CN1311792A - Meiosis regulating compound - Google Patents

Abstract

This invention relates to certain novel sterol derivatives having no hydroxy group in the 3 position can be used to regulate the meiosis in oocytes and in male germ cells.

Description

Meiosis regulating compound

Invention field

The present invention relates to some novel pharmaceutically active compounds, contain these compounds as the new application of the new pharmaceutical composition of active substance and these compounds as medicine.More particularly, have been found that compound as herein described can be used for reduction division.

Background of invention

Reduction division is based on the important and unique process of sexual cell of sexual propagation.Reduction division comprises twice reduction division.In first division, at karyomit(e) to the exchange between maternal gene and the male parent's gene takes place before being dispensed into two filial generation cells.This comprises half (1n) karyomit(e) and 2c DNA.The second meiotic division process does not have DNA synthetic.Therefore, divide the result specifically and generate the monoploid sexual cell that has only 1c DNA.

The reduction division process is similarly in male and female sex cell, but the time-program(me) and the atomization that produce ovum and sperm are far from each other.All female sex cells enter early stage of initial meiosis at life early stage (often being in utero), are ovocyte but just grow in the later stage (dictyotic stage state) in early stage during ovulation after pubescence.Therefore, from the early stage female ovocyte original seed that just had of life, it is grown gradually, is consumed up to original seed.Female meiosis is just complete up to after fertilization, and each sexual cell only produces an ovum and two undergrown polar bodys as a result.On the contrary, have only from pubescence some male sex-cells that begin just enter reduction division, whole life all produces the trunk colony of sexual cell.Once you begin, significantly do not delay with regard to carrying out reduction division in the male sex cell, and produce 4 sperms.

People know little about it for the initial mechanism of male and female control reduction division.New studies show that, in ovocyte, and the ovarian follicle purine, xanthoglobulin, or adenosine may be stagnated work (Downs, SM etc., developmental biology (Dev.Biol.) 82 (1985) 454-458 to reduction division; Eppig, J.J. etc., developmental biology 119 (1986) 313-321; And Downs, S.M., molecule reproductive development (Mol Reprod Dev.) 35 (1993) 82-94).Reported first such as Byskov exist in mouse tire sexual gland culture system can spread meiosis regulating material (Byskov, AG etc., developmental biology 52 (1976) 193-200).A kind of reduction division activated material (MAS) is secreted by wherein experiencing maiotic tire mouse ovarian, and a kind of maiotic material of prevention (MPS) discharges from the testis that the morphology that has resting cell, ameiosis sexual cell breaks up.The relative concentration that people have proposed MAS and MPS can regulate and control male and female sex cell in maiotic initial, stagnate and recover (Byskov, AG etc., " physiology of reproduction " (The Physiology ofReproduction) (Knobil, E and Neill, JD writes, Raven publishes, New York (1994)).Very clear, if reduction division can be regulated and control, then can control reproduction.At " nature " (Nature) 374 (1995) 559-562) in, Byskov, reports such as AG are from bull, ox testis and the more isolated sterol that can activate Oocyte Meiosis of human follicle liquid.Therefore regrettably, these sterol rather unstables are if can obtain more stable reduction division activated compounds then will help utilizing this interesting discovery greatly.

Biological chemistry and biophysics circular (Biochem.Biophys.Acta) 1299 (1996), 313, discuss the mechanism and the structural requirement of transspecific enzymatic conversion substrate, and mentioned for example courage steroid-4,8,24-triolefin and 25-azepine courage steroid-5-alkene (compound 21﹠amp among Fig. 2; 42).

Bull.Chem.Soc.Belg.92 (1983) has introduced some steroides in 731, for example the nuclear magnetic resonance spectroscopy of cholestane (the compound g in the table V).

Collect.Czech.Chem.Comm.63 (1998) has discussed some steroides in 549, courage steroid-3 for example, 5-diene, courage steroid-2-alkene and courage steroid-5-alkene (compound 2,5﹠amp; 7) preparation.

Discuss the chemical composition of feature of environmental protection tobacco fumigant in the environmental science and technology (Environ.Sci.Tech.) 23 (1989), 688, and mentioned for example courage steroid-3,5-diene; 24-methyl courage steroid-3, the 5-diene; 24-ethyl courage steroid-3,5, the 22-diene; With 24-ethyl courage steroid-3,5-diene (Verbindung among Fig. 6, f, g﹠amp; H).

Geochim.Cosmochim.51 (1987) has discussed the geochemistry of the torrid zone, east, North Pacific oxygen level lowest region steroide in 3051, and has mentioned for example courage steroid-2-alkene and courage steroid-3,5-diene (the compound 5﹠amp in the table 6; 8).

Geochim.Cosmochim.55 (1991) has analyzed C in oil and the source rock stone in 1065 ₂₆Prednisolone have a situation, and for example mentioned 24-demethyl-5 α-cholestane and 24-demethyl-5 β-cholestane (the compound 1Bb﹠amp among Fig. 3 for example; 1Ba).

Geochim.Cosmochim.Acta 57 (1993), and 4539, discuss the situation that exists of falling cholestane in the siliceous sediment of Japanese MioceneOnnagawa, and mentioned for example (20R)-5 β, 14 α, 17 α (H)-cholestane; (20R)-5 α, 14 β, 17 β (H)-cholestane; (20R)-5 α, 14 α, 17 α (H)-cholestane; (20R)-5 β, 14 α, 17 α (H)-24-methylcholestane; (20R)-5 α, 14 α, 17 α (H)-24-methylcholestane; (20R)-5 β, 14 α, 17 α (H)-24-ethyl cholestane; (20R)-5 α, 14 α, 17 α (H)-24-ethyl cholestane (peak 3a, 3b, 6,8,10,12﹠amp; 13).

Deep-sea drilling progress preliminary study (Initial Reports of the Deep Sea DrillingProject) 62,923 has been discussed last A Er than the liposome in generation (albian) the phase Wingdale, and has for example mentioned that cholestane falls in 4-methyl-5 α-24-; 5 α-cholestane; 5 β-cholestane; Courage steroid-4-alkene; Courage steroid-5-alkene; With 4-methylcholestane (compound L in the table 1, O﹠amp; Compound X IV a ﹠amp among the N, table 3; Compound 9 in X V a and the table 14).

Deep-sea drilling progress preliminary study 63,763 has been discussed the initial analysis situation of lipid in the settling of east, North Pacific, and has been mentioned for example (20S)-5 α, 14 α, 17 α-cholestane; (20R)-5 α, 14 α, 17 α-cholestane; 19-demethyl-5 α-cholestane; 5 β-cholestane; 5 α-cholestane; Courage steroid-2-alkene; Courage steroid-3, the 5-diene; Courage steroid-4-alkene; With courage steroid-5-alkene (compound VII i﹠amp in the table 1; Compound X V j among the VII j, table 2, VII j﹠amp; Compound XI j﹠amp among the VII j, table 3; Compound XII j﹠amp in X IV j and the table 5; X III j).

Deep-sea drilling progress preliminary study 63,837 has been discussed the sedimental organic geochemistry in southern markon Fu Niya forntier region, and has been mentioned and for example fallen cholestane; 5 α, 8 β, 14 β-cholestane; With 5 β, 8 β, 14 β-cholestane (compound Ⅸ ﹠amp; X).Initial Report ofthe Deep Sea Drilling Project 64,837 has discussed the organic petrography of markon Fu Niya estuarine deposit thing and can extract hydro carbons, and mentioned for example 5 α-demethyl cholestane; 5 β-cholestane; Courage steroid-4-alkene; Courage steroid-5-alkene; With 5 α-cholestane (the peak e in the table 2, f, h, i﹠amp; J).

Chromatogram magazine (J.Chromatog.) 116 (1976), 207 has been discussed the chromatogram of saturated steroid hydro carbons on aluminum oxide, and has mentioned for example 5 β-cholestane; 5 α, 14 β-cholestane; 5 α, 17 β (H)-cholestane; (20S)-5 α, 17 β (H)-cholestane; (24R)-24-methyl-5 β-cholestane; (24S)-24-methyl-5 β-cholestane; 5 α, 8 α, 14 β-cholestane; (20S)-5 α-cholestane; (24R)-24-methyl-5 α-cholestane; (24S)-24-ethyl-5 α-cholestane; (24S)-24-ethyl-5 α-cholestane; 5 α-cholestane; 4 Alpha-Methyls-5 α-cholestane; 4 Beta-methyls-5 α-cholestane; (24S)-24-methyl-5 α-cholestane (table 1).

Organic chemistry magazine (J.Org.Chem.) 37 (1972), 2108 has been discussed by the diazo-ketones of cholanic acid acquisition and the chemistry of derivative thereof, and has been mentioned for example 24-methylol courage-24-ketone and 24-methylol courage-24-alcohol (compound 6﹠amp; 12).

Ocean and petroleum geography (Marine and Petroleum Geology) 5 (1988), 205, discussed and utilized Brazilian national fishing shelf oil sedimental geochemistry of environment and biomarker assessment, and mentioned for example (20S)-5 α, 14 α, 17 α-cholestane and (20R)-5 α, 14 α, 17 α-cholestane (compound 8﹠amp; 10).

OPPI Briefs, 16, discussed by Wittig reaction is synthetic and had the situation of modification side chain sterol, and mentioned for example courage steroid-24-alkene and 24-cyclohexyl courage-24-alkene (compound Ⅴ ﹠amp; VI).

Organically physics and chemistry is learned (Org.Geochem.) 9 (1986), 331, has discussed the sedimental lipid of crab, its ight soil and organic granular of North Pacific, equator and has formed, and mentioned for example courage steroid-2-alkene; Courage steroid-3, the 5-diene; 24-methyl courage steroid-2-alkene; With 24-ethyl courage steroid-2-alkene (compound 2,5 in the table 1,9﹠amp; 15).

Organically physics and chemistry learns 19 (1991), 351, has discussed the structural research of rich sulphur macromole oil distillate and petrologen being carried out by the order chemical degradation, and has mentioned for example 24-propyl group cholestane (Figure 15).

At the publication " rearrangement reaction in the organic mass spectrometry spectroscopy " of C.Djerassi, in 199, mentioned for example 5 α-cholestane (Fig. 1).

Sterol (Steroids) 18 (1971), 649 has been discussed steroid triphenyl salt, improves the general intermediate of side chain, and has mentioned for example courage steroid-25-alkene and 24-cyclohexyl courage-24-alkene (compound 4﹠amp; 5).

