and in this case for example the carboxylic acid of the formula III is initially converted in the presence of a tertiary amine such as, for example, triethylamine with isobutyl chloroformate into the mixed anhydride.
Reaction of the mixed anhydride with the alkali metal salt of the appropriate amine takes place in an inert solvent or solvent mixture such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures between -300C and + 600C, preferably at 0°C to 300C. A further possibility is to activate the carboxylic acid by reagents such as, for example, HOBt or HATU. Reaction of the acid takes place for example with HATU in an inert solvent such as, for example, DMF in the presence of the appropriate amine of the general formula III and a tertiary amine such as, for example, ethyldiisopropylamine at temperatures between -50 and +600C, preferably at 00C to 300C.
In the case where R5 is d-Cβ-alkyl it is also possible for example to carry out a direct amidolysis of the ester with the appropriate amine, possibly with the assistance of thalkylaluminum reagents, preferably thmethylaluminum.
In the case where R5 is a chlorine or bromine atom it is possible for example to carry out the reaction for example in pyridine or an inert solvent such as, for example, DMF in the presence of the appropriate amine of the general formula Il and a tertiary amine such as, for example, ethyldiisopropylamine at temperatures between -50 and +60°C, preferably at 00C to 300C.
The compounds in which X is -CH2-CH2- can also be prepared by hydrogenation of the corresponding compound with X = -C≡C- or -CH=CH- by methods known to the skilled worker, such as, for example, stirring in a hydrogen atmosphere in an inert solvent, e.g. tetrahydrofuran, methylene chloride, methanol or else ethyl acetate, in the presence of a palladium catalyst.
The compounds of the general formula Il which serve as starting materials are either known or can be prepared for example by reacting in a manner known per se the known hydrazines IV, where appropriate prepared from the corresponding known anilines by nitrosation followed by a reduction,
Figure imgf000047_0001
in which R2 has the meaning indicated above, a) with a ketone of the general formula V in which R1 and Y have the meaning indicated above, and n = 2 and 3, in a Fischer indole cyclization
Figure imgf000048_0001
or
b) with an enol ether of the general formula Vl in which R1 and Y have the meaning indicated above, and n = 2 and 3, in a Fischer indole cyclization (Org. Lett. 2004, 79ff),
Figure imgf000048_0002
and converting the subsequently obtained alcohol by methods known to the skilled worker by conversion into a leaving group such as tosylate, mesylate, trifluoromesylate, chloride, bromide or iodide and subsequent reaction with, for example, sodium azide followed by a hydrolysis with PPh3/H2O in tetrahydrofuran into the amino function,
or
c) with a keto ester of the general formula VII in the case of Y with n = 1
Figure imgf000048_0003
in which R1 has the meaning indicated above, and R6 is a CrC6-alkyl radical, in a Fischer indole cyclization, and subsequently reducing the resulting ester by methods known to the skilled worker such as, for example, diisobutylaluminum hydride in an inert solvent at temperatures between -50 and 25°C, preferably between -30 and 00C, to the corresponding alcohol which is in turn converted into the amino function by conversion into a leaving group such as tosylate, mesylate, trifluoromesylate, chloride, bromide or iodide and subsequent reaction with, for example, sodium azide, followed by a hydrolysis with PPh3/H2O in tetrahydrofuran. The invention additionally relates to an alternative process for preparing the compounds of the invention of the general formula I, which comprises firstly reacting a compound of the formula Il
Figure imgf000049_0001
in which R1, R2 and Y have the meanings indicated above, with acryloyl chloride to give the compounds of the general formula VIII
Figure imgf000049_0002
The compounds of the general formula VIII are then reacted in a Heck reaction which is known to the skilled worker, with uses of palladium catalysts such as, for example, Pd(OAc)2, Pd2(dba)3, PdCI2 or PdCI2(PhCN)2 with compounds of the general formula IX
Figure imgf000049_0003
in which A, R3 and R4 have the meanings indicated above, and Hal is a chlorine, bromine or iodine atom, and is preferably a bromine atom, to give the compounds of the general formula I, and in which where appropriate for the case of Y = -CH2-CH2- the double bond which is present must be hydrogenated by methods known to the skilled worker, such as, for example, stirring in a hydrogen atmosphere in an inert solvent, e.g. tetrahydrofuran, methylene chloride, methanol or else ethyl acetate, in the presence of a palladium catalyst, and protective groups which are required where appropriate are subsequently cleaved.
The invention additionally relates to a further alternative process for preparing the compounds of the invention of the general formula I, which comprises firstly reacting a compound of the formula Il
Figure imgf000050_0001
(II)
in which R »11 DR2 and Y have the meanings indicated above, with propiolic acid to give the compounds of the general formula X
Figure imgf000050_0002
The compounds of the general formula X are then reacted in a Sonogashira reaction known to the skilled worker, with uses of palladium catalysts such as, for example, Pd(OAc)2, Pd2(dba)3, PdCI2(PPhIs)2, PdCI2 or PdCI2(PhCN)2 in the presence of a Cu salt such as, for example, CuI, with compounds of the general formula IX
Figure imgf000050_0003
in which A, R3 and R4 have the meanings indicated above, and Hal is a chlorine, bromine or iodine atom, and is preferably a bromine atom, to give the compounds of the general formula I, and in which where appropriate in the case of Y = -CH2-CH2- the double bond which is present must be hydrogenated by methods known to the skilled worker, such as, for example, stirring in a hydrogen atmosphere in an inert solvent, e.g. tetrahydrofuran, methylene chloride, methanol or else ethyl acetate, in the presence of a palladium catalyst, and protective groups which are required where appropriate are subsequently cleaved.
