CA2646650A1

CA2646650A1 - Soluble adenylate cyclase inhibitors

Info

Publication number: CA2646650A1
Application number: CA002646650A
Authority: CA
Inventors: Bernd Buchmann; Dirk Kosemund; Bernd Menzenbach; Martin Fritsch
Original assignee: Bayer Schering Pharma Aktiengesellschaft; Bernd Buchmann; Dirk Kosemund; Bernd Menzenbach; Martin Fritsch
Current assignee: Bayer Pharma AG
Priority date: 2006-03-23
Filing date: 2007-03-22
Publication date: 2007-09-27
Also published as: KR20090007351A; DE102006014320B4; DOP2007000059A; WO2007107385A2; PE20080012A1; UY30236A1; WO2007107385A3; EP2001847A2; JP2009531319A; TW200815347A; DE102006014320A1; AR063661A1; CN101448789A

Abstract

The invention relates to compounds of general formula (I), to their production and to their use as a medicament.

Description

SOLUBLE ADENYLATE CYCLASE INHIBITORS

The present invention relates to inhibitors of soluble adenylate cyclase, production thereof and use thereof for the production of a medicinal product for contraception.

A large number of modern methods of contraception are currently available for women, but very few methods are available for male fertility control (condom and sterilization). Development of reliable new means of male fertility control is urgently needed. The infertility brought about by a "male pill" should be reversible and should be just as effective as the existing methods available to women. Infertility should be developed relatively quickly and should persist for as long as possible. Such a method of contraception should have no side-effects, and the preparations may be non-hormonal as well as hormonal. A
possible starting point is regulation of the activity of an enzyme that plays an important role in fertilization of the ovum: soluble adenylate cyclase (sAC).
This enzyme is mainly expressed in the testicular stem cells and is present in mature sperm.

In 1999, the authors Levin and Buck succeeded in purifying and cloning an isoform of sAC from rat testes (Proc. Natl. Acad. Sci. USA 96 (1): 79-84).

The recombinant rat enzyme can be stimulated by bicarbonate. It was demonstrated, using antibodies, that the catalytic domain of the enzyme is localized in testes, sperm, kidneys and the choroid plexus. These disclosures are the subject of application WO01/85753, which was granted in the USA
(US6544768).

WO01/21829 (Conti et al.) claims isolated polynucleotide sequences that code for the human isoform of sAC, isolated sAC polypeptides and test systems, using which it is possible to identify substances that inhibit the activity of sAC.
The possibility of using these substances to achieve a reversible reduction in the motile sperm count, and their use as a means of controlling male fertility, is disclosed.

John Herr's group demonstrated the isolation and characterization of the human isoform of sAC from sperm. WO 02/20745 claims, in addition to nucleic acids that code for sAC, also test systems for identifying substances that modulate the expression or the activity of human sAC. Such compounds might, for example, selectively inhibit the activity of sAC, as a consequence of which the sperm would lose the capacity to fertilize an ovum. These sAC inhibitors might therefore serve as medicinal products for non-hormonal contraception.
However, the sAC inhibitors that are already known display specific problems:
catechol estrogens (T. Braun, Proc Soc Exp Biol Med 1990, 194(1): 58ff) and gossypol (KL Olgiati, Arch Biochem Biophys 1984, 231(2): 411ff) are inherently toxic, whereas adenosine analogs only have a very weak inhibitory action (MA
Brown and ER Casillas, J Androl 1984, 5:361ff). The inhibitors of recombinant human sAC described by Zippin et al. are somewhat more potent (IC50 < 10 pM) (JH Zippin et al., J Cell Biol 2004, 164(4): 527ff).

In order to provide a means for male fertility control, there is an increasing demand for substances that lead to infertility quickly, reversibly and successfully.

This problem is solved by the provision of the compounds of general Formula I, SiN ~ O
I ~

O/\\O /
H j -R5 R4 (I) where the following notation is used:
R' hydrogen, halogen, CF3, C3-C6-cycloaikyl, which is optionally multiply saturated and optionally multiply substituted, or the group Cl-C6-alkyl, Cl-C6-aryl, CrC6-acyl, halo-Cl-C6-alkyl, Cl-C6-aIkyl-Cj-C6-aIkyl, C,-C6-aIkyl-C,-C6-acyl, C,-C6-acyl-C,-C6-acyl, C1-C6-alkyl-Cj-C6-aryl, C,-C6-aryl-Cj-C6-alkyl or CF3, in which C,-C6-alkyl, C,-C6-aryl, C,-C6-acyl, halo-C,-C6-alkyl, C,-C6-alkyl-C,-C6-alkyl, C,-C6-alkyl-C,-C6-acyl, C,-C6-acyl-C,-C6-acyl, C,-C6-alkyl-C,-C6-aryl or C1-C6-aryl-C,-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-Cl-C6-alkyl, sulfonamide, or cyano, R 2 halogen, CF3, C3-C6-cycloalkyl, which is optionally multiply saturated and optionally multiply substituted, or the group Cl-C6-alkyl, Cl-C6-aryl, C,-C6-acyl, halo-C,-C6-alkyl, Cl-C6-alkyl-Cl-C6-alkyl, C,-C6-alkyl-Cj-C6-acyl, CI-C6-acyl-C,-C6-acyl, C,-C6-alkyl-C,-C6-aryl, Cl-C6-aryl-C1-C6-alkyl or CF3, in which Cl-C6-alkyl, Cl-C6-aryl, C,-C6-acyl, halo-Cl-C6-alkyl, C,-C6-alkyl-Cl-C6-alkyl, CI-C6-alkyl-CI-C6-acyl, CI-C6-acyl-Cj-C6-acyl, C,-C6-alkyl-CI-C6-aryl or C1-C6-aryl-Cj-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-Cl-C6-alkyl, sulfonamide, or cyano, R3 C6-C12-aryl, which can optionally be substituted singly or multiply, identically or differently with halogen, Cl-C6-alkyl or CI-C6-acyl, which can optionally be singly or multiply substituted, or can be substituted with C,-C6-alkoxy, hydroxy, cyano, C02-(Cl-C6-alkyl), N-(Cl-C6-alkyl)2, CO-NR4R5 or with CF3, C5-C12-heteroaryl, which can optionally be substituted singly or multiply, identically or differently with halogen, C,-C6-alkyl, C,-C6-acyl, C,-Cs-alkoxy, hydroxy, cyano, C02-(C,-C6-alkyl), N-(Cl-C6-alkyl)2, CO-NR4R5 or with CF3 or C3-C6-cycloalkyl, which can optionally be substituted singly or multiply, identically or differently with halogen, CF3, hydroxy, cyano, C02-P-C6-alkyl), C,-C6-alkyl, C,-C6-acyl, N-(Cl-C6-alkyl)2, CO-NR4R5 or C,-C6-alkoxy, R4 hydrogen, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with Cl-Cs-alkyl, Cl-C6-acyl, Cl-C6-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, with C,-C6-alkyl, CI-C6-acyl, Cl-C6-alkoxy, N-Cj-C6-alkyl-Cj-C6-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C6-alkyl, C,-C6-acyl, C,-C6-alkoxy, N-Cl-C6-alkyl-C,-C6-alkyl, CF3 or cyano, or C,-C6-alkyl, which can be substituted arbitrarily, R5 hydrogen, C,-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, Cl-C6-acyl, C,-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C,-C6-alkyl, C,-C6-acyl, Cl-C6-alkoxy or CF3, Cs-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C6-alkyl, Cl-C6-acyl, C,-C6-alkoxy, N-C,-C6-alkyl-C,-C6-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, C,-C6-alkyl, Cl-C6-acyl, C,-C6-alkoxy, N-C,-C6-alkyl-C,-C6-aIkyl, CF3 or cyano, or Cl-C6-alkyl, which can be substituted arbitrarily, and R4 and R5 together form a 5-8-membered ring, which can contain further heteroatoms, and R6 the group C,-C6-alkyl, C,-C6-acyl, C,-C6-alkylcyclo-C3-C6-alkyl, C,-C6-alkyl-C6-C,2-aryl, in which Cl-C6-alkyl, Cl-C6-acyl, C,-C6-alkylcyclo-C3-C6-alkyl, Cj-C6-aIkyI-C6-C12-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, ethoxy, iso-propoxy, chlorine, bromine, fluorine, cyano, methylsulfonyl or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts, which overcome the known drawbacks and display improved properties, i.e. display good efficacy, good solubility and stability.