Tetrahedron communication (Tetrahedron Letters) 22 (1981), 2583 has been discussed the dissolving metal reduction reaction that utilizes crown ether, and has been mentioned for example 5 α-cholestane and courage steroid-5-alkene (compound 3﹠amp; 6).

Tetrahedron communication 34 (1973), 3715, discussed and utilized the P.M.R. spectrograph C ₂₄The evaluation of alkylation prednisolone, and mentioned for example 5 α-cholestane and 24-dimethyl-5 α-cholane (compound 1﹠amp; 2).

In 21 pieces of above-mentioned documents, we do not find that the relevant particular compound of quoting as proof has any description of pharmacological property.

International Patent Application WO 96/00235,96/27658,97/00884,98/52965 and WO98/55498 in put down in writing and can stimulate maiotic compound, but they are different from the present patent application claimed compounds.

Compare with known compound, compound of the present invention has multiple advantage.

Summary of the invention

Main purpose of the present invention provides and can be used for regulating and control maiotic compound.

An object of the present invention is to provide be used for the treatment of female and male, particularly Mammals, the more especially Compounds and methods for of people's Infertility.

On the other hand, it is female and male in treatment to the present invention relates to formula I b compound (seeing below described in the claim) and ester, salt, active metabolite and prodrug, particularly Mammals, the more especially application of people's Infertility aspect.

In another preferred embodiment, the present invention relates to be used as formula I b compound and ester, salt, active metabolite and the prodrug of medicine.

In a further preferred embodiment, the present invention relates to be used for regulating and control formula I b compound or its ester, salt, active metabolite and the prodrug that maiotic medicine uses in preparation.

The further preferred aspect of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug as the medicine application of (particularly as being used to regulate and control maiotic medicine).This compound can directly use, and perhaps uses with the liquid or solid composition forms that contains the conventional auxiliary component that uses in this area.

In specification sheets of the present invention, term " regulation and control reduction division " is used to represent that the compound of some formula I a and I b can be used in external, the body or exsomatize (ex vivo) stimulates reduction division.Therefore, can be these compounds of the agonist of naturally occurring reduction division activated material, can be used for the treatment of owing to female and male meiosis stimulate insufficient Infertility that causes.And may be other formula I a and the I b compound of the antagonist of the reduction division activated material that exists naturally, then can be so that its mode that is suitable as contraceptive bian is used to regulate and control reduction division (regulation and control in the preferred body).In this case, " regulation and control " refer to part or all of inhibition.

A preferred aspect more of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are being regulated and control ovocyte, particularly mammal ovocyte, the more particularly purposes in the reduction division of human oocyte.

The another preferred aspect of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are stimulating ovocyte, particularly mammal ovocyte, the more particularly purposes in the reduction division of human oocyte.

A preferred aspect more of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are suppressing ovocyte, particularly mammal ovocyte, the more particularly purposes in the reduction division of human oocyte.

A preferred aspect more of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are being regulated and control male sex-cell, particularly Mammals male sex-cell, the more particularly purposes in the reduction division of male germ cell.

A preferred aspect more of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are stimulating male sex-cell, particularly Mammals male sex-cell, the more particularly purposes in the reduction division of male germ cell.

A preferred aspect more of the present invention relates to above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are suppressing male sex-cell, particularly Mammals male sex-cell, the more particularly purposes in the reduction division of male germ cell.

The further preferred aspect of the present invention relates to maiotic method in the regulation and control Mammals sexual cell, and this method comprises above-mentioned formula I b compound or its ester, salt, active metabolite and the prodrug of using significant quantity to the sexual cell of this treatment of needs.

A preferred aspect more of the present invention relates to maiotic method in a kind of regulation and control Mammals sexual cell, wherein the Mammals of described cell is arranged and sexual cell is given and above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug by this compound being granted boarding.

A preferred aspect more of the present invention relates to a kind of method, and wherein will regulate and control its maiotic sexual cell by a kind of above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug is ovocyte.

A preferred aspect more of the present invention relates to maiotic method in a kind of regulation and control ovocyte, wherein ovocyte is exsomatized and uses above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug.

A preferred aspect more of the present invention relates to a kind ofly uses the maiotic method that above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug are regulated and control male sex-cell by pair cell.

A preferred aspect more of the present invention relates to a kind of method, and this method is by in the body or external the testis tissue that comprises immature cell is used above-mentioned formula I b compound or its ester, salt, active metabolite and prodrug, and produces ripe male sex-cell.

The compound that relates in one aspect to again of the present invention with superior vitro characteristics.Detailed Description Of The Invention

The invention provides compound with valuable pharmacological character.The compounds of this invention is used to regulate and control the reduction division of ovocyte and male sex-cell.

Surprisingly, have found that not having the formula I b compound of hydroxyl on 3 has good action for maiotic regulation and control.One of this beyond thought reason is natural cholesterol and participates in its biosynthetic compound and (comprise 4,4-dimethyl-5 α-courage steroid-8,14,24-triolefin-3 β-alcohol (below be called FF-MAS) and 4,4-dimethyl-5 α-courage steroid-8,24-diene-3 β-alcohol) 3 hydroxyls of existence.

Preferred formula I a and I b compound are the compounds that wherein has at least one two key.

Other preferred formula I a and I b compound are R wherein ¹Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹Compound for halogen.

Other preferred formula I a and I b compound are R wherein ¹Compound for methyl.

Other preferred formula I a and I b compound are R wherein ¹Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹Compound for oxo.

Other preferred formula I a and I b compound are R wherein ²With R ³Represent between R together ²And R ³The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ²Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ²Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ²Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ²Be C ₁-C ₃The compound of alkoxyl group.

Other preferred formula I a and I b compound are R wherein ²Compound for halogen.

Other preferred formula I a and I b compound are R wherein ³Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ³Be C ₁-C ₄The compound of alkyl.

Preferred formula I a and I b compound are R wherein ⁴And R ' ⁴Be the compound of hydrogen.

Preferred formula I a and I b compound are R wherein ⁴And R ' ⁴One of be hydrogen, and another is the compound of methyl.

Other preferred formula I a and I b compound are R wherein ⁴And R ' ⁴Be the compound of methyl.

Other preferred formula I a and I b compound are R wherein ⁴Be optional side chain or the straight chain C that is replaced by halogen, hydroxyl or cyano group _1-6The compound of alkyl.

Other preferred formula I a and I b compound are R ' wherein ⁴Be optional side chain or the straight chain C that is replaced by halogen, hydroxyl or cyano group _1-6The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ⁴Be hydroxyl, and R ' ⁴Be selected from hydrogen and can choose side chain or the straight chain C that is replaced by halogen, hydroxyl or cyano group wantonly ₁-C ₆The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ⁴And R ' ⁴The compound of representing methylene radical together.

Other preferred formula I a and I b compound are R wherein ⁴And R ' ⁴Form the compound of cyclopropane ring with the carbon atom of their institute's bondings.

Other preferred formula I a and I b compound are R wherein ⁴And R ' ⁴Form the compound of pentamethylene ring with the carbon atom of their institute's bondings.

Other preferred formula I a and I b compound are R wherein ⁴And R ' ⁴Form the compound of cyclohexane ring with the carbon atom of their institute's bondings.

Other preferred formula I a and I b compound are R wherein ⁵Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ⁵Compound for halogen.

Other preferred formula I a and I b compound are R wherein ⁵Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ⁶Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ⁶Compound for halogen.

Other preferred formula I a and I b compound are R wherein ⁶Compound for oxo.

Other preferred formula I a and I b compound are R wherein ⁶Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ⁶With R ⁵Represent between R together ⁵And R ⁶The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ⁷Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ⁷And R ' ⁷Be the compound of methylene radical together.

Other preferred formula I a and I b compound are R wherein ⁷Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ⁷Compound for methoxyl group or acetoxyl group.

Other preferred formula I a and I b compound are R wherein ⁷Compound for halogen.

Other preferred formula I a and I b compound are R wherein ⁷And R ' ⁷Be the compound of oxo together.

Other preferred formula I a and I b compound are R wherein ⁷And R ' ⁷Be the compound of group=NOH together.

Other preferred formula I a and I b compound are R wherein ⁷And R ' ⁷Be general formula=NOR together ³⁶Group, and R wherein ³⁶Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ⁷Be hydroxyl and R ' ⁷Be C ₁-C ₄The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ⁷With R ⁶Represent between R together ⁷And R ⁶The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ⁷With R ⁸Represent between R together ⁷And R ⁸The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ⁸With R ⁹Represent between R together ⁸And R ⁹The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ⁹Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ⁸Compound for halogen.

Other preferred formula I a and I b compound are R wherein ⁸Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ⁹Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ⁹Compound for halogen.

Other preferred formula I a and I b compound are R wherein ⁹Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹¹Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹¹And R ' ¹¹Be the compound of methylene radical together.

Other preferred formula I a and I b compound are R wherein ¹¹Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹¹Compound for halogen.

Other preferred formula I a and I b compound are R wherein ¹¹Compound for methoxyl group or acetoxyl group.

Other preferred formula I a and I b compound are R wherein ¹¹And R ' ¹¹Be the compound of oxo together.

Other preferred formula I a and I b compound are R wherein ¹¹And R ' ¹¹Be the compound of group=NOH together.

Other preferred formula I a and I b compound are R wherein ¹¹And R ' ¹¹Be general formula=NOR together ³⁷Group, and R wherein ³⁷Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹¹Be hydroxyl and R ' ¹¹Be C ₁-C ₄The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹¹With R ⁹Represent between R together ¹¹And R ⁹The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ¹¹With R ¹²Represent between R together ¹¹And R ¹²The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ¹²Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹²Compound for halogen.

Other preferred formula I a and I b compound are R wherein ¹²Be C ₁-C ₄The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹²Compound for methylene radical.

Other preferred formula I a and I b compound are R wherein ¹²Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹²Compound for methoxyl group or acetoxyl group.

Other preferred formula I a and I b compound are R wherein ¹²Compound for oxo.

Other preferred formula I a and I b compound are R wherein ¹²Compound for group=NOH.

Other preferred formula I a and I b compound are R1 wherein ²Be general formula=NOR ³³Group, and R wherein ³³Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹⁴Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹⁴Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹⁴With R ⁸Represent between R together ¹⁴And R ⁸The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for halogen.

Other preferred formula I a and I b compound are R wherein ¹⁵Be C ₁-C ₄The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for methylene radical.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for methoxyl group.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for oxo.

Other preferred formula I a and I b compound are R wherein ¹⁵Compound for group=NOH.