It is possible where appropriate for the compounds of the general formula (I) with R2 = CN also to be prepared starting from the corresponding halides, preferably bromine or chlorine, by a Cu- or Pd-catalyzed (e.g. Pd(OAc)2) cyanide introduction with Zn(CN)2 or else K3[Fe(CN)6] in an inert solvent such as dimethylacetamide, dimethylformamide or N-methylpyrolidone at temperatures between 600C and the boiling point of the respective solvent.
Preparation of the compounds of the invention
The following examples illustrate the preparation of the compounds of the invention of the general formula (I) without restricting the scope of the claimed compounds to these examples.
The compounds of the invention of the general formula (I) can be prepared as described below.
Example 1 : (E)-3-Benzo[1 ,3]dioxol-5-yl-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol- 3-yl)ethyl]acrylamide
Figure imgf000052_0001
172 mg of N-[(dimethylamino)-1 /-/-1 ,2,3-triazolo[4,5-ib]pyridin-1 -ylmethylene]-/\/- methylmethanaminium hexafluorophosphate N-oxide (HATU) and 100 mg of 2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)-ethylamine hydrochloride are added to a solution of 79 mg of (E)-3-benzo[1 ,3]dioxol-5-ylacrylic acid in 3 ml of dimethylformamide. Then, at 00C, 0.2 ml of ethyldiisopropylamine is added dropwise and stirred at 25°C for 20 hours. 50 ml of a mixture of ice and cone, aqueous bicarbonate solution are subsequently added, and extraction three times with ethyl acetate is carried out. The combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue obtained in this way is purified by chromatography on silica gel with hexane/0-100% ethyl acetate. 78 mg of the title compound are obtained in this way. NMR (300 MHz, DMSO-d6): δ = 2.28 (3H), 2.55 (3H), 2.87 (2H), 3.23 (2H), 6.03 (2H), 6.42 (1 H), 6.51 -6.67 (2H), 6.91 (1 H), 7.02 (1 H), 7.10 (1 H), 7.33 (1 H), 8.12 (1 H), 11.11 (1 H). Example 2: (E/Z)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyridin-4-yl- acrylamide
Figure imgf000053_0001
42 mg of the title compound are obtained in analogy to example 1 from 62 mg of (E/Z)-3-(4-pyridyl)acrylic acid and 100 mg of 2-(7-fluoro-2,4-dimethyl-1 H-indol- 3-yl)ethylamine hydrochloride.
NMR (300 MHz, DMSO-d6): δ = 2.28/2.31 (3H), 2.52/2.56 (3H), 2.8-3.0 (2H), 3.1 -3.3 (2H), 6.52-6.68 (2.5H), 6.77-6.84 (1 H), 7.36-7.44 (1.5H), 7.50 (2H), 8.58 (2H), 7.74/8.40 (1 H), 11.14/11.22 (1 H).
Example 3: (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-phenoxy- phenyl)acrylamide
Figure imgf000053_0002
49 mg of palladium diacetate, 232 mg of th-ortho-tolylphosphine, 0.32 ml of triethylamine and 217 mg of 1 -bromo-4-phenoxybenzene are added to a solution of 255 mg of N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]acrylamide in 2 ml of dimethylformamide, and the mixture is stirred at 110°C for 4 hours. After cooling, the reaction mixture is added to water and extracted three times with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue obtained in this way is purified by HPLC (reversed phase) chromatography with water/1-99% acetonithle plus 1 % TFA. 28 mg of the title compound are obtained in this way.
NMR (300 MHz, DMSO-d6): δ = 2.31 (3H), 2.58 (3H), 2.91 (2H), 3.28 (2H), 6.52 (1 H), 6.55-6.69 (2H), 7.01 (2H), 7.06 (2H), 7.18 (1 H), 7.42 (1 H), 7.43 (2H), 7.57 (2H), 8.23 (1 H), 11.15 (1 H).
The starting material for the above title compound is prepared as follows:
3a) N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]acrylamide
Figure imgf000054_0001
11.4 ml of thethylamine, followed by 2.67 ml of acryloyl chloride, are added to a solution of 8.O g of 2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylamine hydrochloride in 240 ml of dimethylformamide at 25°C. After stirring at 25°C for 60 min, 50 ml of the reaction mixture are added to ice-water and extracted three times with 200 ml of ethyl acetate each time. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue obtained in this way is purified by chromatography on silica gel with hexane/0-100% ethyl acetate. 5.84 g of the title compound are obtained in this way.
NMR (300 MHz, DMSO-d6): δ = 2.31 (3H), 2.58 (3H), 2.90 (2H), 3.24 (2H), 5.59 (1 H), 6.09 (1 H), 6.22 (1 H), 6.56-6.71 (2H), 8.27 (1 H), 11.17 (1 H).
The following examples are prepared in analogy to example 1 or 3 and purified by HPLC:
HPLC method:
HPLC-MS (analytical) of the purified product
Instrument: analytical 4-channel MUX system with CTC Pal injector, Waters
1525 pumps, Waters 2488 UV detector and Waters ZQ 2000 single quad MS detector. Column X-Bridge RP C184.6x503.5 μm; detection wavelength 214 nm; flow rate 2 ml/min; eluents A: 0.1% TFA in H2O, B 0.1% TFA in ACN; gradient in each case based on B: 1% to 99% (51) to 99% (T) to 1% (0.251) to 1% (1.751)
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Biological Examples:
1. Detection of the antagonism of the human prostaglandin E? (subtype EP?) receptor signal 1.1 Principle of detection
The binding of PGE2 to the EP2 subtype of the human PGE2 receptor induces activation of membrane-associated adenylate cyclases and leads to the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP which has accumulated due to this stimulation and been released by cell lysis is employed in a competitive detection method. In this assay, the cAMP in the lysate competes with cAMP-XL665 for binding of an Eu cryptate-labelled anti-cAMP antibody.
