EP2001846A1

EP2001846A1 - Indole derivatives as inhibitors of the soluble adenylate cyclase

Info

Publication number: EP2001846A1
Application number: EP07723650A
Authority: EP
Inventors: Bernd Buchmann; Bernd Menzenbach; Dirk Kosemund; Martin Fritsch
Original assignee: Bayer Schering Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2006-03-23
Filing date: 2007-03-22
Publication date: 2008-12-17
Also published as: WO2007107383A1; DE102006014324A1; UY30235A1; CA2647092A1; US7449459B2; AR060075A1; KR20090007352A; US20070232605A1; JP2009530338A; DOP2007000058A; TW200815346A; CN101448788A; DE102006014324B4; PE20080127A1

Abstract

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

Description

INDOLDER DERIVATIVES AS INHIBITORS OF THE SOLUBLE ADENYLATE CYCLASE

The present invention relates to inhibitors of soluble adenylate cyclase, their preparation and their use for the manufacture of a medicament for contraception.

Women currently have a variety of modern contraceptive methods available, but very few methods are available for male fertility control (condom and sterilization). The development of new reliable means for male fertility control is imperative. The infertility caused by a "male pill" should be completely reversible and just as effective as the existing methods available to women. Infertility should start relatively quickly and be long-lasting. Such a method of contraception should have no side effects In addition to hormonal approaches, this can also be non-hormonal approaches. One possible starting point is the regulation of the activity of an enzyme that plays an important role in the fertilization of the egg cell, the soluble adenylate cyclase (sAC). This enzyme is mainly used in the testicular Stem cells expressed and is present in mature sperm.

In 1999, the authors Levin and Bück (Proc. Natl. Acad. Sei. USA 96 (1): 79-84) succeeded in cleaning and cloning an isoform of the sAC from the rat's testes.

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, sperm, kidneys and the choroid plexus. These disclosures are the subject of application WO01 / 85753, which was issued in the US (US6544768).

In WO01 / 21829 (Conti et al.) Isolated polynucleotide sequences coding for the human isoform of the sAC, isolated sAC polypeptides and Test systems are claimed which can be used to identify substances which inhibit the activity of the sAC. The possibility of using these substances to reversibly reduce the number of motile sperm cells and their use as a means of male fertility control is disclosed.

John Herr's group demonstrated the isolation and characterization of the human isoform of sAC from sperm. In addition to nucleic acids which code for the sAC, WO 02/20745 also claims test systems which can be used to identify substances which modulate the expression or the activity of the human sAC. Such compounds could, for example, selectively inhibit the activity of the sAC, with the result that the sperm cells lose the ability to fertilize an egg cell. These sAC inhibitors could therefore serve as drugs for non-hormonal contraception.

However, the already known sAC inhibitors show specific problems: catechol oestrogens (T. Braun, Proc Soc Exp Biol Med 1990, 194 (1): 58ff) and Gossypol (KL Olgiati, Arch Biochem Biophys 1984, 231 (2): 411ff) inherently toxic, while adenosine analogs inhibit only with very weak effects (MA Brown and ER Casillas, J Androl 1984, 5: 361ff). The inhibitors (IC ₅₀ £ 10 μM) of the recombinant human sAC, which were described by Zippin et al. (JH Zippin et al. J Cell Biol 2004, 164 (4): 527ff).

In order to be able to provide a means for male fertility control, there is an increasing need for substances which lead to infertility reversibly, quickly and with good success.

This object is achieved by providing the compounds of the general formula I where R ^{1 is} hydrogen, halogen, CF ₃ , C ₃ -C ₆ -cycloalkyl, which is optionally multiply saturated and optionally multiply substituted, or the group C ₁ -C ₆ -AIKyI, Ci-C ₆ -aryl, Ci-C ₆ -Acyl, halo-CrC ₆ -alkyl, CrCe-alkyl-d-Ce-alkyl. d-Ce-alkyl-CrCe-acyl, Ci-C ₆ -ACyI-C ₁ -C ₆ - acyl, CrCe-alkyl-d-Ce-aryl, dC ₆ -aryl-dC ₆ -alkyl or CF ₃ , in which Ci-Cβ-alkyl, d-Ce-aryl, C ₁ -C ₆ -acyl, halo-dC ₆ alkyl, C ₁ -C ₆ - alkyl-dC ₆ alkyl, C ₁ -C ₆ -alkyl ky 1- C ₁ -C ₆ -ACy I, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, d-Ce-alkyl-d-Ce-aryl or d-Ce-aryl-d-Ce-alkyl, if appropriate or can be interrupted several times, identically or differently by oxygen, sulfur or nitrogen, or the group sulfonyl-dC ₆ -alkyl, sulfonamide, or cyano,

R ^ halogen, CF ₃ , C ₃ -C ₆ cycloalkyl, which is optionally poly-saturated and optionally poly-substituted, or the group dC ₆ -alkyl, C ₁ -C ₆ -AIyI, C ₁ -C ₆ -ACyI, halo -dC ₆ alkyl, d-Ce-alkyl-d-Ce-alkyl, alkyl-dC dC ₆ ₆ acyl, C ₁ -C ₆ -acyl-C ₁ -C ₆ - acyl, dC ₆ alkyl-dC ₆ -aryl, d-Ce-aryl-d-Ce-alkyl or CF ₃ , in which Ci-C ₆ -alkyl, Ci-C ₆ -aryl, C ₁ -C ₆ -ACyI, halo-dC ₆ -alkyl, C ₁ -C ₆ -alkyl-d-Ce-alkyl. CrCe-alkyl-d-Ce-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, CrCe-alkyl-CrCe-aryl or dC ₆ -aryl-dC ₆ -alkyl, optionally one or more times, the same or can be interrupted differently by oxygen, sulfur or nitrogen, or the group sulfonyl-dC ₆ -alkyl, sulfonamide, or cyano,

R ^J C ₆ -d ₂ -aryl, which may be substituted one or more times, identically or differently with halogen, with dC ₆ -alkyl or C ₁ -C ₆ -aryl, which may optionally be substituted one or more times, or substituted with C ₁ -C ₆ -AlKOXy, hydroxy, cyano, CO ₂ - (Ci-C ₆ -alkyl), N- (C ₁ - C ₆ -alkyl) ₂ , CO-NR ⁴ R ⁵ or with CF ₃ can be C ₅ -C ₁₂ heteroary !, which may be one or more, identical or different with halogen, with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -acyl, C ₁ -C ₆ -alkoxy, hydroxy, cyano , CO ₂ - (CrC ₆ -alkyl), N- (C ₁ -C ₆ -AIkVl) ₂ ,

CO-NR ⁴ R ⁵ or can be substituted with CF ₃ or C ₃ -C ₆ cycloalkyl, which may be one or more, identical or different with halogen, CF ₃ , hydroxy, cyano, CO ₂ - (Ci-Cβ- Alkyl), d-Ce-alkyl, C ₁ -C ₆ -ACyI, N- (C ₁ -C ₆ -alkyl) ₂ , CO-NR ⁴ R ⁵ or Ci-C ₆ -alkoxy may be substituted,

R ^{4 is} hydrogen, C ₃ -C ₆ -cycloalkyl, which is optionally substituted one or more times, identically or differently, with dC ₆ -alkyl, C ₁ -C ₆ -ACyI, C ₁ - C ₆ -alkoxy or CF ₃ , C ₆ -C ₁₂ aryl, which optionally one or more, the same or different with halogen, d-Ce-alkyl, Ci-C ₆ -acyl, C ₁ -C ₆ -alkoxy, Nd-Ce-alkyl-d-Ce Alkyl, CF ₃ or cyano is substituted, or C ₅ -C ₁₂ heteroaryl, which may be one or more, identical or different, with halogen,

Ci-Cβ-alkyl, C ₁ -C ₆ -ACyI, C ₁ -C ₆ -AIkOXy, Nd-Ce-alkyl-d-Ce-alkyl,

CF ₃ or cyano, is substituted, or d-Ce-alkyl, which can be substituted as desired,

R ^{5 is} hydrogen, dC ₆ -alkyl-C ₃ -C ₆ -cycloalkyl, which is optionally one or more, identical or different 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 monosubstituted or polysubstituted, identically or differently with Ci-C ₆ alkyl, C ₁ -C ₆ -acyl, C ₁ -C ₆ -alkoxy or CF ₃ substituted is

C ₆ -C ₁₂ aryl, which may be one or more, identical or different with halogen, with dC ₆ alkyl, C ₁ -C ₆ -ACyI, C ₁ -C ₆ - Alkoxy, N-Ci-C ₆ alkyl-Ci-C ₆ alkyl, CF ₃ or cyano is substituted, or

Cs-C ^ heteroary !, which optionally one or more, the same or different with halogen, Ci-Cβ-alkyl, Ci-C ₆ -acyl, Ci-C ₆ -AIkOXy, N-Ci-Ce-alkyl-d -Ce-alkyl, CF ₃ or cyano, or CrCβ-alkyl, which can be substituted as desired,

R ⁴ and R ⁵ together form a 5-8 membered ring, which may contain further heteroatoms, and

X is the groups sulfonyl, (CH ₂ ) _n or carbonyl,

Y - (CH ₂ ) _n - or -CH = CH-,

n 1 - 4,

mean, and their isomers, diastereomers, enantiomers and salts, which overcome the known disadvantages and have improved properties, i.e. have good effectiveness, good solubility and stability. The compounds according to the invention inhibit the soluble adenylate cyclase and thus prevent the sperm from capacitating and thus serve for male fertility control.

Alkyl is in each case a straight-chain or branched alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, isopentyl and hexyl.

