EP2001847A2 - Inhibiteurs de l'adénylate-cyclase soluble - Google Patents

Inhibiteurs de l'adénylate-cyclase soluble

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Publication number
EP2001847A2
EP2001847A2 EP07723654A EP07723654A EP2001847A2 EP 2001847 A2 EP2001847 A2 EP 2001847A2 EP 07723654 A EP07723654 A EP 07723654A EP 07723654 A EP07723654 A EP 07723654A EP 2001847 A2 EP2001847 A2 EP 2001847A2
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EP
European Patent Office
Prior art keywords
alkyl
acyl
substituted
cyano
aryl
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Withdrawn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
EP07723654A
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German (de)
English (en)
Inventor
Bernd Buchmann
Dirk Kosemund
Bernd Menzenbach
Martin Fritsch
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Bayer Pharma AG
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Bayer Schering Pharma AG
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Publication of EP2001847A2 publication Critical patent/EP2001847A2/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to inhibitors of soluble adenylate cyclase, their preparation and their use for the manufacture 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.
  • WO01 / 85753, issued to the US (US6544768) are the subject of application WO01 / 85753, issued to the US (US6544768).
  • WO01 / 21829 Conti et al.
  • Isolated polynucleotide sequences encoding the human isoform of sAC are claimed isolated sAC polypeptides and test systems that can be used to identify substances that inhibit sAC activity. The ability to use these substances to reversibly reduce the number of motile spermatozoa and their use as male fertility control agents is disclosed.
  • Nucleic acids that code for the sAC also claimed test systems that can be used to identify substances that affect the expression or the
  • Modulate activity of the human sAC For example, such compounds could selectively inhibit sAC activity, resulting in sperm cells losing the ability to fertilize an ovum.
  • Inhibitors of sAC could therefore be used as medicines for non-hormonal
  • Gossypol KL Olgiati, Arch Biochem Biophys 1984, 231 (2): 411ff
  • Gossypol KL Olgiati, Arch Biochem Biophys 1984, 231 (2): 411ff
  • adenosine analogs inhibit only very weakly
  • Inhibitors (IC 50 1 10 ⁇ M) of the recombinant human sAC described by Zippin et al. (JH Zippin et al J Cell Biol 2004, 164 (4): 527ff).
  • R 1 is hydrogen, halogen, CF 3 , C 3 -C 6 -cycloalkyl, which is optionally poly-saturated and optionally polysubstituted, or the group dC 6 alkyl, C 1 -C 6 -An / !, Ci-C 6 acyl, halo-Ci-C 6 -alkyl, d-Ce-alkyl-d-Ce-alkyl, alkyl-dC dC 6 6 acyl, d-C6 -acyl-C 1 -C 6 - acyl, C r C 6 alkyl-dC 6 aryl, C 6 aryl-Ci-C 6 alkyl, or CF 3, in the Ci-C 6 alkyl, dC 6 aryl, C 1 -C 6 -acyl, Halo-dC 6 alkyl, Ci-6 alkyl dC C 6 alkyl, dC dC 6 alkyl-6 acyl
  • R 2 is halogen, CF 3 , C 3 -C 6 -cycloalkyl, which is optionally poly-saturated and optionally polysubstituted, or the group dC 6 alkyl, C 1 -C 6 -AIyI, C 1 -C 6 acyl, halo -C-C 6 -alkyl, CRCE alkyl CRCE alkyl, CRCE-alkyl-d-Ce-acyl, C 1 -C 6 -acyl-C 1 -C 6 - acyl, d-Ce-alkyl-d- Ce-aryl, C 1 -C 6 -AIyI-C 1 -C 6 -alkyl ky I or CF 3, in the 6 -alkyl, C 1 -C 6 -AIyI, Ci-C 6 acyl, halo-dC 6 alkyl, dC 6 alkyl dC 6 alkyl, d-Ce-al
