EP2001843A2 - Inhibiteurs de l'adénylate-cyclase soluble - Google Patents

Inhibiteurs de l'adénylate-cyclase soluble

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Publication number
EP2001843A2
EP2001843A2 EP07723652A EP07723652A EP2001843A2 EP 2001843 A2 EP2001843 A2 EP 2001843A2 EP 07723652 A EP07723652 A EP 07723652A EP 07723652 A EP07723652 A EP 07723652A EP 2001843 A2 EP2001843 A2 EP 2001843A2
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EP
European Patent Office
Prior art keywords
alkyl
substituted
acyi
identically
differently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07723652A
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German (de)
English (en)
Inventor
Bernd Buchmann
Dirk Kosemund
Bernd Menzenbach
Martin Fritsch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
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Bayer Schering Pharma AG
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Publication of EP2001843A2 publication Critical patent/EP2001843A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P15/16—Masculine contraceptives
    • 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
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to inhibitors of the soluble adenylate cyclase, their preparation and their use for the preparation of a medicament for contraception.
  • the rat recombinant enzyme can be stimulated by bicarbonate. With the help of antibodies it could be proven that the catalytic domain of the enzyme is localized in testes, semen, kidneys and the choroid plexus. These disclosures are the subject of application WO01 / 85753, issued to the US (US6544768).
  • Assays test systems that can be used to identify substances that inhibit the activity of sAC. The ability to use these substances to reversibly reduce the number of mobile seed lines and their use as a male fertility control agent is disclosed.
  • WO 02/20745 claims test systems which can be used to identify substances which modulate the expression or the activity of the human sAC. For example, such compounds could selectively inhibit sAC activity, resulting in sperm cells losing the ability to fertilize an egg cell. These sAC inhibitors could therefore serve as drugs for non-hormonal contraception.
  • R 1 is hydrogen, halogen, CF 3 , C 3 -C 6 -Cycioaikyi, which is optionally poly-saturated and optionally polysubstituted, or the group Ci-C 6 alkyl, Ci-C 6 -aryl, C r C 6 acyl , Haio-C 1 -C 6 - alkyl, Ci-Ce-alkyl-d-Ce-alkyl, alkyl-dC dC 6 6 acyl, dC 6 acyl Ci-C 6 acyl, CrC 6 alkyl dC 6 aryl, C 6 aryl-Ci-C 6 alkyl, or CF 3, in which Ci-Ce-alkyl, dC 6 aryl, C 6 -acyl, halo-Ci-C 6 alkyl , 6 -alkyl-Ci-C 6 alkyl, Ci-C 6 alkyl-C 6 acyl, Ci-C 6 -acy
  • C 1 -C 6 -alkyl-C 1 -C 6 -aryl or C 1 -C 6 -aryl-C 1 -C 6 -alkyl optionally mono- or polysubstituted, identically or differently, by oxygen, sulfur or nitrogen, or Group sulfonyl-dC 6 alkyl, sulfonamide, or cyano,
  • R 2 is halogen, CF 3 , C 3 -C 6 -cycloalkyl, which is optionally poly-saturated and optionally polysubstituted, or the group Ci-C 6 alkyl, Ci-C 6 -aryl, Ci-C 6 acyl, Halo -C-C 6 - alkyl, Ci-C 6 alkyl-C 6 alkyl, C r C 6 alkyl-C 6 acyl, C 1 -C 6 -ACyI- Ci-C 6 acyl , C 1 -C 6 -alkylCrCe-aryl, C 1 -C 6 -aryl-C 1 -C 6 -alkyl or
  • CF 3 in the 6 -alkyl, dC 6 aryl, C 6 acyl, halo-Ci-C 6 alkyl, dC 6 alkyl-C 6 alkyl, Ci-C 6 alkyl Ci-C 6 alkyl Ci-C 6 acyl, C iC 6 -Acy 1-C 6 - acyl, d-Ce-alkyl-d-Ce-aryl or C 6 aryl-Ci-C 6 alkyl optionally mono- or may be the same or different interrupted by oxygen, sulfur or nitrogen, or the group sulfonyl-dC 6 alkyl, sulfonamide, or cyano,
