TW200815347A - Inhibitors of soluble adenylate cyclase - Google Patents

Abstract

The invention relates to compounds of general formula I as well as the production and use thereof as a medication.

Description

200815347 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to an inhibitor of soluble malonate cyclase and its use for the preparation of a medicament for contraception. [Prior Art]

There are a large number of modern methods of contraception available to women; however, only a few methods of male birth control are available (condoms and sterilization). It is absolutely necessary to develop: a novel and reliable agent for male birth control. In this connection, the infertility produced by male remedies should be completely reversible and just as effective as the existing methods available to women. Infertility should begin relatively quickly and last as long as possible. Such contraceptive methods should not have any side effects; in this connection, in addition to hormone preparations, non-hormonal preparations may also be present. The possible starting point is the activity of the enzyme that plays an important role in the regulation of oocyte cytoplasm, soluble adenylate cyclase 〇Ac). This enzyme is mainly expressed in testicular stem cells and is present in mature sperm. In 1999, authors Levin and Buck (Proc. Natl. Acad. Sci. USA 96 (1): 79-84) were able to purify from rat testis and colonize the isoforms of s ac. Stimulated by bicarbonate. With the aid of antibodies, it is possible to prove that the catalytic domain of the enzyme is located in the testis, sperm, kidney and choroid plexus. The disclosures are the subject matter of the application WO 01/85753 to U.S. Patent No. 6,654,768. In WO 01/21829 (Conti et al.), an isolated polynucleotide sequence encoding an isoform of human sAC, an isolated sAC polypeptide and a test line 119676.doc 200815347 can be identified with the aid of the system. A substance that inhibits the activity of S AC. The use of such materials to reversibly reduce the number of active sperm cells and the use of such materials as medicaments for male birth control are disclosed.

The John Herr group demonstrates human isoforms that separate and characterize sac from sperm. In WO 02/20745, in addition to nucleic acids, a test system that also encodes sAC is also claimed, with the aid of which a substance that modulates the performance or activity of human sAC can be identified. Such compounds can selectively inhibit, for example, the activity of sAC; this results in the loss of sperm cells the ability to fertilize oocytes. Therefore, these sAC inhibitors can be used as non-hormonal contraceptive medicinal agents. However, 'known sAC inhibitors show specific problems: catechol estrogen (T. Braun, Proc Soc Exp Biol Med 1990, 194(1): 58 pages) and cotton hops (Κ·L· Olgiati, Arch Biochem Biophys 1984, 231(2): 411 pages) is inherently toxic, while adenosine analogues are only inhibited by very weak effects (M. A. Brown and E. R. Casillas, j Androl 1984, 5:361 rpm) page). The inhibitor of recombinant human sAC (IC^IO μηιοί) described by Zippin et al., H Zippin et al., j CeU Bi〇1 2004' 164(4): 527 pages, is somewhat more effective. In order to be able to manufacture agents for male birth control, there is an increasing need for reversible, rapid and successful substances that lead to infertility. SUMMARY OF THE INVENTION This object is achieved by providing a compound of formula j: 119676.doc 200815347 wherein

R 2 is hydrogen, element, (3), as the case is multi-saturated and

Multi-substituted C3_C6 cycloalkyl; or group 匕-^alkyl, Ci-c6 aryl, Cl_c6 fluorenyl, g_Ci_C6 alkyl, Ci-c6 alkyl _Ci_c6 alkyl, Ci_c6 alkyl _Ci_C6 fluorenyl , CrC6 fluorenyl _Cl_c6 fluorenyl, Ci_C6 alkyl _Ci_G aryl, C^C6 aryl _Cl_C6 alkyl or C5, wherein alkyl, CrC6 aryl, Cl_C6 fluorenyl, halo-Ci_C6 alkyl, q_C6 alkane a base-CVC6 alkyl group, a Cl_C6 alkyl group _Ci_C6 fluorenyl group, a Ci_c6 fluorenyl group _^(:6-branched group, a Cl_c6 alkyl group, a Ci_c6 aryl group or a Ci_C6 aryl group CpC:6 alkyl group may be the same in one or more places as the case may be Or intervene in oxygen, sulfur or nitrogen in different ways; or a group of sulfonyl-Ci_C6 alkyl, sulfonamide or cyano; R means dentate, CF3, optionally saturated, and optionally substituted C ^C: 6 cycloalkyl; or a group CrCe alkyl, Cl_c6 aryl, Ci-C6 fluorenyl, halo-CVC6 alkyl, (^-(:6 alkyl), C"C6 alkyl thiol , Ci-C^ fluorenyl-Ci_C6 fluorenyl, Ci_C6 alkyl-Ci-C6 aryl, Ci-C6 aryl-Ci_C6 alkyl or CF3 'where Ci_C6 alkyl, Ci_C6 aryl, fluorenyl, halo-Ci -C^alkyl, alkyl, Ci-C6 alkyl-Ci-Cis thiol, Ci-C^ fluorenyl-(^1_(1;6醯) 119676.doc 200815347

a CVC6 alkyl-Cl_C6 aryl group or a Ci_c6 aryl group may optionally intercalate Z sulfur or nitrogen in one or more places in the same or different manner; or a group of a hydrazine group _Cl_C6 alkyl group, a reductive amine group; R: Γ Means that the C6-CJ group may be substituted at one or more places in the same or different manner by dentate, optionally as the case--substituted 匸丨-匕 alkyl or C1_C6 thiol, or may be 01_decanoyloxyl hydroxy, cyano, CCVA-Ce alkyl), N_(Ci_c^yl)2, CO-NR4R5 or cf3 substituted; a few c^Cl2 heteroaryl, which may optionally be one or more The same or different ways via halogen, Cl-C6 alkyl, Ci_c6 thiol, Ci_c6 alkoxy, hydroxy, cyano, c〇2_(Ci_c6 alkyl), N-(C1_C6), 2, CO-NR4R5 or Cf3 Substituted; or 3 C6 cycloalkyl, which may optionally be halogen, CF3, hydroxy, cyano, c〇2_(Ci_C6 alkyl), CVC6 alkyl, Cl-C6 fluorenyl, in one or more, at one or more , n_(Ci_c6 alkyl) 2, C〇-NR4R5 or cvc6 alkoxy substituted; think of gas; CrC6 cycloalkyl, which may optionally be in the same or different ways via Cl_c6 alkyl, Cl-c6 at one or more Base, CVC6 Oxygen or CF3 substituted; C6 C12 aryl 'which may, depending on the situation, be oxidized in one or more places by the same or different means, Ci_C6 alkyl, Ci_c6 fluorenyl, Cl-C6 alkoxy, N-CVC6 alkyl _Cl_c6 Substituted, Cf3 or cyano substituted; or heteroaryl, which may, depending on the situation, be the same or not in the same manner as 119676.doc -9- 200815347 by halogen, oxime, C"c6 alkyl, Cl-C6 Mercapto, (:" (: 6 alkoxy, N-CVc, ^ > g 1 h alkyl _Cl_C6 alkyl, Cf3 or cyano substitution; or 5 ^ C6 alkyl) which can be any desired Substituted; 'R w : hydrogen, Cl*C6 alkyl-C3-C6 cycloalkyl, which may, in the same or different manner, pass through C^C6 alkyl, q_C6 fluorenyl, C1 <6 alkane, as appropriate Alternate or substituted with oxy or CF3; 3 C6 decyl group, which may or may not be substituted at one or more positions in the same manner by 1 匕6匕6, Cl_c6 fluorenyl, Cl-c6 alkoxy or cf3; C6 a C12 aryl group which, in the case of one or more, is carried out in the same or different manner by a cyclin, a Cl-c6 alkyl group, a Ci_c6 fluorenyl group, a Ci-C6 alkoxy group, an N-CVC6 alkyl group _Ci_C6 alkyl group, a cf3 or a cyanogen group. Substituted; or

Cs-Cu heteroaryl, which may, depending on the situation, be oxidized in the same or different manner by _, Ci_C6 alkyl, Ci_C6, C "C6 (J oxy, N-Cl_C6 alkyl-Ci-C6 alkane) a radical, a CF3 or a cyano group; or a 4 5 Ci_C6 alkyl group, which may be substituted in any desired manner; and • R: and R5 - form a 5 to 8 membered ring which may contain other heteroatoms; And R6 meaning, a group of Cl-C6 alkyl, CrC6 fluorenyl, Cl_c6, a ring, a CVC: 6 alkyl or a Cl-C: 6 alkyl-C6_Cl2 aryl, wherein Ci_c thiol, Cl_C6 fluorenyl, Cl_C6 The base-ring c3-c6 alkyl or CVC6 alkyl-c6-c12 aryl may optionally be in one or more of the same or different ways via a benzyl, methoxy, ethoxy, #propoxy, 119676. Doc -10 - 200815347 gas, bromine, fluorine, cyano, methyl-methyl or amino group _ continued hydrazino substitution; and it overcomes known disadvantages and exhibits improved properties, ie good utility, good solubility And stable isomers, diastereomers, enantiomers and salts. The compounds according to the invention inhibit soluble adenylate cyclase and thus prevent sperm capacitation and thus for men Yu.

The hydrazine group is defined in each case as a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl Base, isopentyl and hexyl. Alkoxy is in each case defined as straight-chain or branched alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, iso Butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxycarbonyl are each defined as a straight or branched chain group, such as formazanyl, propyl Base, butyl, isopropyl, thiol and benzamidine. - A cycloalkyl group is defined as a monocyclic alkyl ring such as cyclopropylpentyl and cyclohexyl. The base may be combined with one or more heteroatoms such as oxygen, sulfur and/or nitrogen to form a slave atom. Preferred are heterocycloalkyl groups having 3 to 6 ring atoms. Depending on the situation - or a number of possible double bond ring systems are defined as j such as: read a base 'such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, ring [ Alkenyl or cycloheptane, _ this can be linked with a double bond and a single bond with H9676.doc 200815347. Halogen is defined in each case as fluorine, gas, bromine or iodine. In each case, the aryl group contains from 6 to 12 carbon atoms and may be, for example, phenylhydrazine condensed. For example, the following groups may be mentioned: phenyl, torazine, cyclooctadienyl, indenyl, naphthyl, biphenyl, decyl, fluorenyl and the like. A heteroaryl group in each case contains from 5 to 16 ring atoms and the ring may contain one or more of the same or different heteroatoms such as oxygen, sulfur or nitrogen in place of the carbon source.