This results, in the absence of cellular cAMP, in a maximum signal which derives from coupling of this antibody to the CAMP-XL665 molecule. After excitation at
337 nm, this results in a FRET (fluorescence resonance energy transfer)-based, long-lived emission signal at 665 nm (and at 620 nM). The two signals are measured in a suitable measuring instrument with a time lag, i.e. after the background fluorescence has declined. Any increase in the low FRET signal caused by prostaglandin E2 addition (measured as well ratio change = emission665 nm/emission62o nm * 10 000) shows the effect of antagonists.
1.2. Detection method
1.2.1 Antagonism assay (data for each well of a 384-well plate): The substance solutions (0.75 μl) introduced into an assay plate and 30% DMSO are dissolved in 16 μl of a KRSB+IBMX stimulation solution (1 X Krebs- Ringer Bicarbonate Buffer; Sigma-Aldrich # K-4002; including 750 μM 3-isobutyl- 1 -methylxanthine Sigma-Aldrich # 1-7018), and then 15 μl thereof are transferred into a media-free cell culture plate which has been washed with KRSB shortly beforehand.
After preincubation at room temperature (RT) for 30 minutes, 5 μl of a 4 x PGE2 solution (11 nM) are added, and incubation is carried out in the presence of the agonist at RT for a further 60 min (volume: -20 μl) before the reaction is then stopped by adding 5 μl of lysis buffer and incubated at RT for a further 20 min (volume: -25 μl). The cell lysate is then transferred into a measuring plate and measured in accordance with the manufacturer's information (cyclic AMP kit Cisbio International # 62AMPPEC). 1.2.2 Agonism assay (data for each well of a 384-well plate):
The substance solutions (0.75 μl) introduced into an assay plate and 30% DMSO are dissolved in 16 μl of a KRSB+IBMX stimulation solution (1 X Krebs- Ringer Bicarbonate Buffer; Sigma-Aldrich # K-4002; including 750 μM 3-isobutyl- 1 -methylxanthine Sigma-Aldrich # 1-7018), and then 15 μl thereof are transferred into a media-free cell culture plate which has been washed with KRSB shortly beforehand.
After incubation at room temperature (RT; volume: -15 μl) for 60 minutes, the reaction is then stopped by adding 5 μl of lysis buffer and incubated at RT for a further 20 min (volume: -20 μl). The cell lysate is then transferred into a measuring plate and measured in accordance with the manufacturer's information (cyclic AMP kit Cisbio International # 62AMPPEC).
2. The EP2 subtype of the PGE2 receptor and the preovulatory cumulus expansion
2.1. Background:
In the preovulatory antral follicle, the oocyte is surrounded by cumulus cells which form a dense ring of cells around the oocyte. After the LH peak (lutenizing hormone), a series of processes is activated and leads to a large morphological change in this ring of cells composed of cumulus cells. In this case, the cumulus cells form an extracellular matrix which leads to so-called cumulus expansion
(Vanderhyden et al. Dev Biol. 1990 Aug;140(2):307-317). This cumulus expansion is an important component of the ovulatory process and of the subsequent possibility of fertilization.
Prostaglandins, and here prostaglandin E2, whose synthesis is induced by the LH peak, are of crucial importance in cumulus expansion. Prostanoid EP2 knockout mice (Hizaki et al. Proc Natl Acad Sci U S A. 1999 Aug 31 ;96(18):10501 -6.) show a markedly reduced cumulus expansion and severe subfertility, demonstrating the importance of the prostanoid EP2 receptor for this process.
2.2 Cumulus expansion assay in vitro Folliculogenesis is induced in immature female mice (strain: CD1 (ICR) from Charles River) at an age of 14-18 days by a single dose (intraperitoneal) of 10 I. U. of PMSG (Pregnant Mare Serum Gonadotropine; Sigma G-4877, Lot 68H0909). 47-50 hours after the injection, the ovaries are removed and the cumulus-oocyte complexes are removed. The cumulus complex is not yet expanded at this stage.
The cumulus-oocyte complexes are then incubated with prostaglandin E2 (PGE2) (0.3 μM), vehicle control (ethanol) or test substances for 20-24 hours. Medium: alpha-MEM medium with 0.1 mM IBMX, pyruvates (0.23 mM) glutamines (2 mM), pen/strep 100 IU/ml pen. and 100 μg/ml strep.) and HSA (8 mg/ml)). Cumulus expansion is then established through the division into four stages (according to Vanderhyden et al. Dev Biol. 1990 Aug;140(2):307-317).