The compounds according to the invention inhibit soluble adenylate cyclase and so prevent capacitation of the sperm and thus provide male fertility control.
Alkyl means in each case a linear or branched alkyl residue, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl and hexyl.

Alkoxy means in each case a linear or branched alkoxy residue, such as methoxy-, ethoxy-, n-propoxy-, iso-propoxy-, n-butoxy-, sec-butoxy-, iso-butoxy-, tert. butyloxy-, pentoxy-, iso-pentoxy- and hexoxy-.

Acyl means in each case a linear or branched residue, such as formyl, acetyl, propionyl, butyroyl, iso-butyroyl, valeroyl and benzoyl.

Cycloalkyl means monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The cycloalkyl residues can contain one or more heteroatoms, such as oxygen, sulfur and/or nitrogen, instead of the carbon atoms. Such heterocycloalkyls with 3 to 6 ring atoms are preferred. The ring systems, in which optionally one or more possible double bonds can be contained in the ring, mean for example cycloalkenyls such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyt, cycloheptenyl, where the coupling can take place both on the double bond and on the single bonds.

Halogen means in each case fluorine, chlorine, bromine or iodine.

In each case the aryl residue comprises 6-12 carbon atoms and can for example be benzocondensed. The following may be mentioned as examples:
phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, florenyl, anthracenyl etc.

In each case the heteroaryl residue comprises 5-16 ring atoms and can contain one or more, identical or different heteroatoms, such as oxygen, sulfur or nitrogen in the ring instead of carbon, and can be mono-, bi- or tricyclic and can additionally be benzocondensed in each case.

The following may be mentioned as exampies:
thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyi, isoxazolyi, isothiazolyl, 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, e.g. quinolyl, isoquinolyl, etc; or azozinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.
The heteroaryl residue can be benzocondensed in each case. For example, the following may be mentioned as 5-ring heteroaromatics: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof and as 6-ring-heteroaromatics pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives.

Heteroatoms is to be taken to mean oxygen, nitrogen or sulfur atoms.

If an acid function is present, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as the readily soluble alkali and alkaline-earth salts and N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethylaminomethane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.

If a basic function is present, the physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid etc.

Compounds of general Formula I in which the symbols have the following meanings are especially preferred, R' hydrogen, halogen, CF3, C3-C6-cycloalkyl, or the group Cl-C6-alkyl, C,-C6-aryl, C,-C6-acyl, halo-Cl-C6-alkyl, Cl-C6-alkyl-C,-C6-alkyl, C,-C6-alkyl-C,-C6-acyl, C,-C6-acyl-C,-C6-acyi, C,-C6-alkyl-C,-C6-aryl, C,-C6-aryI-C,-C6-aIkyl or CF3, in which Cl-C6-alkyl, CI-C6-aryl, C,-C6-acyl, halo-C,-C6-alkyl, C,-C6-aIkyl-Cj-C6-aIkyl, Cl-C6-alkyl-Cti-C6-acyl, C,-C6-acyl-C,-C6-acyl, C,-C6-aIkyl-C,-C6-aryI or C,-C6-aryl-Cl-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-C,-C6-alkyl, sulfonamide, or cyano, R2 halogen, CF3, C3-C6-cycloalkyl, or the group C,-C6-alkyl, C1-C6-aryl, Cl-C6-acyl, halo-Cl-C6-alkyl, C,-Cs-alkyl-C,-C6-alkyl, Cl-C6-alkyl-C,-C6-acyl, Cl-C6-acyl-Cl-C6-acyl, CI-C6-alkyl-Cl-C6-aryl, C,-C6-aryl-C,-C6-alkyl or CF3, in which C,-C6-alkyl, C,-C6-aryl, C1-C6-acyl, halo-C,-C6-alkyl, C1-C6-aIkyl-Cj-C6-alkyl, C,-C6-aIkyl-Cj-C6-acyl, C1-C6-acyl-C,-C6-acyl, Cj-C6-alkyl-Cj-C6-aryl or C1-C6-aryI-C,-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-Cl-C6-alkyl, sulfonamide, or cyano, R3 C6-C12-aryl, which can optionally be substituted singly or multiply, identically or differently with halogen, Cl-C6-alkyl, Cl-C3-acyl, C,-C3-alkoxy, cyano, hydroxy, N-(CH3)2, C02-(Cl-C3-alkyl), CO-NR4R5 or CF3, C5-C12-heteroaryl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, with CI-C6-alkyl, Cl-C3-acyl, Cl-C3-alkoxy, cyano, hydroxy, N-(CH3)2, C02-(Cl-C3-alkyl), CO-NR4R5 or with CF3, C3-C6-cycloalkyl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, CF3, cyano, Cl-C3-alkyl, CI-C3-acyl, hydroxy, N-(CH3)2, C02-(CI-C3-alkyl), CO-NR4R5 or Cl-C3-alkoxy, R4 hydrogen, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with Cl-C3-alkyl, CI-C3-acyl, Cl-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C3-alkyl, Cl-C3-acyl, C,-C3-alkoxy, N-C,-C3-alkyl-C,-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C3-alkyl, Cl-C3-acyl, Cl-C3-alkoxy, N-Cj-C3-aIkyI-C1-C3-alkyl, CF3 or cyano, or Cl-C6-alkyl, which can be substituted arbitrarily, R5 hydrogen, CI-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C,-C6-alkyl, C,-C6-acyl, C,-Cs-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C,-C3-alkyl, CI-C3-acyl, CI-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C3-alkyl, C,-C3-acyl, Cl-C3-alkoxy, N-Cj-C3-alkyl-Cj-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, with C,-C3-alkyl, Cl-C3-acyl, CI-C3-alkoxy, N-C,-C3-alkyl-Cj-C3-aIkyl, CF3 or cyano, or Cl-C6-alkyl, which can be substituted arbitrarily, R4 and R5 together form a 5-8-membered ring, which can contain further heteroatoms, and R6 the group C,-C6-alkyl, C1-C6-alkylcyclo-C3-C6-alkyl, C,-C6-alkyl-C6-C,2-aryl, in which C,-C6-alkyl, C,-C6-alkylcyclo-C3-C6-alkyl, C,-C6-alkyl-C6-C,2-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, ethoxy, iso-propoxy, chlorine, bromine, fluorine, cyano, methylsulfonyl or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.
Compounds of general Formula I in which the symbols have the following meanings are also preferred, R' hydrogen, R2 C3-C6-cycloalkyl, CI-C6-afkyl, CF3, cyano, bromine, or the group -OCF3, -S02-CH3, R3 C6-C,2-aryl, which can optionally be substituted singly or multiply, identically or differently with halogen, Cl-C6-alkyl, Cl-C3-acyl, C,-C3-alkoxy, cyano, hydroxy, N-(CH3)2, C02-(Cl-C3-alkyl), CO-NR4R5 or CF3, C5-C12-heteroaryl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, with C,-C6-alkyl, CI-C3-acyl, CI-C3-alkoxy, cyano, hydroxy, N-(CH3)2, C02-(C,-C3-alkyl), CO-NR4R5 or with CF3, C3-C6-cycloalkyl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, CF3, cyano, C,-C3-alkyl, CI-C3-acyl, hydroxy, N-(CH3)2, CO2-(Cl-C3-alkyl), CO-NR4R5 or Cl-C3-alkoxy, R4 hydrogen, R5 hydrogen, C,-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C,-C6-alkyl, CI-C6-acyl, Cl-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with Cl-C3-alkyl, Cl-C3-acyl, C,-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C3-alkyl, C,-C3-acyl, Cl-C3-alkoxy, N-C,-C3-alkyl-C,-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, CI-C3-alkyl, C,-C3-acyl, C,-C3-alkoxy, N-C,-C3-alkyl-C,-C3-alkyl, CF3 or cyano, or CI-C6-alkyl, which can be substituted arbitrarily, R6 the group Cl-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl, in which Cl-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, chlorine, fluorine, cyano or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.
Compounds of general Formula I in which the symbols have the following meanings are also preferred, R' hydrogen, R2 C3-C6-cycloalkyl, CI-C6-alkyl, CF3, cyano, bromine, or the group -OCF3, -S02-CH3 in the para-position, R3 C6-C12-aryl, which can optionally be substituted singly or doubly, identically or differently with halogen, Cl-C3-alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N-(CH3)2, C02-(C,-C3-alkyl), CO-NHR5 or CF3, C5-C12-heteroaryl, which can optionally be substituted singly or doubly, identically or differently with chlorine and/or fluorine, with CI-C3-alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N-(CH3)2, C02-(C1-C3-alkyl), CO-NHR5 or with CF3, C3-C6-cycloalkyl, R4 hydrogen, R5 hydrogen, C1-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C,-C6-alkyl, C,-C6-acyl, C,-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with Cl-C3-alkyl, C,-C3-acyl, C,-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, Cl-C3-alkyl, CI-C3-acyl, Cl-C3-alkoxy, N-Cj-C3-alkyl-Cj-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, C,-C3-alkyl, C,-C3-acyl, C,-C3-alkoxy, N-C,-C3-alkyl-C,-C3-alkyl, CF3 or cyano, or Cl-C6-alkyl, which can be substituted arbitrarily, R6 the group C,-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl, in which C,-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-Cs-C,2-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, chlorine, fluorine, cyano or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.
Compounds of general Formula I in which the symbols have the following meanings are also preferred, R' hydrogen, R2 tertiary butyl, iso-propyl, iso-butyl, sec. butyl, cyano, bromine, or the group -O-CF3, -S02-CH3 in the para-position, R3 the group \ ~CH I \ C H3 I / 3 CH3 ( \ I \ ( \ ~CFF
OH O~CH CH3 o__===cI c' cl ci R4 hydrogen, R5 hydrogen or the group -(CH2)R,-N-(CH3)2, -(CH2)2-CH3, -(CH2)2-NH-COCH3, -(CH2)-CHCH3-OH, -(CH2) 2-O-CH3, -(CH2)2-OH, -CHCH3-CH2-OH, where m = 1-3, I \ N~ \ N
N /
I ~ H