  • R 3 is C 6 -C 2 aryl, which is optionally substituted one or more times, identically or differently with halogen, with C 6 alkyl or C 1 -C 6 -acyl, which is optionally substituted or may be substituted multiple times, or with C 1 -C 6 -alkoxy, hydroxy, cyano, CO 2 - (6 -alkyl), N- (C 1 -
  • C 5 -C 2 -heteroaryl which is optionally monosubstituted or polysubstituted, identically or differently with halogen, C 6 alkyl, C 1 -C 6 -acyl, C 1 - Ce alkoxy, hydroxy, cyano, CO 2 - (C -C 6 -alkyl), N- (C 1 -C 6 -alkyl) 2) CO-NR 4 R 5 or may be substituted by CF 3 or C 3 -C 6 -
  • Cycloalkyl which is optionally monosubstituted or polysubstituted, identically or differently with halogen, CF 3, hydroxy, cyano, CO 2 - (C 1 -C 6 - alkyl), dC 6 alkyl, C r C 6 acyl, N- ( C 1 -C 6 -alkyl) 2 , CO-NR 4 R 5 or C 1 -C 6 -alkoxy may be substituted,
  • R 4 is hydrogen, C 3 -C 6 -cycloalkyl which is optionally substituted singly or multiply, identically or differently with C 6 alkyl, Ci-C 6 acyl, C 1 - C 6 alkoxy or is substituted CF 3, C 6 Ci2-aryl, which is optionally monosubstituted or polysubstituted, identically or differently, with halogen, with C 6 alkyl, C r C 6 acyl, C 1 -C 6 -alkoxy, NdC 6 alkyl dC 6 - alkyl, CF 3 or cyano, or C 5 -C 12 - heteroaryl, which is optionally substituted one or more times, identically or differently with halogen, Ci-C 6 alkyl, Ci-C 6 acyl, C 1 -C 6 - alkoxy, N-CrCe-alkyl-CrC ⁇ -alkyl, CF 3 or cyano, substituted, or d-Ce-alkyl
  • R 5 is hydrogen, C- ⁇ -C 6 alkyl-C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identically or differently, with CrC 6 alkyl, C 1 - Ce-acyl, C 1 -C 6 - AIkOXy or CF 3 is substituted, C 3 -C 6 -cycloalkyl, which is optionally mono- or polysubstituted, identical or different with C- ⁇ -C 6 alkyl, C 1 -C 6 acyl, C 1 -C 6 -alkoxy or CF 3 is substituted,
  • C 6 -C 12 aryl which is optionally substituted one or more times, identically or differently with halogen, C r C 6 alkyl, C 1 -C 6 -acyl, C 6 - alkoxy, Nd-C ⁇ -alkyl-CRCE Alkyl, CF 3 or cyano, or C 5 -C 12 heteroaryl, which is optionally mono- or polysubstituted, identical or different, with halogen, C 1 -C 6 -alkyl, C 1 -C 6 -acyl, C 1 -C 4 -alkyl 6 -alkoxy, N-CrCe-alkyl-d-Ce-alkyl, CF 3 or cyano, substituted, or d-C ⁇ -alkyl, which may be arbitrarily substituted, and
  • R 4 and R 5 together form a 5-8 membered ring which may contain other heteroatoms
  • the compounds according to the invention inhibit the soluble adenylate cyclase and thus prevent the capacitation of the sperm and thus serve the purpose of male fertility control.
  • Alkyl is 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, to understand.
  • alkyl radical such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl and hexyl, to understand.
  • Alkoxy is in each case a straight-chain or branched alkoxy radical, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert. Butyloxy, pentoxy, iso-pentoxy and hexoxy, to understand.
  • Acyl is in each case to be understood as meaning a straight-chain or branched radical such as, for example, formyl, acetyl, propionyl, butyroyl, isobutyryl, valeroyl and benzoyl.
  • cycloalkyl monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkylyl radicals may contain one or more heteroatoms, such as oxygen, sulfur and / or nitrogen, instead of the carbon atoms. Preference is given to those heterocycloalkyls having 3 to 6 ring atoms.
  • cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl to understand, where the attachment can be done both on the double bond as well as on the single bonds.
  • Halogen is in each case fluorine, chlorine, bromine or iodine.
  • the aryl radical comprises in each case 6 to 12 carbon atoms and may, for example, be benzo-fused. Examples include: phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, florenyl, anthracenyl, etc.