Table 1 : Example of the biological activity of the compounds of the invention (measured by the cAMP antagonism assay):
Figure imgf000065_0001

Claims

Claims:
1. A compound of the formula (I)
Figure imgf000066_0001
where A is a C5-C12 heteroaryl radical which may optionally be substituted one or more times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-,
-S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-,
-CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-,
-O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, hydroxy, R4 or by R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical
R4 and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, Ci-C6-acyl or NH-CO-
Ci-C6-alkyl radical, cyano, -CONH2 a Ci-Cθ-alkoxy group which is substituted by cyano, hydroxy,
C3-C6-cycloal kyl, COOH, CONH2, CO2-(Ci-C6-alkyl),
CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2> N-(Ci-C6-alkyl)2 or
NH-CO-d-Cβ-alkyl, a C-i-Cβ-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C6-alkyl), CO-NH(Ci-C6-alkyl),
CO-N(Ci-C6-alkyl)2, N-(Ci-C6-alkyl)2 or NH-CO-d-Cβ-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(d-C6-alkyl), CO-NH(Ci-C6-alkyl)> CO-N(Ci-C6-alkyl)2> a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, CrCθ-alkyl, Ci-Cθ-acyl, Ci-Cθ-alkoxy, hydroxy, cyano, CO2-(Ci -Cβ-alkyl), N-(Ci-C6-alkyl)2> CO-NH(Ci-C6-alkyl) or
CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by d-Cβ-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or CrC6- alkoxy,
R1 is a hydrogen, a C-i-Cβ-alkyl radical which may optionally be substituted,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or C-i-Cβ-alkyl radical, where this radical may be substituted in any way,
R3 is a hydrogen, halogen, amino, an -S(O)p-Ci-C6-alkyl group or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl, NH-(CrC6-alkyl), N-(CrC6-alkyl)2 or NH-CO-CrC6-alkyl radical, a d-Cβ-alkyl which may optionally be substituted one or more times, identically or differently, by d-Cβ-acyl, Ci-Cθ-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO- NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci -C6-alkyl)2, a Ci-C6-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(CrC6-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(CrC6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(d-C6-alkyl), O-CO-(d-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(CrC6-alkyl),
CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6- alkyl), N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl,
Ci-Cθ-acyl, Ci-Cθ-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by d-Cβ-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
is a hydrogen, halogen, amino, -S(O)p-Ci-C6-alkyl or -S(O)P-C3-C6- cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl, NH-(CrC6-alkyl), N-(CrC6-alkyl)2 or NH-CO-CrC6-alkyl or a Ci-C6-alkyl group which may optionally be substituted one or more times, identically or differently, by d-Cβ-acyl, d-Cβ-alkoxy, hydroxy, cyano, CO2-(d-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(d-C6-alkyl)2, a Ci-Cθ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(CrC6- alkyl), N-(d-C6-alkyl)2, NH-Ca-Cβ-cycloalkyl, COOH, CO-NH2,
CO-NH(Ci-C6-alkyl) or by CO-N(d-C6-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-d2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(d-C6-alkyl), O-CO-(d-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(d-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6- alkyl), N-(d-C6-alkyl)2, COOH, CO-NH2, CO-NH(d-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by d-C6-alkyl, d-Cθ-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by d-Cβ-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-acyl, N-(Ci-C6-alkyl)2, COOH,
CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-,
-O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
2. A compound as claimed in claim 1 , where
A is a Cs-Ci2 heteroaryl radical which may optionally be substituted one or more times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-,
-O-(CH2)m-O-, -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical R4 and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, Ci-C6-acyl or NH-CO- Ci-C6-alkyl radical, a Ci-Cθ-alkoxy group which is substituted by cyano, hydroxy, C3- Cβ-cycloalkyl, COOH, CONH2, CO2-(Ci -C6-alkyl), CO-NH(CrC6- alkyl), CO-N(Ci-C6-alkyl)2> N-(Ci-C6-alkyl)2 or NH-CO-Ci-C6-alkyl, a Ci-Cβ-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C6-alkyl), CO-NH(Ci-C6-alkyl),
CO-N(Ci-C6-alkyl)2, N-(Ci-C6-alkyl)2 or N H-CO-Ci -C6-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C6-alkyl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino,
CONH2, Ci-C6-alkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci -Cβ-alkyl), N-(Ci-C6-alkyl)2> CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2or CrC6- alkoxy,
R1 is a hydrogen, a Ci-C6-alkyl radical which may be substituted one or more times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or Ci-C6-alkyl radical which may be substituted one or more times by halogen,
R3 is a hydrogen, halogen, amino, an -S(O)p-Ci-C6-alkyl group or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl, NH-(CrC6-alkyl), N-(CrC6-alkyl)2 or NH-CO-Ci-C6-alkyl radical, a Ci-C6-alkyl which may optionally be substituted one or more times, identically or differently, by CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2> COOH, CO- NH2, CO-NH(Ci-C6-alkyl) or by CO-N(Ci -C6-alkyl)2, a Ci-Cθ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(Ci-C6-alkyl)2> NH-Ca-Cβ-cycloalkyl, COOH, CO-NH2,
CO-NH(Ci-C6-alkyl) or by CO-N(Ci-C6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(Ci-C6-alkyl), O-CO-(d-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2> a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by C-i-Cβ-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6- alkyl), N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, Ci-Cθ-acyl, Ci-Cθ-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
is a hydrogen, halogen, amino, -S(O)p-Ci-C6-alkyl or -S(O)P-C3-C6- cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl, NH-(CrC6-alkyl), N-(CrC6-alkyl)2 or NH-CO-CrC6-alkyl or a d-Cβ-alkyl which may optionally be substituted one or more times, identically or differently, by Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(d-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(CrC6-alkyl)2> a Ci-C6-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(CrC6- alkyl), N-(CrC6-alkyl)2> NH-Ca-Cβ-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or by CO-N(CrC6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(Ci-C6-alkyl), O-CO-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, NH-(Ci-C6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by d-Cβ-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, Ci-Cθ-acyl, Ci-Cθ-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl) or CO-N(Ci-C6-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-Cβ-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-acyl, N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2 or Ci-C6-alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
3. A compound as claimed in claim 1 -2, where