Alkoxy in each case is a straight-chain or branched alkoxy radical, such as, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert. To understand butyloxy, pentoxy, isopentoxy and hexoxy. Acyl is in each case a straight-chain or branched radical, such as, for example, formyl, acetyl, propiony !, butyroyl, isobutyroy !, valercyl and benzoy! to understand.

Cycloalkyl is to be understood as meaning monocyclic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The cycloalkyl radicals can contain one or more heteroatoms, such as oxygen, sulfur and / or nitrogen, instead of the carbon atoms. Such heterocycloalkyls having 3 to 6 ring atoms are preferred. Among the ring systems in which one or more possible double bonds in the

Ring can be included, for example, cycloalkenyls such as cyclopropenyl,

To understand cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, where the linkage can take place both on the double bond and on the single bonds.

Halogen is to be understood as fluorine, chlorine, bromine or iodine.

The aryl radical each has 6 to 12 carbon atoms and can be benzo-fused, for example. Examples include: phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, florenyl, anthracenyl etc.

The heteroaryl radical each 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 benzo-fused in each case.

Examples include: thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzooxazolyl, benzimdazolol, indazoldazolol, indazazolyl, indazazolyl, indazoldazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazyldolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indazolyl, indol, etc. or pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and Benzo derivatives thereof such as quinolyl, isoquinolyl, etc; or azocinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnoüny !, phthalazinyl, ghinazoüny !, quinoxalinyl, naphthyridiny !, pteridiny !, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxepinyl, etc.

The heteroaryl radical can in each case be benzo-condensed. Examples include 5-ring heteroaromatics: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and benzo derivatives thereof, and 6-ring heteroaromatics pyridine, pyrimidine, triazine, quinoline, isoquinoline and benzo derivatives.

Heteroatoms are understood to mean oxygen, nitrogen or sulfur atoms.

If an acidic 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 metal salts and N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, 1,6-hexadiamine , Ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methylamino-methane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol.

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

Those compounds of the general formula (I) are particularly preferred, wherein

R ^{1 is} hydrogen, halogen, CF ₃ , C ₃ -C ₆ cycloalkyl, or the group C ₁ -

Cβ-alkyl, CrC ₆ -aryl, C ₁ -C ₆ -ACyI, halo-CrC ₆ -alkyl, Ci-C ₆ -alkyl-d- C ₆ -alkyl, CrC ₆ -alkyl-CrC ₆ -acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, C ₁ -C ₆ - alkyl-CrCβ-aryl, CrC ₆ -aryl-Ci-C ₆ -alkyl or CF ₃ , in the C ₁ -C ₆ -alkyl , CrC ₆ -aryl, Ci-C ₆ -acyl, halo-C _r C ₆ -alkyl, C ₁ -C ₆ -A ^ yI-C ₁ -C ₆ - Alkyl, Ci-C ₆ -AIkYl-C ₁ -C ₆ -ACyI ₁ Ci-C ₆ -ACyI-C ₁ -C ₆ -ACyI, C ₁ -C ₆ -AIKyI- dC ₆ -aryl or dC ₆ -aryl- d -C ₆ -alkyl may optionally be interrupted one or more times, identically or differently, by oxygen, sulfur or nitrogen, or the group sulfonyl-C ₁ -C ₆ -alkyl, sulfonamide or cyano,

R ^{2 is} halogen, CF ₃ , C ₃ -C ₆ cycloalkyl, or for the group Ci-C ₆ alkyl,

Ci-C ₆ -aryl, C ₁ -C ₆ -ACyI, halo-Ci-C ₆ -alkyl, Ci-C ₆ -alkyl-Ci-C ₆ -alkyl, d-Ce-alkyl-Ci-Ce-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, C ₁ -C ₆ -AIkYl-C ₁ -C ₆ - aryl, C ₁ -C ₆ -AIyI-C ₁ -C ₆ -alkyl or CF. ₃ , in the C ₁ -C ₆ alkyl, C ₁ -C ₆ -

Aryl, C ₁ -C ₆ -acyl, halo-dC ₆ alkyl, d-Ce-alkyl-d-Ce-alkyl, C ₁ -C ₆ - alkyl-dC ₆ acyl, C ₁ -C ₆ -ACyI- C ₁ -C ₆ -ACyI, dC ₆ -alkyl-dC ₆ -aryl or d-Ce-aryl-d-Cβ-alkyl optionally one or more times, identically or differently, can be interrupted by oxygen, sulfur or nitrogen, or the Group sulfonyl-dC ₆ -alkyl, sulfonamide, or cyano,

R ^{3 is} C ₆ -C ₁₂ aryl, which may be one or more, identical or different with halogen, with C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, cyano, Hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (dC ₃ -alkyl), CO-NR ⁴ R ⁵ or can be substituted by CF ₃ ,

C ₅ -C ₁₂ heteroaryl, which may be one or more, identical or different with chlorine and / or fluorine, with C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, Cyano, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (C ₁ -C ₃ -alkyl), CO-NR ⁴ R ⁵ or can be substituted by CF ₃ ,

C ₃ -C ₆ cycloalkyl, which may be one or more, identical or different, with chlorine and / or fluorine, CF _3, cyano, dC ₃ alkyl, C ₁ -C ₃ alkyl, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (C ₁ -C ₃ -alkyl), CO-

NR ⁴ R ⁵ or Ci-C ₃ alkoxy may be substituted,

R ^■ > 4 hydrogen, C ₃ -C ₆ cycloalkyl, which is optionally substituted one or more times, identically or differently, with dC ₃ alkyl, C ₁ -C ₃ alkyl, C ₁ - C ₃ alkoxy or CF ₃ , C ₆ -Ci ₂ aryl, which may be one or more, identical or different with halogen, Ci-C ₃ alkyl, Ci-C ₃ -acyl, CrC ₃ - alkoxy, NC ₁ -C ₃ -AIKyUCi-C ₃ -AIkV '!, CF ₃ or cyano is substituted, or C ₅ -C ₁₂ heteroaryl, which optionally one or more times, identically or differently, with halogen, Ci-C ₃ -alkyl, Ci-C ₃ -acyl, Cr C ₃ -alkoxy, N-CrC ₃ -alkyl-Ci-C ₃ -alkyl, CF ₃ or cyano, or CrC ₆ -alkyl, which can be substituted as desired,

R ^{5 is} hydrogen, CrC ₆ -alkyl-C ₃ -C ₆ -cycloalkyl, which may be one or more, identical or different with d-Cβ-alkyl, Cr C ₆ -acyl, C ₁ -C ₆ -alkoxy or CF ₃ C ₃ -C ₆ cycloalkyl which is optionally substituted one or more times, identically or differently, with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, CrC ₃ alkoxy or CF ₃ ,

C ₆ -C ₁₂ aryl, which may be one or more, the same or different, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, NC ₁ -C ₃ -AIkVl-Ci-C ₃ -AIkVl, CF ₃ or cyano is substituted, or

C ₅ -Ci ₂ heteroaryl, which may be one or more, identical or different, with halogen, CrC ₃ alkyl, CrC ₃ acyl, Cr C ₃ alkoxy, N-Ci-C ₃ -alkyl-Ci-C3- Alkyl, CF ₃ or cyano, or Ci-Cβ-alkyl, which can be substituted as desired,

X is the groups sulfonyl, (CH ₂ ) _n or carbonyl,

Y - (CH ₂ ) ,, - or -CH = CH-, n 1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

Also preferred are those compounds of general formula I, wherein

R ^{1 is} hydrogen,

R ² C ₃ -C ₆ cycloalkyl, Ci-C ₆ alkyl, CF ₃ , cyano, bromine, or the group

-OCF ₃ , -SO ₂ -CH ₃ ,

R ^{3 is} C ₆ -Ci ₂ aryl, which may be one or more, identical or different with halogen, C ₁ -C ₆ -alkyl, CrC ₃ -acyl, CrC ₃ -

Alkoxy, cyano, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (Ci-C ₃ -alkyl), CO-NR ⁴ R ⁵ or CF ₃ can be substituted,

C ₅ -Ci ₂ heteroaryl, which optionally one or more times, identically or differently with chlorine and / or fluorine, with CrCβ-alkyl, Ci-C ₃ -acyl, Ci-C ₃ -alkoxy, cyano, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (CrC ₃ -

Alkyl), CO-NR ⁴ R ⁵ or can be substituted with CF ₃ , C ₃ -C ₆ cycloalkyl, which may be one or more, identical or different with chlorine and / or fluorine, CF _3, cyano, d-Ca -Alkyl, C ₁ -C ₃ -ACyI, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (C ₁ -C ₃ -alkyl), CO- NR ⁴ R ⁵ or CrC ₃ -alkoxy may be substituted,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen, Ci-C ₆ alkyl-C ₃ -C ₆ cycloalkyl, which may be one or more, the same or different with CrCβ-alkyl, Cr

C ₆ -acyl, CrCβ-alkoxy or CF _{3 is} substituted, C ₃ -C ₆ cycloalkyl, which may be one or more, identical or is differently substituted with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -acyl, C ₁ -C ₃ -alkoxy or CF ₃ ,

C ₆ -Ci ₂ -ArVl, which may be one or more, identical or different with halogen, Ci-C ₃ alkyl, Ci-C ₃ -acyl, Ci-C ₃ - alkoxy, N-Ci-C ₃ alkyl -Ci-C ₃ alkyl, CF ₃ or cyano is substituted, or

C ₅ -Ci ₂ heteroaryl, which is optionally one or more, identical or different with halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ acyl, C ₁ -C ₃ alkoxy, NC _r C ₃ alkyl -Ci-C ₃ alkyl, CF ₃ or cyano, is substituted, or

