CN1368977A - Unsaturated cholestane derivatives and their use for preparation of meiosis regulating medicaments - Google Patents
Unsaturated cholestane derivatives and their use for preparation of meiosis regulating medicaments Download PDFInfo
- Publication number
- CN1368977A CN1368977A CN00803662A CN00803662A CN1368977A CN 1368977 A CN1368977 A CN 1368977A CN 00803662 A CN00803662 A CN 00803662A CN 00803662 A CN00803662 A CN 00803662A CN 1368977 A CN1368977 A CN 1368977A
- Authority
- CN
- China
- Prior art keywords
- cholestane
- dimethyl
- diene
- hydrogen atom
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001837 cholestane derivatives Chemical class 0.000 title abstract description 7
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- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Reproductive Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmacology & Pharmacy (AREA)
- Endocrinology (AREA)
- Animal Behavior & Ethology (AREA)
- Gynecology & Obstetrics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to pharmaceutically active unsaturated cholestane derivatives, to pharmaceutical compositions comprising them as active substances and to the use of these novel compounds for the preparation of medicaments. More particularly it has been found that the unsaturated cholestane derivatives of the invention can be used for regulating meiosis.
Description
The present invention relates to the unsaturated cholestane derivative of pharmaceutical activity, comprise the pharmaceutical composition of these derivatives as active substance, and the application of these new compounds in the preparation medicine.More specifically, found that unsaturated cholestane derivative of the present invention can be used for regulating reduction division.
Reduction division is the unique of sexual cell and is final process.Reduction division comprises two reduction division processes.In first fission process, carry out the exchange between maternal gene and the male parent's gene earlier, karyomit(e) is to splitting into two daughter cells then.These cells only comprise half of karyomit(e) and 2c DNA quantity (1n).Second reduction division process do not relate to DNA and synthesizes.Therefore, this fission process causes only having the single times of sexual cell of 1c DNA to form.
The reduction division process is similarly in male and female sexual cell, but the atomization of time-program(me) and formation ovum and sperm has very large difference.Early stage at life, usually before birth, all female sexual cell all enter the early stage of first reduction division process, but all cells subsequently in this early stage all the form with ovocyte stop (dictyate state), after pubescence, begin the ovulation.Like this, early stage from life, female just had the ovocyte deposit, and use to this deposit and exhaust.Reduction division in female is just finished at after fertilization, and each sexual cell only produces an ovum and two miscarriage polar bodys.On the contrary, some in the male sex-cell only enter reduction division after pubescence, and form cadres and masses (stem population) sexual cell in whole vital process.Once you begin, the reduction division in the male cell will be less than significantly lingeringly carrying out, and produce 4 sperms.
Only know seldom for the mechanism that the male and female middle reduction division of control starts.In ovocyte, new studies show that ovarian follicle purine, xanthoglobulin or VITAMIN B4 might be reason (Downs, people such as S.M., Dev Biol 82 (1985) 454-458 that reduction division stops; Epplg.J.J. wait the people, Dev Biol 119 (1986) 313-312; And Downs, S.M., Mol Reprod Dev35 (1993) 82-94).People such as Byskov have described first and had diffustivity meiosis regulation material (Byskov, people such as A.G., Dev Biol 52 (1976) 193-200) in the culture systems of mouse embryo sexual gland.Meiosis activating material (MAS) is being by wherein just carrying out maiotic mouse embryo ovarian secretion, and prevents that maiotic material (MPS) from stopping and ameiotic sexual cell, take place that the testis of form differentiation discharges by having.This relative concentration that shows MAS and MPS is regulated maiotic beginning in male and the female sexual cell, stops and restarting (Byskov, A.G. wait the people, at The Physiology of Reproduction[Knobil, E. and Neil, J.D. edit] in, Raven Press, New York (1994)).Know clearly, if can regulate reduction division, then may command breeding.(Nature 374 (1995) for Byskov, people such as A.G., 559-562) are described to the sterol that can divide some activation Oocyte Meiosis from bull testis and hFF for one piece of nearest article.Regrettably, these sterols are very unstable.Thereby, if can access more stable meiosis activating compound, then can use this interesting discovery easily.