(N) O
O O O O O O N
OO

R6 methyl, ethyl, propyl, 2-methoxyethyl, -CH2-CF3-, -(CH2)2-CF3 and benzyl, as well as their isomers, diastereomers, enantiomers and salts.

Compounds of general Formula I in which the symbols have the following meanings are also preferred, R' hydrogen, R2 tertiary butyl, iso-propyl, iso-butyl, sec. butyl, cyano, bromine, or the group -O-CF3, -S02-CH3 in the para-position, R3 the group O F N

Q1~ CH3 R4 hydrogen, R5 hydrogen or the group, -(CH2)-CHCH3-OH, -(CH2) 2-O-CH3, -CHCH3-CH2-OH, (N) I
I / O Q
~ (")6 O N O O O Q

R6 methyl, ethyl, propyl, 2-methoxyethyl, -CH2-CF3-, -(CH2)2-CF3 and benzyl, as well as their isomers, diastereomers, enantiomers and salts.

The following compounds according to the present invention are quite especially preferred:

1. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(tetrahydropyran-4-yl )amide 2. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid (2-morpholin-4-ylethyl)amide 3. ( )-5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(2-hydroxy-1-methylethyl)amide 4. ( )-5-[(4-tert-butylphenyfsuffonyl)methylamino]-3-phenyf-1 H-indole-2-carboxylic acid-(2-hydroxypropyl)amide 5. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(pyridin-4-yl)amide 6. 5-[(4-tert-butyfphenylsulfonyl)benzylaminoj-3-phenyl-1 H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide 7. 5-[(4-tert-butylphenylsulfonyl)benzylamino]-3-phenyl-1 H-indole-2-carboxylic acid (2-morpholin-4-yiethyl)amide 8. ( )-5-[(4-tert-butyfphenyfsuffonyl)benzylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(2-hydroxy-1-methyfethyf)amide 9. ( )-5-[(4-tert-butylphenylsulfonyl)benzylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(2-hydroxypropyl)amide 10. 5-[(4-tert-butyfphenyisulfonyl)-(2-methoxyethyl)amino]-3-phenyl-1 H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide 11. 5-[(4-tert-butylphenylsulfonyl)-(2-methoxyethyl)aminoj-3-phenyl-1 H-indole-2-carboxylic acid (2-morpholin-4-yiethyl)amide 12. ( )-5-[(4-tert-butylphenylsulfonyl)-(2-methoxyethyl)amino]-3-phenyl-1 H-indofe-2-carboxyiic acid-(2-hydroxy-l-methylethyl)amide 13. ( )-5-[(4-tert-butylphenylsuffonyl)-(2-methoxyethyl)aminoj-3-phenyl-1 H-indole-2-carboxylic acid-(2-hydroxypropyl)amide 14. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-fluorophenyl)-1 H-indole-carboxylic acid-(tetrahydropyran-4-yl)amide 15. 5-[(4-tert-butyfphenyfsulfonyl)methyfamino]-3-(3-fluorophenyl)-1 H-indole-carboxylic acid (2-morphofin-4-yiethyl)amide 16. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-methoxyphenyl)-1 H-indofe-2-carboxylic acid-(tetrahydropyran-4-y!)amide 17. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-methoxyphenyl)-1 H-indole-2-carboxylic acid (2-morpholin-4-ylethyl)amide The invention also provides a process for preparing the compounds of general Formula I according to the present invention, which process is characterized in that a compound of Formula 11, 1-:ZZ R6 R3 SiN O
R2 //\\ ):):N O O 5 o-R7 (II) where R1, R2, R3 and R6 are each as defined above and R' may be hydrogen or C,-C6-alkyl preferably is hydrogen, methyl or ethyl, is reacted with an amine of general Formula II1 /
HN
\
R4 (III) where R4 and R5 are each as defined above, according to methods known to one skilled in the art, and any required protective groups are subsequently cleaved.
When R' is hydrogen, the reaction may initially be effected by the activation of the acid function, for example by initially converting the carboxylic acid of general Formula 11 in the presence of a tertiary amine, as for example triethylamine, with isobutyl chloroformate into the mixed anhydride. The reaction of the mixed anhydride with the alkali metal salt of the corresponding amine is effected in an inert solvent or solvent mixture, such as for example tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoramide, at temperatures between -20 C and +60 C, preferably at 0 C to 30 C.
A further possibility consists in activating the carboxylic acid of general Formula 11 by means of reagents such as for example HOBt or HATU. The reaction of the acid with HATU, for example, is carried out 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 for example ethyldiisopropylamine at temperatures between -50 and +60 C, preferably at 0 C to 30 C.

When R6 is C,-C6-alkyl, it is also possible for example to carry out a direct amidolysis of the ester with the corresponding amine with or without assistance of aluminum trialkyl reagents, preferably aluminum trimethyl.

The compounds of general Formula II which serve as starting materials are obtainable for example by proceeding in a conventional manner to reduce the nitro group in the known indole esters IV

o2H ~ /~ \ o N o-R7 H (IV) where R7 is Cl-C6-alkyl, preferably methyl or ethyl, in a hydrogen atmosphere or hydrogen source such as for example ammonium formate in the presence of a palladium catalyst to the amino function and then to react this amine with a halide of general Formula V

/ .,Hal R2 // \\
O O M, where R' and R2 are each as defined above and Hal represents halogen, preferably fluoride, chloride or bromide, in the presence of a base such as for example pyridine, diisopropylethylamine, triethylamine or potassium carbonate to form the compounds of general Formula VI

11-~

~N O
R2 O// \\ I \ ~
O /

(VI).

The esters of general Formula VI are then halogenated in the 3-position for examples by means of iodine, NBI, NBS or else CuBr2 to obtain the compounds of general Formula VII

R1 H Br iN O
R2 // \\ I
O O /

where R1, R2 and R' are each as defined above.