  • 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 or C 1 -C 6 -acyl, which is optionally substituted or may be substituted more than once, or C 1 -C 6 -alkoxy, hydroxy, cyano, CO 2 - (C 1 -C 6 alkyl), N- (C 1 - C 6 alkyl) 2, CO-NR 4 R 5 or be substituted by CF 3 can, C ⁇ -C ⁇ heteroaryl, which is optionally mono- or polysubstituted, identical or different with halogen, Ci-C 6 alkyl, C 1 -C 6 acyl, C 1 - Ce alkoxy, hydroxy, cyano, CO 2 - (C 1 -C 6 alkyl), N-fCVCe-alkyl ⁇ , CO-NR 4 R 5 or CF 3 may be substituted or C 3 -C 6 cycloalky
  • R 4 is hydrogen, 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 -C 12 aryl which is optionally substituted one or more times, identically or differently with halogen, C- ⁇ -C 6 alkyl, C 1 -C 6 -acyl, C 1 -C 6 - alkoxy, N-Ci -Ce-alkyl-d-Ce-alkyl, CF 3 or cyano substituted, or
  • C 5 -C 12 -heteroaryl which is optionally substituted one or more times, identically or differently with halogen, Ci-C 6 alkyl, C 1 -C 6 -acyl, C 1 - C 6 alkoxy, N-alkyl-CRCE C 1 -C 4 -alkyl, CF 3 or cyano, or C 1 -C 6 -alkyl, which may be arbitrarily substituted, ⁇ 0 ⁇
  • R 5 is hydrogen, Ci-C6 alkyl-C3-C 6 cycloalkyl, which is optionally monosubstituted or polysubstituted, identically or differently with Ci-C 6 alkyl, CrC 6 - acyl, Ci-C 6 alkoxy or CF 3 Ci-C is substituted, C 3 -C 6 -cycloalkyl which is optionally substituted singly or multiply, identically or differently with Ci-C 6 alkyl, 6 acyl, Ci-C 6 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-C 6 alkyl, C 1 -C 6 -acyl, C 1 -C 6 - alkoxy, Nd-Ce-alkyl d-Ce-alkyl, CF 3 or cyano substituted, or
  • R 4 and R 5 together form a 5-8 membered ring which may contain other heteroatoms
  • R 6 is the group dC 6 alkyl, C 1 -C 6 -acyl, dC 6 alkyl-cyclo-C 3 -C 6 alkyl, dC 6 alkyl-C 6 aryl-d 2 in which dC 6 - alkyl, C 1 -C 6 -acyl, dC 6 alkyl cyclo-C 3 -C 6 alkyl, d-Ce-alkyl-Ce-C ⁇ -aryl optionally substituted one or more times, identically or differently, by hydroxy, methoxy , Ethoxy, iso-propoxy, chlorine, bromine, fluorine, cyano, methylsulfonyl or amino-sulfonyl may be substituted,
  • 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.
  • the ring systems which may optionally contain one or more possible double bonds in the ring are, for example, cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl to understand the attachment to both the double bond and to the single bonds can be done.
  • Halogen is in each case fluorine, chlorine, bromine or iodine.
  • the aryl radical comprises in each case 6 to 12 carbon atoms and may be benzo-fused, for example. 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.
  • the heteroaryl radical may each be benzo-fused.
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • the salts are the physiologically acceptable ones
  • Salts of organic and inorganic bases such as, for example, the readily soluble alkali and alkaline earth salts and N-methyl-glucamine, dimethyl-glucamine,
  • Serinol tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.