And may be monocyclic, bicyclic or tricyclic' and additionally may in each case be benzoquinone condensed. For example, mention may be made of: thienyl, phenyl group... piroxime, oxalyl, cyano, oxime, iso. Anthraquinone, singular thiol, oxadiamine, trisal, succinyl, and the like, and benzoquinone derivatives thereof, such as benzoquinone, benzophenanyl, benzoquinone, benzene幷味唾基...引哇基基"引D基基,异"基等; or 嗓基基,啦咬基...Bidazinyl, triazinyl, etc. and its benzoquinone derivatives, such as 啥, 基-异圭琳基等' or '丫辛因基, $卜秦基, 吟基基, etc. and its natives; or 啥致^, S ηΛ. «11 Feilinlin, isoquinolinyl, porphyrin, Pyridazinyl, quinalinyl, (iv), material base, base, sulfhydryl"bite base, non-methyl group, morphazinyl, oxazinyl, (10) group, oxo group, etc. In each case, it may be 芏, _ j horse 幷 condensed. For example, thiophene, ϋ 喃 °, ° σ 坐 sit, 嗟 坐 sit, 5 miscellaneous - silly, oxazol and its benzoquinone The derivative may be mentioned as a 5% heteropoly compound, and the benzoquinone derivative may be mentioned as a sulfazine, a sulfonium, a ruthenium, and a 6 hexaheteroaromatic compound. The hetero atom is defined as oxygen. , nitrogen or (four) +. 119676.doc -12 - 200815347 if acidic The group, as a glutinous glutinous glutinous rice, is, for example, a soluble metal salt of an organic and inorganic bis-glucosamine, a bis-base-glucone, and a t-, base grape Amine, ethyl-glucosamine, lysine, hexamethylenediamine, ethanolamine, window #amine, sarcosine, serinol, cis-hydroxy-methyl-amino-methane, amine melamine, SoVak Alkali and 1-amino-2,3,4-butanetriol. If an inducible group is included, suitable organic and inorganic substances in the arteries such as hydrochloric acid, thiocyanate, linoleic acid, citric acid, and tartaric acid Physiologically compatible salts of acids. Particularly preferred are the compounds of formula (I) wherein R1 means hydrogen, dentate, cf3, C3_C6m alkyl; or group (tetra)alkyl, CVC6, and Cl_c6 Sulfhydryl, dentate core group, alkyl group-CVC^ group, Cl_c6 alkyl group _Ci_c6 fluorenyl group, Ci_c6 fluorenyl group _Ci-C6 fluorenyl group, CrC6 alkyl group, Cl_C6 aryl group, Ci_C6 aryl group _Ci_C6 alkyl group or CF;, wherein CVQ alkyl group, Cl_C6 aryl group, Ci_C6 brewing group, _based core group, G-C6 yard base _Cl_c6 alkyl group, c"c6 alkyl group _Ci_c base, Ci_C6 thiol-CA group, Cl_c6 burning base_Ci _C6 aryl or Ci_C6 aryl·Ci_c6 may optionally intercalate oxygen, sulfur or nitrogen in one or more of the same or different ways; 2 or a group of sulfonyl-Cl-C6 alkyl, sulfonamide or cyano R2 means - prime, cf3 or. 3_. 6 cycloalkyl; or a group Ci_c6 alkyl, (VC6 aryl, Ci-C6, ke group, alkyl 4 alkyl, Cl_c6 alkyl-Cl_C6 fluorenyl, Ci_C6 fluorenyl _Ci_C6 Stuffed base, Ci_C6 alkyl-Ci-C6 aryl, Cl_c6 aryl-Ci_c6 alkyl or Cf3, wherein Ci_C6 alkyl, Ci-C6 aryl, CVQ fluorenyl, phenyl group, 119676.doc -13- 200815347 base-cvc6 alkyl, CVC6 alkyl-CVC6, (^-(:6醯-(VC6 fluorenyl, Ci-C6 alkyl-Ci-C:6 aryl or Cl_c6 aryl-Ci_c6 alkyl) Depending on the situation, oxygen, sulfur or nitrogen may be intercalated in one or more places in the same or different manner; or a group of sulfonyl-C 1 -C 6 alkyl, a chiral amine or a cyano group; R3 means a CrCu aryl group, The same may be carried out in one or more of the same or different ways via halogen, C "C6 alkyl, Cl-C3 fluorenyl, Cl-C3 alkoxy, cyano, hydroxy, N-(CH3)2, COHCkC^ alkyl) Replace with co-nr4r5 or cf3;

Cs-C! 2 heteroaryl, which may optionally be in one or more of the same or different ways K fluorine and / or fluorine, Ci-C6 alkyl, C1-C3, C1-C3 alkoxy, cyano , hydroxy, N-(CH3)2, COHCi-C; alkyl), CO-NR4R5 or CF3 substituted;

CrC6 cycloalkyl group, which may optionally be subjected to gas and/or fluorine, CF3, cyano, Cl_c3 alkyl, cKc3 decyl, hydroxy, N-(CH3)2, COHCi-Cs in one or more places at one or more points. Alkyl), CO_NR4R5 or CVC3 alkoxy substituted; R means hydrogen; CrC: 6 cycloalkyl, optionally in one or more of the same or different ways via C!-C3 alkyl, CVC3 decyl, Ci- Cs alkoxy or cf3 substituted;

CyC!2^• group, which may, depending on the situation, be halogen, CVC3 alkyl, CVC3 thiol, CiA alkoxy, N_Cl_c& base-C^C:3 alkyl, cf3 or cyanide in one or more different ways. Substituted; or

Cs-Cu heteroaryl, optionally in one or more of the same or different ways via halogen, CVC3 alkyl, CrCs thiol, CVC3 alkoxy, N-(Vc3 119676.doc -14-200815347 alkyl-C ^C: 3 alkyl, CF3 or cyano substituted; or

Ci-C6 alkyl group 'which may be substituted in any desired manner; R5 means hydrogen; CrC6 alkyl-Cs_C6 cycloalkyl group, which may optionally be C1-C6 alkyl, Ci_C6 in one or more places in the same or different manner. Substituted, Ci_C6 alkoxy or CF3 substituted;

The CrC6 cycloalkyl group is optionally substituted in the same or different manner at one or more positions by <^-(:3 alkyl, (VC3 fluorenyl, CrCs alkoxy or CF3;

a CpCu aryl group optionally substituted at one or more times by halogen, CVC3 alkyl, CVC3 thiol, CVC3 alkoxy, N-CVC3 alkyl-C "C3 alkyl, cf3 or cyano"; Or a heteroaryl group, optionally in one or more, in the same or different manner via li, CVC3 alkyl, Cl-C3 fluorenyl, Cl-C3 alkoxy, n_Ci-C3 alkyl-CVC3 alkyl, cf3 or Cyano substitution; or

Ci-C0 alkyl group' which may be substituted in any desired manner; R and R5 together form a 5 to 8 membered ring which may contain other heteroatoms; and R6 means a group of a heteronuclear group, (VC6 alkane) a base-cyclic c3-c6 alkyl group or an alkyl-CVC12 aryl group, wherein the CVC6 alkyl group, the alkyl-ring c3-C6 alkyl group or the CrC6 alkyl-CrCu aryl group may be the same or different in one or three places, as the case may be. Substituted by a hydroxyl group, a decyloxy group, an ethoxy group, an isopropoxy group, a gas, a desert, a fluorine, an oxy group, a methyl-renewed or an amine group; and an isomer thereof, a diastereomer thereof The structure, the enantiomer and the salt are also preferably the compounds of the formula I, wherein R1 means 氲; R is c3-C6 cycloalkyl, Ci_c; 6 alkyl, cf3, cyano, desert Or 119676.doc -15· 200815347 团-OCF3 or ·8〇2_(:Η3; R means CpCu aryl, which may optionally be halogen, Cl_c6 alkyl, Cl-, in one or more, in one or more different ways. C3 thiol, Cl-C3 alkoxy, cyano, hydroxy, N-(CH3)2, alkyl), co-nr4r5 or cf3 substituted; C^Ci2 heteroaryl, which may optionally be one or more The same or different ways via chlorine and / or fluorine, CVC6 alkyl, CrCg fluorenyl, C!-C3 alkoxy, cyano, thiol, N_(CH3)2, cOHCrCs alkyl), CO-NR4R5 or cf3;

CrC6 cycloalkyl group, which may, depending on the case, be oxidized by chlorine and/or fluorine, CF3, cyano, Cl_c3 alkyl, Ci_c3 fluorenyl, hydroxy, N-(CH3)2, COHCVCs in one or more places in the same or different manner. , c〇-NR4R5 or CVC3 alkoxy substituted; R4 means hydrogen; R means hydrogen, CVC6 alkyl-CrC6 cycloalkyl, which optionally passes in the same or different ways at one or more points (^-(: 6 alkyl, Cl_c0 fluorenyl, Ci_c6 alkoxy or CF3 substituted;

CrC6 cycloalkyl, optionally in the same or different manner via one or more alkyl, cvc3 decyl, Cl-C3 alkoxy or substituted; aryl, as the case may be the same or at one or more Different ways of elemental, CVC3 alkyl, Cl_c3 thiol, Ci_c3 oxy, N_Ci_C3 alkyl-Ci-C3 alkyl, CF3 or cyano; or q-Cu heteroaryl, depending on the situation one or more Substituting i, CVC3 alkyl, Cl_c3, Ci_c3 oxy, N_Ci_c 119676.doc -16 - 200815347 alkyl-Ci-q alkyl, CL or cyano in the same or different manner; or 〇1_匕An alkyl group which may be substituted in any desired manner; R is a group (ν<:4 alkyl, ch2-cyclo c3-c6 alkyl or ch2_c6-c12 aryl, wherein (VC4 alkyl, CHr ring) The CVC6 alkyl or CH2_C6_Ci2 aryl group may be optionally substituted in one or three places with a hydroxyl group, a decyloxy group, a gas, a fluorine, a gas group or an amine group; or an isomer thereof or a diastereomer thereof. Isomers, enantiomers and salts. Also preferred are the compounds of the formula I, in which R1 means hydrogen; R means alkyl, cvc^alkyl, cf3, cyano, bromo or a group - OCF3 or - S02_CH3 and in the para position; 3 R means a CpCu aryl group, which may optionally be in one or two places via the halogen 'Ci-C:3 alkyl, ethyl methoxy, ethoxy, ethoxy, in one or two places. Cyano, hydroxy, N-(CH3)2, CCVfi-C^ alkyl), CO-NHR5 or cf3 substituted;