These esters are subsequently reacted in the presence of a base such as for example diisopropylethylamine, potassium carbonate or caesium carbonate in acetone or tetrahydrofuran with the halide of general Formula VIII

,Hal R6 (Vi 11), where R6 is as defined above and Hal represents halogen, preferably iodide, chloride or bromide, to form the compounds of general Formula IX

R6 Br SiN O
R2 // \\
O O

(IX).
The esters of general Formula IX are then converted in the 3-position, in a Pd-catalyzed reaction with boronic acid derivatives of general Formula X

R3 "IB(oH)2 ~X1 where R3 is as defined above, if appropriate after detachment of required protective groups in R6, if appropriate followed by a saponification, for example with sodium hydroxide solution, into the compounds of general Formula II

iN O
R2 // \\ I \
O O

(II).
Alternatively, it would also be possible to convert the esters of general Formula VII initially in the 3-position in a Pd-catalyzed reaction with the boronic acid derivatives of the general Formula X

,B(OH)2 R3 X ( ) , where R3 is as defined above, into the compounds of general Formula XI

SI~N ~ O
2 // \\ I \
O O /
H O-R7 (Xl) where R', R2, R3 and R7 are each as defined above, and subsequently to carry out the N-alkylation step in the presence of a base such as for example diisopropylethylamine, potassium carbonate or caesium carbonate in acetone or tetrahydrofuran and the halide of general Formula VIII

~Hal R6 (VIII), where R6 is as defined above and Hal represents halogen, preferably iodide, chloride or bromide, if appropriate after detachment of required protective groups in R6, if appropriate followed by a saponification, for example with sodium hydroxide solution, to form the compounds of general Formula 11.

The compounds according to the invention inhibit soluble adenylate cyclase, and this is also the basis of their action for example in male fertility control.
Adenylate cyclases are the effector molecules for one of the most-used signal-transduction pathways, they synthesize the second messenger molecule cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) with splitting-off of pyrophosphate (PP). cAMP mediates numerous cellular responses to a large number of neurotransmitters and hormones. Soluble, sperm-specific adenylate cyclase (sAC, human mRNA sequence (GenBank) nm_018417, human gene ADCY X) is one out of ten adenylate cyclases described in the human genome. sAC exhibits some specific properties that distinguish it from the other adenylate cyclases. In contrast to all other adenylate cyclases, sAC is stimulated by the concentration of bicarbonate in the surrounding medium and not by G proteins. sAC does not possess any transmembrane regions in its amino acid sequence, it cannot be inhibited by forskolin, can be stimulated much more strongly by manganese than by magnesium, and only displays slight sequence homologies to the other adenylate cyclases (s 26% identity of the catalytic domains I and II of sAC
with other adenylate cyclases at the amino acid level).

Specific, manganese-dependent activity of sAC was first described by T. Braun et al. (1975, PNAS 73:1097ff) in rat testis and sperm. N. Okamura et al.
(1985, J. Biol. Chem 260(17):9699ff) showed that the substance which stimulates the activity of sAC in boar seminal fluid is bicarbonate. It was also shown that AC
activity that can be stimulated by bicarbonate can only be detected in rat testis and sperm, but not in other tissues. sAC was purified from rat testis and sequenced for the first time by the Buck and Levin group (J. Buck et al. 1999, PNAS 96:79ff, WO 01/85753). The expected properties (e.g. capacity to be stimulated by bicarbonate and magnesium) were confirmed on recombinantly expressed protein (Y. Chen et al. 2000, Science 289:625ff).

Testis-specific and sperm-specific expression of the enzymes can be concluded from data on the distribution of sAC mRNA and on sAC activity that can be stimulated by bicarbonate (ML Sinclair et al. 2000, Mol Reprod Develop 56:6ff;
N Okamura et al. 1985, J. Biol. Chem 260(17):9699ff; J. Buck et al. 1999, PNAS
96:79ff). In the testis, sAC mRNA is only expressed in later stages, of the gametes developing to sperm, but not in somatic cells (ML Sinclair et al.
2000, Mol Reprod Develop 56:6ff).

There have been a number of pharmacological investigations into the function of sAC in sperm in mammals. Before sperm can penetrate the zona pellucida of the ovum and then fuse with the oolemma of the ovum, sperm must be prepared for this functionality. This process, sperm capacitation, has been thoroughly investigated. A capacitated sperm is characterized by an altered pattern of movement and by the ability to go through the process of the acrosome reaction (release of lytic enzymes which presumably serve for penetration of the zona pellucida by the sperm) when suitably stimulated.
Sperm capacitation takes place in vivo and in vitro and among other things independently of a raised 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 can also be stimulated by adding suitable membrane-passing cAMP analogs, e.g. db-cAMP, and an inhibitor that prevents their degradation (e.g. IBMX). The presumed dependence of sperm function on sAC was confirmed only recently by a genetic deletion model, a so-called knock-out mouse (G Esposito et al. 2004, PNAS 101(9):2993ff). Male mice lacking the gene for sAC exhibit spermatogenesis that proceeds normally, but are infertile. The sperm have motility defects and are not capable of fertilizing an egg. The animals did not display any other defects or abnormal findings, which contradicts other hypothesized functions of sAC (JH Zippin et al.
2003, FASEB 17:82ff)).

sAC has a unique sequence and only slight homology to other somatic adenylate cyclases. It is the only adenylate cyclase in mammalian sperm and the activity is essential for sperm motility and capacitation. Specific sAC
inhibitors accordingly represent an important possibility for controlling male fertility.
The present invention therefore relates to medicinal products that contain at least one of the compounds as claimed in claims 1-7.

The present invention also relates to the use of the compounds as claimed in claims 1-7.

For use of the compounds according to the invention as medicinal products they are converted to the form of a pharmaceutical preparation, which contains, in addition to the active substance, pharmaceutical, organic or inorganic inert vehicles that are suitable for enteral or parenteral application, for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. The pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, or capsules, or in liquid form, for example as solutions, suspensions or emulsions. If necessary they also contain excipients, such as preservatives, stabilizers, wetting agents or emulsifiers; salts for altering osmotic pressure or buffers. These pharmaceutical preparations are also the object of the present invention.
Injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral application.

Surface-active excipients such as salts of bile acids or animal or vegetable phospholipids, as well as mixtures thereof and liposomes or their constituents, can also be used as carrier systems.

In particular, tablets, dragees or capsules with talc and/or hydrocarbon vehicles or binders, for example lactose, maize starch or potato starch, are suitable for oral application. Application can also be in liquid form, for example as juice, to which a sweetener is added if required.

For vaginal application, for example suppositories are suitable and conventional.

The present invention also relates to enteral, parenteral, vaginal and oral application.

The dosage of the active substances can vary depending on the route of administration, the patient's age and weight, the nature and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, and the dose can be a single dose that is to be administered once, or can be divided into 2 or more daily doses.

The compounds according to the invention of general Formula I are, among other things, excellent inhibitors of soluble adenylate cyclase. Inhibitors of soluble adenylate cyclase lead to depression of the cAMP signal. The cAMP
level is decisive for control of the processes that play an important role in cell proliferation, cell differentiation and apoptosis. Diseases, e.g. cancer, in which depression of the cAMP level is decisive, can be modulated by inhibitors of soluble adenylate cyclase. This modulation can have prophylactic and therapeutic effects for patients suffering such a disease. At the present time diseases which are, like cancer, associated with increased cell pro;`feration, are treated for example by radiotherapy and chemotherapy. These methods are nonspecific and have a high potential for side-effects. The provision of new substances, which act directly on particular target sites, is therefore advantageous. The present invention relates to substances that modulate cAMP
production by the inhibition of soluble adenylate cyclase. For example, abnormal cell proliferation can be reduced or prevented by regulation or inhibition of cAMP production. Soluble adenylate cyclase can be inhibited by the use of the substances according to the invention, with a consequent reduction in cell proliferation. The present invention relates to medicinal products for the treatment of diseases that contain at least one compound according to general Formula I, and medicinal products with suitable vehicles and excipients. The diseases are characterized in that they are caused by disturbances of metabolism of the second messenger cAMP.
Lowering of the cAMP concentration by inhibition of soluble adenylate cyclase can provide a means of modulation of sperm capacitation. The present invention relates to the use of the substances according to the invention for the lowering and/or inhibition of male gamete fertility, mediated by the reduction or inhibition of soluble adenylate cyclase activity and accordingly of sperm capacitation.

Fertilization of the ovum can be prevented by administering an effective amount of a substance that leads to inhibition of cAMP production. The present invention also relates to the use of the compound of general Formula I for the production of a medicinal product for non-hormonal contraception.

If the production of the starting compounds is not described, these are known or can be produced similarly to known compounds or methods described here. It is also possible to carry out all the reactions described here in parallel reactors or using combinatorial techniques.

The mixtures of isomers can be separated into the enantiomers or E/Z isomers by usual methods, for example crystallization, chromatography or salt formation.
The salts are produced in the usual manner, by adding the equivalent amount or an excess of a base or acid, which is in solution if necessary, to a solution of the compound of Formula 1, separating the precipitate or processing the solution in the usual way.