  • 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 -
  • Ce-alkyl Ci-C 6 aryl, C 6 acyl, halo-dC 6 alkyl, dC 6 alkyl-d- Ce-alkyl, C 1 -C 6 -alkyl-C r C 6 - Acyl, C 1 -C 6 -acyl-C 1 -C 6 -acyl, C 1 -C 6 -alkyl-C 1 -C 6 -aryl, C 1 -C 6 -aryl-C 1 -C 6 -alkyl or CF 3 , in the Ci-C 6- alkyl, C 1 -
  • R 2 is halogen, CF 3 , C 3 -C 6 -cycloalkyl, or the group dC 6 -alkyl, C 1 -
  • R 3 is C 6 -C 2 -Aryi, soft optionally mono- or polysubstituted, identically or differently with halogen, Ci-C 6 alkyl, C 1 -C 3 -acyl, C 1 -C 3
  • C 5 -C 12 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 ) 2 , CO 2 - (C 1 -C 3 -alkyl), CO-NR 4 R 5 or may be substituted by CF 3 , C 3 -C 6 -cycloalkyl, which may optionally be substituted by or multiply, identically or differently with chlorine and / or fluorine, CF 3 , cyano, C 1 -C 8 -alkyl, C 1 -C 3 -acyl, hydroxy, N- (CH 3 J 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, C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identically or differently, with CrC 3 alkyl, C 1 -C 3 -acyl, C 1-3 -alkoxy or CF 3 C 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 - alkoxy, N-alkyl CRCS d-Cralkyl, CF 3 or cyano, or
  • C 5 -C 12 -heteroaryl which is optionally substituted one or more times, identically or differently, by halogen, by C 3 alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy, Nd-Cs-alkyl -d-Cs-alkyl, CF 3 or cyano, or dC 6 -alkyl, which may be arbitrarily substituted,
  • R 5 is hydrogen, 6 -alkyl-C 3 -Ce-cycloalkyl, which is optionally monosubstituted or polysubstituted, identically or differently with Ci-Ce 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, equaI or differently, with C 1 -C 3 -alkyl, C 3 acyl, C 1 -C 3 -alkoxy or CF 3 being substituted,
  • C6 -Ci2-aryl which is optionally substituted one or more times, identically or differently with halogen, Ci-C ß -alkyl, C 3 acyl, C 1 -C 3 -
  • C 5 -C 12 -Heteroaryl which is optionally mono- or polysubstituted, identical or different, with halogen, with C 1 -C 3 -alkyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, NC 1 -C 3 -alkyl-C 1 -C 3 -alkyl, CF 3 or cyano, or
  • R 4 and R 5 together form a 5-8 membered ring which may contain other heteroatoms
  • R 6 is the group C r C 6 -alkyl, C 1 -C 6 -alkyl-cyclo-C 1 -C 12 -alkyl, C 1 -C 6 -alkyl-
  • C 6 -C 12 -aryl in which C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-cyclo-C 1 -C 12 -alkyl, C 1 -C 6 -alkyl-C 6 -C 12 -aryl optionally mono- or trisubstituted , identical or different, by hydroxy, methoxy, ethoxy, isopropoxy, chlorine,
  • Bromine, fluorine, cyano, methylsulfonyl or amino-sulfonyl may be 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, Ci-C 6 alkyl, Ci-C3 acyl, Ci-C 3 -
  • Alkoxy, cyano, hydroxy, N- (CH 3 ) 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 monosubstituted or polysubstituted, identically or differently with chlorine and / or fluorine, with Ci-C ⁇ -alkyl, -C 3 -acyl, Ci-C 3 alkoxy, cyano, hydroxy, N- (CH 3 ) 2 , CO 2 - (C 1 -C 3 -
  • CO-NR 4 R 5 or may be substituted by CF 3 , C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identical or different, with chlorine and / or fluorine, CF 3 , cyano, Ci- 3 alkyl, C 1 -C 3 -acyl, hydroxy, N- (CH 3) 2, CO 2 - (C 3 alkyl), CO- NR may be substituted 4 R 5 or C 3 alkoxy .