Cs-Cu heteroaryl, which may optionally be in one or two different positions via chlorine and/or fluorine, C1-C3 alkyl, ethyl, methoxy, ethoxy, cyano, hydroxy, N-(CH3)2, ¢: 02-((^-(^3 alkyl), CO-NHR5 or CF3 substituted; or C3-C6 cycloalkyl; R4 means hydrogen; R means hydrogen, or Ci- C6 alkyl-C3-C6 cyclodextrin' is optionally substituted in the same or different manner by Cl-c6 alkyl, CrC6 fluorenyl, CrCs alkoxy or CF3;

CrC6 cycloalkyl, which may be substituted in the same or different manner by one or more of 119676.doc • 17- 200815347 via Ci_C3 alkyl, CVC3 fluorenyl, cc垆k 1匕3 thiol or cf3; C6-Cu aryl, It may, in the same or different manner, be halogen, (VC3 alkyl, Cl_C fluorenyl, Ll'C3 alkoxy, N-(VC3 alkyl-C^C:3 alkyl, CF3 or a cyano group; or a C5-Cu heteroaryl group, optionally substituted with a halogen, (VC3 alkyl, Cl-C3 fluorenyl, alkyl-C^-C:3 alkyl, CF3 or cyano; Alkoxy, n_k3 or Ο in the same or different ways

Ci-C6 alkyl, which may be substituted in any desired manner; R is a group CVC4 alkyl, CH2·cyclo c3-c6 alkyl or CH2-C6_C12 aryl, wherein CrC4 alkyl, CH2-cyclo c3 The -c6 alkyl or CHrCdd group may be optionally substituted at one or three positions with a hydroxy, methoxy, chloro, fluoro, cyano or amino-sulfonyl group in the same or different manner; u and its isomers, non-pairs Enantiomers, enantiomers and salts. Also preferred are the compounds of the formula I, which are meant to be hydrogen; 12 means the third butyl, isopropyl, isobutyl, t-butyl, cyano, moie or group -0-CF3 or - S02-CH3 and in the opposite position; meaning the group 119676.doc -18- 200815347

Eight means hydrogen; meaning hydrogen or a group -(CH2)nN-(CH3)2, -(CH2)2-CH3, -(ch2)2-nh-coch3, -(CH2)-CHCH3-OH, - (CH2)2-0-CH3, -(CH2)2-〇H or -CHCH3-CH2-OH, where n=l-3, 119676.doc -19- 200815347

Γ R6 means methyl, ethyl, propyl, 2-methoxy-ethyl, -CH2-CF3, -(CH2)2-CF3 and benzyl; and isomers, diastereomers thereof , enantiomers and salts. Also preferred are the compounds of formula I wherein R1 is hydrogen; U R2 means tributyl, isopropyl, isobutyl, t-butyl, cyano, bromo or the group - 〇-cf3 Or -so2-ch3 and in the para position; R3 means the group

R4 means hydrogen; 119676.doc -20- 200815347 means hydrogen or a group -(CH2)-CHCH3-OH, -(CH2)2-〇_ch3 or -chch3-ch2-oh,

Means methyl, ethyl, propyl '2-methoxy-ethyl, -CH2_CF3, -(CH2)2-CF3 and a nodal group; and isomers, diastereomers, enantiomers thereof Structure and salt. The following compounds corresponding to the present invention are very particularly preferred: h 5_[(4-t-butylphenylsulfonylmethyl, benzyl)-p-phenyl·1H_ 引 朵 -2_carboxylic acid _ (tetrahydrogen ratio _4 base) 醯 醯 2 2· 5-[(4-t-butyl-phenylsulfonyl)-methyl-amino]_3_phenyl_1Ή_ 吲哚-2-carboxylic acid (2_? Porphyrin_4_yl-ethyl)-decylamine 3· (±)-5-[(4·t-butyl-phenyl fluorenyl)-methyl-amino]_3_phenyl _ 1Η·叫卜朵-2-carboxylic acid _(2_ mercapto-methyl-ethyl)-decylamine 4· (±)-5·[(4-tert-butyl-phenylsulfonyl)-methyl-amino] _3_phenyl_1Η-called hydrazine formic acid _(2-hydroxy-propyl)-decylamine 5·5_[(4-tert-butyl-phenylsulfonyl)-methyl-aminophenyl _1Η_ , ΰdocarboxylic acid-(pyridin-4-yl)-nonylamine 6·5_[(4-tert-butyl-phenylsulfonyl)-benzyl-amino]_3_phenyl_1Η· °弓I bee-2·formic acid·(tetrahydro-pyran-4-yl)-decylamine 7·5_[(4_t-butyl-phenylsulfonyl)-benzyl-amino]-3_ Phenyl_1Η_ 119676.doc -21- 200815347 0 引0多-2 -formic acid (2-norphin-4-yl-ethyl)-bristamine 8·(土)-5-[(4-third Base-phenylsulfonyl)-benzyl-amino]-3- Phenyl-1H-indole-2-carboxylic acid-(2-hydroxy-1-indolyl-ethyl)-decylamine 9·(土)-5-[(4-tert-butyl-phenylsulfonyl) )-benzylamino]-3-phenyl-1H-indole-2-carboxylic acid-(2.hydroxypropyl)-decylamine 10· 5-[(4-tert-butyl-phenylsulfonate) Indenyl)-(2-methoxy-ethylamino)-3-phenyl-1Η-°bendo-2-indole-(tetrahydro-pyran-4-yl)nonylamine 11· 5-[(4_Terti-butyl-phenyl fluorenyl)-(2-methoxy-ethyl)-amino]_ 3-phenyl-1Η-σ引11 朵·2_ decanoic acid (2-淋 -4 _ -4 -4 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± -3 -phenyl·1 HS budo-2-decanoic acid-(2-carbyl-1-methyl-ethyl) decylamine 13· (±)-5-[(4·t-butyl- Phenylsulfonyl)-(2-decyloxy-ethyl)-amino]-3-phenylbuto-2-carboxylic acid-(2-hydroxy-propyl)-bristamine 14. 5-[( 4-tert-butyl-phenyl fluorenyl)-methyl-amino]_3_(3-fluoro-phenyl)-1Η-indole-2-carboxylic acid-(tetrahydro-pyran-4-yl)-indole Amine 1 5 · 5-[(4-Ternyl-phenyl fluorenyl)-methyl-amino]_3-(3-fluoro-phenyl)-1Η-indole-2-carboxylic acid (2-morpholine) -4-base- Ethyl)-decylamine 16· 5-[(4-Ternyl-phenylphenyl)-methyl-amino]_3_(3_decyloxy-phenyl)_1Η-吲哚-2- Formic acid-(tetrahydro-pyran-4-yl)-decylamine I7·5_[(4-indolyl-phenyl fluorenyl)-fluorenyl-amino]decyloxy-phenyl MH-吲哚- 2-Indolic acid (2-morpholin-4-yl-ethyl)-amine 18. In addition, the present invention relates to a process for the preparation of a compound of the formula according to the invention, characterized in that it is according to those skilled in the art. The compound of formula II is known by the method 119676.doc -22- 200815347

八中 R R 汉和汉6 has the meaning indicated above and R7 may be hydrogen or 1 C6 alkyl and the ruthenium is preferably gas, methyl or ethyl, and reacts with the amine of formula (1)

R4(III), wherein R and R have the meanings indicated on IX, and then the desired protecting group is cleaved, as appropriate. In the case where R is hydrogen, the reaction first activates the acid functional group; in this case, for example, first, in the presence of a tertiary amine such as triethylamine, the isobutyl chloroformate is used to effect the general acid conversion. For mixing sour liver. At _3〇. Preferably, the temperature is between 〇 and +60 ° C. (: to 3 〇. (:, mixed anhydride in a y inert solvent or solvent mixture such as tetrahydrofuran I-monomethoxyethane, dimethyl decylamine or dimethyl cyanoic acid tridecylamine Reaction with an alkali metal salt of the corresponding amine. Alternatively, the compound of the formula η can be reductively activated by a reagent such as HOBt or HATU. At a temperature between -50 ° C and +60 ° C, preferably 〇 The reaction of an acid with, for example, haTu is carried out in the presence of a corresponding amine of the formula 及 and a tertiary amine such as ethyl monoisopropylamine in an inert solvent such as DMF. In the case where R is a ci-C6 ray group, for example, a direct guanamine solution of the ester with the corresponding amine can be carried out by means of 119676.doc -23-200815347 in a di-alkali-aluminum reagent, preferably a trimethylaluminum. The compound of the formula II as a starting material can be prepared, for example, by methods known in the art wherein a known oxime ester IV is obtained in the presence of a Pd catalyst under a hydrogen atmosphere or a hydrogen source such as ammonium formate. Nitro

Wherein R is C^C: 6 alkyl group, preferably methyl or ethyl, first reduced to the amine B energy group' and subsequently at. Reaction of the amine with a dentate of the formula V in the presence of a base of a bite, diisopropylethylamine, triethylamine or potassium carbonate

(V), wherein R1 and R2 have the meanings indicated above and Hal represents halogen, preferably fluorine, gas or bromine to form a compound of formula VI

Subsequently, the formula Vlg is intended to be converted at the 3-position, for example by means of iodine, NBI, NBS or CuBr*2, and thus a compound of the formula VII is obtained

- P7 M (VII), wherein R1, R2 and R7 have the meanings indicated above. 119676.doc -24- 200815347 Subsequently, the ester is reacted with a halide of the formula VIII in acetone or tetrahydrofuran in the presence of, for example, diisopropylethylamine, potassium carbonate or a carbonic acid plan. Hal R6 (VIII), wherein R6 has the meaning indicated above, and Hal represents halogen, preferably iodine, gas or bromine, to form a compound of formula IX

Subsequently, in the catalytic reaction with Pd of the formula X-acid derivative, R3〆(X), wherein R3 has the meaning indicated above, optionally cleaves the protecting group required in R6, optionally with hydrogen, for example After saponification of the sodium oxide solution, the ester of the formula IX is converted to the compound of the formula II at the 3-position