C ₁ -C ₆ alkyl, which can be substituted as desired,

X the group sulfonyl,

Y - (CH ₂ ) _n - or -CH = CH-,

1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

Such compounds of the general formula I ₁ are also preferred

R ^{1 is} hydrogen,

R ² C ₃ -C ₆ cycloalkyl, d-Ce-alkyl, CF ₃ , cyano, bromine, or the group

-OCF ₃ , -SO ₂ -CH ₃ and are in the para position,

R ³ C ₆ -Ci ₂ -aryl, which may be mono- or bivalent, identical or different with halogen, Ci-C ₃ -alkyl, acetyl, methoxy, E Etthhooxxyy ,, CCyyaannoo ,, HHyyddrrooxxyy ,, NN - ((CCHH ; ₃ ) ₂ , CO ₂ - (Ci-C ₃ alkyl), CO-NHR ⁵ or CF ₃ can be substituted, C ₅ -Ci ₂ heteroaryl, which may be mono- or discrete, identical or different with chlorine and / or fluorine, with Ci-C _ß- alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N- (CHa) ₂ , CO ₂ - (C ₁ -C ₃ alkyl), CO-NHR ⁵ or can be substituted by CF ₃ , C ₃ -C ₆ cycloalkyl,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen, CrCβ-alkyl-Cs-Cβ-cycloalkyl, which may be one or more, identical or different with Ci-Cβ-alkyl, C ₁ -

C ₆ -acyl, Ci-C ₆ -alkoxy or CF _{3 is} substituted, C ₃ -C ₆ -cycloalkyl, which may be one or more, identical or different with Ci-C ₃ -alkyl, CrC ₃ -acyl, C ₁ -C ₃ -alkoxy or CF ₃ being substituted, C ₆ -C ₁₂ aryl, which is optionally substituted one or more times, identically or differently with halogen, C-ι-C ₃ -alkyl, C ₃ acyl, C ₁ -C ₃ -

Alkoxy, N-CrCs-alkyl-CrCs-alkyl, CF ₃ or cyano is substituted, or

C ₅ -C ₁₂ heteroaryl, which may be one or more, identical or different with halogen, C ₁ -C ₃ -A ^ yI, C ₁ -C ₃ -ACyI, C ₁ -

C ₃ -alkoxy, N-CrCs-alkyl-d-Cs-alkyl, CF ₃ or cyano, or d-Cβ-alkyl, which can be substituted as desired,

X the group sulfonyl,

Y - (CH ₂ ) _n - or -CH = CH-,

n 1 - 2

mean, and their isomers, diastereomers, enantiomers and salts. Such compounds of the general formula I ₁ are also preferred

R ^{1 is} hydrogen,

R ² tertiary butyl, iso-propyl, iso-butyl, sec. Butyl, cyano, bromine or the group -0-CF ₃ , -SO ₂ -CH ₃ and is in the para position,

R ^J the group

,

R «hydrogen, R ^{5 is} hydrogen or the group - (CH ₂ ) nN- (CH ₃ ) 2, - (CH ₂ ) 2-CH ₃ , - (CHz) ₂ -NH-COCH ₃ , - (CHz) -CHCH ₃ -OH, - (CH ₂ ) 2-O-CH3, - (CHo) ₂ -OH, -CHCH ₃ -CH ₂ -OH,

X the group sulfonyl,

Y - (CH ₂ ) _n - or -CH = CH-,

1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

Also preferred are those compounds of general formula I, wherein R ^{1 is} hydrogen,

R 'tertiary butyl, iso-propyl, iso-butyl, sec. Butyl, cyano, bromine or the group -0-CF ₃ , -SO ₂ -CH ₃ and is in the para position,

R ^J the group

R is hydrogen,

R "is hydrogen or the group, - (CH ₂ ) -CHCH ₃ -OH, - (CHz) ₂ -O-CH ₃ , -CHCH ₃ -CH ₂ -OH,

the group sulfonyl,

Y - (CH ₂ J _n - or -CH = CH-, and

1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

The following compounds according to the present invention are very particularly preferred:

1. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (tetrahydropyran-4-yl) acrylic acid amide

2. (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-morpholin-4-yl-ethyl) - acrylic acid amide

3 .. (±) - (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-hydroxy-1- methyl ethyl) acrylic acid amide 4 .. (±) - (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] - N- ( 2-hydroxypropyl) acrylic acid amide 5. 3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-morpholin-4-yl -ethyl) -propionic acid amide

6. (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3- (3-fluorophenyl) -1H-indol-2-yl] - N- (tetrahydro-pyran-4- yl) acrylic acid amide

7. (E) -3- [5- (4-tert-Butyl-ρhenylsulfonylamino) -3- (3-fluorophenyl) -1 H -indol-2-yl] - N- (2-morpholin-4 -yl-ethyl) -acrylamide

8. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3- (3-methoxyphenyl) -1 H -indol-2-yl] -N- (tetrahydropyran-4 -yl) acrylic acid amide

9. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3- (3-methoxyphenyl) -1 H -indol-2-yl] -N- (2-morpholin-4 -yl-ethyl) -acrylamide 10. (E) -3- [5- (4-tert-Butyl-phenylsulfonylamino) -3- (3-fluorophenyl) -1 H -indol-2-yl] -

N- (pyridin-4-yl) acrylic acid amide

11. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3- (3-methoxyphenyl) -1 H -indol-2-yl] -N- (pyrindin-4-yl ) acrylic acid amide

The invention also relates to a process for the preparation of the compounds of the general formula I according to the invention, which is characterized in that a compound of the formula II,

wherein R ¹ , R ² , R ³ , X and Y have the meanings given above and R ^{6 can be} a hydrogen or a CrC ₆ -alkyl radical, preference is given to hydrogen, the methyl or ethyl radical, with an amine of the general formula IN THE

/ ^R5 ^R4 (III) in which R ⁴ and R ^{5 have} the meaning given above, are reacted by methods known to the person skilled in the art and / or protective groups which may be required are subsequently cleaved and / or any double bonds which are present are hydrogenated.

In the event that R ⁶ is hydrogen, the reaction can first be carried out by activating the acid function, in this case, for example, the carboxylic acid of the general formula II is first in the presence of a tertiary amine, such as triethylamine, with isobutyl chloroformate in the mixed anhydride transferred. The reaction of the mixed anhydride with the alkali salt of the corresponding amine is carried out in an inert solvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric säuretriamid, at temperatures between -30 ° C and +60 ⁰ C, preferably from 0 ⁰ C to 30 ⁰ C.

Another possibility is to activate the carboxylic acid of the general formula II by reagents such as HOBt or HATU. The acid is reacted, for example, with HATU in an inert solvent such as DMF in the presence of the corresponding amine of the general type Formula III and a tertiary amine such as ethyldiisopropylamine at temperatures between -50 and +60 ⁰ C, preferably at 0 ⁰ C to 30 ⁰ C.

In the event that R ⁶ is C ₁ -C ₆ -alkyl, for example direct amidolysis of the ester with the corresponding amine can 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 the nitro group in the known indole esters IV

wherein R ^{7 is} a C ₁ -C ₆ -alkyl radical, preferably a methyl or ethyl radical, is first reduced to the amino function in a hydrogen atmosphere or a hydrogen source such as ammonium formate in the presence of a Pd catalyst and then this amine with a halide of the general formula V

wherein R ¹ , R ² and X have the meanings given above and HaI represents a halogen, preferably chloride or bromide, in the presence of a base such as pyridine, diisopropylethylamine, triethylamine or potassium carbonate to give the compounds of the general formula VI

The esters of the general formula VI are then halogenated in the 3-position, for example by means of! Od, NBI ₁ NBS or also CuBr ₂ and then in a Pd-catalyzed reaction with boronic acid derivatives of the general formula VII

, B (OH) ₂

R3 '(VII), in which R ^{3 has} the meaning given above, and subsequent reduction, for example with diisobutylaluminum hydride, into the alcohols of the general formula VIII

wherein R ¹ , R ² , R ³ , R ⁷ and X have the meanings given above, transferred.

The conversion of the alcohols VIII into the compounds of the general formula II takes place either

a) by converting the alcohol into a leaving group, for example by reaction with PBr ₃ , thionyl chloride, tosyl chloride or mesyl chloride or CBr ₄ / PPh ₃ and subsequent reaction with cyanide. The cyanides obtained in this way can either be saponified to the corresponding carboxylic acids and, if appropriate, then subsequently esterified with R ⁶ -OH by the methods known to the person skilled in the art.

The corresponding carboxylic acids could alternatively also be obtained by a reduction, for example with diisobutylaluminum hydride, hydrolysis followed by an oxidation, for example with a Jones reagent, or b) by manganese dioxide oxidation of the alcohols followed by a Horner-Wittig reaction of the resulting aldehydes with reagents such as

wherein R ^{6 has} the meaning given above but not hydrogen and R ⁸ is methyl, ethyl or trifluoroethyl, optionally followed by hydrogenation in a hydrogen atmosphere in the presence of a Pd catalyst and, if appropriate, then the esters obtained are saponified by methods known to those skilled in the art , or

c) by reducing the cyanides obtained under a) e.g. with diisobutyl aluminum hydride and hydrolysis followed by a Horner-Wittig

Reaction of the resulting aldehydes with reagents such as

wherein R ⁶ and R ^{8 have} the meanings given above, but R ^{6 is} not equal to hydrogen, followed by hydrogenation in a hydrogen atmosphere in the presence of a Pd catalyst and, if appropriate, subsequently the resulting esters are saponified by methods known to those skilled in the art.