Production of the compounds according to the invention The following examples explain the production of the compounds of general Formula I according to the invention, without limiting the scope of the claimed compounds to these examples.
The compounds of general Formula I according to the invention can be produced as described below.
Example 1: 5-[(4-tert-Butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide /
~ I -SiN ~ O
O O ~
\ N N-CO
H H

A solution in 0.75 ml of dimethylformamide of 45 mg of the acid prepared in Example 1f) is admixed with 40.3 mg of N-[(dimethylamino)-1 H-1,2,3-triazolo[4,5-b]pyridin-1 -ylmethylene]-N-methylmethanaminium hexafluoro-phosphate N-oxide (HATU) and 9.84 mg of 4-aminotetrahydropyran. Then 18.0 NI of ethyldiisopropylamine are added dropwise at 0 C before stirring at room temperature for 20 hours. This is followed by addition of 25 ml of water, stirring for 30 minutes and filtering with suction. The residue thus obtained is purified by chromatography over silica gel with hexane/0-70% ethyl acetate to obtain 49.7 mg of the title compound.
NMR (300 MHz, DMSO-d6): 8= 1.22 (2H), 1.26 (s, 9H), 1.65 (2H), 3.07 (3H), 3.32 (2H), 3.68 (2H), 3.89 (1 H), 6.91 (1 H), 6.99 (1 H), 7.26-7.33 (4H), 7.34-7.41 (5H), 7.54 (2H), 11.85 (1 H).
The starting material for the title compound above is prepared as follows:
1 a) Ethyl 5-amino-1 H-indole-2-carboxylate "2" o ¾--\

5 g of ethyl 5-nitro-1 H-indole-2-carboxylate are initially charged in 170 ml of methanol and 0.5 ml of water, admixed with 6.73 g of ammonium formate and with 50 mg of palladium on carbon (10%) and refluxed at 90 C for 1 hour. This is followed by filtration through Celite with suction and washing with warm methanol. After solvent removal, the residue is admixed with 100 ml of water and stirred for 10 minutes and the precipitated solid material is dried under reduced pressure to obtain 4.12 g of the title compound.

NMR (300 MHz, DMSO-d6): 8 = 1.28 (3H), 4.25 (2H), 4.63 (2H), 6.62-6.68 (2H), 6.79 (1H), 7.12 (1H), 11.35 (1H).

1 b) Ethyl 5-(4-tert-butylphenylsulfonylamino)-1 H-indole-2-carboxylate H
u Q

i <):)N
H o A solution, in 195 mi of DMF, of 4.12 g of the amine prepared in Example 1 a) is admixed at 0 C with 5.18 ml of ethyidiisopropylamine and 4.69 g of 4-tert-butylphenyisulfonyl chloride and stirred at room temperature for two hours.
The solvent is removed under reduced pressure and the residue is purified by chromatography over silica gel with hexane/0-80% ethyl acetate to obtain 7.56 g of the title compound.

NMR (300 MHz, DMSO-d6): S= 1.20 (9H), 1.27 (3H), 4.27 (2H), 6.97-7.03 (2H), 7.25 (1H), 7.31 (1H), 7.48 (2H), 7.59 (2H), 9.93 (1H), 11.80 (1H).

1 c) Ethyl 3-bromo-5-(4-tert-butylphenylsulfonylamino)-1 H-indole-2-carboxylate H Br O
OSO / ! \

A solution, in 217 ml of tetrahydrofuran, of 7.56 g of the sulfonamide prepared in Example 1 b) is admixed with 3.36 g of N-bromosuccinimide and stirred at room temperature for 40 minutes. After diluting with 300 ml of ethyl acetate, washing once with 50 ml of water and twice with 50 ml of saturated sodium chloride solution each time, the organic phase is dried over sodium sulfate. After filtration and concentrating under reduced pressure, the residue thus obtained is recrystallized from hexane/ethyl acetate to obtain 8.11 g of the title compound.

NMR (300 MHz, DMSO-d6): 8= 1.20 (9H), 1.30 (3H), 4.31 (2H), 7.08-7.15 (2H), 7.33 (1 H), 7.50 (2H), 7.60 (2H), 10.08 (1H), 12.16 (IH).

1 d) Ethyl 3-bromo-5-[(4-tert-butylphenylsulfonyl)methylamino]-1 H-indole-2-carboxylate I I o o H
A suspension, in 10 ml of acetone, of 1 g of the bromide prepared in Example 1 c) is admixed with 375 mg of potassium carbonate and 0.13 ml of methyl iodide and stirred at room temperature for 24 hours. The mixture is diluted with 300 ml of ethyl acetate and washed once with 50 ml of water and once with 50 ml of saturated sodium chloride solution. Drying over sodium sulfate and filtration is followed by concentrating under reduced pressure. The residue thus obtained is purified by medium pressure chromatography over silica gel with hexane/ethyl acetate in a ratio of 7:3 to obtain 670 mg of the title compound.
NMR (300 MHz, DMSO-d6): S= 1.27 (9H), 1.32 (3H), 3.14 (3H), 4.34 (2H), 6.92 (1 H), 7.08 (1 H), 7.39 (1 H), 7.41 (2H), 7.56 (2H), 12.33 (1 H).

1 e) Ethyl 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylate 'I o io N
"
A solution, in a mixture of 25.5 ml of ethanol and 25.5 ml of toluene, of 666 mg of the ester prepared in Example 1d) is admixed with 239 mg of phenylboronic acid and 3.37 ml of 1 M aqueous sodium carbonate solution and also 160 mg of lithium chloride. After addition of 125 mg of tetrakis(triphenylphosphine)-palladium the reaction mixture is refluxed for 20 hours. After cooling to room temperature, the reaction mixture is filtered through Celite with suction and the filter residue is washed with ethyl acetate. The organic phase thus obtained is washed with 10 ml of saturated sodium bicarbonate and saturated sodium chloride solution and dried over sodium sulfate. After concentrating under reduced pressure, the residue thus obtained is purified by chromatography over silica gel with hexane/0-60% ethyl acetate to obtain 626 mg of the title compound.
NMR (300 MHz, DMSO-d6): S= 1.13 (3H), 1.27 (9H), 3.06 (3H), 4.18 (2H), 6.90 (1 H), 7.07 (1 H), 7.25-7.7.36 (5H), 7.39 (2H), 7.43 (1 H), 7.55 (2H), 10.24 (1 H).

1 f) 5-[(4-tert-Butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid I

N OH
H
A mixture of 600 mg of the ester prepared in Example le) in 14.5 ml of ethanol, and 7.25 ml of ethanol is admixed with 905 mg of sodium hydroxide and stirred at room temperature for 20 hours. The mixture is then diluted with 100 ml of water and acidified with 5% of sulfuric acid. The precipitate is filtered off and dried to obtain 205 mg of the title compound which is further reacted without further purification.
NMR (300 MHz, DMSO-d6): S= 1.26 (9H), 3.06 (3H), 6.88 (1H), 7.04 (1H), 7.24-7.35 (5H), 7.36-7.43 (3H), 7.55 (2H), 11.94 (1 H), 12.93 (1 H).

Example 2: 5-[(4-tert-Butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(2-morpholin-4-ylethyl)amide /
~ I -( N 0 o/\o 1 N N
H H

Example 1 is repeated with 45 mg of the acid of Example 1f) and 12.8 NI of 2-(morpholin-4-yl)ethylamine to obtain 36.2 mg of the title compound.
NMR (300 MHz, DMSO-d6): 8= 1.27 (9H), 2.18 (4H), 2.25 (2H), 3.06 (3H), 3.25 (2H), 3.38 (4H), 6.85 (1 H), 6.98 (1 H), 7.27-7.42 (9H), 7.55 (2H), 11.85 (1 H).
Example 3: ( )-5-[(4-tert-Butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(2-hydroxy-l-methylethyl)amide O/\O / I O OH
~ H N~
H

Example 1 is repeated with 45 mg of the acid of Example 1f) and 7.75 NI of 2-amino-l-propanol to obtain 42.6 mg of the title compound.
NMR (300 MHz, DMSO-d6): 8= 0.94 (3H), 1.26 (9H), 3.07 (3H), 3.13-3.30 (2H), 3.89 (1 H), 4.62 (1 H), 6.89 (1 H), 6.96 (1 H), 6.99 (1 H), 7.26-7.41 (8H), 7.54 (2H), 11.83 (1 H).