A is a Cs-Ci2 heteroaryl radical which may optionally be substituted one or more times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)m-0-> -0-C-(CHs)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by radical
R4 and which is substituted at least once or else more than once, identically or differently, by R', where R' is an -S(O)p-Ci-C6-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, Ci-C6-acyl or NH-CO- d-Ce-alkyl radical, a Ci-Cθ-alkoxy group which is substituted by cyano, hydroxy, C3-C6-cycloal kyl, COOH, CONH2, CO2-(Ci-C6-alkyl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2> N-(Ci-C6-alkyl)2 or
NH-CO-d-Cβ-alkyl, a C-i-Cβ-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C6-alkyl), CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2, N-(CrC6-alkyl)2 or N H-CO-Ci -C6-al kyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C6-alkyl),
CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, Ci-C6-alkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(Ci -C6-al kyl), N-(Ci-C6-alkyl)2> CO-NH(Ci-C6-alkyl) or
CO-N(Ci-C6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C6-alkyl, hydroxy, cyano, CO2-(Ci-C6-alkyl), Ci-C6-alkyl, Ci-C6-acyl, N-(Ci-C6-alkyl)2, CO-NH(Ci-C6-alkyl), CO-N(Ci-C6-alkyl)2or Ci-C6- alkoxy,
R1 is a hydrogen, a Ci-C6-alkyl radical which may be substituted one or more times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or CrC6-alkyl radical which may be substituted one or more times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC6- acyl, NH-(CrC6-alkyl), N-(CrC6-alkyl)2 or NH-CO-CrC6-alkyl radical, a d-Cβ-alkyl which may optionally be substituted one or more times, identically or differently, by CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(Ci-C6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or by CO-N(CrC6-alkyl)2> a d-Cθ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(CrC6- alkyl), N-(CrC6-alkyl)2> NH-Ca-Cβ-cycloalkyl, COOH, CO-NH2, CO-NH(CrC6-alkyl) or by CO-N(CrC6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(CrC6-alkyl), N-(Ci-C6-alkyl)2> NH-(CrC6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C6-alkyl), CO-N(CrC6-alkyl)2, a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC6-alkyl, C3-C6- cycloalkyl, CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6- alkyl), N-(CrC6-alkyl)2> COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(CrC6-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC6-alkyl,
CrC6-acyl, CrC6-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(CrC6-alkyl)2, COOH, CO-NH2, CO-NH(CrC6-alkyl) or CO-N(CrC6-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC6-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), CrC6-alkyl, CrC6-acyl, N-(CrC6-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C6-alkyl), CO-N(CrC6-alkyl)2 or CrC6-alkoxy, R4 is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, d-C6-acyl-, NH-(Ci-C6-alkyl), N-(CrC6- alkyl)2 or NH-CO-Ci-Ce-alkyl- or a d-Cθ-alkyl which is optionally substituted one or more times, identically or differently, by CrCβ-acyl, d-Cβ-alkoxy, hydroxy, cyano, CO2-(CrC6-alkyl), N-(CrC6-alkyl)2> COOH, CO-NH2, CO-NH(CrC6-alkyl) or by CO-N(CrC6-alkyl)2> a d-Cθ-alkoxy which may optionally be substituted one or more times, identically or differently, by hydroxy, cyano, CO2-(Ci-C6- alkyl), N-(CrC6-alkyl)2> NH-Ca-Cβ-cycloalkyl, COOH, CO-NH2, CO-NH(CrC6-alkyl) or by CO-N(CrC6-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(CrC6-alkyl), O-CO-(CrC6-alkyl), N-(Ci-C6-alkyl)2, NH-(CrC6-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(CrC6-alkyl),
CO-N(CrC6-alkyl)2> a C6-Ci2-aryl which may optionally be substituted one or more times, identically or differently, by halogen, by d-Cβ-alkyl, C3-C6- cycloalkyl, Ci-C6-acyl, Ci-C6-alkoxy, hydroxy, cyano, CO2-(CrC6- alkyl), N-(CrC6-alkyl)2> COOH, CO-NH2, CO-NH(d-C6-alkyl) or
CO-N(CrC6-alkyl)2> a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, by CrC6-alkyl, d-Cβ-acyl, d-Cβ-alkoxy, hydroxy, cyano, CO2-(Ci-C6-alkyl), N-(CrC6-alkyl)2> COOH, CO-NH2, CO-NH(d-C6-alkyl) or
CO-N(CrC6-alkyl)2> a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by d-Cβ-alkyl, hydroxy, cyano, CO2-(CrC6-alkyl), d-Cβ-acyl, N-(Ci-C6-alkyl)2> COOH, CO-NH2, CO-NH(d-C6-alkyl), CO-N(d-C6-alkyl)2 or CrC6- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-,
-O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -0-(CH2)^1-O-, -0-C-(CHs)2-O-, where m is 1 -3, X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodextrin clathrates.
4. A compound as claimed in claim 1 -3, where
A is a C5-C12 heteroaryl radical which may optionally be substituted once, twice, three or four times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-,
-S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else more than once, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4, and which is substituted at least once or else more than once, identically or differently, by R', where
R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, d-C4-acyl or NH-CO-Ci-C4-alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy, C3-C6-cycloal kyl, COOH, CONH2, CO2-( Ci-C4-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> N-(Ci-C4-alkyl)2 or NH-CO-Ci-C4-alkyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> N-(Ci-C4-alkyl)2 or NH-CO-Ci-C4-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C2-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2j a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2> CO-NH(Ci-C4-alkyl) or
CO-N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2or
Ci-C4-alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted one or more times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a Ci-C4 alkoxy radical or Ci-C4-alkyl radical which may be substituted one or more times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, Ci-C4-acyl, NH-(Ci-C4-alkyl), N-(CrC4-alkyl)2 or NH-CO-Ci-C4- alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice, three or four times, identically or differently, by Ci-C4-acyl, Ci-C4- alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice, three or four times, identically or differently, by hydroxy, cyano,
CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by
Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4- alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy,
is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH, CO-
NH2, NH-CO-NH2, Ci-C4-acyl-, NH-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2 or N H-CO-Ci -C4-alkyl, a Ci-C4-alkyl group which may optionally be substituted once, twice, three or four times, identically or differently, by Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2,
COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice, three or four times, identically or differently, by hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-Cs-Ciβ-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2> a C5-Ci2-heteroaryl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4- alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted once, twice, three or four times, identically or differently, by halogen, by Ci-C4- alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-acyl, N-(Ci-C4- alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-,
-O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodexthn clathrates.