R1

R6 R2 119676.doc -25- 200815347

Wherein R1, R2, R3 and R7 have the meanings indicated above, and are subsequently R6 in acetone or tetrahydrofuran and the halide of the formula VIII in the presence of a base such as diisopropylethylamine 'potassium carbonate or a carbonate base (VIII), wherein R6 has the meaning indicated above, and Hal represents halogen, preferably iodine, gas or bromine, optionally cleavage of the desired protecting group in R6, optionally with, for example, sodium hydroxide solution After the post-saponification, an N_alkylation step is performed to form a compound of formula II. The compounds according to the invention inhibit soluble adenylate cyclase, for example in the case of male birth control, the function of which is based on this. Adenylate cyclase is one of the most commonly used signal transduction methods; it is synthesized by adenosine triphosphate (ATP) pyrophosphate (pp) to synthesize a second messenger molecule of cyclic adenosine monophosphate (cAMP). . cAMP mediates numerous cellular responses to a large number of neurotransmitters and hormones. Soluble sperm-specific adenylate cyclase (sAC, human mRNA sequence (gene bank) NM-〇18417, human gene ADCY X) is one of the adenylate cyclases of the human genome. Under this condition, sAC displays several specific qualities different from other adenylate cyclases. A compared to all other adenylate cyclases. It is stimulated by the concentration of bicarbonate in the surrounding medium and is not stimulated by prion protein. sAC does not have any transmembrane region in its amino acid sequence; it cannot be inhibited by forskolin, and it can be stimulated by manganese to be more strongly stimulated by magnesium than 119676.doc -26-200815347, and only shows Low sequence homology of other adenylate cyclases (at the amino acid level, catalytic domains I and II of sAC are $26% identical to other adenylyl cyclases). The specific manganese-dependent activity of sAC was first described by T. Braun et al., 1975, PNAS 73: 1097 pages in rat testis and sperm. N. Okamura et al. (1985, J. Biol Chem 260 (17) : 9699 pages) The substance that exhibits the activity of sAC in stimulating pig semen is bicarbonate. It can also be displayed in rat testis and sperm, but sAC activity is not detected in other tissues and can be stimulated by bicarbonate. The Buck and Levin groups purified sAC from rat testes and first sequenced (J. Buck et al., 1999 PNAS 96: 79 pages, WO 01/8 5753). Expected properties (eg, stimulation of bicarbonate and magnesium) Capacity) was confirmed in recombinant expression proteins (Y. Chen et al., 2000 Science 289: 625 pages). Information on the distribution of sAC mRNA and the activity of sAC stimulated by bicarbonate can indicate testicular and sperm specificity of the enzyme. Performance (M·L·Sinclair et al., 2000 Mol Reprod Develop 56:6 page turning; N. Okamura et al., 1985, J. Biol. Chem 260(17): 9699 pages; J. Buck et al., 1999 PNAS96 : 79 pages). In this condition, in the testis, sAC mRNA is only expressed in the development of gametes. Later, but not in somatic cells (ML Sinclair et al., 2000 Mol Reprod Develop 56:6 pages). There are a large number of pharmacological studies on the function of sAC in mammalian sperm. The band must be prepared for this function before it is subsequently fused with the yolk membrane. The sperm capacitation process has been deeply penetrated by 119676.doc -27- 200815347

the study. Capacitated sperm differs depending on the mode of activity of the change and the ability of the stimulant to undergo an acrosome reaction process (estimated for the release of cytosolic enzymes that may pass through the zona pellucida). Based on the high concentration of bicarbonate in the medium, sperm capacitation is performed in vivo and in vitro through the artery (p E

Visconti and G. S. Kopf (1998) Biol Reprod 59:1 turn; E heart

Lamirande et al., 1997 M〇1 Hum Repr〇d 3(3): 175-turn blister" sub-energy can also be achieved by adding a suitable transmembrane AMP analog such as db_cAMp and inhibiting its degradation (eg, ΙΒΜχ Inhibitors to stimulate. The expected dependence of sperm function on sAC has only recently been confirmed by the so-called gene knockout mouse gene deletion model. (G·Esp〇sh〇 et al., 2〇〇4 10 1(9): 2993 pages). Male mice lacking the sAC gene display normal sperm formation but are infertile. Sperm has a mobility disadvantage and does not allow the egg to be fertilized. These animals do not display other missing or abnormal findings corresponding to other hypothetical functions of sAC (j. H. Zippin et al., 2003 FASEB 17:82 pages). sAC has a unique sequence and has only minor homology to other adenosine cyclases. It is the only adenylate cyclase in mammalian sperm and its activity is indispensable for sperm motility and capacitation. Therefore, the specific inhibitor of sAC represents an important possibility to regulate male fertility. Thus, a pharmaceutical agent containing at least one compound as claimed in claim 1-7 is the subject of the present invention. The use of the compounds of the formula 1-7 is also the subject of the invention. In order to use the compound according to the invention as a medicinal agent, the latter is also included as an active ingredient in addition to enteral or parenteral administration, and also contains a suitable pharmaceutical organic or 119676.doc •28·200815347 inorganic inert carrier substance In the form of a formulation, such carrier materials are, for example, gum arabic, lactose, starch, stearic acid, talc, vegetable oil, polyalkylene glycol, and the like. The pharmaceutical preparation may be in the form of a solid form, such as a key, a coating, a suppository or a capsule, or a liquid form such as a solution, suspension or emulsion. In addition, it contains adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts or buffers which are devoid of osmotic pressure. These pharmaceutical preparations are also the subject of the present invention. For parenteral administration, suitable are, in particular, injection solutions or suspensions, especially aqueous solutions of the active compound in polyhydroxyethoxylated cannabis oil. As the carrier system, an interfacial active adjuvant such as a salt of cholic acid or an animal or vegetable phospholipid, a mixture thereof, and a liposome or a component thereof can also be used. For oral administration, suitable are lozenges, coated lozenges or capsules having, in particular, talc and/or a hydrocarbon vehicle or binder such as sugar, corn or potato starch. Administration can also be carried out, for example, in the form of a liquid in which a sweetener-containing juice is added as appropriate. Suitable and common for vaginal administration are, for example, suppositories. Enteral, parenteral and oral administration are also the subject of the present invention. The dose of the two active ingredients may vary depending on the method of administration, the age and weight of the patient, the type and severity of the condition to be treated, and the like. The daily dose is 00 mg, and the carrier is preferably 50-200 mg. Thus, the dose can be administered in a single-human dose or divided into two or more daily doses. The compound of the formula 1 according to the present invention is an excellent inhibitor of intra-arterial soluble adenylate-reducing enzyme. An inhibitor of soluble glucuronide cyclase attenuates the cAMP signal of 119676.doc -29-200815347. The cAMP content is decisive for monitoring the important role of cell proliferation, cell differentiation and cell death. A disease such as a reduced amount of a decisive cancer can be modulated by a soluble glandular acid cyclase inhibitor. This modulation has a preventive and therapeutic effect on patients suffering from the disease. Diseases such as cancers with increased cell weight gain are currently treated by, for example, radiation therapy and chemotherapy. These methods are non-specific and have high side-effect potential. Therefore, the preparation of new substrates that directly attack specific dry sites is advantageous. A substance which modulates the production of cAMP by inhibiting soluble gland acid cyclase is the subject of the present invention, for example, abnormal cell proliferation can be reduced or inhibited by regulating or inhibiting the production of cAMp. By using the substance according to the present invention, soluble adenosine cyclase can be inhibited; this results in a decrease in cell proliferation. The subject matter of the present invention is a pharmaceutical agent containing at least one psychic compound for use in the treatment of a disease, and a pharmaceutical agent having a suitable formulation and vehicle. Therefore, the disease is characterized by its metabolic disorder caused by the second messenger cAMP. The use of a medicament to modulate sperm capacitation by inhibiting soluble adenylate cyclase to reduce the concentration of cAMp. The subject of the present invention is the use of a substance according to the invention to reduce and/or inhibit male accommodation by reducing or inhibiting the activity of soluble glucuronide cyclase and the resulting sperm capacitation. The fertilization of the knife can be prevented by administering an effective amount to the effect of the production. general formula! The use of a compound for the preparation of a pharmaceutical agent for non-hormonal contraception is also a subject of the present invention. If the preparation of the starting materials is not described, the starting materials are known or can be classified as 119676.doc 200815347. It is also possible to carry out the reaction in any of the reactors described in the description of the known compounds or the methods described herein or by means of a combination of procedures. Separation into an enantiomer or E/Z isomer according to a mixture of normals such as crystallization, chromatography or salt formation can be carried out in the usual manner by making the solution of the compound with an equivalent amount or condition. Mix the base or acid in the form of Loose, one. Liyue solution is ready for use. ^ Way to separate the sink or the temple

[Embodiment] Preparation of the compound according to the present invention The following examples illustrate the preparation of the compound of the formula (1) according to the present invention, and do not limit the scope of the claimed compound to the examples. The compound of the formula (I) according to the invention can be prepared as follows. Example 1: 54(4-Tertiary-phenylsulfonyl)-methyl-amino]_3_phenyl_1Η_吲哚-2_carboxylic acid-(tetrahydro-pyran-4-yl) _ guanamine

40.3 mg of Ν-[(dimethylamino)-1//-1,2,3-tri.幷[4,5-&]σ-pyridin-1-ylindenyl]-iV-methyldecane ammonium hexafluorophosphate-Ν-oxide (HATU) and 9.84 mg 4-aminotetrahydro α The oxime was added to a solution of 45 mg of the acid prepared in Example If) in 0.75 ml of dimethylformamide. Subsequently, 18.0 μM of ethyldiisopropylamine was added dropwise at 0 ° C and stirred at room temperature for 20 hours. After 119676.doc -31- 200815347, 25 ml of water was added, stirred for 30 minutes and aspirated. The residue obtained was purified by oxime chromatography using hexane / 0-70% ethyl acetate. 49.7 mg of the title compound was obtained in this manner. NMR (300 MHz, DMSO-d6): δ=1·22 (2H), ι·26 (s 9H) 1·65 (2Η), 3·〇7 (3Η), 3.32 (2Η), 3·68 ( 2Η), 3·89 (1Η), 6 91 ΟΗ), 6.99 (1Η), 7.26-7.33 (4Η), 7.34-7.41 (5Η), 7.54 (2Η), 11.85 (1Η). The starting materials for the title compounds mentioned above were prepared as follows: la) 5-Amino-indole-π-bendoic acid ethyl ester

G 5 nitro-1H 』 卜 -2 -2- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ After 1 hour, the IL was returned to IL for 1 hour. After the sputum was taken, it was aspirated on Shixiatu soil and washed again with warm methanol. After removing the solvent, the residue was mixed with 1 ml of water and stirred. After a few minutes, the precipitated solid was suctioned on a G4 frit. The obtained solid was dried in vacuo. In this way, 4.12 g of the title compound was obtained. NMR (3 〇〇 MHz 5 DMSO-d6): δ^Ι.28 (3Η ) 5 4.25 (2Η)5 4·63 (2Η), 6.62-6.68 (2Η), 6.79 (1Η)? 7.12 (1Η)5 11.35 (1Η) 〇' ^)5-(4-Second-butyl-benzene Ethylsulfonylamino)_1Η_吲哚carboxylic acid ethyl ester 119676.doc -32- 200815347