The compounds according to the invention inhibit the soluble adenylate cyclase, on which their action is based, for example, on male fertility control. Adenylate cyclases are the effector molecules for one of the most commonly used signal transduction pathways, they synthesize the second messenger molecule, cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) with elimination of pyrophosphate (PP). cAMP provides numerous cellular responses for 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 adenylate cyclases described in the human genome. sAC shows 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 has no transmembrane regions in its amino acid sequence, it cannot be inhibited by forskolin, is much more stimulable by manganese than by magnesium, and shows only low sequence homologies 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).

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 that stimulates the activity of the sAC in boar seminal fluid is bicarbonate. It could also be shown that bicarbonate-stimulable AC activity can only be detected in rat testis and sperm, but not in other tissues. sAC was purified from the rat testis by the group Bück and Levin and sequenced for the first time (J. Bück et al. 1999 PNAS 96: 79ff, WO 01/85753). The expected properties (e.g. bicarbonate and magnesium stimulability) were confirmed on the recombinantly expressed protein (Y. Chen et al. 2000 Science 289: 625ff).

Data on the distribution of sAC mRNA and on bicarbonate-stimulable sAC activity suggest testis and sperm-specific expression of the enzyme (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, the germ cells developing into sperm, but not in somatic cells (ML Sinclair et al. 2000 Mol Reprod Develop 56: 6ff).

There are a number of pharmacological studies on the function of sAC in sperm in mammals. Sperm must be prepared for this functionality before they can penetrate the egg's zona pellucida and then fuse with the egg's oolemma. This process, sperm capacitation, has been studied fairly well. A capacitated sperm is characterized by a changed pattern of movement and by the ability to use a suitable stimulus to go through the process of the acrosomal reaction (a release of lytic enzymes that presumably serve to penetrate the zona pellucida through the sperm). Sperm capacitation takes place in vivo and in vitro, among others. depending on an increased bicarbonate concentration in the medium (PE Visconti & GS Kopf (1998) Biol Reprod 59: 1 ff; E de Lamirande et al. 1997 Mol Hum Reprod 3 (3): 175ff). Sperm capacity can also be stimulated by the addition of suitable membrane-compatible cAMP analogs, e.g. db-cAMP, and an inhibitor that inhibits their breakdown (e.g. IBMX). The suspected dependence of sperm function on sAC was only recently confirmed by a genetic deletion model, a so-called knock-out mouse (G Esposito et al. 2004 PNAS 101 (9): 2993ff). Male 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 ef al 2003 FASEB 17: 82ff).

The sAC has a unique sequence and little homology to other somatic adenylate cyclases. It is the only adenylate cyclase in mammalian sperm and the activity is for sperm motility and activity Capacitation essential. Specific sAC inhibitors are therefore an important way to regulate male fertility.

Medicaments which contain at least one of the compounds according to claims 1- 7 are therefore the subject of the present invention.

The present invention also relates to the use of the compounds according to claims 1-7.

To use the compounds according to the invention as pharmaceuticals, they are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch , Magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can be in solid form, for example as tablets, dragées, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers; Salts to change 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.

Surface-active auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems. Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. It can also be used in liquid form, for example as juice, to which a sweetener may be added.

For vaginal application z. B. suppositories suitable and common.

The enteral, parenteral, vaginal and oral applications are also the subject of the present invention.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can 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, among other things, 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 controlling 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 crucial can be modulated by inhibitors of the soluble adenylate cyclase. This modulation can have prophylactic and therapeutic effects for the patients suffering from such a disease. At the moment, diseases that, like cancer, are associated with increased cell proliferation, are being treated, for example, by radiation therapy and chemotherapy. These procedures are non-specific and have a high potential for side effects. The provision of new substances that intervene directly at certain target locations is therefore advantageous. The present invention relates to substances that cause cAMP production modulate the inhibition of soluble adenylate cyclase. For example, the abnormal cell proliferation can be reduced or inhibited by regulating or inhibiting cAMP production. By using the substances according to the invention, the soluble adenylate cyclase can be inhibited, which results in a decrease in cell proliferation. The present invention relates to medicaments for the treatment of diseases which contain at least one compound of the general formula I, and to medicaments with suitable formulations and carriers. The diseases are characterized by the fact that they are caused by disorders in the metabolism of the second messenger cAMP.

Lowering the cAMP concentration by inhibiting the soluble adenylate cyclase can provide means for modulating sperm capacitation. The present invention relates to the use of the substances according to the invention for lowering and / or inhibiting male germ cell fertility mediated by the reduction or inhibition of the soluble adenylate cyclase activity and, as a result, the sperm capacity.

By administering an effective amount of a substance that inhibits cAMP production, fertilization of the ovum can be prevented. The present invention also relates to the use of the compound of the general formula I for the manufacture of a medicament for non-hormonal contraception.

If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds or processes described here. It is also possible to carry out all the reactions described here in parallel reactors or using combinatorial working techniques. 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 salts are prepared in a customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of a base or acid, which is optionally in solution, and separating off the precipitate or working up the solution in a customary manner.

Preparation of the compounds according to the invention

The following examples illustrate the preparation of the compounds of the general formula (I) according to the invention, without restricting the scope of the claimed compounds to these examples.

The compounds of the general formula (I) according to the invention can be prepared as described below.

Example 1: (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] - N- (tetrahydro-pyran-4-yl) acrylic acid amide

43.7 mg of N - [(dimethylamino) -1 / - / - 1, 2,3-triazolo [4,5- b] pyridine-1- are added to a solution of 50 mg of the acid prepared in Example 1h) in 0.84 ml of dimethylformamide. ylmethylene] -Λ / -Methylmethanaminiumhexafluorophosphat-N-oxide

(HATU) and 10.7mg 4-aminotetrahydropyran. At 0 ⁰ C then 19.5μl ethyldiisopropylamine are added dropwise and stirred for 20 hours at room temperature. Then add 15 ml of water, stir for 30 minutes and suction. The residue thus obtained is purified by chromatography on silica gel with hexane / 0-70% ethyl acetate. 44 mg of the title compound are obtained in this way.

NMR (300 MHz, DMSO-d6): δ = 1.20 (s, 9H), 1.42 (2H), 1.68 (2H), 3.32 (2H), 3.79 (3H), 6.48 (1 H), 6.99 (1 H) , 7.10 (1 H), 7.20 (2H), 7.28 (1 H), 7.36 (1 H), 7.37 (1H), 7.42-7.53 (4H), 7.57 (2H), 8.13 (1 H), 9.79 (1 H), 11.63 (1H). The starting material for the above title compound is prepared as follows:

1 a) 5-Amino-1 H-indole-2-carboxylic acid ethyl ester

5g of 5-nitro-1 H-indole-2-carboxylic acid ethyl ester are placed in 170 ml of methanol and 0.5 ml of water, treated with 6.73g of ammonium formate and 50 mg palladium on charcoal (10%) and boiled for 1 hour at 90 ⁰ C to reflux . It is then suctioned off through Celite and washed with warm methanol. After removal of the solvent, the residue is mixed with 100 ml of water, stirred for 10 minutes and the precipitated solid is suctioned off through a G4 frit. The solid obtained in this way is dried in vacuo. In this way, 4.12 g of the title compound are obtained. NMR (300 MHz, DMSO-d6): δ = 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) 5- (4-tert-butylphenylsulfonylamino) -1 H-indole-2-carboxylic acid ethyl ester

5.18 ml of ethyldiisopropylamine and 4.69 g of 4-tert-butylphenylsulfonyl chloride are added to a solution of 4.12 g of the amine prepared in Example 1a) in 195 ml of DMF at ⁰ ° C. and the mixture is stirred for two hours at room temperature. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel with hexane / 0-80% ethyl acetate. In this way, 7.56 g of the title compound are obtained. NMR (300 MHz, DMSO-d6): δ = 1.20 (9H), 1.27 (3H), 4.27 (2H), 6.97-7.03 (2H), 7.25 (1 H), 7.31 (1 H), 7.48 (2H) , 7.59 (2H), 9.93 (1H), 11.80 (1H). 1 c) 3-bromo-5- (4-tert-butyl-phenylsulfonylamino) -1 H-indole-2-carboxylic acid, ethyl ester

3.36 g of N-bromosuccinimide are added to a solution of 7.56 g of the sulfonamide prepared in Example 1b) in 217 ml of tetrahydrofuran and the mixture is stirred for 40 minutes at room temperature. It is diluted with 300 ml of ethyl acetate, washed once with 50 ml of water and twice with 50 ml of saturated sodium chloride solution each time and the organic phase is dried over sodium sulfate. After filtration and concentration in vacuo, the residue thus obtained is recrystallized from hexane / ethyl acetate. 8.11 g of the title compound are obtained in this way. NMR (300 MHz, DMSO-d6): δ = 1.20 (9H), 1.30 (3H), 4.31 (2H), 7.08-7.15 (2H), 7.33 (1 H), 7.50 (2H) ₁ 7.60 (2H), 10.08 (1H), 12.16 (1H).

1 d) 5- (4-tert-Butyl-phenylsulfonylamino) -3-phenyl-1 H-indole-2-carboxylic acid, ethyl ester

4.86 g of phenylboronic acid and 70 ml of a 1M aqueous sodium carbonate solution and 3.29 g of lithium chloride are added to a solution of 13.3 g of the bromide prepared above in a mixture of 531 ml of ethanol and 531 ml of toluene. After adding 2.58 g of tetrakis (triphenylphosphine) palladium, the reaction mixture is refluxed for 20 hours. After cooling to room temperature, the product is filtered off with suction through Celite and washed with ethyl acetate. The organic phase thus obtained is washed with 500 ml of saturated sodium bicarbonate and saturated sodium chloride solution and dried over sodium sulfate. After concentration in a vacuum, this is how it works residue obtained purified by chromatography on silica gel with hexane / 0-70% ethyl acetate. In this way, 10.8 g of the title compound are obtained. NMR (300 MHz _: DMSO-d6): δ = 1.12 (3H), 1.21 (9H), 4.15 (2H), 7.03 (IH), 7.08 (1H), 7.21-7.41 (6H), 7.49 (2H), 7.52 (2H), 9.79 (1H), 11.84 (1H).