  • R 4 is hydrogen
  • R 5 is hydrogen, Ci-C 6 alkyl-C 3 -C 6 cycloalkyl, which is optionally monosubstituted or polysubstituted, identically or differently with Ci-C 6 alkyl, Ci-C 6 -
  • C 5 -C 2 -heteroaryl which is optionally mono- or polysubstituted, identically or differently, with halogen, C 1 -C 3 -alkyl, C 1 -C 3 -acyl, C 3 -AlkOXy 1 NC 1 -C 3 -AIKyI-CrC 3 -Alkyl, CF 3 or cyano, substituted, or
  • R 6 is the group dC 4 alkyl, CH 2 -cyclo-C 3 -C 6 alkyl, CH 2 -C 6 -C 2 aryl, in which Ci-C 4 alkyl, CH 2 -cyclo-C 3 - C 6 alkyl, CH 2 -C 6 -C 2 -aryl optionally mono- or trisubstituted, identically or differently, by hydroxy, methoxy, chlorine, fluorine, cyano or amino-sulfonyl,
  • R 1 is hydrogen
  • R 2 is C 3 -C 6 cycloalkyl, -C 6 alkyl, CF 3, cyano, bromine, or the group -
  • R 3 is C 6 -C 2 aryl, which is optionally mono- or disubstituted, identically or differently with halogen, C 3 alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N- (CH 3 J 2, CO 2 - ( C 1 -C 3 -alkyl), CO-NHR 5 or CF 3 may be substituted, C 5 -C 2 -heteroaryl which is optionally mono- or disubstituted, identical or different, with chlorine and / or fluorine, with C 1 -C 3 - alkyl,
  • R 4 is hydrogen
  • R 5 is hydrogen
  • Ci-C 6 alkyl-C 3 -C 6 -cycloalkyl which is optionally mono- or polysubstituted, identically or differently, with C 1 -C 6 -alkyl, C 6 - acyl, Ci-C 6 - Alkoxy or CF 3 is substituted
  • C 3 -C 6 -cycloalkyl which is optionally monosubstituted 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 substituted one or more times, identically or differently with halogen, Ci-C3 alkyl, Ci-C3-acyl, Ci-C 3 - alkoxy, N-Ci-C 3 alkyl -CrC 3 alkyl, CF 3 or cyano substituted, or
  • C 5 -C 2 -heteroaryl which is optionally mono- or polysubstituted, identically or differently, with halogen, C 1 -C 3 -alkyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy, N-C 1 -C 5 -alkyl-C 1 -C 4 -alkyl, Cs-alkyl, CF 3 or cyano, or Ci-C 6 -alkyl, which may be arbitrarily substituted,
  • R 6 is the group Ci-C 4 alkyl, CH 2 -cyclo-C 3 -C 6 alkyl, CH 2 -C 6 -C 12 aryl, in the -C 4 alkyl, CH 2 -cyclo-C 3 - C 6 alkyl, CH 2 -C 6 -C 2 -aryl optionally mono- or trisubstituted, identically or differently, by hydroxy, methoxy, chlorine, fluorine, cyano or amino-sulfonyl,
  • R 1 is hydrogen
  • R 2 tertiary butyl, iso-propyl, iso-butyl, sec. Butyl, cyano, bromine, or the
  • Group -Q-CF 3 , -SO 2 represents -CH 3 and is in the para position, - -
  • R fc is methyl, ethyl, propyl, 2-methoxy-ethyl, -CH 2 -CF 3 , - (CH 2 ) 2 -CF 3 and benzyl,
  • R 1 is hydrogen
  • R tertiary butyl, iso-propyl, iso-butyl, sec. Butyl, cyano, bromine, or the group -O-CF 3 , -SO 2 -CH 3 and is in the para position,
  • R a is hydrogen or the group, - (CH 2 ) -CHCH 3 -OH, - (CHz) 2 -O-CH 3 , -CHCH 3 -CH 2 -OH,
  • R b is methyl, ethyl, propyl, 2-methoxy-ethyl, -CH 2 -CF 3 , - (CH 2 ) 2 -CF 3 and benzyl,
  • 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 , R 3 and R 6 have the meanings given above and R 7 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 IM
  • the reaction can first be carried out by activating the acid function, in this case, for example, first the carboxylic acid of 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 alkali salt 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 3O 0 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 is carried out, for example, with HATU in an inert solvent such as for example, DMF in the presence of the corresponding amine of general formula III and a tertiary amine such as ethyldiisopropylamine at temperatures between -50 and +60 0 C 1, preferably at 0 0 C to 30 0 C.