Adding 5.18 ml of ethyldiisopropylamine and 4.69 g of 4_t-butyl-phenyl-indenyl chloride to 4·12 g of the amine prepared in Example la) at 〇C This was stirred in a solution of 195 ml of DMF and allowed to stand at room temperature for 2 hours. The solution was removed under reduced pressure and the residue was purified eluting with EtOAc EtOAc In this way, 7.56 g of the title compound was obtained. NMR (300 MHz, DMSO-d6): 5 = 1.20 (9H) 1 27 (3H) 4.27 (2H)5 6.97-7.03 (2H), 7.25 (1H)5 7.31 (1H)5 7.48 (2H)? 7.59 ( 2H), 9.93 (1H), 11.80 (1H) 〇lc)3-bromo-5-(4-t-butylphenylsulfonylamino)_1H_吲哚·2-carboxylate

3·3 6 g of N-glycolide was added to a solution of 7·5 6 g of the sulfonamide prepared in Example 1 b) in 217 ml of tetrahydrofuran, and it was disturbed at room temperature. 40 minutes. It was diluted with 300 ml of ethyl acetate, washed once with (10) water, twice with each 50 ml of saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. After the transition and concentration by vacuum evaporation, the obtained residue was crystallized from ethyl acetate/ethyl acetate. In this way, 8 § title compound was obtained. NMR (300 MHz, DMSO-d6): δ=1.2〇(9Η)5 ι.3〇(3Η) 119676.doc -33- 200815347 4_31 (2H),7.08-7.15 (2H),7·33 (1H) , 7.50 (2H), 7·60 (2H), 10·08 (1H), 12.16 (1H) 〇ld) 3-bromo-5-[(4-tert-butyl-phenylsulfonyl)_曱Ethyl-amino 2-ethyl ester

375 nig%i acid clock and 0.13 ml of hydrazine hydrazine were added to a suspension of 1 g of the bromide prepared in Example 1 c) in 10 ml of acetone, and stirred at room temperature for 24 hours. Subsequently, it was diluted with 300 ml of ethyl acetate and washed once with 5 ml of water and 50 ml of a saturated sodium carbonate solution. After drying over sodium sulfate and filtered, it was concentrated in vacuo. The residue obtained was purified by medium pressure sepal chromatography eluting with hexane/ethyl acetate ratio of 7:3. In this way, 670 mg of the title compound was obtained. NMR (300 MHz, DMSO-d6): 5 = 1.27 (9H)? 1.32 (3H)5 y 3·14 (3H), 4.34 (2H), 6.92 (1H), 7·08 (1H), 7.39 (1H) ),7·41 (2H), 7.56 (2H), 12.33 (1H) 〇le)5-[(4-Ternyl-phenylsulfonylmethylamino)-3-phenyl-1H -吲咕-2-carboxylic acid

Add 239 mg of phenyldipontate and 3.37 ml of 1 Μ sodium carbonate aqueous solution and 160 mg of 119676.doc •34-200815347 lithium hydride to 666 mg of the sample Id) to prepare the ester from 25·5 ml of ethanol and 25· 5 mi of toluene in a mixture of solutions. After the addition of ία瓜肆(diphenylphosphine)-palladium, the reaction mixture was refluxed for 2 hr. After cooling to room temperature, it was suctioned on diatomaceous earth and washed again with ethyl acetate. The obtained organic phase was washed with 10 ml of a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over sodium sulfate. After concentration by evaporation in vacuo, the obtained residue was purified eluting with EtOAc EtOAc In this way, 626 mg of the title compound was obtained. NMR (300 MHz, DMSO-d6): δ = 1·13 (3H), 1_27 (9H), 3·06 (3H), 4·18 (2H), 6.90 (1H), 7.07 (1H), 7.25- 7.36 (5H), 7.39 (2Η), 7·43 (1Η), 7·55 (2Η), 10.24 (1Η). (1)"(4) Ternyl-phenylsulfonyl-methyl-amino-based phenyl phenyl guanidine 11-formaldehyde

905 mg of sodium hydroxide was added to a mixture of 600 mg of the sample le) prepared from 14.5 ml of ethanol and 7.25 ml of ethanol, and it was spoiled at room temperature for 20 hours. Subsequently, it was diluted with 1 μl of water and acidified with 5% sulfuric acid. The deposited precipitate was filtered off and dried. In this way, 205 mg of the title compound was obtained, which was further reacted without further purification. NMR (300 MHz, DMSO_d6)··δ=1·26 (9H), 3·06 (3H), 6.88 (1Η), 7·〇4 (1Η), 7·24-7_35 (5Η), 7.36-7.43 (3Η), 7.55 (2H), 11.94 (1H), 12.93 (1H) 〇119676.doc -35- 200815347 Example 2: 5-[(4-Tertiary-phenylsulfonyl)-indenyl- Amino]-3-phenyl-1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-decylamine

Analogously to Example 1, 36.2 mg of the title compound was obtained from 45 mg of the acid of Example If) and 12·8 μs of 2-(morpholin-4-yl)-ethylamine. NMR (300 MHz, DMSO-d6): 5 = 1.27 (9H)? 2.18 (4H), 2.25 (2H), 3.06 (3H), 3·25 (2H), 3·38 (4H), 6.85 (1H) , 6.98 (1Η), 7.27-7.42 (9Η), 7.55 (2Η), 11.85 (1Η). Example 3: (±)-5-[(4-Ternyl-phenylsulfonyl)-methyl-amino]-3-phenyl-1Η-indole-2-carboxylic acid-(2-hydroxyl -1-methyl-ethyl)-guanamine

Analogously to Example 1, 46.2 mg of the title compound was obtained from 45 mg of the acid of Example If) and 7.75 μM 2-amino-1-propanol. NMR (300 MHz, DMSO-d6): δ=0·94 (3H),1·26 (9H), 3·〇7 (3Η), 3.13-3.30 (2Η), 3.89 (1Η), 4.62 (1Η) , 6.89 (1Η), 6.96 (1H), 6.99 (1H), 7·26·7·41 (8H), 7·54 (2H), 11.83 (1H) 〇 Example 4: (±)-5_[(4 -T-butyl-phenylsulfonyl)-methyl-amino]-3-phenyl-1H-indole-2-carboxylic acid-(2-hydroxy-propyl)-decylamine 119676.doc -36 - 200815347

Analogously to Example 1, 45.4 mg of the title compound was obtained from 45 mg of the acid of Example If) and 7.31 mg of 1-amino-2-propanol. NMR (300 MHz, DMSO-d6): δ = 0·91 (3H), 1_27 (9H), 3.00-3.17 (2Η), 3.06 (3Η), 3·58 (1Η), 4·59 (1Η), 6.87 (1Η), 6·99 (1H), 7·15 (1H), 7.26-7.41 (8H), 7.54 (2H), 11.84 〇 (1H). 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. Subsequently, free c AMP produced in this manner was used in a competitive debt test process in which an anti-cAMP antibody (anti-cAMP-Eu[K]-AK) labeled with europium kryptate (Eu[K]) was used. The binding of hydrazine to the modified allophycocyanine-1 molecule (CAMP-XL665) by cAMP molecular markers is prevented. Fluorescence resonance energy transfer between anti-cAMP-Eu[K]-AK (FRET donor) and CAMP-XL665 molecule (FRET acceptor) after excitation at 335 nm without exogenous cAMP (FRET). The process was quantified at different times (time resolved) based on the emission of the FRET acceptor XL665 (665 nm and 620 nm). Signal drop (measured as wave ratio; calculation: [(E665 nm / E620 nm) x 10000]) can be attributed to the presence of cAMP and is therefore attributed to the activity of 119676.doc -37 - 200815347 sAC. First, 1.5 μM of the test substance (in 30% DMSO) was introduced into each of the 384-well test plates (polystyrene; 384, NV) in a solvent control of only 30% DMSO. Subsequently, 10 μΐ of dilute sAC enzyme solution (enzyme stock solution in 300 mmol NaCl, 10% glycerol; pH 7.6; intermediate and final enzyme dilution a) 1:10 and b)l:2〇00 are recovered in each case. In the following solutions: 1·0 mmol MnCb in η2〇; 0.2% BSA; 50 mmol tris, pH 7.5). The enzymatic reaction was initiated by the addition of 5 μΐ ATP substrate (200 μηηοΐ ATP in H2〇) and after incubation (25 minutes at room temperature), the solution was stopped by adding 5 μM (200 in PBS). Ηηιοί EDTA) ends. Finally, the entire reaction was adjusted to a total volume of 91.5 μl by the addition of 70 μM PBS. Subsequently, 8 μΐ detection solution 1 was introduced into one of the 384-well measurement plates (measuring plate: polystyrene; 3 84, SV-black; detection solution 1: 50 μ1 CAMP-XL665; 950 μΐ recovery) Flush; 2200 μΐ PBS; CAMP-XL665: Prepared by adding 5 ml H20 to the freeze-dried product as described in the Cis Bio kit #62AMPPEC instruction; storage: aliquoted at jot ''J). Subsequently, 3 μΐ from 91.5 μΐ was added to the corresponding recess of the test plate. Finally, add 8 μΐ detection solution 2 (detection solution 2: 50 μΐ anti-cAMP-Eu[K]-AK; 950 μΐ recovery buffer; 2200 μM PBS; anti-cAMP_Eu[K]-AK: eg CisBic^^ #62AMPPEC^W Description of preparation; storage: aliquot at -80 ° C). After incubation for an additional 90 minutes at room temperature, the HTRF results were measured on a Packard Discovery or with a RubiStar HTRF measuring device (delay: 50 ps; integration time: 400 ps). 119676.doc -38 - 200815347 Example 2 · Separation of human sperm from semen and capacitation 2·1·Separation of sperm by two-layer gradient system based on silica gel particles (trade name · Percol14IS〇late) Human sperm are purified from semen. Each 2.5 ml of each semen has been preheated ("90% isolate", Irvine Company) into a 15 ml centrifuge tube (conical, plastic) and pre-heated with 2.5 ml (丨丨50 % iS〇late upper layer,,, Irvine c〇mpany) Carefully covered and braked in a water bath for less than } hours at 37 °C. Carefully cover the gradient with up to 3 ml of normal (relative to sperm count, mobility and liquefaction) semen. Sperm sedimentation was carried out at l〇〇〇Xg for 25 minutes at room temperature. With the aid of a glass capillary, the two layers are aspirated to a point just above the sperm globule. The ISolate gradient was washed out and the sperm pellets resuspended in each 200 μμ were transferred to a 15 ml plastic test tube with 12 ml mHTF medium (4 mmol NaHC03; 〇.〇1〇/.BSa; 37 °C). The sperm was sedimented for 2 〇 minutes at 1 〇〇〇 Xg. Pump the medium to the point just above the pellet and use mHTF medium (4 mmol NaHC〇3; 0.01% BSA; 37. 〇 adjusted to 1 μ μΐ.