5. A compound as claimed in claim 1 -4, where
A is a C5-Ci2 heteroaryl radical which may optionally be substituted once, twice or three times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, metaposition, or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice or three times, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4 and which is substituted at least once or else twice or three times, identically or differently, by R', where R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, d-C4-acyl or NH-CO-Ci-C4 alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy,
C3-C6-cycloal kyl, COOH, CONH2, CO2-( Ci-C4-alkyl), CO-
NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> N-(Ci-C4-alkyl)2 or NH-CO-
Ci-C4-alkyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2> N-(Ci-C4-alkyl)2 or N H-CO-Ci -C4-al kyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C2-alkyl), CO-
NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino,
CONH2, Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano,
CO2-(Ci -C4-al kyl), N-(Ci-C4-alkyl)2> CO-NH(Ci-C4-alkyl) or
CO-N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl,
N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2or CrC4- alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a
Ci-C4-alkoxy radical or Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC4- acyl, NH-(CrC4-alkyl), N-(CrC4-alkyl)2 or NH-CO-Ci-C4-alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice or three times, identically or differently, by CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> NH-Ca-Cβ-cycloalkyl, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(CrC4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy,
is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, Ci-C4-acyl-, NH-(Ci-C4-alkyl), N-(CrC4- alkyl)2 or NH-CO-Ci-C4-alkyl- or a Ci-C4-alkyl group which may optionally be substituted once, twice or three times, identically or differently, by CrC4-acyl, CrC4- alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-
(CrC4-alkyl), N-(CrC4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(CrC4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-Cs-Ciβ-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2>
NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl,
C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-
(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl),
N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or
CO-N(Ci-C4-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-acyl, N-(Ci-C4-alkyl)2,
COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -C≡C- or -CH=CH- group, and
Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodexthn clathrates.
6. A compound as claimed in claim 1-5, where A is a Cs-Ci2 heteroaryl radical which may optionally be substituted once, twice or three times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, meta position or meta, para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice or three times, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4, and which is substituted at least once or else two or three times, identically or differently, by R', where
R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, d-C4-acyl or
N H-CO-Ci -C4-alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy, C3-C6-cycloal kyl, COOH, CONH2, CO2-( Ci-C4-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, N-(Ci-C4-alkyl)2 or N H-CO-Ci -C4-al kyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, N-(Ci-C4-alkyl)2 or N H-CO-Ci -C4-al kyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C2-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-al kyl), N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2or Ci-C4-alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted one, two or three times by halogen, R is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a Ci-C4 alkoxy radical or Ci-C4-alkyl radical which may be substituted one, two or three times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, Ci-C4-acyl, NH-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2 or NH-CO-Ci-C4- alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO- NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci -C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(Ci- C4-alkyl), N-(Ci-C4-alkyl)2, NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2,
NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-
(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl),
N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO- N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Cr
C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(CrC4- alkyl)2 or Ci-C4-alkoxy, R4 is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH, CO-
NH2, NH-CO-NH2, Ci-C4-acyl, NH-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2 or NH-CO-Ci-C4-alkyl or a Ci-C4-alkyl group which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, Ci-C4- alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(Ci- C4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2,
CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-Cs-Ciβ-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2> NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(Ci-C4-alkyl)2> COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or CO- N(Ci-C4-alkyl)2, a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, - S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-,
-O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3,
X is a -CH=CH- group, and Y is a -(CH2)n- group, where n is 2 or 3,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodexthn clathrates.