  • the heteroaryl radical comprises in each case 5-16 ring atoms and may contain one or more, identical or different, heteroatoms, such as oxygen, sulfur or nitrogen in the ring instead of the carbon, and may be mono-, bi- or tricyclic and may additionally each be benzo-fused.
  • Oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof e.g. Benzofuranyl, benzothienyl, benzooxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof such as e.g. Quinolyl, isoquinolyl, etc .; or azocinyl, indolizinyl, purinyl, etc.
  • quinolinyl isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.
  • the heteroaryl radical may each be benzo-fused.
  • Heteroatoms are 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 and alkaline earth salts and N-methyl-glucamine, dimethylglucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
  • organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethylglucamine, ethyl-glucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, amino
  • physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and the like.
  • R 1 is hydrogen, halogen, CF 3, C 3 -C 6 cycloalkyl, or the group C 1 - C 6 alkyl, d-Ce-aryl, -C 6 acyl, halo-CrC 6 alkyl, dC 6 alkyl -d-
  • R 2 is halogen, CF 3 , C 3 -C 6 -cycloalkyl, or the group dC 6 -alkyl, C 1 -
  • C 6 -acyl, C 6 acyl-C 6 acyl, Ci-C 6 alkyl-C 6 aryl or C 6 - aryl-Ci-C 6 alkyl optionally mono- or may be the same or different interrupted by oxygen, sulfur or nitrogen, or the group sulfonyl-C 1 -C 6 -alkyl, sulfonamide, or cyano,
  • R 3 is C 6 -C 2 aryl, which is optionally substituted one or more times, identically or differently with halogen, Ci-C 6 -alkyl, C 3 acyl, C 1 -C 3 - alkoxy, cyano, hydroxy, N - (CH 3 J 2 , CO 2 - (C 1 -C 3 -alkyl), CO-NR 4 R 5 or CF 3 may be substituted,
  • C 5 -C 2 -Heteroaryl which is optionally mono- or polysubstituted, identically or differently, with chlorine and / or fluorine, with C 1 -C 6 -alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy, cyano, hydroxy , N (CH 3 J 2, CO 2 - (C 3 - alkyl), CO-NR 4 R 5 may be substituted by CF 3, or C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identical or different with chlorine and / or fluorine, CF 3 , cyano, C 1 -C 3 -alkyl, C 1 -C 3 -acyl, hydroxy, N- (CH 3 J 2 , CO 2 - (C r C 3 -alkyl) , CO-NR 4 R 5 or C 1 -C 3 -alkoxy may be substituted,
  • R 4 is hydrogen, C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identically or differently, by C 1 -C 3 -alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy or CF 3 ,
  • C 6 -C 2 -aryl which is optionally mono- or polysubstituted, identical or different, with halogen, C 1 -C 3 -alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy, N-C 1 -C 3 -alkylCrC 3- alkyl, CF 3 or cyano, or C 5 -C 2 -heteroaryl, which is optionally mono- or polysubstituted, identical or different, with halogen, C 1 -C 3 -alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy , N-C 1 -C 3 -alkyl-C r C 3 -alkyl, CF 3 or cyano, or C 1 -C 6 -alkyl, which may be arbitrarily substituted,
  • R 5 is hydrogen, C 1 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, which is optionally mono- or polysubstituted, identically or differently, with C 1 -C 6 -alkyl, C r C ⁇ -acyl, Ci-C ⁇ -alkoxy or CF 3 is substituted, C 3 -C 6 -cycloalkyl, which is optionally mono- or polysubstituted, identical or different with Ci-C 3 -AiKyI, Ci-C 3 -acyl, C 1 -C 3 -alkoxy or CF 3 being substituted, C 6 -C 2 aryl, which is optionally substituted one or more times, identically or differently with halogen, Ci-C3 alkyl, Ci-C3-acyl, Ci-C 3 -