The number of spermatozoa was determined in a Neubauer counter and, if appropriate, mHTF medium (4 mmol NaHC〇3; 0·01% bSA; 37. 〇 adjusted to 4χ1〇6 sperm/150 μΐ for subsequent capacitation. 2.2 Capacitance If the effect of the test substance on the acrosome reaction is tested, the sperm must be pre-incubated with the test substance. At the beginning of the capacitation, the binding site in the substance, especially the substance that does not pass through the membrane wall, is reached. Prior to pre-saturation, the pre-incubation (15 minutes in an incubator at 37 ° C) is necessary to allow the test substance to pass through the 119676.doc •39· 200815347 sperm. In addition, because of the high lipid binding by BSA The increase in the concentration of BSA in the resulting capacitation can result in a decrease in the concentration of the effective test substance in the formulation, so pre-culture is necessary. The test substance is dissolved in DMSO and used in mHTF medium (4 mmol NaHC03; 0.01% BSA; 37) 〇C) Dilute so that the DMSO concentration is 0.5% in the 400 μΐ final capacitation formulation. In each case, each 150 μΐ of the above-mentioned blended test substance solution was transferred to a 150 μΐ sperm suspension and pre-treated at 37 ° C. Raise for 15 minutes. Start the sperm capacitation by adding 100 μΐ mHTF medium (88 mmol NaHC03; 4% BSA; 3 7 ° C). In the final 400 μΐ capacitation preparation, the sperm concentration is 10×10 6 /ml. The bicarbonate concentration was 4 mmol and the BSA concentration was 1%. The capacitation was allowed to proceed for 3 hours at 37 ° C in an incubator. To complete the capacitation, the formulations (400 μM each) were completely transferred to 1.5. In a 15 ml sample tube of ml mHTF (4 mmol NaHC03; 37 ° C), centrifuge at 1000 xg for 5 minutes and remove the supernatant. By means of this step, a large amount of protein and test substance were removed. Example 3: Acrosome Flow Cytometry of Reactions 3.1. Acrosome reaction (AR) introduced by ionophore treatment and simultaneous introduction of CD46-FITC staining into acrosome-reacted sperm is triggered by binding sperm to zona pellucida (ZP). The release of the enzyme from the acrosome makes it possible for sperm to penetrate into the oocyte via ZP. In the case of AR, in the sperm, this causes the plasma membrane to partially fuse with the outer acrosomal membrane (OAM). The head of the sperm cell is only the end. Limited by internal acrosomal membrane (IAM). CD46 antigen can only be used on IAM Measured 0 119676.doc -40- 200815347 Although the acrosome reaction can be used on activated sperm in vitro, non-uncapacity sperm or capacitation is inhibited by the test substance, the appropriate concentration of calcium-ionophore A23187 induction. By means of FITC-labeled anti-CD46 antibody (Pharmingen Company) relative to IAM, spermatozoa and acrosome intact spermatozoa can be distinguished in flow cytometry, and IAM is not exposed in acrosome intact sperm. Dead sperm and live sperm can be distinguished by simultaneous staining with the DNA dye ethidium homodimer (EhD) of cells killed only by staining DNA membrane defects. Π Since the ionophore dilution appears to be extremely unstable in triggering AR and must be mixed with the CD46-FITC solution for simultaneous staining, these solutions should not be prepared prior to the start of the test and must be prepared during the treatment of the capacitative formulation. The sperm pellet was resuspended in the residual supernatant and diluted with 450 μM mHTF (4 mmol NaHC03; 0.01% BSA; 37 ° C) in a water bath (37 ° C). An aliquot of 100 μΐ sperm suspension was transferred to the prepared FACS flow test tube sample (in a water bath). 150 μL of a solution with an ionophore and FITC-labeled anti-CD46 antibody was transferred to the sperm. The final concentration was a 1:125 dilution of 800 nmol ionophore and anti-CD46 antibody in mHTF (4 mmol NaHC03; 0.01% BSA; 37 °C). The sperm was cultured therein at 37 ° C in a water bath to avoid light irradiation for 30 minutes. The culture was stopped by adding 3.5 ml of PBS [0.1% BSA]/formulation, followed by centrifugation at 7 〇〇 xg (room temperature) for 5 minutes and then aspirating the supernatant. After centrifugation, the sample was kept warm on the hot plate until the measurement was completed. 3.2.EhD staining (used to distinguish dead/live acrosome-resolved sperm) After aspiration, the sperm globules were mixed with 500 μl of freshly prepared EhD solution (in 119676.doc -41 - 200815347 PBS [without BSA] Mix in 150 nmol EhD; 3 7 ° C). The samples can then be measured in a flow cytometer (BD Facs Calibur). Measurements were taken at a laser excitation wavelength of 488 nm; each measurement was matched with 10,000 sperm. The acrosome-reacted sperm can be measured by CD46-FITC at 530 nm in a FL-1 filter. Dead sperm were measured by EhD-DNA-staining at 634 nm in FL-2 filtration. First, make the measurement channels properly compensate each other. 3.3. Evaluation Sperm with a very uniform cell population was selected by FSC-Η (forward scatter) versus SSC-H (side scatter). Because of the two-color fluorescent staining, the sperm group selected by FSC to the SSC point collapse method is FL-1 (EhD, X-axis) versus FL-2 (FITC-CD46, Y-axis). Evaluate in quadrant analysis. FL-1 on the FL-2 point of the ink method quadrant analysis staining analysis Q1=UL upper upper limit only EhD body reaction sperm Q2-UR right upper limit EhD and FITC-CD46 dead, acrosome reaction sperm Q3-LL left Lower limit unstained live, acrosome-free sperm Q4-LR lower right limit only FITC-CD46 live, acrosome-reacted sperm is singularly induced, acrosome-reactive sperm% (:=”IAr[ %],,), only live sperm from Q3 and Q4 are used, and the total number is set equal to 100%. Subsequently, the IAR is calculated as follows: IAR[%]=

LRxlOO LL + LR 119676.doc -42- 200815347 A part of sperm has spontaneously undergoes acrosome reaction (=''SAR[%]") without the addition of an ionophore. Therefore, it is always carried out without adding an ionophore. The control of the sperm treated with the same treatment. The SAR system is similar to the IAR calculation. The acrosome reaction (=''ARIC[%])) actually triggered by the ionophore is calculated as the difference: ARIC=IAR_SAR. For the analysis of the effects of our inhibitors on sAC-mediated capacitation (measuring the ability of sperm to undergo ionophore-induced acrosome reaction), sperm with acrosome reaction is positively controlled ( = The percentage in the medium with 25 (, 'mmol NaHC〇3, 1% BSA, no test substance in mHTF medium) is set to 100 ° /. The ability of the sperm mixed with the test substance to undergo acrosome reaction is indicated with the maximum top Related to the body reaction. The substance used is mHTF = modified human tubule fluid (Irvine Scientific Company), Dulbecco*s phosphate-buffered saline (Gibco Company) (with Ca2+, Mg2+, 1 gy^l D-glucose, 36 mgH sodium pyruvate, no age red, no NaHC〇3); bovine serum albumin, component V (Fluka Company); dimethyl sulfoxide (DMSO), anhydrous (Merck Company); 7.5% sodium bicarbonate solution (893 mmol) (Irvine Scientific Company); separation gradient (Irvine Scientific Company); ionophore A23187 free acid (Calbiochem Company); ethidium homodimer (EhD) (Molecular Probe Company) ) ' small Anti-human CD46: FITC (Pharmingen Company) References:. 119676.doc -43- 200815347 J. W. Carver-Ward, Human Reproduction Vol. 11, No. 9, pp. 1923 (continued on page), 1996

High Fertilization Prediction by Flow-Cytometric Analysis of the CD46 Antigen on the Inner Acrosomal Membrane of Spermatozoa 0· J. D'Cruz, GG Haas, Fertility and Sterility Vol. 65, No. 4, p. 843 (transfer), 1996 Ο

Fluorescence-Labeled Fucolectins are Superior Markers for Flow-Cytometric Quantitation of the Sperm Acrosome Reaction E. Nieschlag, Η. M. Behre, Andrologie [Andrology], Springer Verlag 1996

119676.doc 44 - 200815347 Example: ~1 ^ R6 ^5〇(μΜ) ^oC〇2 6 ch3 2.6 Η Η 4 _ch2- CHCHrOH ch3 1.3 OH Factory vs. Army: 0 ~Ϊ3 ;X)^ 2-OH- Estrogen OH vs. palmity ~ ΓΪ According to the table, the soluble adenylate cyclase expressed by ICso value

Inhibition, the compounds according to the invention sometimes have an activity about 10 times higher than the already known catechol estrogen (OH-estradiol). The catechol estrogen is toxic, so the compound according to the invention is superior to the known compounds. The compounds according to the invention are also about 10 times more potent than the compounds provided by Zippin. 119676.doc -45-

Claims (1)