7. A compound as claimed in claim 1-6, where
A is a C5-C12 heteroaryl radical which may optionally be substituted once, twice or three times by R4 and/or R3, or a phenyl radical which may be substituted by two radicals which are either in ortho position, metaposition, or meta,para position relative to one another and together have the meaning -O-CO-S-,
-S-CO-O-, CH2-CO-O-, 0-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CH2-CO-NH-, -NH-CO-CH2-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-,
-O-(CH2)m-O-, -O-C-(CH3)2-O-, where m is 1 -3, or a naphthyl radical which is optionally unsubstituted or substituted at least once or else twice or three times, identically or differently, by hydroxy, R4 or R', or a phenyl radical which may optionally also be substituted additionally one or more times, identically or differently, by the radical R4 and which is substituted at least once or else twice or three times, identically or differently, by R', where R' is an -S(O)p-Ci-C4-alkyl group or -S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, CF3, COOH, d-C4-acyl or NH-CO-Ci-C4 alkyl radical, a Ci-C4-alkoxy group which is substituted by cyano, hydroxy, C3-C6-cycloal kyl, COOH, CONH2, CO2-( Ci-C4-alkyl), CO-
NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> N-(Ci-C4-alkyl)2 or NH-CO-
Ci-C4-alkyl, a Ci-C4-alkyl group which is substituted by cyano, hydroxy, C3-C6- cycloalkyl, COOH, CONH2, CO2-(Ci-C4-alkyl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2> N-(Ci-C4-alkyl)2 or NH-CO-Ci-C4-alkyl, an O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, CO2-(Ci-C2-alkyl), CO-
NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted one or more times, identically or differently, by halogen, COOH, amino, CONH2, Ci-C4-alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci -C4-alkyl), N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl) or CO-N(Ci-C4-alkyl)2, or a C3-C6-cycloalkyl which may optionally be substituted one or more times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2or d-C4- alkoxy,
R1 is a hydrogen, a Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R2 is a hydrogen, halogen, cyano, -S(O)q-CH3, where q is 0-2, a Ci-C4-alkoxy radical or Ci-C4-alkyl radical which may be substituted once, twice or three times by halogen,
R3 is a hydrogen, halogen, amino, an SCF3, -S(O)P-CH3 or
-S(O)p-C3-C6-cycloalkyl group, where p is 0-2, an SO2NH2, SO2NH-CH3, COOH, CO-NH2, NH-CO-NH2, CrC4- acyl, NH-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2 or NH-CO-Ci-C4-alkyl radical, a Ci-C4-alkyl which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, COOH,
CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or by CO-N(Ci-C4-alkyl)2, an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-C5-Ci6-heteroaryl, hydroxy, cyano, CO2-(Ci-C4-alkyl), O-CO-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, NH-(Ci-C4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2, a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2- (Ci-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4- alkyl) or CO-N(Ci-C4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4- alkyl, Ci-C4-acyl, Ci-C4-alkoxy, hydroxy, cyano, CO2-(Ci-C4-alkyl), N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl) or
CO-N(Ci-C4-alkyl)2 or a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-alkyl, Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl),
CO-N(Ci-C4-alkyl)2 or Ci-C4-alkoxy,
is a hydrogen, halogen, amino, SO2NH2, SO2NH-CH3, COOH,
CO-NH2, NH-CO-NH2, Ci-C4-acyl-, NH-(Ci-C4-alkyl), N-(CrC4- alkyl)2 or NH-CO-CrC4-alkyl-, a Ci-C4-alkyl group which may optionally be substituted once, twice or three times, identically or differently, by Ci-C4-acyl, CrC4- alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl), N-(CrC4-alkyl)2, COOH, CO-NH2, CO-NH(CrC4-alkyl) or by CO-N(Ci-C4-alkyl)2> a Ci-C4-alkoxy which may optionally be substituted once, twice or three times, identically or differently, by hydroxy, cyano, CO2- (CrC4-alkyl), N-(Ci-C4-alkyl)2> NH-C3-C6-cycloalkyl, COOH, CO-NH2, CO-NH(CrC4-alkyl) or by CO-N(Ci-C4-alkyl)2> an O-C6-Ci2-aryl, CH2-O-C6-Ci2-aryl, O-Cs-Ciβ-heteroaryl, hydroxy, cyano, CO2-(CrC4-alkyl), 0-C0-(CrC4-alkyl), N-(Ci-C4-alkyl)2>
NH-(CrC4-alkyl), CO-NH(C5-Ci2-heteroaryl), CO-NH(CrC4-alkyl),
CO-N(CrC4-alkyl)2> a C6-Ci2-aryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4-alkyl, C3-C6-cycloalkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-
(CrC4-alkyl), N-(CrC4-alkyl)2> COOH, CO-NH2, CO-NH(CrC4- alkyl) or CO-N(CrC4-alkyl)2, a C5-Ci2-heteroaryl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by CrC4- alkyl, CrC4-acyl, CrC4-alkoxy, hydroxy, cyano, CO2-(CrC4-alkyl),
N-(CrC4-alkyl)2> COOH, CO-NH2, CO-NH(CrC4-alkyl) or CO-N(CrC4-alkyl)2> a C3-C6-cycloalkyl which may optionally be substituted once, twice or three times, identically or differently, by halogen, by Ci-C4-alkyl, hydroxy, cyano, CO2-(Ci-C4-alkyl), Ci-C4-acyl, N-(Ci-C4-alkyl)2, COOH, CO-NH2, CO-NH(Ci-C4-alkyl), CO-N(Ci-C4-alkyl)2 or Ci-C4- alkoxy,
R3 and R4 are either in ortho position, meta position or meta,para position relative to one another and together have the meaning -O-CO-S-, -S-CO-O-, CH2-CO-O-, -0-CO-CH2-, -CH2-CO-NH-, -NH-CO-CH2-, -O-CO-NH-, -NH-CO-O-, -CO-CH2-(CH2)m-, -CH2-(CH2)m-CO-, -O-(CH2)m-O-, -0-C-(CHs)2-O-, where m is 1 -3,
X is a -CH=CH- group, and
Y is a -(CH2)2- group,
and the isomers, diastereomers, enantiomers and salts thereof, and cyclodexthn clathrates.
