WO2007107384A2 - Inhibitoren der löslichen adenylatzyklase - Google Patents
Inhibitoren der löslichen adenylatzyklase Download PDFInfo
- Publication number
- WO2007107384A2 WO2007107384A2 PCT/EP2007/002706 EP2007002706W WO2007107384A2 WO 2007107384 A2 WO2007107384 A2 WO 2007107384A2 EP 2007002706 W EP2007002706 W EP 2007002706W WO 2007107384 A2 WO2007107384 A2 WO 2007107384A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- substituted
- acyi
- identically
- differently
- Prior art date
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- 108060000200 adenylate cyclase Proteins 0.000 title claims description 24
- 102000030621 adenylate cyclase Human genes 0.000 title claims description 24
- 239000003112 inhibitor Substances 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 41
- -1 cyano, hydroxy Chemical group 0.000 claims description 32
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 13
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- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
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- 230000002101 lytic effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000003794 male germ cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
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- 230000003204 osmotic effect Effects 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003585 oxepinyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000005019 pattern of movement Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940127198 soluble adenylyl cyclase inhibitor Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical group C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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
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Claims
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EP07723652A EP2001843A2 (de) | 2006-03-23 | 2007-03-22 | Inhibitoren der löslichen adenylatzyklase |
CA002646594A CA2646594A1 (en) | 2006-03-23 | 2007-03-22 | Soluble adenylate cyclase inhibitors |
JP2009500786A JP2009530339A (ja) | 2006-03-23 | 2007-03-22 | 可溶性アデニル酸シクラーゼインヒビター |
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WO2005070419A1 (en) * | 2004-01-21 | 2005-08-04 | Cornell Research Foundation, Inc. | Chemical inhibitors of soluble adenylyl cyclase (sac) |
WO2006032541A1 (de) * | 2004-09-24 | 2006-03-30 | Bayer Schering Pharma Aktiengesellschaft | Indol derivative als inhibitoren der löslichen adenylatzyklase |
WO2006131398A2 (en) * | 2005-06-08 | 2006-12-14 | Bayer Schering Pharma Aktiengesellschaft | Inhibitors of soluble adenylate cyclase |
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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 |
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- 2007-03-22 WO PCT/EP2007/002706 patent/WO2007107384A2/de active Application Filing
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WO2005070419A1 (en) * | 2004-01-21 | 2005-08-04 | Cornell Research Foundation, Inc. | Chemical inhibitors of soluble adenylyl cyclase (sac) |
WO2006032541A1 (de) * | 2004-09-24 | 2006-03-30 | Bayer Schering Pharma Aktiengesellschaft | Indol derivative als inhibitoren der löslichen adenylatzyklase |
WO2006131398A2 (en) * | 2005-06-08 | 2006-12-14 | Bayer Schering Pharma Aktiengesellschaft | Inhibitors of soluble adenylate cyclase |
Non-Patent Citations (1)
Title |
---|
SINCLAIR, M. L. ET AL.: "SPECIFIC EXPRESSION OF SOLUBLE ADENYLYL CYCLASE IN MALE GERM CELLS" MOLECULAR REPRODUCTION AND DEVELOPMENT, LISSS, NEW YORK, NY, US, Bd. 56, Nr. 1, Mai 2000 (2000-05), Seiten 6-11, XP009040771 ISSN: 1040-452X in der Anmeldung erwähnt * |
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WO2009030725A2 (en) * | 2007-09-05 | 2009-03-12 | Bayer Schering Pharma Aktiengesellschaft | Azaindoles as inhibitors of soluble adenylate cyclase |
EP2036906A1 (de) * | 2007-09-05 | 2009-03-18 | Bayer Schering Pharma Aktiengesellschaft | Azaindole als Inhibitoren der löslichen Adenylatzyklase |
WO2009030725A3 (en) * | 2007-09-05 | 2009-04-30 | Bayer Schering Pharma Ag | Azaindoles as inhibitors of soluble adenylate cyclase |
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US20070259872A1 (en) | 2007-11-08 |
UY30237A1 (es) | 2007-10-31 |
CN101448787A (zh) | 2009-06-03 |
WO2007107384A3 (de) | 2007-11-15 |
CA2646594A1 (en) | 2007-09-27 |
DOP2007000060A (es) | 2007-10-15 |
DE102006014319A1 (de) | 2007-09-27 |
AR060074A1 (es) | 2008-05-21 |
PE20080173A1 (es) | 2008-04-30 |
KR20090008261A (ko) | 2009-01-21 |
EP2001843A2 (de) | 2008-12-17 |
DE102006014319B4 (de) | 2009-01-08 |
JP2009530339A (ja) | 2009-08-27 |
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