1 e) 5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indole-2-methanol

65 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene are slowly added dropwise to a solution of 10.3 g of the ester prepared in Example 1d), cooled to -70 ° C., in 93 ml of toluene. After the addition, the mixture is warmed to 0 ^° C. and stirred at this temperature for 2 hours. Then 4.3 ml of isopropanol and, after 10 minutes, 29 ml of water are carefully added dropwise and the mixture is stirred for 2 hours at room temperature. The white precipitate is filtered off, washed with 40 ml of ethyl acetate and the organic phase thus obtained is concentrated in vacuo. The residue is purified by chromatography on silica gel with hexane / 0-70% ethyl acetate. In this way, 4.2 g of the title compound are obtained.

NMR (300 MHz, DMSO-d6): δ = 1.25 (9H), 4.60 (2H), 5.34 (1H), 6.91 (1H), 7.18 (1H), 7.23-7.34 (4H), 7.39-7.49 (2H), 7.54 (2H), 7.59 (2H), 9.72 (1H), 11.31 (1H).

1 f) 5- (4-tert-butyl-phenylsulfonylamino) -3-phenyl-1 H-indole-2-carbaldehyde

800 mg is added to a solution of 500 mg of the alcohol prepared in Example 1e) in 7.5 ml of methylene chloride with stirring at room temperature Manganese dioxide in portions and stirred for a further 18 hours at this temperature. It is then suctioned off through Celite and washed well with ethyl acetate. After concentrating the organic phase in vacuo, 330 mg of the title compound are obtained, which is used in the next step without further purification.

NMR (300 MHz, DMSO-d6): δ = 1.20 (9H), 7.15 (1 H), 7.26 (1 H), 7.33-7.60 (10H), 9.71 (1 H), 9.93 (1 H), 12.05 ( 1H).

1 g) (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] - ethyl acrylate

To a suspension of NaH 106mg in 1.5ml of dimethoxyethane is added dropwise at 0 ⁰ C under nitrogen, a solution of 511mg of triethyl phosphonoacetate in 1.5 mL of dimethoxyethane and the mixture is stirred for 1 hour at room temperature. Subsequently, a solution of the aldehyde prepared in Example 1f) in 1.5ml of dimethoxyethane are added and stirred first for 1 hour at room temperature, then 1 hour at 50 ⁰ C. After cooling, 10ml of saturated ammonium chloride solution was added and after phase separation the aqueous phase three times extracted with 30 ml of diethyl ether each. The combined organic phases are washed once with 20 ml of water and once with 20 ml of saturated sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel with hexane / 0-70% ethyl acetate. In this way, 280 mg of the title compound are obtained.

NMR (300 MHz, DMSO-d6): δ = 1.18 (3H), 1.20 (9H), 4.11 (2H), 6.57 (1 H) ₁ 7.04 (1 H), 7.11 (1 H), 7.18-7.32 (3H ), 7.35-7.63 (8H), 9.83 (1H), 11.74 (1H). 1 h) (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] acrylic acid

383 mg of sodium hydroxide are added to a mixture of 260 mg of the ester prepared in Example 1g) in 6.1 ml of ethanol and 3.1 ml of ethanol and the mixture is stirred at room temperature for 17 hours. Then it is diluted with 30 ml of water and acidified with 5% sulfuric acid. The precipitate is filtered off and dried. In this way, 225 mg of the title compound are obtained, which is reacted further without further purification. NMR (300 MHz, DMSO-d6): δ = 1.20 (9H), 6.48 (1H), 7.03 (1 H), 7.11 (1 H), 7.18-7.31 (3H), 7.34-7.61 (8H), 9.82 ( 1H), 11.72 (1H), 12.20 (1H).

Example 2: (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] - N- (2-morpholin-4-yl-ethyl) -acrylic acid amide

Analogously to Example 1, 43.0 mg of the title compound are obtained from 50 mg of the acid from Example 1 h) and 13.8 μl of 2- (morpholin-4-yl) ethylamine. NMR (300 MHz, DMSO-d6): δ = 1.20 (9H), 2.30-2.38 (6H), 3.24 (2H), 3.52 (4H), 6.51 (1H), 7.00 (1H), 7.10 (1H ), 7.20 (2H), 7.27 (1 H) ₁ 7.33 (1H), 7.36 (1 H), 7.43- 7.53 (4H) ₁ 7.56 (2H), 8.03 (1 H), 9.79 (1 H), 11.85 ( 1 H). Example 3: (±) - (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-hydroxy-1- methyl ethyl) acrylic acid amide

Analogously to Example 1, 44 mg of the title compound are obtained from 50 mg of the acid from Example 1h) and 8.39 μl of 2-amino-1-propanol.

NMR (300 MHz, DMSO-d6): δ = 1.02 (3H), 1.21 (9H), 3.19-3.39 (2H), 3.83 (1H), 4.67 (1H), 6.50 (1H), 7.00 (1H), 7.10 (1H), 7.20 (2H), 7.28 (1H), 7.34 (1H), 7.35 (1H), 7.43-7.53 (4H), 7.56 (2H), 7.92 (1H), 9.79 (1H), 11.62 (1H) .

Example 4: (±) - (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] - N- (2-hydroxypropyl) -acrylic acid amide

Analogously to Example 1, 47 mg of the title compound are obtained from 50 mg of the acid from Example 1h) and 8.24 μl of 1-amino-2-propanol.

NMR (300 MHz, DMSO-d6): δ = 0.99 (3H), 1.21 (9H), 3.06 (2H) ₁ 3.66 (1H), 4.68 (1H), 6.54 (1H) ₁ 7.00 (1H), 7.10 (1H ), 7.20 (2H), 7.28 (1H), 7.34 (1H), 7.36 (1H), 7.43-7.53 (4H), 7.56 (2H), 8.11 (1H), 9.79 (1H), 11.63 (1H). Example 5: 3- [5- (4-tert-butyl-phenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-morpholin-4-yl-ethyl) propionic acid amide

2.5 mg of palladium on carbon (10%) are added to a solution of 25 mg of the title compound prepared in Example 2) in 1.0 ml of ethyl acetate and the mixture is stirred for 21 hours at room temperature in a hydrogen atmosphere. Then it is suctioned off through Celite, washed well with ethyl acetate and the organic phase is concentrated in vacuo. The residue thus obtained is purified by preparative thin layer chromatography on silica gel plates with ethyl acetate / acetone in a ratio of 1: 1. In this way, 6.7 mg of the title compound is obtained.

NMR (300 MHz, DMSO-d6): δ = 1.21 (9H), 2.18-2.38 (6H), 2.92 (2H), 3.11 (2H), 3.25-3.35 (2H), 3.47 (4H), 6.83 (1H ), 7.05 (1H), 7.17-7.27 (4H), 7.39 (2H), 7.50 (2H), 7.56 (2H), 7.73 (1H), 9.66 (1H) ₁ 11.05 (1H).

Biological examples:

Example 1: sAC assay

In a suitable buffer system, the 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 method in which the binding of an anti-cAMP antibody (anti CAMP-Eu [K] -AK) labeled with europium cryptate (Eu [K]) to a with cAMP molecules labeled, modified allophycocyanin-1 molecule (cAMP-XL665) is prevented. In the absence of exogenous cAMP, fluorescence resonance energy transfer (FRET) occurs between the anti CAMP-Eu [K] -AK (FRET donor) and the cAMP-XL665 molecule (FRET acceptor) after excitation at 335 nm. This process is time-resolved based on the emission of the FRET acceptor XL665 (665nm and 620nm) quantified. A signal drop (measured as a well ratio; calculation formula: [(E665nm / E620nm) X 10000]) can be attributed to the presence of cAMP and thus to the activity of the sAC. For each well of a 384-hole test plate (polystyrene; 384, NV), 1.5 μl of the test substance (in 30% DMSO) are initially placed, in the solvent controls only 30% DMSO. Then 10 μl of a diluted sAC enzyme solution are applied (enzyme stock solution in 300 mM NaCI, 10% glycerol; pH 7.6; intermediate and final dilution a) 1:10 and b) 1: 2000 each in: 1.0 mM MnCI ₂ ; 0.2% BSA; 50 mM Tris pH 7.5 in H ₂ O). The enzyme reaction is started by adding 5 μl of the ATP substrate solution (200 μM ATP in H ₂ O) and after incubation (25 min. At room temperature) by adding 5 μl of the stop solution (200 μM EDTA in PBS) ended. Finally, the entire reaction is adjusted to a total volume of 91.5 μl by adding 70 μl PBS. 8 μl of detection solution 1 are then placed in a recess in the 384-hole measuring plate (measuring plate: polystyrene; 384, SV - black; detection solution 1: 50 μl CAMP-XL665; 950 μl reconstitution buffer; 2200 μl PBS; cAMP-XL- 665: Preparation by adding 5 ml H ₂ O to the lyophilized Product according to the Cis bio Kit: # 62AMPPEC; Storage: aliquoted at - 80 ⁰ C). Then 3μl from the 91.5 μl of the corresponding well of the test plate are added. Finally, 8 μ is added! detection solution 2 (detection solution 2: 50 μl anti CAMP-Eu [K] -AK; 950 μl reconstitution buffer; 2200 μl PBS; anti CAMP-Eu [K] -AK: preparation according to the Cis bio Kit instructions: # 62AMPPEC; storage: aliquoted at -8O ⁰ C). After a further incubation of 90 min at room temperature, the HTRF result is measured either on the Packard Discovery or with the RubiStar HTRF measuring device (delay: 50 μs; integration time: 400 μs).