200815347 X. Patent application scope: 1. A compound of general formula (I) Where Ri Li Meaning hydrogen, halogen, CF3, optionally saturated, and optionally substituted alkyl; or group Cl_C6 alkyl, Ci_C6 aryl, Ci-C6 fluorenyl, halo-(^_(:6) Alkyl, CVC6 alkyl-CVC6 alkyl, CVC6 alkyl-CVC6 sulfhydryl, CVC6 fluorenyl-CVC6 fluorenyl, Cl-C6 alkyl-CVC6 aryl, CVC6 aryl-c!-c6 alkyl or cf3, Wherein CVC6 alkyl, Ci-C6 aryl, fluorenyl, halo-CVC6 alkyl, CVC6 alkyl-(VC6 alkyl, CVC6 alkyl acid group, CVC6 fluorenyl-CVC6 fluorenyl, (VC6 alkyl-CVC6) Aryl or C"C6 aryl-C^C:6 alkyl may optionally intervene in the same or different manner at one or more of oxygen, sulfur or nitrogen; or a group of sulfoalkyl, sulfonamide or cyano R2 means halogen, CF3, optionally a C3_C0 cycloalkyl group which is multi-saturated and optionally substituted; or a group Ci-C6^, C"C6 aryl, CVC6 fluorenyl, halo" 1_(: 6 alkyl, CVC6 alkyl-CVC6 alkyl, CVC6 alkyl-CVC6 fluorenyl, CVC6 fluorenyl-CVC6 fluorenyl, (VC6 alkyl-CrQ aryl, CrC6 aryl-CVC6 alkyl or CF3, Wherein Cl_c6 119676.doc alkyl, Ci-C^aryl, (VC6 fluorenyl, halo _(^-(:6) Base, Ci-C6 alkyl-CVC6 alkyl, Ci-Cs alkyl-CVC6 sulfhydryl, Ci-Ce fluorenyl-CVC6 fluorenyl, CVC6 alkyl-CVC6 aryl or Ci-C6 aryl-C "C6 alkane The base-like condition may intercalate oxygen, sulfur or nitrogen in one or more places in the same or different ways; or the group of tartaric acid-Ci_C6, yttrium or cyano; meaning C^-C!2 aryl , optionally, in one or more places, may be substituted by halogen, optionally with one or more substituted Ci-C6 alkyl or Ci-C6 alkyl groups, or may be Ci-C6 alkoxy, in the same or different manner. , hydroxy, cyano, c〇2_(Cl-c6 alkyl), c〇-NR4R5 or cf3 substituted; Cs-Cu heteroaryl' may optionally be halogen or CVC6 in one or more places in the same or different manner Alkyl, (^-(^醯, Ci-C6 alkoxy, hydroxy, cyano, c〇2jCi_c6 alkyl), Ν-((ν(:6 alkyl)2, c〇-NR4R5 or cf3 substituted Or a CrC6 cycloalkyl group, which may, depending on the situation, be halogen, CF3, meridin, gas, C02-(Ci_C6Enter: base), Ci_C6 entertainment: base 'cKC6 fluorenyl, N, in one or more different ways. -(C "C6 alkyl" 2, CO-NR4R5 or Cl_c^oxy substituted; Hydrogen; CrC6 cycloalkyl, which is optionally substituted in the same or different manner by Cl-C0 alkyl, (^-^-yl, CVC6 alkoxy or CF3; C6_Ci2 aryl) as appropriate Or multiple sites in the same or different manner via halogen, CVC6 alkyl, (^(:6醯, Ci-Ce alkoxy, N-CrCs alkyl-CVC6 alkyl, cf3 or cyano; or C^Ci2) An aryl group which, as the case may be, is substituted in the same or different manner by halogen, CVC6 alkyl, 〇1_〇6 fluorenyl, Ci-C6 alkoxy, N-CVC6 alkyl, CF3 or cyano Or a CrC6 alkyl group, which may be substituted in any desired manner; meaning hydrogen; CrC6 alkyl-C3_C6 cycloalkyl, which may optionally be Ci_c6 alkyl, CVC6 in one or more places in the same or different manner. Substituted, cvc6 alkoxy or ^^^ substituted; C3-C6 cycloalkyl, optionally substituted at one or more positions by CrC6 alkyl, Cl_c6 fluorenyl, Ci_oxy or cf3 in the same or different manner; 70 aryl , optionally in one or more places, in the same or different manner, via _, Cl_C6 alkyl, Ci_c6 fluorenyl, Cl_C6 alkoxy, N_Ci-C6 alkyl-CVC6 alkyl, CF3 or cyano Or 3 c5-c12 heteroaryl, optionally in one or more, in the same or different manner via _, Ci-C6 alkyl, K6 fluorenyl, Cl-C6 alkoxy, N-CrC6 alkyl-Cl -C6 alkyl, CF3 or cyano substituted; or 200815347 CrC6 alkyl' which may be substituted in any desired manner; R and R together form a 5 to 8 membered ring which may contain other heteroatoms; a group of Ci-C6 alkyl, Ci-C6 fluorenyl, Ci_c6 alkyl _ ring C3-C6 alkyl or Cl-c6 alkyl _c6-c12 aryl, wherein Cl_C6 alkyl, Cl_C6 thiol, (^_ (6-alkyl-cyclo C3-C6 alkyl or CrC: 6-alkyl-C6_Ci2 aryl may optionally be hydroxy, methoxy, ethoxy, isopropoxy, in one or more, in one or more different ways. Chloro, bromo, fluoro, cyano, methyl-sulfonyl or amino-sulfonyl; and isomers, diastereomers, enantiomers and salts thereof. 2. A compound according to claim 1, wherein R is hydrogen, halogen, CF3, c3-c6 cycloalkyl; or a group CVC6 alkyl, κ6 aryl, Cl_C6 fluorenyl, haloalkyl, cvc6 alkyl Ci_C6 alkyl, Cl_c^-CVC6 fluorenyl, cKc6 fluorenyl _Cl_c6 thiol, alkyl-Cl-C6 aryl, C^c6 aryl-Ci-C: 6 alkyl or cf3, wherein CVC6 alkyl, Ci_c6 aryl, Ci_c6. group, halo-(VC6 alkyl, Ci-C6 alkyl_Ci_c6 alkyl, Cl-C6 alkyl group_C"C6it group, d-Cs fluorenyl-(VC6 fluorenyl, Cl_C6 burnt a base-Ci-c6 aryl or a Cl_c6 aryl-cvc6 alkyl group optionally intercalating oxygen, sulfur or nitrogen in one or more places at one or more; or a group sulfonyl, sulfonamide or cyano; R2 Means dentin, CF3 or (^匕cycloalkyl; or a group (VC6 119676.doc 200815347 alkyl, Ci-C6 aryl, fluorenyl, halo, Crh alkyl-CVC6 alkyl, CVC6 alkyl Sulfhydryl, CVC6 fluorenyl-Ci-Cs fluorenyl, CVC6 alkyl-CVC6 aryl, Ci-C6 aryl-CVC6 alkyl or CF3, wherein CVC6 alkyl, Ci-C6 aryl, Ci-C6 fluorenyl, Halo-(^-(^), C"c6 alkyl-CVC6 alkyl, (VC6 alkyl-CVC6 fluorenyl, CKC6 fluorenyl-Ci-Cs醯, CVC6 alkyl-CVC6 aryl or C^C:6 aryl-C^-C:6 alkyl, optionally in one or more places intercalated with oxygen, sulfur or nitrogen in the same or different manner; or a group of sulfonyl groups -Ci-Cs alkyl, sulfonamide or cyano; 3 R means CcCi2 aryl, optionally in one or more of the same or different ways via halogen, Cl-c6 alkyl, CVc3, CkCs Oxy, cyano, hydroxy, N-(CH3)2, C〇2' (Ci-C3 alkyl), CO_NR4R5 or cf3 substituted; C5-Cu heteroaryl, which may optionally be the same or at one or more Different ways via chlorine and / or fluorine, Cl-c6 alkyl, CrC3, CVC3 alkoxy, cyano, hydroxyl, N-(ch3)2, C〇2-((Vc3 alkyl), CO-NR4R5 Or CF3 substituted; C3-C6 cycloalkyl, which may optionally be in one or more of the same or different ways via chlorine and/or fluorine, CF3, cyano, leuco, (VC3 decyl, hydroxy, N-(CH3) 2, ChU-Cs alkyl), CO-NR4R5*Cl-C3 alkoxy substitution; R4 means hydrazine; CrC6 cycloalkyl, depending on the situation at one or more positions 119676.doc in the same or different way via CVC3 Alkyl, CVC3 fluorenyl, CVC3 alkoxy or CF3 substituted; c6-c12 aryl Substituting one or more in the same or different manner via halogen, CVC3 alkyl, CVC3 thiol, C!-C3 alkoxy, N-CVC3 alkyl-CVC3 alkyl, CF3 or cyano; or c5- a c12 heteroaryl group which, as the case may be, is substituted in the same or different manner by halogen, CVC3 alkyl, CVC3 thiol, CVC3 alkoxy, N-CVC3 alkyl-CVC3 alkyl, cf3 or cyano; Ci-Cs alkyl, which may be substituted in any desired manner; meaning hydrogen; CrC6 alkyl-c3-c6 cycloalkyl, optionally in the same or different manner via one or more Ci-Cs alkyl groups , CVC6 fluorenyl, (^-(:6 alkoxy or CF3 substituted; c3-c6 cycloalkyl, optionally in one or more of the same or different ways via Ci-Cs alkyl, CVC3 fluorenyl, (VC3) Alkoxy or CF3 substituted; C 6 -C 1 2 aryl', optionally in one or more, in the same or different manner via halogen, CVC3 alkyl, CVC3 fluorenyl, CVC3 alkoxy, N-CVC3 alkyl- CVC3 alkyl, CF3 or cyano substituted; or C 5 -C 1 2 heteroaryl, optionally in the same or different manner via one or more halogens, (VC3 alkyl, CVC3 fluorenyl, CVC3 alkoxy) N-CVC3 alkyl-CVC3 alkyl, 200815347 R4 and R6 CF3 or cyano substituted; or CrC6 alkyl, which may be substituted in any desired manner; R together form a 5 to 8 membered ring which may contain other a hetero atom 丨 and means a group 匕-decyl, Ci_C0 alkyl jtC3_C6 alkyl or Cl_c6 alkyl-c6-Cl2 aryl, wherein Cl_C6 alkyl, Crc6 alkyl-ring C3-C6 alkyl or Cl-C6 The alkyl group _c6_Ci2 aryl may optionally be hydroxy, methoxy, ethoxy, isopropoxy, argon, bromo, fluoro, cyano, methyl-sulfonyl in one or three places in the same or different manner. Or an amino-sulfonyl group; and isomers, diastereomers, enantiomers and salts thereof. 3. A compound according to claim 1 or 2, wherein R1 means 氲; R2 means c3-c6 cycloalkyl, Cl-C6 alkyl, CF3, cyano, desert or a group - 〇cf3 or -so2_ch3; R3 / ! Think CcC 2 aryl, which may optionally be halogen, Cl-C6 alkyl, Ci-C3 decyl, CpC3 alkoxy, cyano, hydroxy, N, in one or more different ways. -(CH3)2, c〇2_(Cl_c3 alkyl), C0_Nr4r54 cf3 substituted; CyCi2 heteroaryl, optionally in one or more of the same or different ways via chlorine and/or fluorine, CrCs alkyl, Ci_c: Stuffed, (VC3 alkoxy, cyano, hydroxy, n<ch3)2, CO^CCrCs alkyl), CO-NR4R5 or CF3 substituted; 119676.doc 200815347 c3 C6 cycloalkyl group Or multiple in the same or different ways of gas and / or fluorine, CF3, cyano, cr alkyl, Κ3 醯, hydroxy, N_(Cjj3)2, COHCVC; alkyl), CO-NE^R^CVCs alkoxy Substituent; & think of hydrogen; μ alum 'C1 - C6 alkyl-C3 _ C6 cycloalkyl, which may be Ci-C^, C1-C6醯 in one or more places in the same or different ways, as the case may be. Substituted, CVC6 alkoxy or CF3 substituted; C3 C6J, which is optionally substituted in the same or different manner by C!