Example 4: ( )- 5-[(4-tert-Butylphenylsulfonyl)methylamino]-3-phenyl-1 H-indole-2-carboxylic acid-(2-hydroxypropyl)amide N

pp / ( \ --OH
N N
H H

Example 1 is repeated with 45 mg of the acid of Example 1f) and 7.31 mg of 1 -amino-2-propanol to obtain 45.4 mg of the title compound.
NMR (300 MHz, DMSO-d6): 8= 0.91 (3H), 1.27 (9H), 3.00-3.17 (2H), 3.06 (3H), 3.58 (1 H), 4.59 (1 H), 6.87 (1 H), 6.99 (1 H), 7.15 (1 H), 7.26-7.41 (8H), 7.54 (2H), 11.84 (1 H).

Biological examples:
Example 1: sAC assay In a suitable buffer system, soluble, sperm-specific adenylate cyclase catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and pyrophosphate. Free cAMP generated in this way is then used in a competitive detection technique, in which the binding of a europium cryptate Eu[K]-labeled anti-cAMP antibody (anti-cAMP-Eu[K]-AB) to a modified allophycocyanine-1 molecule labeled with cAMP molecules (cAMP-XL665) is prevented. In the absence of exogenous cAMP, after excitation at 335 nm there is Fluorescence Resonance Energy Transfer (FRET) between the anti-cAMP-Eu[K]-AB (FRET donor) and the cAMP-XL665 molecule (FRET
acceptor). This process is quantified, time-resolved, on the basis of the emission of the FRET acceptor XL665 (665nm and 620nm). A decrease in signal (measured as Well Ratio; calculated from the Formula:
[(E665nm/E620nm) x 10000] ) can be attributed to the presence of cAMP and thus to the activity of sAC. First, 1.5 NI of the test substance (in 30% DMSO) is placed in each well of a 384-well test plate (polystyrene; 384, NV), and in the solvent controls only 30% DMSO. Then 10 ul of a dilute sAC enzyme solution is applied (enzyme stock solution in 300 mM NaCl, 10% glycerol; pH 7.6; enzyme intermediate and final dilution a) 1:10 and b) 1:2000 in each case in: 1.0 mM
MnC12; 0.2% BSA; 50 mM Tris pH 7.5 in H20). The enzyme reaction is started by adding 5 NI of the ATP substrate solution (200 pM ATP in H20) and after incubation (25 min at room temperature) stopped by adding 5pI of the stop solution (200 pM EDTA in PBS). Finally the whole reaction is adjusted to a total volume of 91.5 NI by adding 70 pl PBS.

Next, 8 pl of detection solution 1 is placed in a well of the 384-well measuring plate (measuring plate: polystyrene; 384, SV - black; detection solution 1: 50 pl cAMP-XL665; 950 pl reconstituted buffer; 2200 pl PBS; cAMP-XL665: prepared by adding 5 ml H20 to the lyophilized product according to the instructions in Cis bio Kit: #62AMPPEC; storage: in aliquots at -80 C). Next, 3 pl from the 91.5 NI is added to the corresponding well of the test plate. Finally, 8 NI of detection solution 2 is added (detection solution 2: 50 pl anti-cAMP-Eu[K]-AB; 950 pl reconstituted buffer; 2200 pl PBS; anti-cAMP-Eu[K]-AB: prepared according to the instructions in Cis bio Kit: #62AMPPEC; storage: in aliquots at -80 C).
After further incubation for 90 min at room temperature, the HTRF result is measured either on the Packard Discovery or with the RubiStar HTRF
measuring instrument (delay: 50 ps; integration time: 400 ps).

Example 2. Isolation of human sperm from ejaculates and capacitation 2.1. Isolation of the sperm Human sperm from ejaculate are purified in a two-layer gradient system based on colloidal silica particles (trade name: Percoll or ISolate).
Per ejaculate, 2.5 ml of pre-warmed lower layer ("90% ISolate lower layer", from Irvine) is placed in a 15 ml centrifuge tube (conical, plastic) and is carefully covered with 2.5 ml of pre-warmed upper layer ("50% ISolate upper layer", from Irvine) and held at 37 C for < lh on a water bath. The gradient is carefully covered with max. 3 ml of normal (with respect to sperm count, motility and liquefaction) ejaculate. Sedimentation of the sperm is carried out at 1000 x g for min at room temperature. Using a glass capillary, the two layers are removed 25 by suction to just above the sperm pellet. For elutriation of the ISolate gradients, the sperm pellets, each resuspended in approx. 200 NI, are transferred to a 15 ml plastic tube with 12 ml mHTF medium (4 mM NaHCO3; 0.01% BSA; 37 C) and the sperm are sedimented at 1000 x g for 20 min. The medium is removed by suction to just above the pellet and adjusted with mHTF medium (4 mM
NaHCO3; 0.01 % BSA; 37 C) to 1000 pl. The sperm count is determined in a Neubauer counter and for subsequent capacitation is adjusted if necessary to 4x106 sperm/150 pl with mHTF medium (4 mM NaHCO3; 0.01 % BSA; 37 C).

2.2. Capacitation If the influence of test substances on the acrosome reaction is to be tested, the sperm must be preincubated with the test substances. This preincubation (15 min in a heating cabinet at 37 C) is necessary to permit penetration of the test substances into the sperm before the start of capacitation, i.e. to achieve presaturation of the binding sites in the sperm, especially in the case of substances that do not pass through the membrane easily. It is also necessary because the increase in BSA concentration during capacitation due to the high lipid binding of the BSA could lead to a decrease in the effective concentration of test substance in the sample.
The test substances are dissolved in DMSO and diluted with mHTF medium (4 mM NaHCO3; 0.01 % BSA; 37 C), so that in the final 400-NI capacitation sample the DMSO concentration is 0.5%. In each case 150 ul of sperm suspension is added by pipette to 150 NI of the aforementioned temperature-controlled solution of test substance, followed by preincubation at 37 C for 15 min. Capacitation of the sperm is started by adding 100 NI of mHTF medium (88 mM NaHCO3; 4% BSA; 37 C). In the final 400-NI capacitation sample, the concentration of sperm is 10x106/ml, the bicarbonate concentration is 4 mM and the BSA concentration is 1%. Capacitation is carried out for 3 hours at 37 C
in the heating cabinet.
For stopping capacitation, the samples (each of 400 pi) are each transferred completely to a 15-m1 sample tube with 1.5 ml mHTF (4 mM NaHCO3; 37 C), centrifuged for 5 min at 1000 x g and the supernatant is removed. This step removes both the large amount of protein and the test substances.
Example 3. Flow cytometric determination of the acrosome reaction 3.1. lnitiation of the acrosome reaction by treatment with ionophore and simultaneous CD46-FITC staining The acrosome reaction (AR) of the sperm is triggered by binding of the sperm to the zona pellucida (ZP). This releases enzymes from the acrosome, enabling the sperm to penetrate the ZP and reach the ovum. In the AR, there is partial fusion, at the sperm, of the plasma membrane with the outer acrosomal membrane (OAM). At the end the sperm head is still restricted by the inner acrosomal membrane (IAM). The CD46 antigen is only detectable at the IAM.
In vitro the acrosome reaction can only be induced with a suitable concentration of the calcium ionophore A23187 on capacitated sperm, but not on uncapacitated sperm or sperm for which capacitation was inhibited by test substances. By means of the FITC-labeled anti-CD46 antibody (from Pharmingen) to the IAM, the acrosome-reacted sperm can be differentiated from the acrosome-intact sperm, in which the IAM is not exposed, in the flow cytometer. With simultaneous staining of the sperm with the DNA stain ethidium homodimer (EhD), which only stains cells that have defective DNA membranes, i.e. are dead, it is possible to distinguish dead sperm from live sperm.
Because the ionophore dilutions for initiating the AR appear to be very unstable and must be mixed with the CD46-FITC solution for simultaneous staining, the solutions cannot be prepared before the start of the test, but must be prepared during processing of the capacitation samples.
The sperm pellets are resuspended in the residue of the supernatant and are diluted with 450 pI mHTF (4 mM NaHCO3; 0.01% BSA; 37 C) on a water bath (37 C). 100 NI aliquots of the sperm suspensions are transferred by pipette to prepared sample-FACS flow tubes (on the water bath). 150 NI of a solution with ionophore and FITC-labeled anti-CD46 antibody is added by pipette to the sperm. The final concentration is 800 nm 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 therein for 30 min, protected from the light, on a water bath at 37 C.
Incubation is stopped by adding 3.5 ml PBS [0.1% BSA] / sample, followed by centrifugation for 5 min at 700 x g (room temperature) and then removal of the supernatants with suction. After centrifugation, the samples are kept warm on a hot-plate until measurement.