Example 2. Isolation of human sperm from ejaculates and capacitation 2.1. Isolation of the sperm

Human sperm are cleaned from the ejaculate by a two-layer gradient system based on colloidal silica particles (trade name: Percoll or ISolate). For each ejaculate, a 2.5 ml preheated lower layer ("90% ISolate lower layer", from Irvine) is placed in a 15 ml centrifuge tube (conical, plastic) and carefully mixed with 2.5 ml preheated upper layer ("50% ISolate upper layer ", from Irvine) and kept in a water bath at 37 ° C for <1h. The gradient is carefully covered with a maximum of 3 ml of normal (in terms of sperm count, motility and liquefaction) ejaculates. The spermatozoa are sedimented at 1000 xg for 25 min at room temperature. Using a glass capillary, both layers are aspirated to just above the sperm pellets. To wash out the ISolate gradient, the sperm pellets resuspended in approx. 200 μl each are transferred into a 15 ml plastic tube with 12 ml of mHTF medium (4 mM NaHCO ₃ ; 0.01% BSA; 37 ° C) and the spermatozoa at 1000 xg for 20 Min sedimented. The medium is aspirated up to just above the pellet and adjusted to 1000 μl with mHTF medium medium (4mM NaHCO ₃ ; 0.01% BSA; 37 ° C). The number of sperm is determined in a Neubauer counting chamber and for that following capacitation optionally with mHTF medium (4 mM _NaHCO3; 37 ⁰ C; 0.01% BSA) 150 .mu.l adjusted to 4x106 sperm /.

2.2. Capacitation If the influence of test substances on the acrosomal reaction is to be tested, the sperm must be pre-incubated with the test substances. This pre-incubation (15 minutes in the incubator at 37 ⁰ C) is necessary to allow the penetration of the test substances in the sperm prior to the capacitation, that is, a pre-saturation of the binding sites in the sperm to achieve, particularly for substances that do not pass through the membrane . It is also necessary because the increase in the BSA concentration during capacitation due to the high lipid binding of the BSA could lead to a decrease in the effective test substance concentration in the mixture. The test substances are dissolved in DMSO and diluted with mHTF medium (4mM NaHCO ₃ ; 0.01% BSA; 37 ° C) so that the final DMSO concentration of 400 μl is 0.5%. 150 ul of the above tempered test substance solution are pipetted into 150 ul of sperm suspension and pre-incubated for 15 min at 37 ⁰ C. The capacitation of the sperm is started by adding 100 μl of mHTF medium (88 mM NaHCO ₃ ; 4% BSA; 37 ° C.). In the final 400 μl capacity, the sperm concentration is 10x106 / ml, the bicarbonate concentration is 4 mM and the BSA concentration is 1%. The capacitation takes place at 37 ⁰ C for 3 hours in the heating cabinet. To end the capacitation, the batches (400 µl) are completely transferred to 15 ml sample tubes with 1.5 ml mHTF (4mM NaHCO ₃ ; 37 ° C), centrifuged at 1000 xg for 5 min and the supernatant removed. This step removes both the high amount of protein and the test substances. Example 3. Flow cytometric determination of the acrosomal response

3.1. Initiation of the acrosomal reaction by ionophore treatment and simultaneous CD46-FITC staining

The acrosomal response (AR) of the sperm is triggered by the binding of the sperm to the zona pellucida (ZP). The

Acrosome released enzymes that enable the sperm to penetrate through the ZP to the egg. In AR, spermatozoa partially fuse the plasma membrane with the outer acrosomal membrane (OAM). In the end, the sperm head is only limited by the inner acrosomal membrane (IAM). The CD46 antigen is only detectable at the IAM.

The acrosomal reaction can be induced in vitro with a suitable concentration of the calcium ionophore A23187 on capacitated, but not on uncapacitated or on sperm inhibited by test substances on capacitation. With the help of the FITC-labeled anti-CD46 antibody (from Pharmingen) against the IAM, the acrosome-reacted sperm can be distinguished from the acrosome-intact sperm, to which the IAM is not exposed, in the flow cytometer. By simultaneously staining the sperm with the DNA dye Ethidium Homodimer (EhD), which stains only the DNA membrane-defective, i.e. dead cells, the dead can be distinguished from the living sperm.

Because the ionophore dilutions for triggering the AR seem to be very unstable and have to be mixed with the CD46-FITC solution for simultaneous staining, the solutions cannot be prepared before the start of the experiment, but must be prepared during the processing of the capacitation batches.

The sperm pellets were resuspended in the residual supernatant and the water bath (37 ° C) with 450 ul mHTF (4 mM _NaHCO3; 0.01% BSA; 37 ⁰ C) diluted. 100 μl aliquots of the sperm suspensions are pipetted into prepared sample FACS flow tubes (in a water bath). 150 μl of a solution with ionophore and FITC-labeled anti-CD46 antibody are pipetted into the sperm. The final concentration is 80OnM and one ionophore 1: 125 dilution of the anti-CD46 antibody in mHTF (4mM NaHCO ₃ ; 0.01% BSA; 37 ° C). The sperm are incubated for 30 min protected from light in a water bath at 37 ° C.

The incubation is stopped by adding 3.5 ml of PBS [0.1% BSA] / batch, followed by centrifugation for 5 min at 700 x g (room temperature) and then aspirating the supernatants. After centrifugation, the samples are kept warm on the hot plate until measurement.

3.2. EhD stain (to differentiate the dead / living acrosomally reacted sperm)

After aspiration, 500 μl of freshly prepared EhD solution (150 nM EhD in PBS [w / o BSA]; 37 ° C.) are added to the sperm pellets. The samples can then be measured on the flow cytometer (BD Facs Calibur). The measurement is carried out at an excitation wavelength of the laser of 488nm, 10,000 sperm are recorded per measurement. Acrosome-reacted sperm are measured using CD46-FITC in the FL-1 filter at 530nm. Dead sperm are measured using the EhD - DNA staining in the FL-2 filter at 634nm. The measuring channels are previously compensated for each other accordingly.

3.3 Evaluation

The sperm are selected as a very uniform cell population in a FSC-H (forward scatter) versus SSC-H (sideward scatter) dot blot. Since two-color fluorescence staining is used, the evaluation is carried out using quadrant analysis in a 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:

Only the live sperm from Q3 and Q4 are used to calculate the% induced acrosomally reacted sperm (= "IAR [%]") and their total number is set to 100%. IAR is then calculated as follows:

LL + LR

Some of the sperm react spontaneously acrosomally (= "SAR [%]") even without the addition of ionophore. Therefore, a control measurement of spermatozoa treated in the same way without addition of ionophore is always carried out. The SAR calculates analogously to the IAR. "ARIC [%]") is calculated as the difference: ARIC = IAR - SAR For the following analysis of the influence of our inhibitors on sAC-mediated capacitation (measured as the ability of the sperm to ionophore-induced acrosomal reaction), the percentage of acrosomally reacted sperm is shown in the positive capacity control (= incubation with mHTF medium with 25mM NaHCO3; 1% BSA without test substances) = 100%. The ability of the sperm containing the test substances for the acrosomal reaction is indicated relative to this maximum acrosomal reaction.

Materials used 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 NaHCOs); Bovine serum albumin, fraction V (from Fluka); Dimethyl sulfoxide (DMSO), anhydrous (Merck); Sodium bicarbonate 7.5% solution (893mM) (from Irvine Scientific); Isolate gradient (from Irvine Scientific); Ionophore-A23187 free acid, (from Calbiochem); Ethidium homodimer (EhD) (Molecular Probe), Mouse Anti Human CD46: FITC (Pharmingen).

Literature quote:

JW 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 OJ D ^' Cruz, GG Haas, Fertility and Sterility Vol. 65, No. 4, pp: 843 ff, 1996 Fluorescence-Iabeled fucolectins are superior markers for flow cytometric quantitation of the sperm acrosome reaction E. Nieschlag, HM Behre, Andrologie, Springer Verlag 1996

Examples:

It can be seen from the table that the compounds according to the invention have a higher activity than the already known catechol oestrogens (OH estradiols) with regard to the inhibition of soluble adenylate cyclase, expressed by the IC _δ o value. The catechol estrogens are toxic, therefore the compounds according to the invention are superior to the known compounds. The compounds of the invention are also more potent than the compounds presented by Zippin.