  • C 5 -C 2 -Heteroaryl which may be mono- or polysubstituted, identically or differently, with halogen, C 1 -C 3 -alkyl, C 1 -C 3 -acyl, Cr
  • Ci-C 6 -alkyl which may be arbitrarily substituted
  • R 1 is hydrogen
  • R 2 is C 3 -C 6 cycloalkyl, Ci-C 6 alkyl, CF 3, cyano, bromine, or the group
  • R 3 is C 6 -C 2 aryl, which is optionally substituted one or more times, identically or differently with halogen, d-C ⁇ -alkyl, Ci-C3-acyl, CrC 3 - alkoxy, cyano, hydroxy, N- (CH 3 J 2 , CO 2 - (C r C 3 alkyl), CO-NR 4 R 5 or CF 3 may be substituted, C 5 -C 2 -heteroaryl, which may be mono- or polysubstituted, identical or different, with chlorine and / or fluorine, with C 1 -C 6 -alkyl,
  • Ca-C ⁇ cycloalkyl which is optionally monosubstituted or polysubstituted, identically or differently with chlorine and / or fluorine, CF 3, cyano, Ci-C 3 -alkyl, C 1 -C 3 -acyl, hydroxy, N- (CH 3 ) 2 , CO 2 - (C 1 -C 3 -alkyl), CO-NR 4 R 5 or C 1 -C 3 -alkoxy may be substituted,
  • R 4 is hydrogen
  • R 5 is hydrogen, C 1 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, which may be mono- or polysubstituted, identically or differently, with C 1 -C 6 -alkyl, C 1 -C 6 -acyl, C 1 -C 6 -alkoxy or CF 3 being substituted, C 3 -C 6 cycloalkyl, which is optionally monosubstituted or polysubstituted, identically or differently with Ci-C 3 alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy or CF 3 is substituted,
  • C 6 -C 12 aryl which is optionally substituted one or more times, identically or differently with halogen, Ci-C 3 alkyl, C 1 -C 3 -acyl, C 1 -C 3 -
  • C 5 -C 12 -heteroaryl which is optionally substituted one or more times, identically or differently, with halogen, CrC 3 alkyl, C 1 -C 3 -acyl, C 1 - C 3 alkoxy, Nd-Cs-alkyl-CRCS Alkyl, CF 3 or cyano, or
  • Ci-C ⁇ -alkyl which may be arbitrarily substituted
  • R 1 is hydrogen
  • R 2 is C 3 -C 6 cycloalkyl, C r C 6 alkyl, CF 3, cyano, bromine, or the group
  • R 3 is C 6 -C 2 aryl, which is optionally substituted once or twice, identically or differently with halogen, Ci-C3 alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N- (CH 3) 2, CO 2 - (C 1 -C 3 -alkyl), CO-NHR 5 or CF 3 may be substituted,
  • C 5 -C 2 -Heteroaryl which may be mono- or di-lower, identical or different, with chlorine and / or fluorine, with C 1 -C 3 -alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N- (CH 3 ) 2 , CO 2 - (C 1 -C 3 -alkyl), CO-NHR 5 or may be substituted by CF 3 , C 3 -C 6 -cycloalkyl,
  • R 4 is hydrogen
  • R 5 is hydrogen, C 1 -C 6 -alkyl-C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identically or differently, with C 1 -C 6 -alkyl, C 1 -
  • C 6 acyl, C 1 -C 6 alkoxy or CF 3 is substituted, C 3 -C 6 cycloalkyl, which is optionally mono- or polysubstituted, identical or different, with C 1 -C 3 -alkyl, C 1 -C 3 -acyl, Ci-C 3 alkoxy or CF 3 being substituted, C 6 -C 2 aryl, which is optionally substituted one or more times, identically or differently, with halogen, CrC 3 -alkyl, C 3 acyl, C 1 -C 3 -
  • Ci-C 6 -alkyl which may be arbitrarily substituted
  • R 4 is hydrogen
  • R s is hydrogen or the group - (CH 2 ) mN- (CH 3 ) 2, - (CH 2 ) 2 -CH 3 , - (CHz) 2 -NH-COCH 3 , - (CH 2 ) -CHCH 3 -OH , - (CH 2 ) 2 -O-CH 3) - (CH 2 ) 2 -OH, -CHCH 3 -CH 2 -OH, where m is 1-3.