Can stimulate reduction division and the known compound different to be described among the WO 96/27658 with the present patent application claimed compounds.
The purpose of this invention is to provide and be used for treating male and female, the compound of people's infertility particularly by activation reduction division.
A further object of the present invention provide can by suppress reduction division female and male, particularly among the people as the novel cpd of contraceptive bian.
According to the present invention, novel, the stable compound that is provided has interesting pharmacological properties.Particularly, compound described herein can be used for regulating the reduction division in ovocyte and the male sex-cell.
Another purpose of the present invention provides novel compound, and this compound is suitable substrate for introducing fluorescent marker.Molecule through connecting can design and synthesize, and is used for the purpose of bio-imaging.
The present invention relates to unsaturated cholestane derivative or its ester of general formula I:
Wherein: R
1Represent hydrogen atom, C
2-C
6Alkyl, optional phenyl, cyano group, the CH that is substituted
2-NH-COR
1 ', R wherein
1 'Be C
1-C
8Alkyl or the optional phenyl that is substituted are perhaps with R
2
Form another key together; R
2Represent hydrogen atom, C
4-C
8Alkyl, C
3-C
6Thiazolinyl, C
1-C
6Hydroxyalkyl is with R
2 'One
Work forming the optional benzylidene that replaces, with R
2 'Form the hydroxyl methylene radical together, perhaps with R
1
Form another key together; R
2 'Represent hydrogen atom, with R
2Form the optional benzylidene that replaces together, perhaps with R
2Form together
The hydroxyl methylene radical; R
3Represent hydrogen atom or and R
3 'Form another key together; R
3 'Represent hydrogen atom or and R
3Form another key together; R
4Represent hydrogen atom or methyl; R
4 'Represent hydrogen atom or methyl; R
8With R
9Perhaps with R
14Form another key together; R
9Represent hydrogen atom or and R
8Form another key together; R
14Represent α-hydrogen atom or and R
8Form another key together, perhaps with R
15Form together
Another key; R
15Represent hydrogen atom or and R
14Form another key together; R
24Represent hydrogen atom or and R
25Form another key together; R
25Represent hydrogen atom or and R
24Form another key together.
Its condition is to be not included in 1 and 2 not adorned compound R of while
1=R
2=R
2 '=H.
The compound of general formula I has a plurality of chiral centres in molecule, and thereby has several isomeric forms.All these isomeric forms and their mixture be (except as otherwise noted) all within the scope of the invention.
Preferred compound of formula I is wherein: R
1Represent hydrogen atom, phenyl or and R
2Form another key together.Other preferred compounds are wherein: R
2Represent C
4-C
8Alkyl, allyl group or and R
1Form another key.R wherein
2And R
2 'The compound of the optional benzylidene that replaces of representative also is preferred.
In another embodiment, the present invention relates to the ester of compound of Formula I.These esters form with one or more hydroxyls of acid esters compound of Formula I, and described acid for example is selected from following group: succsinic acid and other aliphatic dicarboxylic acids, 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.
Employed alkyl can be the straight or branched alkyl when being used alone or in combination in the present invention's specification sheets and claims.C
2-C
6Alkyl is meant the alkyl with 2-6 carbon atom, and preferred example is ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl and cyclohexyl, more preferably ethyl.Similarly, C
1-C
8Alkyl is meant the alkyl with 1-8 carbon atom, its preferred example is methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl and octyl group, being more preferably methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl, most preferably is methyl and ethyl.