Claims

Expectations

1. Connections of general forms! (!),

in which

R ^{1 is} hydrogen, halogen, CF ₃ , C ₃ -C ₆ -cycloalkyl, which is optionally poly-saturated and optionally poly-substituted, or the group Ci-C ₆ -alkyl, C ₁ -C ₆ -alkyl, Ci-C ₆ - Acyl, halo-Ci-C ₆ -alkyl, d-Ce-alkyl-CrCe-alkyl, d-Ce-alkyl-d-Ce-acyl, Ci-C ₆ -ACyI-C ₁ -C ₆ - acyl, CrCe- Alkyl-d-Ce-aryl, dC ₆ -aryl-Ci-C ₆ -alkyl or CF ₃ , in the CrCe-alkyl, C _r C ₆ -aryl, Ci-C ₆ -acyl, halo-dC ₆ -alkyl, C ₁ -C ₆ -alkyl-CrCe-alkyl, Ci-Ce-alkyl-d-Ce-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, CrCe-alkyl-CrCe-aryl or C ₁ -C ₆ -AIyI-C ₁ -C ₆ -AIkVl can optionally be interrupted one or more times, identically or differently, by oxygen, sulfur or nitrogen, or the group sulfonyl-Ci-C ₆ -alkyl, sulfonamide or cyano,

R 'halogen, CF ₃ , C ₃ -C ₆ cycloalkyl, which is optionally poly-saturated and optionally poly-substituted, or the group dC ₆ -alkyl, Ci-C ₆ -aryl, C ₁ -C ₆ -ACyI, halo- dC ₆ -alkyl, C rC ₆ -alkyl-C ^ Ce-alkyl, d-Ce-alkyl-d-Ce-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ - acyl, d-Ce-alkyl -d-Ce-aryl, d-Ce-aryl-d-Ce-alkyl or CF ₃ , in the dC ₆ -alkyl, C _r C ₆ -aryl, C ₁ -C ₆ -ACyI, halo-dC ₆ -alkyl , C ₁ -C ₆ - alkyl-CrCe-alkyl, d-Ce-alkyl-d-Ce-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, d-Ce-alkyl-d-Ce Aryl or C ₁ -C ₆ -AIyI-C ₁ -C ₆ -AIkVl can optionally be interrupted one or more times, identically or differently, by oxygen, sulfur or nitrogen, or the group sulfonyl-C ₁ -C ₆ -alkyl, sulfonamide or cyano,

R ³ C ₆ -C ₁₂ -Aly !, which may be one or more, identical or different with halogen, with C ₁ -C ₆ -alkyl or C ₁ -C ₆ -acyl, which may optionally be substituted once or more , or with C ₁ -C ₆ alkoxy, hydroxy, cyano, CO ₂ - (C ₁ -C ₆ alkyl), N- (C ₁ - C ₆ alkyl) _2l CO-NR ⁴ R ⁵ or with CF ₃ Can be substituted, C ₅ -C ₁₂ heteroaryl, which is optionally one or more, identical or different with halogen, d-Cβ-alkyl, C ₁ -C ₆ -ACyI, C ₁ - C ₆ -AIkOXy, hydroxy, cyano , CO ₂ - (C rC ₆ -alkyl), N- (C ₁ -C ₆ -alkyl) ₂ ,

CO-NR ⁴ R ⁵ or can be substituted with CF ₃ or C ₃ -C ₆ cycloalkyl, which may be one or more, identical or different, with halogen, CF ₃ , hydroxy, cyano, CO ₂ - (CrCe-alkyl) , C _r C ₆ -alkyl, C ₁ -C ₆ -ACyI, N - (C ₁ -C ₆ -Alky I) ₂ , CO-NR ⁴ R ⁵ or C ₁ -C ₆ -AIkOXy may be substituted,

R ^{4 is} hydrogen, C3-C ₆ -cycloalkyl, which may be one or more, identical or different with d-Ce-alkyl, C ₁ -C ₆ -ACyI, C ₁ -

Cβ-Alkoxy or CF _{3 is} substituted, C ₆ -C ₁₂ aryl, which may be one or more, identical or different with halogen, Ci-C ₆ alkyl, C ₁ -C ₆ -ACyI, C ₁ -C ₆ -

Alkoxy, Nd-Ce-alkyl-CrC _δ -alkyl, CF ₃ or cyano is substituted, or

C ₅ -C ₁₂ heteroaryl, which may be one or more, identical or different with halogen, with d-Ce-alkyl, C ₁ -C ₆ -ACyI ₁

C ₁ -C ₆ -AlKOXy, Nd-Ce-alkyl-CrCe-alkyl, CF ₃ or cyano, is substituted, or

C ^ Ceralkyl, which can be substituted as desired,

R ^{5 is} hydrogen, CrCe-alkyl-Cs-C _ö -cycloalkyl, which may be one or more, identical or different with d-Ce-alkyl, C ₁ - C ₆ -acyl, C ₁ -C ₆ -alkoxy or CF ₃ C3-C substituted, ₆ -cycloalkyl which is optionally mono- or polysubstituted by identical or is differently substituted with CrC ₆ alkyl, CrC ₆ acyl, Ci-C ₆ alkoxy or CF ₃ ,

C ₅ -C ₁₂ -ArV / !, which may be one or more, identical or different with halogen, C ₁ -C ₆ -AIkV / !, C ₁ -C ₆ -AkyI, C ₁ -C ₆ - alkoxy, Nd -Ce-alkyl-d-Ce-alkyl, CF ₃ or cyano is substituted, or

Cs-C ^ heteroaryl, which may be one or more, identical or different with halogen, C ₁ -C ₆ -AIkVl ₁ C ₁ -C ₆ -ACyI, C ₁ - C ₆ -AIkOXy, N-CrCe-alkyl Ci-Ce-alkyl, CF ₃ or cyano, is substituted, or

Ci-Cβ-alkyl, which can be substituted as desired,

X is the groups sulfonyl, (CH2) _n or carbonyl,

Y - (CHa) _n - or -CH = CH-

n 1 - 4,

mean, and their isomers, diastereomers, enantiomers and salts.

2. Compounds according to claim 1, wherein

Cβ-alkyl, C ₁ -C ₆ -AIyI, C ₁ -C ₆ -ACyI, halo-C _r C ₆ -alkyl, Ci-C ₆ -alkyl-Ci- C ₆ -alkyl, CrCe-alkyl-CrCe-acyl , C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, C ₁ -C ₆ -

Alkyl CRCE-aryl, Ci-Ce-aryl-CRCE alkyl or CF _3, in which C ₁ -C ₆ - alkyl, -C ₆ aryl, C ₁ -C ₆ -acyl, halo-C _r C ₆ alkyl , Ci-C ₆ -alkyl-Ci-C ₆ -alkyl, CrCe-alkyl-CrCe-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, C _r C ₆ -alkyl- dC ₆ -aryl or dC ₆ -aryl-Ci-C ₆ -alkyl may optionally be interrupted one or more times, identically or differently, by oxygen, sulfur or nitrogen, or the group sulfonyl-Ci-C ₆ -alkyl, sulfonamide, or Cyano,

R ^{2 is} halogen, CF3, C ₃ -C ₆ -cycloalkyl, or for the group Ci-C ₆ -alkyl,

C ₁ -C ₆ -AiYl, C ₁ -C ₆ -ACyI, halo-dC ₆ -alkyl, dC ₆ -alkyl-dC ₆ -alkyl, CrCe-alkyl-CrCe-acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, d-Ce-alkyl-d-Ce aryl, C ₁ -C ₆ -AJyI-C ₁ -C ₆ -Al ky I or CF ₃ , in the dC ₆ -alkyl, C ₁ - C ₆ - aryl, Ci-C ₆ -acyl, halo-Ci-C ₆ -alkyl, d-Ce-alkyl-d-Ce-alkyl, C ₁ -C ₆ -

Alkyl-dC ₆ -acyl, C ₁ -C ₆ -ACyI-C ₁ -C ₆ -ACyI, d-Ce-alkyl-d-Ce-aryl or dC ₆ -aryl-dC ₆ -alkyl I optionally one or more times, the same or different may be interrupted by oxygen, sulfur or nitrogen, or the group sulfonyl-dC ₆ -alkyl, sulfonamide, or cyano,

R ³ Ce-C ₁₂ aryl, which may be one or more, identical or different with halogen, with dC ₆ -alkyl, C ₁ -C ₃ -ACyI, C ₁ -C ₃ -alkoxy, cyano, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (Ci-C ₃ -alkyl), CO-NR ⁴ R ⁵ or can be substituted with CF ₃ ,

C ₅ -C ₁₂ heteroaryl, which optionally one or more times, identically or differently with chlorine and / or fluorine, with d-Ce-alkyl, C ₁ -C ₃ -ACyI, C ₁ -C ₃ -AIkOXy, cyano, Hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (C ₁ -C ₃ alkyl), CO-NR ⁴ R ⁵ or can be substituted with CF ₃ , C ₃ -C ₆ cycloalkyl, which may be one or Multiple, identical or different with chlorine and / or fluorine, CF _3, cyano, dC ₃ alkyl, C ₁ -C ₃ ACyI, hydroxy, N- (CH ₃ ) _2l CO ₂ - (dC ₃ alkyl), CO - NR ⁴ R ⁵ or C ₁ -C ₃ -AlKOXy can be substituted,

R ^{4 is} hydrogen, C ₃ -C ₆ -cycloalkyl, which is optionally substituted one or more times, identically or differently, with C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy or CF ₃ is which may be one or more, identical or different, with halogen, Ci-C ₃ alkyl, Ci-C ₃ -acyl, CrC ₃ - alkoxy, N-Ci-C ₃ -A! ky! -Ci-C ₃ -A ! ky !, CF ₃ or cyano is substituted, or C ₅ -Ci2 heteroaryl, which may optionally be substituted one or more times, identically or differently, with halogen, Ci-C ₃ -alkyl, CrC ₃ -acyl, d- C ₃ -alkoxy , N-CrC ₃ -alkyl-CrC ₃ -alkyl, CF ₃ or cyano, is substituted, or C-ι-C ₆ -alkyl, which can be substituted as desired,

R ^{5 is} hydrogen, C ₁ -C ₆ -alkyl-C ₃ -C ₆ -cycloalkyl, which is optionally substituted one or more times, identically or differently, with C ₁ -C ₆ -alkyl, Cr Cβ-acyl, CrCβ-alkoxy or CF ₃ C ₃ -C ₆ cycloalkyl, which is optionally substituted one or more times, identically or differently, with CrC ₃ alkyl, CrC ₃ acyl, dC ₃ alkoxy or CF ₃ ,