-C3 alkyl, decyl, CVc3 alkoxy or CF3; C6_Ci2 aryl, which may optionally be the same at one or more points Or in a different manner via halogen, CrC3 alkyl, Cl-C3 fluorenyl, C1-C3 alkoxy, N-CVC3 alkyl-Ci-Cs alkyl, CF3 or cyano; or Cs-C!2 heteroaryl , optionally in one or more places in the same or different manner via halogen, CrCs alkyl, CVC3 fluorenyl, CVC3 alkoxy, N-CVC3 alkyl-CVC3 alkyl, CF3 or a gas group; or CrC6 alkyl, It may be substituted in any desired manner; meaning a group CVC4 alkyl, CH2-cyclo c3-c6 alkyl, CH2-C6_C12 aryl, which has a Ci-C4 alkyl group, a CH2 ring 119676.doc 200815347 CrC6 burned The aryl or aryl group may be optionally substituted at one or three positions with a hydroxy, methoxy, chloro, fluoro, cyano or amino-sulfonyl group in the same or different manner; and isomers, diastereomers thereof 'Enantiomers and salts. 4. A compound of claim 2 or 2, wherein R1 is hydrogen; R2 means c3-c6 cycloalkyl, Cl_c6 alkyl, CF3, cyano, bromo or the group -OCF3 or -S〇2-CH3 and In the para position; 〇R3 means C^C!2 aryl, which may optionally be in one or two places in the same or different ways via _, Ci_c3 alkyl, ethyl methoxy, methoxy, ethoxy, cyanide Substituent, hydroxy, N-(CH3)2, COHCrC^ alkyl), CO_NHR5 4CF3 substituted; U Cs-Ci2 heteroaryl, which may, depending on the situation, be gas or/or fluorine, Ci_c3 in one or two different or different ways. Alkyl, ethoxylated, methoxy, ethoxy, cyano, hydroxy, N-(CH3)2, COHCi-q alkyl), C0_nhr^CF3 substituted; or c3-c6 cycloalkyl; Said hydrogen; R5 means hydrogen; or (: 1-(:6 alkyl_C3_C6 cycloalkyl, which may be the same or different ways in one or more places (^-decyl, CVC6 thiol, ^- (alkoxy or CF3 substituted; C3-C6 cycloalkyl, optionally substituted in the same or different manner by CVC3 alkyl, Cl-c3 thiol, 119676.doc 200815347 oxy or cf3; CpCu Aryl group, depending on the situation at one or more Are identical or different manner by halogen, alkyl, CVC3, CVC3 acyl, burning, CVC3 group, n-cvc3 _Cl-C3 alkyl group, a substituted cf3 or cyano; or a heteroaryl group optionally substituted at one or more times by halogen, CrCs alkyl, sulfhydryl, CVC3 alkoxy, N_C!-C3 alkyl-Ci-Cs alkyl, cf3 or cyano; Or a CrC6 alkyl group which may be substituted in any desired manner; r6 means a group Crq alkyl group, a ch2_ ring c3-c6 alkyl group, a CH2-C6-C12 aryl group, a towel CVC4 alkyl group, CH2- a ring C3-C6 alkyl or CH2_C (5-Ci2 aryl may be optionally substituted at one or three positions with a hydroxyl, methoxy, fluoro, fluoro, cyano or amino-sulfonyl group in the same or different manner; Isomers, diastereomers, enantiomers and salts. 5. The compound of claim 1 or 2, wherein r1 means hydrogen; r2 means tributyl, isopropyl, isobutyl a group, a second butyl group, a cyano group, a bromine group or a group -0-CF3 or _S02-CH3 and in the para position; r3 means a group 119676.doc 200815347 /N\ R4 means hydrogen; R5 means 氲 or a group -(CH2)nN-(CH3)2, -(CH2)2-CH3, -(CH2)2-NH-COCH3, -(CH2)-CHCH3 -OH, -(CH2)2-0-CH3, -(CH2)2-OH or -chch3-CH2-OH, where n=l-3, 119676.doc -11 - 200815347 R6 means methyl, ethyl, propyl, 2-decyloxy-ethyl, -CH2-CF3, -(CH2)2-CF3 and benzyl; and isomers, diastereomers thereof, Enantiomers and salts. 6. A compound according to claim 1 or 2, wherein R1 means hydrogen; R2 means a third butyl group, an isopropyl group, an isobutyl group, a second butyl group, a cyano group, a bromine group or a group - 〇-cf3 or -so2-ch3 and in the opposite position; R3 means the group 119676.doc -12- 200815347 R4 means hydrogen; R5 means hydrogen or a group -(CH2)-CHCH3-OH, -(ch2)2-o-CH3, or -CHCH3-CH2-OH, η R6 means methyl, ethyl, propyl, 2-methoxy-ethyl, -CH2-CF3, -(CH2)2-CF3 and benzyl. 7. A compound according to claim 1 or 2 which is selected from the group consisting of 5-[(4-tert-butyl-phenylsulfonyl)-methyl-amino]-3-benzene -1H-吲口多-2 -formic acid-(tetrahydro-11-pyranyl-4-yl)-bristamine 5-[(4-tert-butyl-phenylsulfonyl)-fluorenyl-amino ]-3-phenyl-1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-decylamine (±)-5-[(4-Ternyl-phenylsulfonyl)-methyl-amino]-3-phenyl-111-indole-2-carboxylic acid-(2-hydroxy-1- Methyl-ethyl)-guanamine (soil)-5-[(4-tert-butyl-phenylsulfonyl)methyl-amino]-3_phenyl-1H-called 丨哚-2 -formic acid-(2-hydroxy-propyl)-decylamine 5-[(4-tert-butyl-phenylsulfonyl)-methyl-amino]-3-phenyl-1H-indole-2 -Citrate-(pyridin-4-yl)-nonylamine 5-[(4-tert-butyl-phenylsulfonyl)-benzyl-amino]-3-phenyl-1H-吲口- 2-carboxylic acid-(tetrahydropyran-4-yl)·guanamine 119676.doc -13- 200815347 5-[(4-Tertiary-phenylsulfonyl)-benzyl-amino]-3 -phenyl-1H-indole-2-carboxylic acid (2-morphin-4-ylethyl)-decylamine (±)-5_[(4-tert-butyl-phenylsulfonyl)_ Benzyl-amino]-3-phenyl-1Η-indole-2-carboxylic acid-(2-hydroxy-1-methyl-ethyl)-decylamine (soil)-5-[(4-third -phenylsulfonyl)-benzyl-amino]-3-phenyl-1Η-°bendo-2-formic acid-(2-trans-propyl) decylamine 5-[(4- Tributyl-phenylsulfonyl)-(2-methoxy-ethyl)-amino]-3-phenyl-1Η_σ弓布多-2·decanoic acid (tetrahydropyran-4-yl)醯amine 8. 5-[(4-Terti-butyl-phenylsulfonyl)-(2-methoxy-ethylamino)-3-phenyl-1Η-°bendo-2_carboxylic acid (2 -Morline _4_yl-ethyl)_decylamine (±)-5_[(4-tert-butyl-phenylsulfonyl)-(1methoxy-ethyl)-amino]-3 -phenyl-1Η-indole-2-carboxylic acid-(2-hydroxymethyl-ethyl)-decylamine (soil)-5-[(4-tert-butyl-phenylsulfonyl)-(2 • methoxyethyl)-amino]-3-phenyl-1Η-. 哚-2-carboxylic acid-(2-trans-propyl)-decylamine 5-[(4-tert-butyl- Phenylsulfonyl)methyl-amino]_3_(3_fluoro-phenyl)-1Η-indole-2-carboxylic acid-(tetrahydropyran-4-yl)-decylamine 5-[(4 _Tertiary butyl-phenyl-decyl)-methyl-amino]_3_(3·gas·phenyl)-1Η-, 哚-2-decanoic acid (2-morpholin-4-yl·ethyl) _ decylamine 5-[(4-tert-butyl-phenyl fluorenyl)-methyl; τ-amino-3-(3-methoxy-phenyl)-1 Η-mouth butyl- 2 -carboxylic acid- (tetrahydro-σ-pyridyl)-decylamine 5_[(4_t-butyl-phenyl fluorenyl ν 就 τ τ _ 胺 胺 胺 胺 胺 _ _ _ _ 胺 胺 胺 胺 Η Η Η Η Η Η Η Η Η σ 卜 朵 -2--2-carboxylic acid (2 _ _ _ _, # 丞, ethyl) - guanamine. A pharmaceutical agent It contains at least one compound as claimed in any one of the items of the present invention. 119676.doc -14- 200815347. The pharmaceutical preparation according to claim 8, wherein the content of the compound of the formula 1 is an effective dose. A compound of the formula I according to claim 1 or 2, which is used for the preparation of a pharmaceutical agent. 11. The pharmaceutical agent according to claim 9 for use in the treatment of a disease. The pharmaceutical agent according to claim 11, wherein the diseases are 13 caused by a disorder of cAMp metabolism. 13. A pharmaceutical agent according to claim 9 for use in contraception. 14. A pharmaceutical agent according to claim 9 for use in inhibiting soluble adenylate cyclase. The pharmaceutical preparation according to any one of the items 9 and 11 to 14 which has a suitable compounding substance and a vehicle. 16 - a compound of the formula 任7 according to any one of claims -7, in the intestine, non-menstrual Use in a pharmaceutical preparation of the enteral, transvaginal and oral administration form. 17. A method of preparing a compound of the formula (I) according to claim 1, wherein the method comprises reacting a compound of the formula (II) to form the compound a compound of formula (1), R2 H , wherein R1, R2, R3 and R6 have the claim The meanings as defined and 7 may be hydrogen alkyl foot 18 - of the general formula (11), (VI) and (νπ), (Ιχ) and (χι) of intermediate: 200815347 wherein Ri, R2, R3 and R6 have the meaning of a hydroalkyl group; %β is as defined in item 1 and R7 〇 〇—R7 (VI) alkyl; ΐ"1 and R2 have the meaning as defined in claim 1 and R, Cl-C’ (VII), :中_ has the meaning of the old definition of the claim and R alkyl; ri-Ql b6 R2 (ιχ), the meaning of 1 is defined and R] is Wherein R1, R2 and R6 have the following items C1-C6; and 119676.doc -16 - 200815347 VII. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The components of the representative figure Brief description of the symbol: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 119676.doc