  • R 1 is hydrogen
  • R A is hydrogen
  • R 5 is hydrogen or the group, - (CH 2 ) -CHCH 3 -OH, - (CH 2 ) 2 -O-CH 3 , -CHCH 3 -CH 2 -OH,
  • the invention relates to a process for the preparation of the compounds of general formula I according to the invention, which is characterized in that a compound of formula II,
  • R 1 , R 2 and R 3 have the meanings given above, and R 6 may be a hydrogen or a C 1 -C 6 -alkyl radical, preference is given to hydrogen, the methyl or ethyl radical, with an amine of the general formula III
  • the reaction can be carried out first by activation of the acid function, in this case, for example, first the carboxylic acid of the general formula II in the presence of a tertiary amine, such as triethylamine, with isobutyl chloroformate in the mixed anhydride.
  • a tertiary amine such as triethylamine
  • isobutyl chloroformate in the mixed anhydride.
  • the reaction of the mixed anhydride with the Aikaiisaiz of the corresponding amine is carried out in an inert solvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide, at temperatures between -30 0 C and + 60 0 C, preferably at 0 0 C to 30 ° C.
  • Another possibility is to activate the carboxylic acid of general formula II by reagents such as HOBt or HATU.
  • the reaction of the acid takes place for example with HATU in an inert solvent such as DMF in the presence of the corresponding amine of the general formula IM and a tertiary amine such as ethyldiisopropylamine at temperatures between -50 and + 60 0 C, preferably at 0 0 C to 30 0 C.
  • R 6 is C 1 -C 6 -alkyl
  • a direct amidolysis of the ester with the corresponding amine may also be carried out with the aid of aluminum trialkyl reagents, preferably aluminum trimethyl.
  • the compounds of the general formula II which serve as starting materials can be prepared, for example, by dissolving the known bromine-indol esters IV in a manner known per se
  • R 6 is a C 1 -C 6 -alkyl radical, preferably a methyl or ethyl radical, first with chlorosulfuric acid to the compounds of general formula V
  • esters of the general formula VII are then reacted in a Pd-catalyzed reaction with boronic acid derivatives of the general formula VIII
  • R3 (VIII), wherein R 3 has the abovementioned meaning, optionally after cleavage of required protecting groups, optionally followed by saponification, for example, with sodium hydroxide solution in the compounds of general formula II transferred
  • R 1 , R 2 , R 3 and R 6 have the meanings given above.
  • the compounds according to the invention inhibit the soluble adenylate cyclase, and their effect is also due, for example, to male fertility control.
  • Adenylate cyclases are the effector molecules for one of the most widely used signal transduction pathways. They synthesize the second messenger molecule cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) with elimination of pyrophosphate (PP). cAMP mediates numerous cellular responses to a variety of neurotransmitters and hormones.
  • the soluble, sperm-specific adenylate cyclase (sAC, human mRNA sequence (GenBank) NM_018417, human gene ADCY X) is one of ten described adenylate cyclases in the human genome. sAC shows some specific properties that distinguish it from the other adenylate cyclases.
  • sAC is stimulated by the concentration of bicarbonate in the surrounding medium and not by G proteins.
  • sAC has no transmembrane regions in its amino acid sequence, is not inhibitable by forskolin, is much more stimulable by manganese than magnesium, and shows little sequence homology to the other adenylate cyclases ( ⁇ 26% identity of the catalytic domains I and II of the sAC with other adenylate cyclases at the amino acid level).
  • sperm must be prepared for this functionality before they can penetrate the zona pellucida of the egg to subsequently fuse with the oolemma of the egg. This process, sperm capacitation, is quite well studied.
  • a capacitated sperm is characterized by an altered pattern of movement and the ability to undergo, through a suitable stimulus, the process of acrosomal reaction (release of lytic enzymes presumably acting on the passage of zona pellucida through the sperm).
  • Sperm capacitation occurs in vivo and in vitro, among other things, depending on an increased bicarbonate concentration in the medium (PE Visconti & GS Kopf (1998) Biol Reprod 59: 1ff; E de Lamirande et al 1997 Mol Hum Reprod 3 (3): 175ff).sperm capacitation may also be stimulated by the addition of suitable membrane-permeable cAMP analogs, eg, db-cAMP, and an inhibitor that inhibits their degradation (eg, IBMX). The suspected dependence of sperm function on sAC has recently been confirmed by a genetic deletion model, a so-called knock-out mouse (G Esposito et al., 2004 PNAS 101 (9): 2993ff).
  • mice lacking the sAC gene show normal spermatogenesis but are infertile.
  • the sperm have movement defects and are unable to fertilize an egg.