Other preferred formula I a and I b compound are R wherein ¹⁵Be general formula=NOR ³²Group, and R wherein ³²Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹⁵With R ¹⁴Represent between R together ¹⁵And R ¹⁴The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for halogen.

Other preferred formula I a and I b compound are R wherein ¹⁶Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for methylene radical.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for methoxyl group.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for oxo.

Other preferred formula I a and I b compound are R wherein ¹⁶Compound for group=NOH.

Other preferred formula I a and I b compound are R wherein ¹⁶Be general formula=NOR ³⁴Group, and R wherein ³⁴Be C ₁-C ₃The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ¹⁶With R ¹⁷Represent between R together ¹⁶And R ¹⁷The compound of the additional key between place's carbon atom.

Other preferred formula I a and I b compound are R wherein ¹⁷Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ¹⁷Compound for hydroxyl.

Other preferred formula I a and I b compound are R wherein ¹⁷Be positioned at the compound of α position.

Other preferred formula I a and I b compound are R wherein ²⁰Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ²⁰Compound for methylol.

Other preferred formula I a and I b compound are R wherein ²⁰Be C ₁-C ₄The compound of alkyl.

Other preferred formula I a and I b compound are R wherein ²⁰With R ' ²⁰The compound of representing methylene radical together.

Other preferred formula I a and I b compound are R wherein ²⁰With R ' ²⁰The compound of representing oxo together.

Other preferred formula I a and I b compound are R ' wherein ²⁰Compound for hydrogen.

Other preferred formula I a and I b compound are R ' wherein ²⁰Compound for halogen.

Other preferred formula I a and I b compound are R ' wherein ²⁰Compound for methyl.

Other preferred formula I a and I b compound are R ' wherein ²⁰Compound for hydroxyl.

Other preferred formula I a and I b compound are R ' wherein ²²Compound for hydrogen.

Other preferred formula I a and I b compound are R wherein ²²Compound for the 3-methyl butyl.

Other preferred formula I a and I b compound are R wherein ²²Compound for isobutyl-.

Other preferred formula I a and I b compound are R wherein ²²Compound for phenyl.

Other preferred formula I a and I b compound are these, the long-chain on 17 wherein, that is-C (R ²⁰) (R ' ²⁰)-CH (R ' ²²)-C (R ²³) (R ' ²³)-C (R ²⁴) (R ' ²⁴)-A (R ²⁵) (R ' ²⁵) (R " ²⁵), be positioned at the β position.

Should be appreciated that above-mentioned preferred substituents can make up by any way each other.

Valuable and preferred formula I a and I b examples for compounds are as follows: courage steroid-5-alkene-16 β-alcohol; Courage steroid-5-alkene-16-ketone; 4,4-dimethyl courage steroid-2,5-diene-16 β-alcohol; Cholestane-16 β-alcohol; Courage steroid-3,5-diene-16 β-alcohol; Courage steroid-5-alkene-15 β-alcohol; Courage steroid-5-alkene-17 α-alcohol; Courage steroid-5-alkene-15 α-alcohol; Courage steroid-5-alkene-16 α-alcohol; 4,4-dimethyl courage steroid-5-alkene-16 β-alcohol; Courage steroid-3-alkene-16 β-alcohol; Courage steroid-4-alkene-16 β-alcohol; Courage steroid-2-alkene-16 β-alcohol; Courage steroid-2,4-diene-16 β-alcohol; Courage steroid-2,5-diene-16 β-alcohol; Courage steroid-5,24-diene-16 β-alcohol; Courage steroid-5,8-diene-16 β-alcohol; Courage steroid-5,7-diene-16 β-alcohol; 4,4-dimethyl courage steroid-5,7-diene-16 β-alcohol; 3-methyl courage steroid-2,5-diene-16 β-alcohol; 3 Beta-methyl courage steroid-5-alkene-16 β-alcohol; 3 Alpha-Methyl courage steroid-5-alkene-16 β-alcohol; 3,4,4-trimethylammonium courage steroid-2,5-diene-16 β-alcohol; 4,4-dimethyl courage steroid-5,8-diene-16-β-alcohol; Courage steroid-5,8-diene-15 β-alcohol; Courage steroid-5,7-diene-15 β-alcohol; 4,4-dimethyl courage steroid-5-alkene-15 β-alcohol; 4,4-dimethyl courage steroid-5-alkene-15 α-alcohol; The pregnant steroid of 20-methyl-21-phenyl-5-alkene-16 β-alcohol; The pregnant steroid of 20-methyl-21-cyclopentyl-5-alkene-16 β-alcohol; 24-demethyl courage steroid-5-alkene-16 β-alcohol; 24-demethyl courage steroid-16 β-alcohol; 24-demethyl courage steroid-5-alkene-15 β-alcohol; The pregnant steroid of 20-methyl-21-(3-aminomethyl phenyl)-5-alkene-16 β-alcohol; The pregnant steroid of 20-methyl-21-(3-hydroxy phenyl)-5-alkene-16 β-alcohol; 20-methyl-21-(3-hydroxy phenyl) pregnant steroid-16 β-alcohol; 20-methyl-21-(3-aminomethyl phenyl) pregnant steroid-15 β-alcohol; 4,4,20-trimethylammonium-(4-aminomethyl phenyl) pregnant steroid-5-alkene-16 β-alcohol; 16 beta-hydroxies courage-5-alkene-24-acid cyclohexyl; Courage steroid-5-alkene-16 β, the 25-glycol; 24-demethyl cholestane-15 β-alcohol; 20-methyl-21-benzyl pregnant steroid-3,5-diene-16 β-alcohol; 24-demethyl-4,4-dimethyl courage steroid-5-alkene-16 β-alcohol; 4,4, the pregnant steroid of 20-trimethylammonium-21-(cyclopentyl)-5-alkene-16 β-alcohol; 16 beta-hydroxy courage steroids-5-alkene-24-ketone; (20S)-and courage steroid-5-alkene-16 β, the 20-glycol; (20R)-and courage steroid-5-alkene-16 β, the 20-glycol; (20S)-and 24-demethyl courage steroid-5-alkene-16 β, the 20-glycol; (20R)-and 24-demethyl courage steroid-5-alkene-16 β, the 20-glycol; (20S)-and courage steroid-5,24-diene-16 β, 20-glycol; (20R)-and courage steroid-5,24-diene-16 β, 20-glycol; (20S)-and 24-demethyl courage steroid-5,23-diene-16 β, 20-glycol; (20R)-and 24-demethyl courage steroid-5,23-diene-16 β, 20-glycol; (20S)-23,24-dinor-courage steroid-5-alkene-16 β, 20-glycol; (20S)-and the pregnant steroid of 20-methyl-21-phenyl-5-alkene-16 β, the 20-glycol; (20R)-and the pregnant steroid of 20-methyl-21-phenyl-5-alkene-16 β, the 20-glycol; (20S)-16 β, 20-dihydroxyl courage-5-alkene-24-acid-N-dimethylformamide; (20R)-16 β, 20-dihydroxyl courage-5-alkene-24-acid-N-dimethylformamide; (20S)-20-hydroxyl courage-5-alkene-24-acid-N-dimethylformamide; (20R)-20-hydroxyl courage-5-alkene-24-acid-N-dimethylformamide; 16 beta-hydroxy courage steroid-5-alkene; Courage steroid-5-alkene-16-ketone; 16 beta-hydroxy cholestane; (25R)-16 β, 26-dihydroxyl courage steroid-5-alkene.

Preferred formula I a and I b compound are these, promptly (below penult embodiment) can demonstrate at least 50 according to following method test agonist properties the time, the compound of preferred at least 80 relative reactivities, or (last embodiment hereinafter) can demonstrate and be lower than 10 μ M according to following method test antagonist properties the time, preferably is lower than the IC of 2 μ M ₅₀The compound of value.

The example of other preferred compound is those at the estrogen receptor site active compound of tool not, and the preferred active compound of tool not at other present known hormone receptor position.The example of these other hormone receptors has PgR, androgen receptor and glucocorticoid receptor.Also have, these compounds should not influence whole ovocyte deposits in the ovary.

Further preferred embodiment is seen described in the claims.

Used low alkyl group in specification sheets of the present invention and claims-no matter be uses separately or is used in combination-and can be the alkyl of straight or branched.The carbonatoms that preferred described alkyl comprises is no more than 6.The preferred embodiment of low alkyl group is methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group and hexyl, more preferably methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl, more preferably methyl and ethyl.In a preferred embodiment of the invention, low alkyl group comprises and is no more than 4 carbon atoms, preferably is no more than 3 carbon atoms.

The low alkyl group that uses in specification sheets of the present invention and claims is meant preferably have the straight or branched alkoxyl group that is no more than 6 carbon atoms, and preferably its carbonatoms is no more than 4, more preferably no more than 3.Preferred embodiment has methoxyl group, oxyethyl group and propoxy-, more preferably methoxyl group and oxyethyl group.

The term halogen of using in specification sheets of the present invention and claims preferably refers to fluorine and chlorine, more preferably fluorine.

Used term C in specification sheets of the present invention and claims ₃-C ₆Cycloalkyl is the cycloalkyl that contains 3-6 carbon atom in the finger ring.Preferred examples has cyclopropyl and cyclopentyl.

Used term acyloxy is meant the C by the optional replacement that connects by carbonyl oxygen base in specification sheets of the present invention and claims ₁-C ₆The monovalence substituting group that alkyl or phenyl forms; As acetoxyl group, propionyloxy, butyryl acyloxy, isobutyl acyloxy, new pentane acyloxy, penta acyloxy, benzoyl etc.

Used wording such as R in specification sheets of the present invention and claims ¹For being meant, oxo has oxo (=O) group (thereby not having hydrogen atom on 1) on 1.Similarly regulation also is applicable to other similar situation.In other cases, two symbols can be represented oxo, for example R together ⁴And R ' ⁴

Used wording such as R in specification sheets of the present invention and claims ¹²For being meant, methylene radical has methylene radical (=CH on 12 ₂), therefore there is not hydrogen atom on this position.Similarly regulation also is applicable to other similar situation.In other cases, two symbols can be represented methylene radical, for example R together ⁴And R ' ⁴

The salt preferred pharmacologically acceptable salt, particularly acid salt of formula I a and I b compound comprise the salt that is become with mineral acid with organic acid.The example of these salt comprises organic acid salt, described organic acid such as formic acid, fumaric acid, acetate, propionic acid, oxyacetic acid, lactic acid, pyruvic acid, oxalic acid, succsinic acid, toxilic acid, tartrate, citric acid, phenylformic acid, Whitfield's ointment etc.Suitable inorganic acid addition salt comprises hydrochloride, hydrobromate, vitriol and phosphoric acid salt etc.The further example of pharmaceutically useful mineral acid or organic acid addition salt comprises pharmaceutical science magazine (Journal ofPharmaceutical Science), 66 (1977), and listed pharmacologically acceptable salt in the page 2 etc.