  • R 6 is C 1 -C 6 -alkyl
  • 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 reacting the nitro group in the known indole esters IV in a manner known per se
  • R 7 is a C 1 -C 6 -alkyl radical, preferably a methyl or ethyl radical, in a hydrogen atmosphere or a hydrogen source such as ammonium formate in the presence of a Pd catalyst is first reduced to the amino function and then this amine with a halide of the general formula V
  • Hal is a halogen, preferably fluoride, chloride or bromide, in the presence of a base such as pyridine, diisopropylethylamine, triethylamine or potassium carbonate to the compounds of general formula VI - -
  • esters of general formula VI are then halogenated in the 3-position, for example by means of iodine, NBI, NBS or CuBr 2 and thus the compounds of general formula VII
  • R 1 , R 2 and R 7 have the meanings given above.
  • esters in the presence of a base such as diisopropylethylamine, potassium carbonate or cesium carbonate in acetone or tetrahydrofuran with the halide of the general formula VIII
  • esters of the general formula IX are then in the 3-position in a Pd-cataiysed reaction with boronic acid derivatives of the general formula X.
  • esters of the general formula VII first in the 3-position in a Pd-catalyzed reaction with the boronic acid derivatives of the general formula X.
  • R 1 , R 2 , R 3 and R 7 have the meanings given above and then the N-alkylation in the presence of a base such as for example, diisopropylethylamine, potassium carbonate or cesium carbonate in acetone or tetrahydrofuran and the halide of the general formula VIII
  • R6 (VIII), wherein R6 has the abovementioned meaning, and Hal is a halogen, preferably iodide, chloride or bromide, optionally after cleavage of required protecting groups in R 6 , optionally followed by saponification, for example with sodium hydroxide solution to the compounds of the general formula Il perform.
  • Hal is a halogen, preferably iodide, chloride or bromide, optionally after cleavage of required protecting groups in R 6 , optionally followed by saponification, for example with sodium hydroxide solution to the compounds of the general formula Il perform.
  • 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, it 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 - -
  • Pellucida penetrate the egg, then to merge with the oolemma of the egg, be prepared for this functionality.
  • Sperm capacitation occurs in vivo and in vitro, among others. 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, e.g. db-cAMP, and an inhibitor that inhibits their degradation (e.g., IBMX).
  • suitable membrane-permeable cAMP analogs e.g. db-cAMP
  • an inhibitor that inhibits their degradation e.g., IBMX
  • 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 cyclases. It is the only adenylate cyclase 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.
  • a pharmaceutical preparation which, in addition to the active substance for enteral or parenteral administration, is suitable for pharmaceutical, organic or inorganic inert carrier materials, such as For example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. contains.
  • 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. If appropriate, they also contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffer.
  • adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers; Salts for changing the osmotic pressure or buffer.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof and liposomes or components thereof can also be used as carrier systems.
  • 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 the like - -
  • 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.
  • 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, resulting in a decrease 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-butylphenylsulfonyl) -methyl-amino] -3-phenyl-1H-indole-2-carboxylic acid (tetrahydro-pyran-4-yl) -amide
  • Example 2 5 - [(4-tert-butylphenylsulfonyl) -methyl-amino] -3-phenyl-1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl) -amide
  • 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. Then 8 ⁇ l of the detection solution 1 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 of reconstitution buffer; 2200 ⁇ l PBS; cAMP-XL665: Preparation by adding 5 ml H 2 O to the lyophilized product according to Cis bio Kit: # 62AMPPEC; Storage: aliquoted at -80 ° C). Subsequently, 3 ⁇ l of the 91.5 ⁇ l of the corresponding well of the test plate are added.
  • detection solution 2 50 ⁇ l of anti-CAMP-Eu [K] -AK; 950 ⁇ l of the reconstitution buffer; 2200 ⁇ l of PBS; anti-CAMP-Eu [K] -AK: Preparation according to Cis bio Kit # 62AMPPEC; storage: in aliquots at -80 0 C).