  • the animals showed no other defects or abnormal findings, which speaks against other hypothesized functions of the sAC (JH Zippin et al 2003 FASEB 17: 82ff).
  • the sAC has a unique sequence and little homology to other somatic adenylate cyclase. It is the only Adenyiatzykiase in the mammalian sperm and the activity is essential for sperm motility and capacitation. Specific inhibitors of sAC are therefore an important way to regulate male fertility.
  • Active substance suitable for enteral or parenteral administration Pharmaceutical, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, lactose, starch,
  • the pharmaceutical preparations may be in solid form, for example as tablets,
  • Dragees, suppositories, capsules or in liquid form for example as
  • Solutions, suspensions or emulsions are present. If appropriate, they also contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffer. These pharmaceutical preparations are also the subject of the present invention
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • carrier systems are surface-active adjuvants such as salts of bile acids or animal or vegetable phospholipids, but also -
  • tablets, dragees or capsules with talc and / or hydrocarbon carriers or binders such as lactose, corn or potato starch
  • talc and / or hydrocarbon carriers or binders such as lactose, corn or potato starch
  • the application can also take place in liquid form, for example as juice, which may be accompanied by a sweetener.
  • enteral, parenteral, vaginal and oral applications are also the subject of the present invention.
  • the dosage of the active ingredients may vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease being treated, and similar factors.
  • the daily dose is 0.5-1000 mg, preferably 50-200 mg, which dose may be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the compounds of general formula I according to the invention are, inter alia, excellent inhibitors of soluble adenylate cyclase.
  • Inhibitors of soluble adenylate cyclase lead to a lowering of the cAMP signal.
  • the cAMP level is crucial for the control of the processes that play an important role in cell proliferation, cell differentiation and apoptosis.
  • Diseases such as cancer in which the lowering of the cAMP level is critical, can be modulated by inhibitors of soluble adenylate cyclase. This modulation can have prophylactic and therapeutic effects for the patients suffering from such disease.
  • diseases that are associated with increased cell proliferation such as cancer, are treated by radiotherapy and chemotherapy, for example. These methods are nonspecific and have one -
  • the present invention relates to substances which modulate cAMP production by the inhibition of soluble adenylate cyclase. For example, abnormal cell proliferation can be decreased or inhibited by regulation or inhibition of cAMP production. By using the substances according to the invention, the soluble adenylate cyclase can be inhibited, which results in a reduction in cell proliferation.
  • the present invention relates to medicaments for the treatment of diseases which contain at least one compound according to the general formula I, as well as medicaments with suitable formulation and carrier substances. The diseases are characterized by the fact that they are caused by disorders of the metabolism of the second messenger cAMP.
  • Decreasing the cAMP concentration by inhibiting soluble adenylate cyclase may provide means for modulating sperm capacitance.
  • the present invention is the use of the substances according to the invention for the reduction and / or inhibition of male germ cell fertility, mediated by the reduction or inhibition of the soluble adenylate cyclase activity and thereby resulting sperm capacitation.
  • the isomer mixtures can be separated into the enantiomers or E / Z isomers by customary methods such as, for example, crystallization, chromatography or salt formation.
  • the preparation of the salts is carried out in a customary manner by adding a solution of the compound of formula I with the equivalent amount or an excess of a base or acid, optionally in solution, and separating the precipitate or working up the solution in a conventional manner.
  • Example 1 5- (4-tert-butylphenylsulfamoyl) -3-phenyl-1H-indole-2-carboxylic acid (tetrahydro-pyran-4-yl) -amide
  • Example 1 In analogy to Example 1 is obtained from 70 mg of the acid from Example 1d) and 12.4 ⁇ l 2-amino-1-propanol 29.2mg of the title compound.
  • the soluble, sperm-specific adenylate cyclase catalyses the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and pyrophosphate.
  • Free cAMP generated in this way is subsequently used in a competitive detection method in which the binding of an europium cryptate (Eu [K]) -labeled anti-cAMP antibody (anti-CAMP-Eu [K] -AK) to a cAMP molecule labeled, modified allophycocyanin-1 molecule (cAMP XL665) is prevented.