The ester of formula I a or I b compound obtains by deriving with one or more hydroxyls of acid esters formula I a or I b compound, and acid wherein for example can be selected from succsinic acid and other aliphatic dicarboxylic acid, nicotinic acid, Yi Yansuan, ethyl carbonate, phosphoric acid, sulfonic acid, thionamic acid, phenylformic acid, acetate, propionic acid and other mono carboxylic acid of aliphatic series.

The metabolite of formula I a or I b compound is the reactive derivative of formula I a or I b compound, produces when formula I a or I b compound carry out metabolism.The evaluation of the metabolite of formula I a or I b compound can be carried out according to any mode hereinafter described: to host's Medicine-feeding type I a or I b compound, analyze host's blood sample then; Perhaps formula I a or I b compound are carried out vitro culture with liver cell, analyze culture then.

The prodrug of formula I a or I b compound is meant the compound that can be converted into formula I a or I b compound in vivo, perhaps is meant the compound that has identical active metabolite with formula I a or I b compound.

Have several chiral centres in the molecule of formula I a and I b compound, thereby have some isomer.All these isomer and composition thereof are all within the scope of the invention.

Formula I a and I b compound can be according to preparing with the similar method of the preparation of known compound.Therefore, the generally acknowledged synthetic route described in can the summary document according to cholesterol and steroide of formula I a and I b compound synthetic is carried out.Following books can be used as synthetic important foundation data: L.F.Fieser﹠amp; M.Fieser:Steroids:Reinhold PublishingCorporation, NY 1959; The Luo Shi chemistry of carbon compound (Rood ' s Chemistry ofCarbon Compounds) (write: S.Coffrey): Elsevier Publishing Company, 1971; J.Fried and J.A.Edwards: steroid chemistry organic reaction (Organic Reactionsin Steroid Chemistry), Vol I and II, Van Nostrand Reinhold Company, New York, 1972; And particularly steroid handbook (Dictinary of Steriods) (is write: R.A.Hill; D.N.Kirk; H.L.J.Makin and G.M.Murphy): Chapmann﹠amp; Hall.Wherein last this school bag has contained the extensive index list that has covered original before nineteen ninety.All these books (comprising index mentioned in last this book) are all incorporated into incorporated by reference at this.In addition, the technical intelligence that relates in all above-mentioned documents (comprising patent specification) that prepare similar formula I a and I b compound is all incorporated into incorporated by reference at this.

The compounds of this invention will influence the reduction division in ovocyte and the male sex-cell.

There is the reduction division inductive substance in known occurring in nature for some time, still, does not also know the discriminating of this class reduction division inductive substance up to date.

It is many-sided influencing maiotic possibility.According to a preferred embodiment of the invention a, formula I a or I b compound or its ester, salt, active metabolite and prodrug can be used to stimulate reduction division.According to another preferred embodiment of the present invention, formula I a or I b compound or its ester, salt, active metabolite and the prodrug reduction division that can be used to stimulate the people.Therefore, formula I a or I b compound or its ester, salt, active metabolite and prodrug are expected as new fertility conditioning agent, and do not have use up to now based on the known hormonal contraceptive class medicine of oestrogenic hormon and/or gestagen to common adverse effect that somatocyte had.

For application as female contraceptive bian, can use the reduction division inductive substance, before maturation, bring out reduction division so that before producing gonad-stimulating hormone ovulation peak, make also at the ovocyte of growing.For the women, maiotic recovery can for example be induced after one week in ischomenia.The most possible nonfertilization of post-mature ovocyte that obtains during ovulation.The normal menstrual cycle may be unaffected.Thus, importantly will note the influence that the biosynthesizing of progesterone in people's granulosa cell (somatocyte of ovarian follicle) of cultivating do not existed by the reduction division inductive substance, and oestrogenic hormon that uses in the hormonal contraceptive that uses up to now and progestogens all there is side effect to the biosynthesizing of progesterone.

According to a further aspect in the invention, by to can not produce female formula I a or I b reduction division inductive substance or its ester, salt, active metabolite and the prodrug used that enough reduction division activated materials can not produce mature oocyte because of self, they can be used for the treatment of the female barrenness symptom that some comprise the women.When in vitro fertilization, when in the substratum of hatching ovocyte, adding formula I a or I b compound or its ester, salt, active metabolite and prodrug, also can obtain better result.

, use formula I a or I b compound or its ester, salt, active metabolite and prodrug and then can alleviate this problem when thereby the male man's of comprising Infertility is to lack the The mature sperm cell and cause owing to self not producing enough reduction division activated materials.

As a variation pattern of aforesaid method, can suppress maiotic formula I a or I b compound or its ester, salt, active metabolite and prodrug by using, make femalely can not produce sophisticated ovocyte, thereby also can reach female contraception purpose.Similarly, suppress maiotic formula I a or I b compound or its ester, salt, active metabolite and prodrug, make malely not produce The mature sperm, and reach the male contraceptive purpose by using.

The route of administration that contains the composition of formula I a or I b compound or its ester, salt, active metabolite and prodrug is any approach that active compound effectively can be transported to its action site.

Therefore when to administration formula I a or I b compound, the form with pharmaceutical composition provides traditionally, and pharmaceutical composition contains at least a formula I a or I b compound or its ester, salt, active metabolite and prodrug and pharmaceutically acceptable carrier.For orally using preferred capsule of composition or tablet form.

From the above, dosage regimen depends on the illness that will treat.Therefore when being used for the treatment of Infertility, administration can disposablely be carried out or continue for some time, for example up to pregnancy.When the contraceptive bian, formula I a or I b compound or its ester, salt, active metabolite and prodrug can be continuously or cyclic application.When as female contraceptive bian not during successive administration, be important the opportunity of grasping with respect to ovulation of using.Pharmaceutical composition

The pharmaceutical composition that comprises formula I a or I b compound or its ester, salt, active metabolite and prodrug can further include carrier, thinner, short absorption agent, sanitas, buffer reagent, osmotic pressure regulator, other composition that tablet disintegrant and this area are commonly used.The example of solid carrier is a magnesiumcarbonate, magnesium stearate, dextrin, lactose, sucrose, talcum powder, gelatin, pectin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax and theobroma oil.

Liquid composition comprises sterile solution, suspensoid and emulsion.This class I liquid I composition can be suitable for injecting or with exsomatize and relevant application in vitro fertilization.Liquid composition can contain conventional other composition that uses in this area, and wherein some are mentioned hereinbefore.

In addition, the composition that is used for the The compounds of this invention of transdermal administration can provide with the form of diaphragm (Patch), and the composition of nose administration can provide with the nasal spray form of liquid or powder type.

The using dosage of the compound of formula I a of the present invention or I b is determined by the doctor, and depends on the particular compound of use, route of administration and application target especially.In general, the present composition can prepare by active compound and liquid or solid auxiliary component uniform mixing, subsequently if necessary, product is configured as required preparation.

Usually, be to be no more than 1000mg every day to the dosage of Mammals (for example people), preferably be no more than 100mg, under some preferred situation, be no more than 10mg formula I a or I b compound.

With every day 1000mg dosage be applied to man-hour, formula I a and I b compound all do not present toxicity.

The present invention is described in further detail by the following examples, but they must not be taken as and limit the scope of the present invention.Above specification sheets and disclosed in the following embodiments feature (can make up by any way) are to understand wide range of forms technical intelligence of the present invention.

Embodiment 116 beta-hydroxy courage steroid-5-alkene

To (25R)-courage steroid-5-alkene-3 β, 16 β, 26-triol (10g, 24mmol; According to people such as Arunachalam at organic chemistry magazine 46 (1981), the preparation of method described in the 2966-2968), add toluene sulfonyl chloride (5.7g in the mixture of pyridine (150mL) and methylene dichloride (150mL), 30mmol), and stir the gained mixture overnight.Add frozen water, the water dichloromethane extraction.And then with 4N HCl washing organic phase; behind the concentrating under reduced pressure residue is passed through purification by flash chromatography; thereby obtain (25R)-3,26-dimethylbenzene alkylsulfonyl courage steroid-5-alkene-16 β-alcohol (4.2g) and (25R)-26-tosyloxy courage steroid-5-alkene-3,16-glycol (6.3g).1H-NMR spectrum (CDCl3, δ) 2.43 (s, 6H), 3.45 (q, 1H), 3.72-3.92 (m, 2H), 4.25-4.40 (M, 1H), 5.23 (m, 1H), 7.32 (m, 4H), 7.78 (M 4H) locates to provide characteristic signal.

To (25R)-3,26-dimethylbenzene alkylsulfonyl courage steroid-5-alkene-16 β-alcohol (360mg, tetrahydrofuran (THF) 0.5mmol) (below be called THF; 5mL) add 1M lithium triethylborohydride solution (16mL) in the solution.Add entry, use the dichloromethane extraction water thereafter, and with dilute hydrochloric acid, sodium bicarbonate aqueous solution, and salt water washing.Concentrating under reduced pressure also passes through purification by flash chromatography, thereby obtains title compound (60mg), fusing point: 107-108 ℃. ¹H-NMR spectrum (CDCl ₃, characteristic signal peak δ) is as follows: 0.83 (s, 3H), 0.90 (s, 3H), 1.00 (s, 3H), 2.15-2.3 (m, 2H), 4.30-4.41 (m, 1H, H-16), 5.25 (d, 1H, H-6). ¹³C-NMR spectrum (CDCl ₃, δ) locate to provide the characteristic signal peak at 72.9 (C-16), 119.1 (C-6), 144.2 (C-5).Mass spectral characteristic peak: 386.4 (M ⁺).