3.2. EhD staining (for differentiation of the dead/live acrosome-reacted sperm}
500 NI of freshly prepared EhD solution (150 nm EhD in PBS [w/o BSA]; 37 C) is added to each of the sperm pellets after removal by suction. The samples can then be measured in the flow cytometer (BD FacsCalibur). Measurement is performed at a laser excitation wavelength of 488 nm, detecting 10000 sperm per measurement. Acrosome-reacted sperm are measured via CD46-FITC in the FL-1 filter at 530 nm. Dead sperm are measured by means of EhD-DNA
staining in the FL-2 filter at 634 nm. The measurement channels are correspondingly compensated relative to one another beforehand.

3.3 Evaluation The sperm are selected as a very uniform cell population in an FSC-H (forward scatter) versus SSC-H (sideward scatter) dot-blot. As two-color fluorescence staining is used, evaluation is performed by quadrant analysis in an FL-1 (EhD;
X axis) vs. FL-2 (FITC-CD46, Y axis) dot-blot with the selected sperm population from the FSC vs. SSC dot-blot:
Quadrant in FL-1 Staining Analysis vs. FL-2 dot-blot Q1 = UL upper left only EhD dead, not acrosome-reacted sperm Q2 = UR upper right EhD and dead, acrosome-reacted sperm Q3 = LL lower left unstained live, not acrosome-reacted sperm Q4 = LR lower right only live, acrosome-reacted sperm To calculate the %-induced acrosome-reacted sperm (= "IAR[%]"), only the live sperm from Q3 and Q4 are taken, and their total count is set equal to 100%.
IAR is then calculated as follows:

IAR[%]- LRx100 LL + LR
A proportion of the sperm undergo the acrosome reaction spontaneously without addition of ionophore (= "SAR[%]"). Therefore a control measurement is always performed on identically-treated sperm without addition of ionophore.
Calculation of SAR is similar to calculation of IAR. The acrosome reaction actually induced by the ionophore (= "ARIC[%]") is calculated as the difference:
ARIC = IAR - SAR.
For subsequent analysis of the influence of our inhibitors on sAC-mediated capacitation (measured as the capacity of the sperm for the ionophore-induced acrosome reaction), the percentage of acrosome-reacted sperm in the positive capacitation control (= incubation with mHTF medium with 25 mM NaHCO3; 1%
BSA without test substances) is set = 100%. The capacity of the sperm to which the test substances have been added, for the acrosome reaction, is stated relative to this maximum acrosome reaction.

Materials used mHTF = modif. human tubular fluid (from Irvine Scientific), Dulbeccos's Phosphate-Buffered-Saline (from Gibco) (with Ca2+, Mg2+, 1 g/L D-glucose, 36 mg/L Na-pyruvate, w/o phenol red, w/o NaHCO3); bovine serum albumin, Fraction V (from Fluka); dimethylsulfoxide (DMSO), anhydrous (from Merck);
sodium bicarbonate 7.5% solution (893mM) (from Irvine Scientific); Isolate-Gradient (from Irvine Scientific); lonophore-A23187 free acid, (from Calbiochem); Ethidium Homodimer (EhD) (from Molecular Probe), Mouse Anti Human CD46:FITC (from Pharmingen).

References:
J. W. Carver-Ward, Human Reproduction Vol. 11, No. 9, pp: 1923 ff, 1996 High fertilization prediction by flow cytometric analysis of the CD46 antigen on the inner acrosomal membrane of spermatozoa O. J. D'Cruz, G. G. Haas, Fertility and Sterility Vol. 65, No. 4, pp: 843 ff, Fluorescence-labeled fucolectins are superior markers for flow cytometric quantitation of the sperm acrosome reaction E. Nieschlag, H.M. Behre, Andrology, Springer Verlag 1996 Examples:

# R R IC50 (NM) CH3 2.6 N p~ N
H H \O/

-CH2-CHCH3-OH CH3 1.3 ~ I -/\0 / I
N C
\ N
H H

OH Ohrtel 13 H
i H H
~
HO

OH

4-OH-estradiol oH~;,a 11 H
HO
H H
HO
2-OH-estradiol It can be seen from the table that with respect to the inhibition of soluble adenylate cyclase, expressed by the IC50 value, the compounds according to the invention display approximately 10-fold greater activity than the known catechol estrogens (OH-estradiols). The catechol estrogens are toxic, therefore the compounds according to the invention are far superior to the known compounds. The compounds according to the invention are also approximately 10-fold more potent than the compounds presented by Zippin.

Claims

1. A compound of general Formula (I), where the following notation is used R1 hydrogen, halogen, CF3, C3-C6-cycloalkyl, which is optionally multiply saturated and optionally multiply substituted, or the group C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3, in which C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-C1-C6-alkyl, sulfonamide, or cyano, R2 halogen, CF3, C3-C6-cycloalkyl, which is optionally multiply saturated and optionally multiply substituted, or the group C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3, in which C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-C1-C6-alkyl, sulfonamide, or cyano, R3 C6-C12-aryl, which can optionally be substituted singly or multiply, identically or differently with halogen, with C1-C6-alkyl or C1-C6-acyl, which can optionally be singly or multiply substituted, or can be substituted with C1-C6-alkoxy, hydroxy, cyano, CO2-(C1-C6-alkyl), N-(C1-C6-alkyl)2, CO-NR4R5 or with CF3, C5-C12-heteroaryl, which can optionally be substituted singly or multiply, identically or differently with halogen, C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy, hydroxy, cyano, CO2-(C1-C6-alkyl), N-(C1-C6-alkyl)2, CO-NR4R5 or with CF3 or C3-C6-cycloalkyl, which can optionally be substituted singly or multiply, identically or differently with halogen, CF3, hydroxy, cyano, CO2-(C1-C6-alkyl), C1-C6-alkyl, C1-C6-acyl, N-(C1-C6-alkyl)2, CO-NR4R5 or C1-C6-alkoxy, R4 hydrogen, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3 or cyano, or C1-C6-alkyl, which can be substituted arbitrarily, R5 hydrogen, C1-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy, N-C1-C6-alkyl-C1-C6-alkyl, CF3 or cyano, or C1-C6-alkyl, which can be substituted arbitrarily, R4 and R5 together form a 5-8-membered ring, which can contain further heteroatoms, and R6 the group C1-C6-alkyl, C1-C6-acyl, C1-C6-alkylcyclo-C3-C6-alkyl, C1-C6-alkyl-C6-C12-aryl, in which C1-C6-alkyl, C1-C6-acyl, C1-C6-alkylcyclo-C3-C6-alkyl, C1-C6-alkyl-C6-C12-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, ethoxy, iso-propoxy, chlorine, bromine, fluorine, cyano, methylsulfonyl or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.

2. The compound as claimed in claim 1, where the symbols have the following meanings:
R1 hydrogen, halogen, CF3, C3-C6-cycloalkyl, or the group C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3, in which C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-C1-C6-alkyl, sulfonamide, or cyano, R2 halogen, CF3, C3-C6-cycloalkyl, or the group C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl, C1-C6-aryl-C1-C6-alkyl or CF3, in which C1-C6-alkyl, C1-C6-aryl, C1-C6-acyl, halo-C1-C6-alkyl, C1-C6-alkyl-C1-C6-alkyl, C1-C6-alkyl-C1-C6-acyl, C1-C6-acyl-C1-C6-acyl, C1-C6-alkyl-C1-C6-aryl or C1-C6-aryl-C1-C6-alkyl can optionally be interrupted singly or multiply, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-C1-C6-alkyl, sulfonamide, or cyano, R3 C6-C12-aryl, which can optionally be substituted singly or multiply, identically or differently with halogen, C1-C6-alkyl, C1-C3-acyl, C1-C3-alkoxy, cyano, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NR4R5 or CF3, C5-C12-heteroaryl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, with C1-C6-alkyl, C1-C3-acyl, C1-C3-alkoxy, cyano, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NR4 R5 or with CF3, C3-C6-cycloalkyl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, CF3, cyano, C1-C3-alkyl, C1-C3-acyl, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NR4R5 or C1-C3-alkoxy, R4 hydrogen, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, with C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C1-C6-alkyl, which can be substituted arbitrarily, R5 hydrogen, C1-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, with C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C1-C6-alkyl, which can be substituted arbitrarily, R4 and R5 together form a 5-8-membered ring, which can contain further heteroatoms, and R6 the group C1-C6-alkyl, C1-C6-alkylcyclo-C3-C6-alkyl, C1-C6-alkyl-C6-C12-aryl, in which C1-C6-alkyl, C1-C6-alkylcyclo-C3-C6-alkyl, C1-C6-alkyl-C6-C12-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, ethoxy, iso-propoxy, chlorine, bromine, fluorine, cyano, methylsulfonyl or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.