  • FRET fluorescence resonance energy transfer
  • the enzyme reaction is started by adding 5 .mu.l of the ATP substrate solution (200 .mu.M ATP in H 2 O) and after incubation (25 min. At room temperature) by the addition of 5 .mu.l of the stop solution (200 .mu.M EDTA in PBS) ended. Finally, the entire reaction is adjusted to a total volume of 91.5 ⁇ l by the addition of 70 ⁇ l PBS.
  • detection solution 1 8 ⁇ l are placed in a well of the 384-well measuring plate (measuring plate: polystyrene; 384, SV - black; detection solution 1: 50 ⁇ l cAMP-XL665; 950 ⁇ l reconstitution buffer; 2200 ⁇ l PBS; cAMP-XL. 665: Preparation by adding 5 ml of H 2 O to the lyophilisate _ _
  • Human sperm are purified from the ejaculate by a two-layered gradient system based on colloidal silica particles (trade name: Percoll or ISolate).
  • the sperm pellets resuspended in about 200 ⁇ l each are transferred to a 15 ml plastic tube containing 12 ml mHTF medium (4 mM NaHCO 3 , 0.01% BSA, 37 ° C.) and the sperm are seeded at 1000 ⁇ g for 20 Min sedimented.
  • the medium is aspirated until just above the pellet and adjusted to 1000 ⁇ l with mHTF medium medium (4 mM NaHCO 3 , 0.01% BSA, 37 ° C.).
  • the number of sperm cells is determined in a Neubauer counting chamber and for the following capacitation optionally with mHTF medium (4 mM NaHCO3; 37 0 C; 0.01% BSA) is set to 4x106 ul sperm / 150th 2.2. capacitation
  • sperm must be preincubated with the test substances. This preincubation (15 min in the oven at 37 0 C) is necessary to allow the penetration of the test substances in the sperm before the beginning of capacitation, ie to achieve a presaturation of the binding sites in the sperm, especially for substances that pass poorly through the membrane , It is also necessary because the increase in the BSA concentration in the capacitance due to the high lipid binding of the BSA could lead to a decrease in the effective test substance concentration.
  • test substances are dissolved in DMSO and diluted with mHTF medium (4 mM NaHCO3; 0.01% BSA; 37 0 C) diluted so that the final capacitation of 400 .mu.l the DMSO concentration 0.5% by weight.
  • mHTF medium 4 mM NaHCO3; 0.01% BSA; 37 0 C
  • Per 150 .mu.l of the temperature-controlled above test substance solution are pipetted to in each case 150 .mu.l sperm suspension and preincubated for 15 min at 37.degree.
  • Sperm capacitance is started by adding 100 ⁇ l of mHTF medium (88 mM NaHCO 3 , 4% BSA, 37 ° C).
  • the sperm concentration is 10x106 / ml
  • the bicarbonate concentration is 4 mM
  • the BSA concentration is 1%.
  • Capacitance is carried out at 37 ° C for 3 hours in a warming cabinet.
  • the batches (400 ⁇ l each) are transferred completely into each of a 15 ml sample tube with 1.5 ml mHTF (4 mM NaHCO 3 , 37 ° C.), centrifuged at 1000 ⁇ g for 5 minutes and the supernatant is removed. This step removes both the high amount of protein and the test substances.
  • sperm acrosomal reaction is triggered by the binding of sperm to the zona pellucida (ZP).
  • ZP zona pellucida
  • enzymes are released from the acrosome that enable the sperm to penetrate through the ZP to the oocyte.
  • OAM outer acrosomal membrane
  • the sperm head is limited in the end only by the inner akrosomaie membrane (IAM). Only at the iAM is the CD46 antigen detectable.
  • the acrosome reaction can be induced.
  • the FITC-labeled anti-CD46 antibody Pieringen
  • the acrosome-reacted sperm can be differentiated from the acrosome-intact sperm, in which the IAM is not exposed, in the flow cytometer.
  • EhD Ethidium Homodimer
  • the solutions can not be prepared prior to the start of the experiment, but must be prepared during the work-up of the capacitation approaches.
  • the sperm pellets are resuspended in the residual supernatant and diluted in the water bath (37 ° C) with 450 ⁇ l mHTF (4 mM NaHCO 3 , 0.01% BSA, 37 ° C). 100 ⁇ l aliquots of the sperm suspensions are pipetted into prepared sample FACS flow tubes (in a water bath). To the sperm 150 ⁇ l of a solution with ionophore and F ITC-labeled anti-CD46 antibody are pipetted. The final concentration of 80OnM ionophore and a 1: 125 dilution of the anti-CD46 antibody in mHTF (4 mM NaHCO3; 0.01% BSA; 37 ° C).