Embodiment 2 courages steroid-5-alkene-16-ketone

(embodiment 1, and 80mg 0.2mmol) is dissolved in glacial acetic acid (4ml) with 16 beta-hydroxy courage steroid-5-alkene, (680mg 5mmol), and then dropwise adds chromium trioxide (20mg to add sodium acetate trihydrate, 0.2mmol) solution in glacial acetic acid and water (0.3mL, 2: 1 mixtures).After 2 hours, add methyl alcohol (2mL), and concentrated gained mixture.Add entry, use the dichloromethane extraction water thereafter.The organic layer that merges sodium bicarbonate, water and salt water washing.Remove the back of desolvating with recrystallizing methanol, thereby obtain title compound (18mg). ¹H-NMR spectrum (CDCl ₃, δ) (d, 1H H-6) locate to provide the characteristic signal peak 5.25. ¹³C-NMR spectrum (CDCl ₃, δ) locate to provide the characteristic signal peak at 118.6 (C-6), 144.2 (C-5), 219.3 (C-16).Mass spectral characteristic peak: 384.2 (M ⁺).

Embodiment 316 beta-hydroxy cholestane

In the presence of palladium-carbon, (embodiment 1,20mg) for normal pressure hydrogenation 16 beta-hydroxy courage steroid-5-alkene.Filter and chromatography, obtain title compound (17mg). ¹H-NMR spectrum (CDCl ₃, δ) (m 1H.H-16) locates to provide characteristic signal at 4.30-4.40.Mass spectral characteristic peak: 388.3 (M ⁺).

Embodiment 4 (25R)-16 β, 26-dihydroxyl courage steroid-5-alkene

Under 40 ℃, and the tetrahydrochysene diosgenin (2.5g, 5.9mmol), tert-butyldimethylsilyl chloride (1.1g, 7.1mmol) and imidazoles (1.6g, 24mmol) solution stirring in dimethyl formamide is 48 hours, pours into thereafter in the water (200mL), uses ethyl acetate extraction.By purification by flash chromatography, thereby obtain (25R)-3,16 beta-dihydroxyies-26-t-butyldimethylsilyloxy base courage steroid-5-alkene (1.3g). ¹H-NMR spectrum (CDCl ₃, characteristic signal peak δ) :-0.05-0.03 (d, 6H), 0.88 (s, 9H), 3.30-3.60 (3H, m, H-3 and 2H-26), 4.30-4.40 (m, 1H, H-16), 5.35 (m, 1H.H-6).

With (25R)-3,16 beta-dihydroxyies-26-t-butyldimethylsilyloxy base courage steroid-5-alkene (0.76g, 1.4mmol) and toluene sulfonyl chloride (0.54g, pyridine 2.8mmol) (20mL) solution stirring at room 48 hours.Concentrating under reduced pressure also passes through purification by flash chromatography, thereby obtains (25R)-3-tosyloxy-16 beta-hydroxies-26-t-butyldimethylsilyloxy base courage steroid-5-alkene (0.855g). ¹H-NMR spectrum (CDCl ₃, characteristic signal peak δ) :-0.05-0.03 (d, 6H), 0.88 (s, 9H), 2.45 (s, 3H), 3.30-3.49 (2H, m, 2H-26), 4.30-4.40 (m, 2H, H-3 and H-16), 5.30 (m, 1H, H-6), 7.30 (d, 2H), 7.73 (d, 2H).

To (25R)-3-tosyloxy-16 beta-hydroxies-26-t-butyldimethylsilyloxy base courage steroid-5-alkene (0.85g, 1.2mmol) the middle Super Hydride (30mL, 1M THF solution) that adds, stirring at room reaction 72 hours, thereafter pour in the frozen water, use ethyl acetate extraction.Removal of solvent under reduced pressure is also passed through purification by flash chromatography, thereby obtains 16 beta-hydroxies-26-t-butyldimethylsilyloxy base courage steroid-5-alkene (0.53g). ¹H-NMR spectrum (CDCl ₃, characteristic signal peak δ) :-0.05-0.03 (d, 6H), 0.88 (s, 9H), 3.30-3.49 (2H, m, 2H-26), 4.30-4.40 (m, 1H, H-16), 5.30 (m, 1H.H-6).

Add tetrabutylammonium fluoride (0.6g) in 16 beta-hydroxies-26-t-butyldimethylsilyloxy base courage steroid-5-alkene/THF, the stirring at room reaction is spent the night.Removal of solvent under reduced pressure is also carried out flash chromatography, thereby obtains title compound. ¹H-NMR spectrum (CDCl ₃, characteristic signal peak δ): 3.40-3.52 (2H, m, 2H-26), 4.30-4.40 (m, 1H, H-16), 5.30 (d, 1H.H-6).

The mensuration of embodiment 5 exciting ovocytes is following carries out:

Ovocyte is taken under controlled temperature (20-22 ℃), light application time (06.00-18.00 illumination) and relative humidity (50-70%) condition and to be raised and body weight reaches the prematurity female mice (C57BL/6J * DBA/2J F1 of 13-16 gram, Bomholtgaard, Denmark).To in the mouse peritoneum injection 0.2ml contain 20IU FSH gonad-stimulating hormone (Gonal-F, Serono), after 48 hours, the sacrificed by decapitation animal.

The taking-up ovary also (sees below) in the Hx-substratum, and by stereoscopic microscope, piercing through ovarian follicle isolates ovocyte by hand with a pair of 27 rule pins.The spherical ovocyte that will have a complete blastocyst (below be called GV) divides Chengqiu to seal ovocyte (below be called CEO) and exposed ovocyte (below be called NO), and place and added 3mg/ml bovine serum albumin (BSA, Sigma Cat.No.A-7030), 5mg/ml human serum albumin (HSA, StatensSeruminstitute, Denmark), 0.23 mM pyruvic acid (Sigma, Cat.No S-8636), 2mM glutamine (Flow Cat.No.16-801), 100 IU/ml penicillin and 100 μ g/ml Streptomycin sulphate (Flow, Cat.No.16-700) α-minimum essential medium (α-MEM that does not contain ribonucleoside, Gibco BRL, Cat.No.22561).Also add 3mM xanthoglobulin (Sigma Cat No.H-9377) in this substratum, and be known as the Hx-substratum.

Ovocyte is washed three times in the Hx-substratum, ovocyte of uniform size is divided into CEO and NO group.Every therein hole contains the middle CEO of cultivation of 4-hole alveolar disk (Nuclon, Denmark) and the NO of 0.4ml Hx-substratum.When cultivating 3 test holess (every hole 35-45 ovocyte, and add test compound), cultivate a control wells (be 35-45 ovocyte, in not adding the same medium of testing compound, cultivate) all the time.

Containing 5%CO ₂Damp atmosphere atmosphere in, cultivated ovocyte 24 hours for 37 ℃.Cultivate latter stage, utilizing stereoscopic microscope (Wildt, Leica MZ12) to count respectively to contain the ovocyte quantity of blastocyst (below be called GV), germinal vesicle breakdown (below be called GVB) and polar body (below be called PB).%GVB (ovocyte that is defined as experiencing GVB accounts for the percentage ratio of ovocyte sum in this hole) is calculated as follows: %GVB=(GVB quantity+PB quantity/ovocyte total quantity) * 100.

%PB is defined as the percentage ratio that the ovocyte that presents an extruding polar body accounts for ovocyte sum in this hole.

The effectiveness of test compounds is with respect to control group level and 4,4-dimethyl-5 α-courage steroid-8,14, and the exponential representation of 24-triolefin-3 β-alcohol (below be called FF-MAS), wherein the efficacy index of control group and FF-MAS is respectively 0 and 100.The relative effectivenes of test compounds is calculated as follows: relative effectivenes=((test GVB%-contrast GVB%)/(FF-MAS) GVB%-contrast GVB%)) * 100.

Utilize this mensuration, find that the GVB of embodiment 1 and 4 made compounds is respectively 72 and 63%, GVB is respectively 88 and 73% relatively.

The mensuration of embodiment 6 antagonism ovocytes is following carries out: animal

Ovocyte is taken from the prematurity female mice (C57BI/6J * DBA/2J F1 hybrid system, Bomholtgaard, Denmark) of the body weight 13-16 gram of raising under control light application time and temperature condition.To injection 0.2ml gonad-stimulating hormone in the mouse peritoneum (SOlna, Sweden contains 20 IU FSH, perhaps, Puregon, Organon, Swords, Ireland contains 20IUFHS for Gonal-F, Serono), after 48 hours, the sacrificed by decapitation animal.Test reduction division inhibitory substance in the ovocyte test

The taking-up ovary also (sees below) in the Hx-substratum, and by stereoscopic microscope, piercing through ovarian follicle isolates ovocyte by hand with a pair of 27 rule pins.The exposed ovocyte (NO) of sphere that will have complete blastocyst (GV) places has added 3mM xanthoglobulin (SigmaCat.No.H-9377), 8mg/ml human serum albumin (HSA, Statens Seruminstitut, Denmark), 0.23 mM pyruvic acid (Sigma, Cat.No S-8636), 2mM glutamine (FlowCat.No.16-801), 100 IU/ml penicillin and 100 μ g/ml Streptomycin sulphate (Flow, Cat.No.16-700) α-minimum essential medium (α-MEM that does not contain ribonucleoside, Gibco BRL, Cat.No.22561).This substratum is called the Hx-substratum.

To expose ovocyte (NO) washes three times in the Hx-substratum.Before proved 4,4-dimethyl-5 α-courage steroid-8.14.24-triolefin-3 β-alcohol (FF-MAS) can external evoked NO take place reduction division (Byskov, A.G. etc., nature 374 (1995), 559-562).Every therein hole contains in the 4 hole alveolar disks (Nuclon, Denmark) of 0.4ml Hx-substratum and 35-45 ovocyte, and NO is cultivated altogether with the different concns test compound in the Hx-substratum of adding 5 μ M FF-MAS.In the test culture test of adding the different concns test-compound, always carry out a hole positive control and cultivate (promptly containing FF-MAS but do not containing in the Hx-substratum of test compound and cultivating 35-45 ovocyte).In addition, when positive control is cultivated, carry out a hole negative control and cultivate (only at 35-45 ovocyte of Hx-culture medium culturing).The inspection of ovocyte

Cultivating latter stage, the inverted microscope counting that utilizes stereoscopic microscope or have differential interference contrast equipment contains the ovocyte quantity of blastocyst (GV) or germinal vesicle breakdown (GVB) and the ovocyte quantity with polar body (PB).Calculate the per-cent that the ovocyte that has GVB+PB in test cultivation group and contrast (positive and negative) the cultivation group accounts for the ovocyte sum.The relative restraining effect of test compound is calculated as follows: the restraining effect of test compound (%)=100-[(GVB _{Test compound}-GVB _{Negative control group}) * 100/ (GVB _{Positive controls}-GVB _{Negative control group})]

According to dose response curve, calculate IC ₅₀Value (promptly producing 50% dosage that suppresses).