The especially preferably following compound of formula I compound of the present invention: 2 α-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, (E)-and 2-benzylidene-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, 5 α-cholestane-1,8,14-triolefin-3 β-alcohol, 5 α-cholestane-1,8,14-triolefin-3-ketone, 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone, 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3 β-alcohol, 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3-ketone, (E)-4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile; (E)-and N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl] decoylamide; (E)-and N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl]-5-(4,4-two fluoro-5,7-dimethyl-4-boron-3a, 4a-diaza-s-indacen-3-yl) valeramide; 2 alpha-hydroxymethyls-4,4-dimethyl-5 α-cholestane-8,14-diene-3 α-alcohol, 2 α-octyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, and (E)-4-[(3-oxo-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile.
The preparation method that compound of Formula I of the present invention can be similar to known compound prepares.Therefore, the synthetic of formula I compound can be followed the known synthesis path of having described in numerous sterols and the steroidal document.In synthetic, can use following books as crucial reference: L.F.Fieser ﹠amp; M.Fieser:Steroids:Reinhold Publishing Corporation, NY 1959; Rod ' s Chemistry ofCarbon Compounds (editor: S.Coffery): Elsevier Publishing Company, 1971; Particularly Dictionary of Steroids (edits: R.A.Hill; D.N.Kirk; H.L.J.Makin and G.M.Murphy:Chapman ﹠amp; Hall.Index list in last this book has comprised the original papers of going up to 1990.
Particularly, compound of the present invention synthesizes according to some total methods:
Sterol as initiator can synthesize according to the method in the document: 4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, 4,4-dimethyl-5 α-courage steroid-8-alkene-3 β-alcohol, 4,4-dimethyl-5 α-courage steroid-8 (14)-alkene-3 β-alcohol (Biochem.J.132 (1973), 439), 4,4-dimethyl-5 α-cholestane-8,24-diene-3 β-alcohol, 4,4-dimethyl-5 α-cholestane-8,14,24-triolefin-3 β-alcohol (J.Am.Chem.Soc.111 (1989), 278), 5 α-cholestane-8,14-diene-3 β-alcohol (J.Am.Chem.Soc.75 (1953), 4404), 5 α-courage steroid-8-alkene-3 β-alcohol (J.Org.Chem.46 (1981), 3421), and 5 α-courage steroid-8 (14)-alkene-3 β-alcohol (Biochem.J.144 (1974), 59).
Below will describe 4 in detail, 4-dimethyl-Δ-8,14-series synthetic.Can synthesize by corresponding initiator according to identical mode and to have or do not have 4,4-dimethylated Δ-8, Δ-8 (14), Δ-8,14,24 and Δ-8, the derivative in the 24-series.
With different reagent oxidation 3 β-alcohol, form corresponding 3-ketone (for example, TetrahedronLett.1967,3699).4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol (1) are used N-methyl-morpholine-N-oxide process when Tetrapropyl ammonium perruthenate exists, form 4,4-dimethyl-5 α-cholestane-8, the 14-diene-3-ketone (2) is (for example, Synthesis 1994,639).Synthetic route 1
In following-step, in chlorobenzene, as oxygenant, in oxidizing reaction, introduce Δ-1 pair key (J.Chem Soc.Chem.Commun.1978,952) with the phenyl selenic anhydride, form 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3-ketone (3).Do not have 4 if use, the dimethylated compound of 4-, this reaction also can be carried out.In these compounds, new two keys can Δ 1-the form of two keys optionally introduce.The 3-ketone group can form 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3 β-alcohol (4) with sodium borohydride reduction (Luche reduction reaction, for example: J.Am.Chem.Soc.100 (1978), 2226) when Cerium II Chloride exists then.