  • the HTRF result is measured on either the Packard Discovery or the RubiStar HTRF meter (delay: 50 ⁇ s, integration time: 400 ⁇ s).
  • Example 2 Isolation of human sperm from ejaculates and capacitation 2.1. Isolation of sperm
  • Human sperm are purified from the ejaculate by a two-layered gradient system based on colloidal silica particles (trade name: Percoll or ISolate). For every ejaculate, 2.5 ml preheated bottom layer ("90% ISolate lower layer", Irvine) are placed in a 15 ml centrifuge tube (conical, plastic) and carefully mixed with 2.5 ml preheated top layer ("50% ISolate upper layer ", Fa. Irvine) and kept in a water bath at 37 ° C for ⁇ 1 h. The gradient is gently overlaid with a maximum of 3 ml of normal (in terms of sperm count, motility and liquefaction) ejaculate.
  • Percoll or ISolate colloidal silica particles
  • the sedimentation of sperm occurs at 1000 xg for 25 min at room temperature. Using a glass capillary, both layers are aspirated until just above the sperm pellets. To wash out the ISolate gradient, the sperm pellets resuspended in approximately 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 medium with mHTF medium (4 mM NaHCO 3 , 0.01% BSA, 37 ° C) to 1000 ⁇ l.
  • mHTF medium 4 mM NaHCO 3 , 0.01% BSA, 37 ° C
  • the number of sperm is determined in a Neubauer counting chamber and adjusted to 4x106 sperm / 150 ⁇ l, optionally with mHTF medium (4 mM NaHCO 3 , 0.01% BSA, 37 ° C) for the following capacitation. 2.2. capacitation
  • the 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 NaHCO 3 , 0.01% BSA, 37 ° C.) so that in the final capacity batch of 400 ⁇ l the DMSO concentration is 0.5%.
  • mHTF medium 4 mM NaHCO 3 , 0.01% BSA, 37 ° 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. With this step, both the high amount of protein and the test substances are removed.
  • the acrosomal reaction (AR) of the sperm is triggered by the binding of the sperm to the zona pellucida (ZP). It will be from the
  • the sperm partially engulfs the plasma membrane with the outer acrosomal membrane (OAM).
  • OAM outer acrosomal membrane
  • the sperm head is limited in the end only by the inner acrosomal membrane (IAM). Only at the IAM is the CD46 antigen detectable.
  • the acrosomal reaction can be induced on capacitated but not on uncapacitated spermatozoa inhibited by test substances.
  • 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 DNA dye 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 in a water bath
  • the sperm are 150 .mu.l of a - -
  • the sperm pellets after aspiration with 500 ul of freshly prepared EhD solution (150 nM in PBS EhD [w / o BSA], 37 0 C) was added.
  • 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 by 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 selected as a very uniform cell population in an FSC-H (forward scatter) vs. SSC-H (sideward scatter) dot blot. Since a two-color fluorescence staining is used, the evaluation is carried out with the aid of quadrant analysis in a FL-1 (EhD, X-axis). FL-2 (FITC-CD46, Y-axis) dot blot with the selected sperm population from the FSC vs SSC dot blot: - -
  • IAR [%] the live sperm from Q3 and Q4 are used and their total number is set equal to 100% and IAR is calculated as follows:
  • 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 - -
  • Fluorescence-Iabeled fucolectins are superior markers for flow cytometric quantitation of the sperm acrosome reaction E. Nieschlag, HM Behre, andrology, Springer Verlag 1996
  • the compounds according to the invention have about 10-fold higher activity than the already known catechol estrogens (OH-estradiols) with respect to the inhibition of the soluble adenylate cyclase expressed by the IC 50 Whel.
  • 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) ainsi que leur fabrication et leur utilisation en tant que médicament.
EP07723654A 2006-03-23 2007-03-22 Inhibiteurs de l'adénylate-cyclase soluble Withdrawn EP2001847A2 (fr)

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