Embodiment 4 made compounds are used this mensuration, find that PB is 5%.

Embodiment 7 tests in vitro fertilization can followingly be carried out:

Under the agonist ovocyte is measured (embodiment 5) described the same terms, separate and cultivate deriving from the prematurity mouse (F of C57B116J * DBAJ/2) ₁Exposed ovocyte (NO) and mound envelope ovocyte (CEO).After 18 hours, in no hypoxanthic substratum, wash the ovocyte that presents germinal vesicle breakdown (GVB) tout court, and it is transferred in the previously prepared insemination dish, wherein include the free motile sperm goods that derive from male mice tail side epididymis.Gas condition (the 5%CO that described dish is being determined ₂) under in 37 ℃ the improvement α-MEM IVF substratum in incubations.Wherein inseminate substratum and IVF substratum do not contain xanthoglobulin.Insemination back was checked ovocyte in 20-22 hour, to examine the fertilization situation and to write down the quantity of 2 somatic embryos.Determine fertilization percentage (=rate of fertilization) according to the ovocyte counting that splits into 2 somatic embryos.

Embodiment 1 made compound is used this test, find that rate of fertilization is 62% (rate of fertilization of control animals is 22%).

Claims (22)

1. the noval chemical compound of general formula I a and ester thereof, salt, active metabolite and prodrug:Wherein, R¹For hydrogen, halogen, methyl, hydroxyl or oxo; R²Be selected from hydrogen, hydroxyl, low alkyl group, vinyl, lower alkoxy and halogen, perhaps R²With R³Represent between R together²And R³Additional key between place's carbon atom; R³For hydrogen or low alkyl group; Perhaps R³With R⁴Represent between R together³And R⁴Additional key between place's carbon atom; Perhaps R³With R²Represent between R together²And R³Additional key between place's carbon atom; R⁴And R '⁴Can be identical or different, can not be simultaneously be hydroxyl but condition is them, and they are selected from hydrogen, halogen, hydroxyl and the low alkyl group that can be replaced by halogen, hydroxyl or cyano group, perhaps R wherein⁴With R '⁴Represent together methylene or oxo, perhaps form cyclopropane ring, pentamethylene ring or cyclohexane ring together with the carbon atom of their institute's bondings; Perhaps R⁴,R’ ⁴And R⁵Represent together the additional key between 4 and 5 carbon atoms; R⁵For hydrogen, halogen or hydroxyl, perhaps R⁵With R⁶Represent between R together⁵And R⁶Additional key between place's carbon atom; R⁶For hydrogen, hydroxyl, halogen or oxo, perhaps R⁶With R⁵Or R⁷Table is basic together, acyloxy, halogen and low alkyl group, perhaps R⁷With R⁶Or R⁸Represent between R together⁷With R⁶Or R⁸Additional key between place's carbon atom; And R '⁷For hydrogen, if perhaps R⁷For low alkyl group, R '⁷For hydrogen or hydroxyl; Perhaps R⁷With R '⁷Be oxo together, methylene or general formula=NOR³⁶Group, R wherein³⁶For hydrogen or low alkyl group; R⁸For hydrogen, hydroxyl or halogen, perhaps R⁸With R⁷、R ⁹Or R¹⁴Represent between R together⁸With R⁷、R ⁹Or R¹⁴Additional key between place's carbon atom; R⁹For hydrogen, hydroxyl or halogen, perhaps R⁹With R⁸Or R¹¹Represent between R together⁹With R⁸Or R¹¹Additional key between place's carbon atom; R¹¹Be selected from hydrogen, hydroxyl, methoxyl group, acyloxy, halogen and low alkyl group, perhaps R¹¹With R⁹Or R¹²Represent between R together¹¹With R⁹Or R¹²Additional key between place's carbon atom; And R '¹¹, for hydrogen, perhaps work as R¹¹During for low alkyl group, R '¹¹For hydrogen or hydroxyl, perhaps R¹¹With R '¹¹Be oxo together, methylene or general formula=NOR³⁷Group, R wherein³⁷For hydrogen or low alkyl group; R¹²Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, acyloxy, oxo and general formula=NOR³³Group, R wherein³³For hydrogen or low alkyl group; Perhaps R¹²With R¹¹Represent between R together¹¹And R¹²Additional key between place's carbon atom; R¹⁴For hydrogen or hydroxyl, perhaps R¹⁴With R¹⁵Represent between R together¹⁴And R¹⁵Additional key between place's carbon atom; R¹⁵Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, oxo and general formula=NOR³²Group, R wherein³²For hydrogen or low alkyl group, perhaps R¹⁵With R¹⁴Represent between R together¹⁵And R¹⁴Additional key between place's carbon atom; R¹⁶Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, oxo and general formula=NOR³⁴Group, R wherein³⁴For hydrogen or low alkyl group, perhaps R¹⁶With R¹⁷Represent between R together¹⁶And R¹⁷Additional key between place's carbon atom; R¹⁷For hydrogen or hydroxyl, perhaps R¹⁷With R¹⁶Represent between R together¹⁷And R¹⁶Additional key between place's carbon atom; R²⁰Be selected from hydrogen, low alkyl group and methylol, perhaps R²⁰With R '²⁰Represent together methylene or oxo; R’²⁰For hydrogen, halogen, low alkyl group or hydroxyl, R '²²For hydrogen, hydroxyl or oxo; R²²Expression general formula-C (R²³)(R’ ²³)-C(R ²⁴)(R’ ²⁴)-A(R ²⁵)(R’ ²⁵)(R” ²⁵) group, R wherein²³And R '²³Be hydrogen, perhaps R²³And R '²³In one be hydrogen, and another is halogen, hydroxyl or methoxyl group, perhaps R²³With R '²³Represent together oxo, work as R²⁴R ' while being not oxo²⁴For hydrogen, and work as R²⁴R ' during for oxo²⁴Do not exist; A is carbon atom or nitrogen-atoms; And when A is carbon atom, R²⁵Be selected from hydrogen, hydroxyl and halogen; And R²⁴Be selected from hydrogen, halogen, hydroxyl, low alkyl group, methylene and oxo, perhaps R²⁵With R²⁴Represent between R together²⁴And R²⁵Additional key between place's carbon atom; R’²⁵Be selected from low alkyl group, trifluoromethyl and C₃-C ₆Cycloalkyl; R”²⁵Be selected from low alkyl group, hydroxyl (low alkyl group), contain the halo of three halogen atoms (low alkyl group) at the most, methoxy, acetoxy-methyl, and C₃-C ₆-cycloalkyl, perhaps R '²⁵And R "²⁵Form C together with their connected carbon atoms₃-C ₆Cycloalkyl ring; And when A is nitrogen-atoms, R²⁵Represent a pair of not share electron pair; And R²⁴Be selected from hydrogen, hydroxyl, low alkyl group, cyano group and oxo; And R '²⁵And R "²⁵Be low alkyl group or C independently₃-C ₆Cycloalkyl; Perhaps R²²For phenyl, toluyl groups, hydroxy phenyl, cyclopenta, cyclohexyl, isobutyl group or cyclohexyloxy carbonyl methyl;

Condition is except the following compounds: courage steroid-4,8,24-triolefin; 25-azepine courage steroid-5-alkene; Courage steroid-3, the 5-diene; Courage steroid-2-alkene; Courage steroid-5-alkene; 24-methyl courage steroid-3, the 5-diene; 24-ethyl courage steroid-3,5, the 22-diene; 24-ethyl courage steroid-3, the 5-diene; 24-demethyl-5 α-cholestane; 24-demethyl-5 β-cholestane; (20R)-5 β, 14 α, 17 α (H)-cholestane; (20R)-5 α, 14 β, 17 β (H)-cholestane; (20R)-5 α, 14 α, 17 α (H)-cholestane; (20R)-5 β, 14 α, 17 α (H)-24-methylcholestane; (20R)-5 α, 14 α, 17 α (H)-24-methylcholestane; (20R)-5 β, 14 α, 17 α (H)-24-ethyl cholestane; (20R)-5 α, 14 α, 17 α (H)-24-ethyl cholestane; 4-methyl-5 α-24-demethyl cholestane; 5 α-cholestane; 5 β-cholestane; Courage steroid-4-alkene; The 4-methylcholestane; (20S)-5 α, 14 α, 17 α-cholestane; 19-demethyl-5 α-cholestane; Courage steroid-4-alkene; Cholestane falls; 5 α, 8 β, 14 β-cholestane; 5 β, 8 β, 14 β-cholestane; 5 α-fall cholestane; 5 α, 17 β (H)-cholestane; (20S)-5 α, 17 β (H)-cholestane; (24R)-24-methyl-5 β-cholestane; (24S)-24.Methyl-5 β-cholestane; 5 α, 8 α, 14 β-cholestane; (20S)-5 α-cholestane; (24R0-24-methyl-5 α-cholestane; (24S)-24-ethyl-5 α-cholestane; (24S)-24-ethyl-5 α-cholestane; 4 Alpha-Methyls-5 α-cholestane; 4 Beta-methyls-5 α-cholestane; (24S)-24-methyl-5 α-cholestane; 24-methylol courage-24-ketone; 24-methylol courage-24-alcohol; Courage steroid-24-alkene; 24-cyclohexyl courage-24-alkene; 24-methyl courage steroid-2-alkene; 24-ethyl courage steroid-2-alkene; 24-propyl group cholestane; Courage steroid-25-alkene; 24-cyclohexyl courage-24-alkene; With 24-dimethyl-5 α-cholane.