C ₆ -Ci ₂ aryl, which may be one or more, identical or different, halogen, CrC ₃ alkyl, CrC ₃ acyl, CrC ₃ alkoxy, N-Ci-C ₃ alkyl-Ci-C ₃ - Alkyl, CF ₃ or cyano is substituted, or

C ₅ -Ci ₂ heteroaryl, which may be one or more, identical or different, with halogen, Ci-C ₃ alkyl, CrC ₃ acyl, Cr C ₃ alkoxy, N-CrC ₃ alkyl-CrC ₃ alkyl , CF ₃ or cyano, or d-Cβ-alkyl, which can be substituted as desired,

X is the groups sulfonyl, (CH ₂ ) _n or carbonyl,

Y - (CH ₂ J _n - or -CH = CH-, n 1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

3. Compounds according to claim 1 and 2, wherein

R ^{1 is} hydrogen,

-OCF ₃ , -SO ₂ -CH ₃ ,

R ³ C ₆ -Ci ₂ aryl, which may be mono- or polysubstituted, identically or differently, with halogen, d-Ce-alkyl, Ci-C ₃ -acyl, C ₁ -C ₃ -

C ₅ -Ci ₂ heteroaryl, which may be one or more, identical or different with chlorine and / or fluorine, with CrC ₆ alkyl, C ₁ -C ₃ -ACyI, C ₁ -C ₃ -AIkOXy ₁ cyano, hydroxy , N- (CH ₃ ) ₂ , CO ₂ - (C ₁ -C ₃ -

Atkyl), CO-NR ⁴ R ⁵ or can be substituted with CF ₃ , C ₃ -C ₆ cycloalkyl, which may be one or more, the same or different with chlorine and / or fluorine, CF _3, cyano, d- Cs-alkyl, C ₁ -C ₃ -ACyI, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - (C _r C ₃ -alkyl), CO-NR ⁴ R ⁵ or C ₁ -C ₃ -AIkOXy can,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen, CrCe-alkyl-Cs-Cβ-cycloalkyl, which may be one or more, identical or different with Ci-Cβ-alkyl, C ₁ -

C ₆ -ACyI, C ₁ -C ₆ -AIkOXy or CF _{3 is} substituted, C ₃ -C ₆ cycloalkyl, which may be one or more, identical or is differently substituted with Ci-C ₃ -alkyl, Ci-C ₃ -ACyI, Ci-C ₃ -alkoxy or CF ₃ ,

C ₆ -Ci ₂ aryl, which may be one or more, identical or different with halogen, Ci-C ₃ alkyl, Ci-C ₃ -acyl, Ci-C ₃ - alkoxy, N-Ci-C ₃ alkyl -CrC ₃ alkyl, CF ₃ or cyano is substituted, or

C ₅ -Ci ₂ heteroaryl, which may be one or more, identical or different with halogen, CrC ₃ alkyl, Ci-C ₃ -acyl, Ci-C ₃ alkoxy, N-Ci-C ₃ alkyl-Ci -C ₃ alkyl, CF ₃ or cyano, is substituted, or

CrCβ-alkyl, which can be substituted as desired,

X the group sulfonyl,

Y - (CH ₂ ) _n - or -CH = CH-,

n 1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

4. Compounds according to claims 1-3, wherein

R ^{1 is} hydrogen,

R ² C ₃ -C ₆ cycloalkyl, Ci-C ₆ alkyl, CF ₃ , sec. Butyl, cyano, bromine or the group -OCF ₃ , -SO ₂ -CH ₃ and is in the para position,

R ³ C ₆ -Ci ₂ aryl, which may be mono- or disubstituted, identically or differently, with halogen, CrC ₃ alkyl, acetyl, methoxy, ethoxy, cyano, hydroxy, N- (CH ₃ ) ₂ , CO ₂ - ( C _r C ₃ alkyl), CO-NHR ⁵ or CF ₃ may be substituted, C ₅ -Ci ₂ heteroaryl, which may be mono- or discrete, 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 - (Ci-C ₃ - alkyl), CO-NHR ⁵ or can be substituted with CF ₃ , C ₃ -C ₆ cycloalkyl,

R ^{4 is} hydrogen,

R ^{5 is} hydrogen, Ci-C ₆ -alkyl-C ₃ -C ₆ -cycloalkyl, which may be one or more, identical or different with C ₁ -C ₆ -AIRyI, C ₁ -

C ₆ -acyl, Ci-C ₆ -alkoxy or CF _{3 is} substituted, C ₃ -C ₆ -cycloalkyl, which may be substituted one or more times, identically or differently with Ci-C ₃ -alkyl, Ci-C ₃ -acyl, Ci-C ₃ alkoxy or CF _{3 is} substituted, C ₆ -Ci ₂ aryl, which optionally one or more times, identically or differently, with halogen, Ci-C ₃ alkyl, Ci-C ₃ acyl, CrC ₃ -

Alkoxy, N-Ci-C ₃ -AIRyI-C ₁ -C ₃ -AIKyI, CF ₃ or cyano is substituted, or

C ₅ -Ci ₂ heteroaryl, which optionally one or more times, identically or differently, with halogen, Ci-C ₃ -alkyl, Ci-C ₃ -acyl, d-

C ₃ alkoxy, N-Ci-C ₃ alkyl-Ci-C ₃ alkyl, CF ₃ or cyano, is substituted, or

Ci-Ce-alkyl, which can be substituted as desired,

X the group sulfonyl,

Y - (CH ₂ ) _n - or -CH = CH-,

n 1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

5. Compounds according to claims 1-4, wherein

R ^{1 is} hydrogen,

R ² for tertiary butyl, iso-propyl, iso-butyl, sec. Butyl, cyano, bromine or the group -0-CF ₃ , -SO ₂ -CH3 and is in the para position,

R "the group

R "hydrogen, R ^{5 is} hydrogen or the group - (CH ₂ ) nN- (CH ₃ ) ₂₎ - (CH ₂ ) ₂ -CH ₃ , - (CH ₂ ) 2-NH-COCH ₃ , - (CH ₂ ) -CHCH ₃ - OH, - (CH ₂ ) ₂ -O-CH ₃ , - (CHa) ₂ -OH. -CHCH ₃ -CH ₂ -OH,

the group sulfonyl,

Y - (CH ₂ J _n - or -CH = CH-,

1 - 2

mean, and their isomers, diastereomers, enantiomers and salts.

6. Compounds according to claims 1-5, wherein

R ^{1 is} hydrogen,

R ^J the group

R ^{4 is} hydrogen,

R ^{5 is} hydrogen or the group, - (CH ₂ ) -CHCH ₃ -OH, - (CH ₂ ) 2-0-CH ₃ , -CHCH ₃ -CH ₂ -OH,

X the group sulfonyl,

Y - (CH ₂ ) ,, - or -CH = CH-, and

n 1 - 2 mean and their isomers, diastereomers, enantiomers and salts.

7. Compounds according to claims 1- 4, selected from a group containing the following compounds:

I. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (tetrahydropyran-4-yl) acrylic acid amide 2. ( E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-morpholin-4-yl-ethyl) acrylic acid amide 3. . (±) - (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-hydroxy-1-methyl- ethyl) acrylic acid amide

4 .. (±) - (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] - N- (2-hydroxypropyl) -acrylic acid amide

5. 3- [5- (4-tert-Butylphenylsulfonylamino) -3-phenyl-1H-indol-2-yl] -N- (2-morpho! In-4-yl-ethyl) propionic acid amide

6. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3- (3-fluorophenyl) -1H-indol-2-yl] - N- (tetrahydropyran-4- yl) acrylic acid amide 7. (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3- (3-fluoro-phenyl) -1 H -indol-2-yl] - N- (2nd -morpholin-4-yl-ethyl) acrylic acid amide

9. (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3- (3-methoxyphenyl) -1H-indol-2-yl] -N- (2-morpholin-4- yl-ethyl) acrylic acid amide

10. (E) -3- [5- (4-tert-Butylphenylsulfonylamino) -3- (3-fluorophenyl) -1 H -indol-2-yl] - N- (pyridin-4-yl ) acrylic acid amide

I 1. (E) -3- [5- (4-tert-butylphenylsulfonylamino) -3- (3-methoxyphenyl) -1 H -indol-2-yl] -N- (pyrindine-4- yl) acrylic acid amide

8. Medicaments containing at least one of the compounds according to claims 1- 7.

9. Medicament according to claim 8, in which the compound of general formula 1 is contained in an effective dose.

10. Compounds of general formula 1 according to claims 1-7 for the manufacture of medicaments.

11. Medicament according to claim 10 for the treatment of diseases.

12. Medicament according to claim 9, wherein the diseases are caused by disorders in the cAMP metabolism.

13. Medicament according to claim 10 for contraception.

14. Medicament according to claim 10 for the inhibition of soluble adenylate cyclase.

15. Medicament according to claim 10 -14 with suitable formulation and carrier substances.

16. Use of the compounds of general formula 1 according to claims 1-7 in the form of a pharmaceutical preparation for enteral, parenteral, vaginal and oral administration.

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

(H) wherein R ¹ , R ² and R ^{3 have} the meanings given above, and R ^{6 can be} a hydrogen or a dC ₆ -alkyl radical, with an amine of the general formula III

/ ^R5

HN

^XR4 (III) is converted to the compounds of the general formula (I) after cleavage of any protective groups required.

18. Intermediates of the general formula (II)

in which R ¹ , R ² , R ³ , X and Y have the meanings given above and R ^{6 can be} a hydrogen or a C 1 -C ₆ -alkyl radical, and the general formula (VIII)

wherein R ¹ , R ² , R ³ and X have the meanings given above.