8. A compound as claimed in the preceding claims selected from a group which comprises the following compounds:
1. (E)-3-Benzo[1 ,3]dioxol-5-yl-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
2. (E/Z)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyhdin-4-yl- acrylamide 3. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-phenoxyphenyl)- acrylamide
4. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyridin-2-ylacrylamide
5. (E)-3-(4-Acetylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide 6. (E)-3-(6-Amino-5-methylpyridin-3-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol- 3-yl)ethyl]acrylamide
7. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-thiophen-2-yl- acrylamide
8. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(2-oxo-2,3-dihydro-1 H- indol-5-yl)acrylamide
9. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(5-nnethylpyπdin-2-yl)- acrylamide
10.5-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- nicotinamide
11. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(2-ethoxycarbonyl- phenyl)acrylamide
12. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-thiophen-3-yl- acrylamide
13. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyridin-3-ylacrylamide
14. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-trifluoromethyl- phenyl)acrylamide
15. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-methoxycarbonyl- phenyl)acrylamide
16. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(5-methoxycarbonyl)- pyridin-3-ylacrylannide
17. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(6-hydroxynaphthalin- 2-yl)acrylamide
18. (E)-3-[4-(2-Dimethylaminoethoxy)phenyl]-N-[2-(7-fluoro-2,4-dimethyl-1 H- indol-3-yl)ethyl]acrylamide
19.5-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}-N- methylnicotinannide
20.3-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzoic acid
21. (E)-3-(2-Aminopyrimidin-5-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
22. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(1 H-indol-5-yl)- acrylamide
23. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-methylpyridin-2-yl)- acrylamide
24. (E)-3-(4-Cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
25. (E)-3-(3-Cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
26. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(3-trifluoromethyl- phenyl)acrylamide
27. (E)-3-(3-Cyanomethylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
28. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-pyrimidin-5-yl- acrylamide
29. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(2-trifluoromethyl- phenyl)acrylamide
30. (E)-3-(2-Cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
31. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-naphthalin-2-yl- acrylamide
32. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-naphthalin-1 -yl- acrylamide
33. (E)-3-(4-Cyanomethylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
34. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-sulfamoylphenyl)- acrylamide
35. (E)-3-(4-Acetylamino-3-fluorophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol- 3-yl)ethyl]acrylamide
Se. CEJ-N-^^-Fluoro^^-dimethyl-I H-indol-S-yOethyll-S-CS-sulfamoylphenyl)- acrylamide
37. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(2-hydroxyethyl)- phenyl]acrylamide
38. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-methanesulfonyl- phenyl)acrylamide
39. (E)-3-(2-Aminobenzothiazol-6-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
40.5-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzofuran-2-carboxylic acid
41. (E)-3-[4-(2-Aminothiazol-4-yl)phenyl]-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-
3-yl)ethyl]acrylamide 42. (E)-3-(3-Chloro-4-cyanophenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
43. (E)-3-(3-Acetylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]- acrylamide
44. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(2-pyrrolidin-1 -yl- ethoxy)phenyl]acrylamide
45. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(morpholine-
4-sulfonyl)phenyl]acrylamide 46. (E)-3-(2-Acetylbenzofuran-5-yl)-N-[2-(7-fluoro-2,4-dimethyl-1 H-indol-3-yl)- ethyl]acrylamide
47. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-isoquinolin-4-yl- acrylamide
48. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(1 H-indol-6-yl)- acrylamide
49. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-isopropylamino- quinazolin-6-yl)acrylamide
50. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-hydroxy-3-hydroxy- methylphenyl)acrylannide
51. (E)-3-(3,5-Difluoro-4-hydroxymethylphenyl)-N-[2-(7-fluoro-2,4-dimethyl-1 H- indol-3-yl)ethyl]acrylamide
52. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-hydroxy-3-isoxazol-
5-ylphenyl)acrylamide
53. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(4-piperazin-1 -yl- phenyl)acrylamide
54. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-(3-piperazin-1 -ylmethyl- phenyl)acrylamide
55. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[4-(1 H-pyrazol-3-yl)- phenyl]acrylamide
56.4-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzamide 57.4-{(E)-2-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}-
3-methylbenzannide
58. (E)-N-[2-(7-Fluoro-2,4-dimethyl-1 H-indol-3-yl)ethyl]-3-[3-(1 H-tetrazol-5-yl)- phenyl]acrylamide
59. (E)-3-[4-(2-Aminothiazol-4-yl)phenyl]-N-[2-(4,7-difluoro-2-methyl-1 H-indol-
3-yl)ethyl]acrylamide 60.5-{(E)-2-[2-(4,7-Difluoro-2-methyl-1 H-indol-3-yl)ethylcarbamoyl]vinyl}- benzofuran-2-carboxylic acid 61. (E)-3-(2-Aminobenzothiazol-6-yl)-N-[2-(4,7-difluoro-2-methyl-1 H-indol-3-yl)- ethyl]acrylamide
9. The use of the compounds as claimed in claims 1 -8 for the manufacture of medicaments which comprise at least one of the compounds of the formula I.
10. A medicament as set forth in claim 9 with suitable formulating substances and carriers.
11. The use of the medicaments as set forth in claim 9 and 10, wherein the medicament is used for the treatment and prophylaxis of disorders.
12. The use as claimed in claim 10 for the treatment and prophylaxis of disorders connected with the EP2 receptor.
13. The use as claimed in claim 10 for the treatment and prophylaxis of fertility impairments.
14. The use as claimed in claim 10 for the treatment and prophylaxis of painful menstruation.
15. The use as claimed in claim 10 for the treatment and prophylaxis of endometriosis.
16. The use of the compounds as claimed in claim 1 -8 for modulating the EP2 receptor.
17. The use as claimed in claim 10 for the treatment and prophylaxis of pain.
18. The use of the compounds as claimed in claim 1 -8 and of the medicaments as set forth in claim 9 for controlling fertility/contraception.
19. The use as claimed in claim 10 for the treatment and prophylaxis of osteoporosis.
20. The use as claimed in claim 10 for the treatment and prophylaxis of cancer.
21. The use of the compounds of the general formula I as claimed in claims 1 -8 in the form of a pharmaceutical product for enteral, parenteral, vaginal and oral administration.
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DE102009049662A1 (en) 2009-10-13 2011-04-14 Bayer Schering Pharma Aktiengesellschaft 2,5-disubstituted 2H-indazoles as EP2 receptor antagonists
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US9062041B2 (en) 2011-11-28 2015-06-23 Bayer Intellectual Property Gmbh 2H-indazoles as EP2 receptor antagonists
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