2. according to compound and ester, salt, active metabolite and the prodrug of claim 1, wherein, R ¹Be hydrogen; R ²Be selected from hydrogen, perhaps R ²With R ³Represent between R together ²And R ³Additional key between place's carbon atom; R ³Be hydrogen or low alkyl group; Perhaps R ³With R ⁴Represent between R together ³And R ⁴Additional key between place's carbon atom; R ⁴And R ' ⁴Can be identical or different, can not be hydroxyl simultaneously but condition is them, and they are selected from hydrogen, hydroxyl and low alkyl group, perhaps R ⁴, R ' ⁴And R ⁵Represent additional key together; R ⁵Be hydrogen, perhaps R ⁵With R ⁶Represent between R together ⁵And R ⁶Additional key between place's carbon atom; R ⁶Be hydrogen, perhaps R ⁶With R ⁵Or R ⁷Represent between R together ⁶With R ⁵Or R ⁷Additional key between place's carbon atom; R ⁷Be selected from hydrogen or hydroxyl, perhaps R ⁷With R ⁶Or R ⁸Represent between R together ⁷With R ⁶Or R ⁸Additional key between place's carbon atom; And R ' ⁷Be hydrogen, perhaps R ⁷With R ' ⁷Represent oxo or methylene radical together; R ⁸Be hydrogen, perhaps R ⁸With R ⁷, R ⁹Or R ¹⁴Represent between R together ⁸With R ⁷, R ⁹Or R ¹⁴Additional key between place's carbon atom; R ⁹Be hydrogen, perhaps R ⁹With R ⁸Or R ¹¹Represent between R together ⁹With R ⁸Or R ¹¹Additional key between place's carbon atom; R ¹¹Be hydrogen or hydroxyl, perhaps R ¹¹With R ⁹Represent between R together ⁹And R ¹¹Additional key between place's carbon atom; R ' ¹¹Be hydrogen; R ¹²Be hydrogen; R ¹⁴Be hydrogen, perhaps R ¹⁴With R ¹⁵Represent between R together ¹⁴And R ¹⁵Additional key between place's carbon atom; R ¹⁵Be hydrogen, hydroxyl or oxo; R ¹⁶Be hydrogen, hydroxyl or oxo, perhaps R ¹⁶With R ¹⁷Represent between R together ¹⁶And R ¹⁷Additional key between place's carbon atom; R ¹⁷Be hydrogen or hydroxyl, perhaps R ¹⁷With R ¹⁶Represent between R together ¹⁷And R ¹⁶Additional key between place's carbon atom; R ²⁰Be hydrogen or low alkyl group, perhaps R ²⁰With R ' ²⁰Represent methylene radical or oxo together; R ' ²⁰Be hydrogen, halogen, low alkyl group or hydroxyl, R ' ²²Be hydrogen, hydroxyl or oxo; And R ²²Be phenyl, toluyl, hydroxy phenyl, cyclopentyl, cyclohexyl, isobutyl-, 3-methyl butyl or cyclohexyloxy carbonyl methyl.

3. according to the compound of claim 1 or 2, substituting group wherein is any one in the preferred substituents of specifically mentioning in the specification sheets of front.

4. according to the compound of aforesaid right requirement, they are courage steroid-5-alkene-16 β-alcohol; Courage steroid-5-alkene-16-ketone; 4,4-dimethyl courage steroid-2,5-diene-16 β-alcohol; Cholestane-16 β-alcohol; Courage steroid-3,5-diene-16 β-alcohol; Courage steroid-5-alkene-15 β-alcohol; Courage steroid-5-alkene-17 α-alcohol; Courage steroid-5-alkene-15 α-alcohol; Courage steroid-5-alkene-16 α-alcohol; 4,4-dimethyl courage steroid-5-alkene-16 β-alcohol; Courage steroid-3-alkene-16 β-alcohol; Courage steroid-4-alkene-16 β-alcohol; Courage steroid-2-alkene-16 β-alcohol; Courage steroid-2,4-diene-16 β-alcohol; Courage steroid-2,5-diene-16 β-alcohol; Courage steroid-5,24-diene-16 β-alcohol; Courage steroid-5,8-diene-16 β-alcohol; Courage steroid-5,7-diene-16 β-alcohol; 4,4-dimethyl courage steroid-5,7-diene-16 β-alcohol; 3-methyl courage steroid-2,5-diene-16 β-alcohol; 3 Beta-methyl courage steroid-5-alkene-16 β-alcohol; 3 Alpha-Methyl courage steroid-5-alkene-16 β-alcohol; 3,4,4-trimethylammonium courage steroid-2,5-diene-16 β-alcohol; 4,4-dimethyl courage steroid-5,8-diene-16 β-alcohol; Courage steroid-5,8-diene-15 β-alcohol; Courage steroid-5,7-diene-15 β-alcohol; 4,4-dimethyl courage steroid-5-alkene-15 β-alcohol; 4,4-dimethyl courage steroid-5-alkene-15 α-alcohol; The pregnant steroid of 20-methyl-21-phenyl-5-alkene-16 β-alcohol; The pregnant steroid of 20-methyl-21-cyclopentyl-5-alkene-16 β-alcohol; 24-demethyl courage steroid-5-alkene-16 β-alcohol; 24-demethyl courage steroid-16 β-alcohol; 24-demethyl courage steroid-5-alkene-15 β-alcohol; The pregnant steroid of 20-methyl-21-(3-aminomethyl phenyl)-5-alkene-16 β-alcohol; The pregnant steroid of 20-methyl-21-(3-hydroxy phenyl)-5-alkene-16 β-alcohol; 20-methyl-21-(3-hydroxy phenyl) pregnant steroid-16 β-alcohol; 20-methyl-21-(3-aminomethyl phenyl) pregnant steroid-15 β-alcohol; 4,4,20-trimethylammonium-(4-aminomethyl phenyl) pregnant steroid-5-alkene-16 β-alcohol; 16 beta-hydroxies courage-5-alkene-24-acid cyclohexyl; Courage steroid-5-alkene-16 β, the 25-glycol; 24-demethyl cholestane-15 β-alcohol; 20-methyl-21-benzyl pregnant steroid-3,5-diene-16 β-alcohol; 24-demethyl-4,4-dimethyl courage steroid-5-alkene-16 β-alcohol; 4,4, the pregnant steroid of 20-trimethylammonium-21-(cyclopentyl)-5-alkene-16 β-alcohol; 16 beta-hydroxy courage steroids-5-alkene-24-ketone; (20S)-and courage steroid-5-alkene-16 β, the 20-glycol; (20R)-and courage steroid-5-alkene-16 β, the 20-glycol; (20S)-and 24-demethyl courage steroid-5-alkene-16 β, the 20-glycol; (20R)-and 24-demethyl courage steroid-5-alkene-16 β, the 20-glycol; (20S)-and courage steroid-5,24-diene-16 β, 20-glycol; (20R)-and courage steroid-5,24-diene-16 β, 20-glycol; (20S)-and 24-demethyl courage steroid-5,23-diene-16 β, 20-glycol; (20R)-and 24-demethyl courage steroid-5,23-diene-16 β, 20-glycol; (20S)-23,24-dinor-courage steroid-5-alkene-16 β, 20-glycol; (20R)-23,24-dinor-courage steroid-5-alkene-16 β, 20-glycol; (20S)-and the pregnant steroid of 20-methyl-21-phenyl-5-alkene-16 β, the 20-glycol; (20R)-and the pregnant steroid of 20-methyl-21-phenyl-5-alkene-16 β, the 20-glycol; (20S)-16 β, 20-dihydroxyl courage-5-alkene-24-acid-N-dimethylformamide; (20R)-16 β, 20-dihydroxyl courage-5-alkene-24-acid-N-dimethylformamide; (20S)-20-hydroxyl courage-5-alkene-24-acid-N-dimethylformamide; (20R)-20-hydroxyl courage-5-alkene-24-acid-N-dimethylformamide; 16 beta-hydroxy courage steroid-5-alkene; Courage steroid-5-alkene-16-ketone; 16 beta-hydroxy cholestane; (25R)-16 β, 26-dihydroxyl courage steroid-5-alkene.

5. general formula I b compound and ester thereof, salt, active metabolite and prodrug are as the purposes of medicine:

Wherein, R¹For hydrogen, halogen, methyl, hydroxyl or oxo; R²Be selected from hydrogen, hydroxyl, low alkyl group, vinyl, lower alkoxy and halogen, perhaps R²With R³Represent between R together²And R³Additional key between place's carbon atom; R³For hydrogen or low alkyl group; Perhaps R³With R⁴Represent between R together³And R⁴Additional key between place's carbon atom; Perhaps R³With R²Represent between R together²And R³Additional key between place's carbon atom; R⁴And R '⁴Can be identical or different, can not be simultaneously be hydroxyl but condition is them, and they are selected from hydrogen, halogen, hydroxyl and the low alkyl group that can be replaced by halogen, hydroxyl or cyano group, perhaps R wherein⁴With R '⁴Represent together methylene or oxo, perhaps form cyclopropane ring, pentamethylene ring or cyclohexane ring together with the carbon atom of their institute's bondings; Perhaps R⁴，R’ ⁴And R⁵Represent together the additional key between 4 and 5 carbon atoms; R⁵For hydrogen, halogen or hydroxyl, perhaps R⁵With R⁶Represent between R together⁵And R⁶Additional key between place's carbon atom; R⁶For hydrogen, hydroxyl, halogen or oxo, perhaps R⁶With R⁵Or R⁷Represent between R together⁶With R⁵Or R⁷Additional key between place's carbon atom; R⁷Be selected from hydrogen, hydroxyl, methoxyl group, acyloxy, halogen and low alkyl group, perhaps R⁷With R⁶Or R⁸Represent between R together⁷With R⁶Or R⁸Additional key between place's carbon atom; And R '⁷For hydrogen, if perhaps R⁷For low alkyl group, R '⁷For hydrogen or hydroxyl; Perhaps R⁷With R '⁷Represent together oxo, methylene or general formula=NOR³⁶Group, R wherein³⁶For hydrogen or low alkyl group; R⁸For hydrogen, hydroxyl or halogen, perhaps R⁸With R⁷、R ⁹Or R¹⁴Represent between R together⁸With R⁷、R ⁹Or R¹⁴Additional key between place's carbon atom; R⁹For hydrogen, hydroxyl or halogen, perhaps R⁹With R⁸Or R¹¹Represent between R together⁹With R⁸Or R¹¹Additional key between place's carbon atom; R¹¹Be selected from hydrogen, hydroxyl, methoxyl group, acyloxy, halogen and low alkyl group, perhaps R¹¹With R⁹Or R¹²Represent between R together¹¹With R⁹Or R¹²Additional key between place's carbon atom; And R '¹¹, for hydrogen, perhaps work as R¹¹During for low alkyl group, R '¹¹For hydrogen or hydroxyl; Perhaps R¹¹With R '¹¹Represent together oxo, methylene or general formula=NOR³⁷Group, R wherein³⁷For hydrogen or low alkyl group; R¹²Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, acyloxy, oxo and general formula=NOR³³Group, R wherein³³For hydrogen or low alkyl group; Perhaps R¹²With R¹¹Represent between R together¹¹And R¹²Additional key between place's carbon atom; R¹⁴For hydrogen or hydroxyl, perhaps R¹⁴With R¹⁵Represent between R together¹⁴And R¹⁵Additional key between place's carbon atom; R¹⁵Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, oxo and general formula=NOR³²Group, R wherein³²For hydrogen or low alkyl group, perhaps R¹⁵With R¹⁴Represent between R together¹⁵And R¹⁴Additional key between place's carbon atom; R¹⁶Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, oxo and general formula=NOR³⁴Group, R wherein³⁴For hydrogen or low alkyl group, perhaps R¹⁶With R¹⁷Represent between R together¹⁶And R¹⁷Additional key between place's carbon atom; R¹⁷For hydrogen or hydroxyl, perhaps R¹⁷With R¹⁶Represent between R together¹⁷And R¹⁶Additional key between place's carbon atom; R²⁰Be selected from hydrogen, low alkyl group and methylol, perhaps R²⁰With R '²⁰Represent together methylene or oxo; R’²⁰For hydrogen, halogen, low alkyl group or hydroxyl, R '²²For hydrogen, hydroxyl or oxo; R²²Expression general formula-C (R²³)(R’ ²³)-C(R ²⁴)(R’ ²⁴)-A(R ²⁵)R’ ²⁵)(R” ²⁵) group, R wherein²³And R '²³Be hydrogen, perhaps R²³And R '²³In one be hydrogen, and another is halogen, hydroxyl or methoxyl group, perhaps R²³With R '²³Represent together oxo, work as R²⁴R ' while being not oxo²⁴For hydrogen, and work as R²⁴R ' during for oxo²⁴Do not exist; A is carbon atom or nitrogen-atoms; And when A is carbon atom, R²⁵Be selected from hydrogen, hydroxyl and halogen; And R²⁴Be selected from hydrogen, halogen, hydroxyl, low alkyl group, methylene and oxo, perhaps R²⁵With R²⁴Represent between R together²⁴And R²⁵Additional key between place's carbon atom; R’²⁵Be selected from low alkyl group, trifluoromethyl and C₃-C ₆Cycloalkyl; R”²⁵Be selected from low alkyl group, hydroxyl (low alkyl group), contain the halo of three halogen atoms (low alkyl group) at the most, methoxy, acetoxy-methyl, and C₃-C ₆-cycloalkyl, perhaps R '²⁵And R "²⁵Form C together with their connected carbon atoms₃-C ₆Cycloalkyl ring; And when A is nitrogen-atoms, R²⁵Represent a pair of not share electron pair; And R²⁴Be selected from hydrogen, hydroxyl, low alkyl group, cyano group and oxo; And R '²⁵And R "²⁵Be low alkyl group or C independently₃-C ₆Cycloalkyl; Perhaps R²²For phenyl, toluyl groups, hydroxy phenyl, cyclopenta, cyclohexyl, isobutyl group or cyclohexyloxy carbonyl methyl.