3. The compound as claimed in claims 1-2, where the symbols have the following meanings:

R1 hydrogen, R2 C3-C6-cycloalkyl, C1-C6-alkyl, CF3, cyano, bromine, or the group -OCF3, -SO2-CH3, R3 C6-C12-aryl, which can optionally be substituted singly or multiply, identically or differently with halogen, C1-C6-alkyl, C1-C3-acyl, C1-C3-alkoxy, cyano, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NR4R5 or CF3, C5-C12-heteroaryl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, with C1-C6-alkyl, C1-C3-acyl, C1-C3-alkoxy, cyano, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NR4R5 or with CF3, C3-C6-cycloalkyl, which can optionally be substituted singly or multiply, identically or differently with chlorine and/or fluorine, CF3, cyano, C1-C3-alkyl, C1-C3-acyl, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NR4R5 or C1-C3-alkoxy, R4 hydrogen, R5 hydrogen, C1-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C1-C6-alkyl, which can be substituted arbitrarily, R6 the group C1-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl, in which C1-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, chlorine, fluorine, cyano or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.

4. The compound as claimed in claims 1-3, where the symbols have the following meanings:

R1 hydrogen, R2 C3-C6-cycloalkyl, C1-C6-alkyl, CF3, cyano, bromine, or the group -OCF3, -SO2-CH3 in the para-position, R3 C6-C12-aryl, which can optionally be substituted singly or doubly, identically or differently with halogen, C1-C3-alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NHR5 or C5-C12-heteroaryl, which can optionally be substituted singly or doubly, identically or differently with chlorine and/or fluorine, with C1-C3-alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N-(CH3)2, CO2-(C1-C3-alkyl), CO-NHR5 or with CF3, C3-C6-cycloalkyl, R4 hydrogen, R5 hydrogen, C1-C6-alkyl-C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C6-alkyl, C1-C6-acyl, C1-C6-alkoxy or CF3, C3-C6-cycloalkyl, which is optionally substituted singly or multiply, identically or differently with C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy or CF3, C6-C12-aryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C5-C12-heteroaryl, which is optionally substituted singly or multiply, identically or differently with halogen, C1-C3-alkyl, C1-C3-acyl, C1-C3-alkoxy, N-C1-C3-alkyl-C1-C3-alkyl, CF3 or cyano, or C1-C6-alkyl, which can be substituted arbitrarily, R6 the group C1-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl, in which C1-C4-alkyl, CH2-cyclo-C3-C6-alkyl, CH2-C6-C12-aryl can optionally be substituted singly or multiply, identically or differently by hydroxy, methoxy, chlorine, fluorine, cyano or aminosulfonyl, as well as their isomers, diastereomers, enantiomers and salts.

5. The compound as claimed in claims 1-4, where the symbols have the following meanings:

R1 hydrogen, R2 tertiary butyl, iso-propyl, iso-butyl, sec. butyl, cyano, bromine, or the group -O-CF3, -SO2-CH3 in the para-position, R3 the group R4 hydrogen, R5 hydrogen or the group -(CH2)m-N-(CH3)2, -(CH2)2-CH3, -(CH2)2-NH-COCH3, -(CH2)-CHCH3-OH, -(CH2) 2-O-CH3, -(CH2)2-OH, -CHCH3-CH2-OH, where m = 1-3, R6 methyl, ethyl, propyl, 2-methoxyethyl, -CH2-CF3-, -(CH2)2-CF3 and benzyl, as well as their isomers, diastereomers, enantiomers and salts.

6. The compound as claimed in claims 1-5, where the symbols have the following meanings:

R1 hydrogen, R2 tertiary butyl, iso-propyl, iso-butyl, sec. butyl, cyano, bromine, or the group -O-CF3, -SO2-CH3 in the para-position, R3 the group R4 hydrogen, R5 hydrogen or the group, -(CH2)-CHCH3-OH, -(CH2)2-O-CH3, -CHCH3-CH2-OH, R6 methyl, ethyl, propyl, 2-methoxyethyl, -CH2-CF3-, -(CH2)2-CF3 and benzyl, as well as their isomers, diastereomers, enantiomers and salts.

7. The compound as claimed in claims 1-6, selected from a group comprising the following compounds:

1. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide 2. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1H-indole-2-carboxylic acid (2-morpholin-4-ylethyl)amide 3. (~)-5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxy-1-methylethyl)amide 4. (~)-5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxypropyl)amide 5. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-phenyl-1H-indole-2-carboxylic acid-(pyridin-4-yl)amide 6. 5-[(4-tert-butylphenylsulfonyl)benzylamino]-3-phenyl-1H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide 7. 5-[(4-tert-butylphenylsulfonyl)benzylamino]-3-phenyl-1H-indole-2-carboxylic acid (2-morpholin-4-ylethyl)amide

8. (~)-5-[(4-tert-butylphenylsulfonyl)benzylamino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxy-1-methylethyl)amide

9. (~)-5-[(4-tert-butylphenylsulfonyl)benzylamino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxypropyl)amide

10. 5-[(4-tert-butylphenylsulfonyl)-(2-methoxyethyl)amino]-3-phenyl-1H-indole-carboxylic acid-(tetrahydropyran-4-yl)amide

11. 5-[(4-tert-butylphenylsulfonyl)-(2-methoxyethyl)amino]-3-phenyl-1H-indole-carboxylic acid (2-morpholin-4-ylethyl)amide

12. (~)-5-[(4-tert-butylphenylsulfonyl)-(2-methoxyethyl)amino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxy-1-methylethyl)amide

13. (~)-5-[(4-tert-butylphenylsulfonyl)-(2-methoxyethyl)amino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxypropyl)amide

14. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-fluorophenyl)-1H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide

15. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-fluorophenyl)-1H-indole-2-carboxylic acid (2-morpholin-4-ylethyl)amide

16. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-methoxyphenyl)-1H-indole-2-carboxylic acid-(tetrahydropyran-4-yl)amide

17. 5-[(4-tert-butylphenylsulfonyl)methylamino]-3-(3-methoxyphenyl)-1H-indole-2-carboxylic acid (2-morpholin-4-ylethyl)amide 8. A medicinal product that contains at least one of the compounds as claimed in claims 1-7.

9. The medicinal product as claimed in claim 8, which contains the compound of general Formula 1 at an effective dose.

10. The compound of general Formula 1 as claimed in claims 1-7 for the production of medicinal products.

11. The medicinal product as claimed in claim 10 for the treatment of diseases.

12. The medicinal product as claimed in claim 11, where the diseases are caused by disturbances in cAMP metabolism.

13. The medicinal product as claimed in claim 10 for contraception.

14. The medicinal product as claimed in claim 10 for the inhibition of soluble adenylate cyclase.

15. The medicinal product as claimed in claims 10-14 with suitable vehicles and excipients.

16. The use of the compound of general Formula 1 as claimed in claims 1-7 in the form of a pharmaceutical preparation for enteral, parenteral, vaginal and oral application.

17. A process for preparing the compounds of general Formula (I), characterized in that a compound of Formula II

where R1, R2, R3 and R6 are each as defined above and R7 can be hydrogen or C1-C6-alkyl, in which case hydrogen is preferred, and where C1-C6-alkyl is preferably methyl or ethyl, is reacted with an amine of general Formula III

to form, after cleavage of any required protective groups, the compounds of general Formula (I).

18. An intermediate of general Formula (II) where R1, R2, R3 and R6 are each as defined above and R7 can be hydrogen or C1-C6-alkyl, of general Formula (VII) where R1, R2 and R7 are each as defined above, or of general formula (IX) where R1, R2, R 6 and R7 are each as defined above.