  • the sperm are incubated for 30 minutes protected from light in a water bath at 37 ° C. Incubation is stopped by adding 3.5 ml of PBS [0.1% BSA] / batch, followed by centrifugation for 5 min at 700 xg (room temperature) and subsequent aspiration of the supernatants. After - -
  • the sperm pellets are each treated with 500 ⁇ l of freshly prepared EhD solution (150 mM EhD in PBS [w / o BSA], 37 ° C.). The samples can then be measured on the Flow Cytometer (BD Facs Calibur). The measurement takes place at an excitation wavelength of the laser of 488nm, it is recorded 10,000 sperm per measurement. Acrosome-reacted sperm are measured via CD46-FITC in filter FL-1 at 530nm. Dead sperm are measured by EhD DNA staining in filter FL-2 at 634nm. The measuring channels are previously compensated accordingly.
  • the sperm are considered to be very uniform cell population in a FSC-H
  • IAR [%] the percentage induced acrosomalous sperm
  • mHTF modif. Human tubularly fluid (Fa. Irvine Scientific), Dulbecco's Phosphate Buffered Saline (Fa. Gibco) (with Ca 2+, Mg 2+, 1 g / L D-glucose, 36 mg / L Na-Pyruvate, w / o phenol red, w / o NaHCO 3 ); Bovine serum albumin, fraction V (from Fluka); Dimethyl sulfoxide (DMSO), anhydrous (Merck); Sodium bicarbonate 7.5% sol.
  • DMSO Dimethyl sulfoxide
  • Merck Sodium bicarbonate 7.5% sol.
  • the compounds according to the invention have an approximately 10-fold higher activity in terms of the inhibition of the soluble adenylate cyclase expressed by the IC 50 value than the already known catechol estrogens (OH estradiols).
  • the catechol estrogens are toxic, therefore, the compounds of the invention are far superior to the known compounds.
  • the compounds of the invention are also about 10-fold more potent than the compounds presented by Zippin.

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Abstract

L'invention concerne les composés représentés par la formule (I), leur fabrication et leur utilisation en tant que médicament.
EP07723652A 2006-03-23 2007-03-22 Inhibiteurs de l'adénylate-cyclase soluble Withdrawn EP2001843A2 (fr)

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EP2036906A1 (fr) * 2007-09-05 2009-03-18 Bayer Schering Pharma Aktiengesellschaft Azaindoles en tant qu'inhibiteurs d'adénylatcyclase soluble
CN108096244B (zh) * 2018-01-25 2020-11-24 昆明医科大学 1-氢-2-吲哚酮-3-苄基/取代苄基-3-甲酸酯类化合物的用途

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US6544768B1 (en) * 1999-05-11 2003-04-08 Cornell Research Foundation, Inc. Mammalian soluble adenylyl cyclase
AU4018101A (en) * 1999-09-21 2001-04-24 Board Of Trustees Of The Leland Stanford Junior University Polynucleotides encoding human soluble adenylyl cyclase, polypeptides encoded thereby, and methods of use thereof
US20020064849A1 (en) * 2000-09-05 2002-05-30 Herr John C. Human soluble testicular adenylyl cyclase
US9649295B2 (en) * 2004-01-21 2017-05-16 Cornell Research Foundation, Inc. Chemical inhibitors of soluble adenylyl cyclase (sAC)
DE102004047272A1 (de) * 2004-09-24 2006-04-06 Schering Ag Inhibitoren der löslichen Adenylatzyklase
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AR060074A1 (es) 2008-05-21
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DOP2007000060A (es) 2007-10-15
CN101448787A (zh) 2009-06-03
KR20090008261A (ko) 2009-01-21
DE102006014319B4 (de) 2009-01-08
TW200815348A (en) 2008-04-01
UY30237A1 (es) 2007-10-31
JP2009530339A (ja) 2009-08-27
US20070259872A1 (en) 2007-11-08
WO2007107384A3 (fr) 2007-11-15
DE102006014319A1 (de) 2007-09-27
PE20080173A1 (es) 2008-04-30

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