6. according to the purposes of aforesaid right requirement, wherein said compound is each described any compound among the claim 2-4.

7. be used for regulating and controlling maiotic general formula I b compound and ester, salt, active metabolite and prodrug:Wherein, R¹For hydrogen, halogen, methyl, hydroxyl or oxo; R²From hydrogen, hydroxyl, low alkyl group, vinyl, lower alkoxy and halogen, perhaps R²With R³Represent between R together²And R³Additional key between place's carbon atom; R³For hydrogen or low alkyl group; Perhaps R³With R⁴Represent between R together³And R⁴Additional key between place's carbon atom; Perhaps R³With R²Represent between R together²And R³Additional key between place's carbon atom; R⁴And R '⁴Can be identical or different, can not be simultaneously be hydroxyl but condition is them, and they are selected from hydrogen, halogen, hydroxyl and the low alkyl group that can be replaced by halogen, hydroxyl or cyano group, perhaps R wherein⁴With R '⁴Represent together methylene or oxo, perhaps form cyclopropane ring, pentamethylene ring or cyclohexane ring together with the carbon atom of their institute's bondings; Perhaps R⁴,R’ ⁴And R⁵Represent together the additional key between 4 and 5 carbon atoms; R⁵For hydrogen, halogen or hydroxyl, perhaps R⁵With R⁶Represent between R together⁵And R⁶Additional key between place's carbon atom; R⁶For hydrogen, hydroxyl, halogen or oxo, perhaps R⁶With R⁵Or R⁷Represent between R together⁶With R⁵Or R⁷Additional key between place's carbon atom; R⁷Be selected from hydrogen, hydroxyl, methoxyl group, acyloxy, halogen and low alkyl group, perhaps R⁷With R⁶Or R⁸Represent between R together⁷With R⁶Or R⁸Additional key between place's carbon atom; And R '⁷For hydrogen, if perhaps R⁷For low alkyl group, R '⁷For hydrogen or hydroxyl; Perhaps R⁷With R '⁷Represent together oxo, methylene or general formula=NOR³⁶Group, R wherein³⁶For hydrogen or low alkyl group; R⁸For hydrogen, hydroxyl or halogen, perhaps R⁸With R⁷、R ⁹Or R¹⁴Represent between R together⁸With R⁷、R ⁹Or R¹⁴Additional key between place's carbon atom; R⁹For hydrogen, hydroxyl or halogen, perhaps R⁹With R⁸Or R¹¹Represent between R together⁹With R⁸Or R¹¹Additional key between place's carbon atom; R¹¹Be selected from hydrogen, hydroxyl, methoxyl group, acyloxy, halogen and low alkyl group, perhaps R¹¹With R⁹Or R¹²Represent between R together¹¹With R⁹Or R¹²Additional key between place's carbon atom; And R '¹¹, for hydrogen, perhaps work as R¹¹During for low alkyl group, R '¹¹For hydrogen or hydroxyl; Perhaps R¹¹With R '¹¹Represent together oxo, methylene or general formula=NOR³⁷Group, R wherein³⁷For hydrogen or low alkyl group; R¹²Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, acyloxy, oxo and general formula=NOR³³Group, R wherein³³For hydrogen or low alkyl group; Perhaps R¹²With R¹¹Represent between R together¹¹And R¹²Additional key between place's carbon atom; R¹⁴For hydrogen or hydroxyl, perhaps R¹⁴With R¹⁵Represent between R together¹⁴And R¹⁵Additional key between place's carbon atom; R¹⁵Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, oxo and general formula=NOR³²Group, R wherein³²For hydrogen or low alkyl group, perhaps R¹⁵With R¹⁴Represent between R together¹⁵And R¹⁴Additional key between place's carbon atom; R¹⁶Be selected from hydrogen, halogen, low alkyl group, methylene, hydroxyl, lower alkoxy, oxo and general formula=NOR³⁴Group, R wherein³⁴For hydrogen or low alkyl group, perhaps R¹⁶With R¹⁷Represent between R together¹⁶And R¹⁷Additional key between place's carbon atom; R¹⁷For hydrogen or hydroxyl, perhaps R¹⁷With R¹⁶Represent between R together¹⁷And R¹⁶Additional key between place's carbon atom; R²⁰Be selected from hydrogen, low alkyl group and methylol, perhaps R²⁰With R '²⁰Represent together methylene or oxo; R’²⁰For hydrogen, halogen, low alkyl group or hydroxyl, R '²²For hydrogen, hydroxyl or oxo; R²²Expression general formula-C (R²³)(R’ ²³)-C(R ²⁴)(R’ ²⁴)-A(R ²⁵)(R’ ²⁵)(R” ²⁵) group, R wherein²³And R '²³Be hydrogen, perhaps R²³And R '²³In one be hydrogen, and another is halogen, hydroxyl or methoxyl group, perhaps R²³With R '²³Represent together oxo, work as R²⁴R ' while being not oxo²⁴For hydrogen, and work as R²⁴R ' during for oxo²⁴Do not exist; A is carbon atom or nitrogen-atoms; And when A is carbon atom, R²⁵Be selected from hydrogen, hydroxyl and halogen; And R²⁴Be selected from hydrogen, halogen, hydroxyl, low alkyl group, methylene and oxo, perhaps R²⁵With R²⁴Represent between R together²⁴And R²⁵Additional key between place's carbon atom; R’²⁵Be selected from low alkyl group, trifluoromethyl and C₃-C ₆Cycloalkyl; R”²⁵Be selected from low alkyl group, hydroxyl (low alkyl group), contain the halo of three halogen atoms (low alkyl group) at the most, methoxy, acetoxy-methyl, and C₃-C ₆-cycloalkyl, perhaps R '²⁵And R "²⁵Form C together with their connected carbon atoms₃-C ₆Cycloalkyl ring; And when A is nitrogen-atoms, R²⁵Represent a pair of not share electron pair; And R²⁴Be selected from hydrogen, hydroxyl, low alkyl group, cyano group and oxo; And R '²⁵And R "²⁵Be low alkyl group or C independently₃-C ₆Cycloalkyl; Perhaps R²²For phenyl, toluyl groups, hydroxy phenyl, cyclopenta, cyclohexyl, isobutyl group or cyclohexyloxy carbonyl methyl.

8. according to the compound of last claim, wherein said compound is each described any compound among the claim 2-4.

9. the application of above-mentioned formula I b compound in preparation meiosis regulating medicine.

10. above-mentioned formula I b compound is used for the treatment of Mammals in preparation, the application in the medicine of preferred people's's (male and female) Infertility.

11. above-mentioned formula I b compound is in preparation contraceptive bian, the application of preferred (male and female) human contraceptive bian aspect.

12. above-mentioned formula I b compound is also containing the Mammals sexual cell, the application in the fertilization substratum of preferred people's cell.

13. according to the application of aforementioned each claim, wherein said compound is each described arbitrary compound among the claim 2-4.

14. the maiotic method of regulation and control, this method comprises that the curee to this regulation and control of needs uses the above-mentioned formula I b compound of significant quantity.

15. maiotic method in the regulation and control Mammals sexual cell, this method comprises the above-mentioned formula I b compound of using significant quantity to the sexual cell of this treatment of needs.

16. one kind by with above-mentioned formula I b compound administration in the Mammals that has described cell and to the method for sexual cell administration.

17. according to each method in the aforementioned claim, wherein will regulate and control maiotic sexual cell is ovocyte.

18., wherein ovocyte is exsomatized or the external formula I b compound of using according to each method in the preceding method claim.

19. according to each method in the preceding method claim, wherein will regulate and control maiotic sexual cell is male sex-cell.

20. according to each method in the preceding method claim, wherein by in the body, exsomatize or the external compound that testis tissue is used above-mentioned formula I b produces sophisticated male sex-cell.

21. according to each method in the preceding method claim, wherein said compound is each described arbitrary compound among the claim 2-4.

22. any new feature of the present invention or these combination of features.