By in beta-unsaturated ketone, adding the copper acid esters, can locate to introduce alkyl and aryl (Tetrahedron Lett.35 (1994), 8591) at 1.Copper acid esters and the reaction of steroidal ketenes by alkyl or aryl lithium and cuprous iodide form form the 1-substitutive derivative.If ketenes (3) is handled with dialkyl group copper acid esters, then can obtain the compound (R of formula (5)
1=alkyl, aryl).These ketone can form two diastereomer alcohol (6) and (7) (R according to known literature method reduction then
1=alkyl, aryl), but they are by the chromatography separate easily.Synthetic route 2
Can introduce cyano group according to similar method.In ketenes (3),, form desirable 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone (5) (R in conjunction with the addition prussiate
1=CN).In this reaction, can use different reagent, for example diethyl cyaniding aluminium (J.Org.Chem.59 (1994), 2766) and some basic metal and alkaline-earth metal (Tetrahedron Lett.28 (1987), 4189; Can.J.Chem.59 (1981), 1641).Cyano group ketone (5) (R
1=CN) also available standards reductive agent such as sodium borohydride reduction forms two diastereomer alcohol (6) and (7) (R
1=CN), but they are by the chromatography separate easily.
If cyano group alcohol (6) (R
1=CN as above synthesizes) handle with lithium aluminum hydride, then can obtain 1 α-aminomethyl-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol (8).This amine can be used for further modification.Acid amides (the R of formula (9)
1 '=alkyl, aryl and fluorescent marker) can come synthetic by the N-Hydroxysuccinimide base ester reaction of described amine and various alkyl or aryl carboxylic acids.(can reference when use comprises the carboxylic acid N-Hydroxysuccinimide base ester of fluorescent marker: Nonradioactive labeling and detection of biomolecules, Kessler C. edits, Springer Verlag, Berlin, 1992).Synthetic route 3
2 substituting group can for example be introduced by reaction of 3-acetaldol and alkylated reaction.If ketone (2) is handled with aromatic aldehyde, then can obtain the steroidal of the 2-benzylidene replacement of formula (10) when alkali exists.Aromatic nucleus can replace.In the presence of Cerium II Chloride, reduce subsequently, optionally form corresponding allyl group 3 β-alcohol (11) with sodium borohydride.Synthetic route 4
Can be as implied above compound (the 11) (R that replaces of synthetic cyano group benzylidene
2 "=4-CN) can be used for further modification.This cyano group can be reduced to benzyl amine (12) with lithium aluminum hydride, the corresponding amides (R of its accepted way of doing sth (13) of can deriving
2 =alkyl, aryl and fluorescent marker).For this purpose, amine (12) is handled with the N-Hydroxysuccinimide base ester derivative of different carboxylic acids.For this reaction, can use the commercially available ester (embodiment 11 in the reference example part) that comprises fluorescent marker.The acid amides that comprises the formula (13) of fluorescent marker can be used as the molecular probe that is used for bio-imaging.Synthetic route 5
Alkyl-and alkenyl group can followingly be introduced on 2: make ketone (2) deprotonation, make then enolate and alkyl-and thiazolinyl halogen react.The available then sodium borohydride reduction of the 3-ketone of formula (14) forms two diastereomer alcohol (15) and (16), but they are by the chromatography separate easily.Synthetic route 6
2 methylol substituting group for example can be introduced by the 3-ketone of deprotonation and the condensation reaction of alkyl formate ester, forms enol (17).It forms two diastereomer alcohol (18) and (19) with different reductive agents such as sodium borohydride reduction.Synthetic route 7
These alcohol can easily separate on column chromatography.By aforesaid alkylated reaction (seeing synthetic route 6), can for example introduce the more hydroxyalkyl substituting group of long-chain.
A further object of the present invention provides and comprises the pharmaceutical composition of one or more compound of Formula I as active substance.These pharmaceutical compositions can further comprise acceptable on the pharmacology, well known by persons skilled in the art vehicle, as carrier, thinner, absorption enhancer, sanitas, buffer reagent, osmotic pressure regulator, tablet disintegrant and be generally used for other compositions in this area.The example of solid carrier is magnesiumcarbonate, Magnesium Stearate, glucose, lactose, sucrose, talcum, gelatin, pectin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax and theobroma oil.
Liquid composition comprises sterile solution, suspension and emulsion.These liquid compositions are applicable to injection or be used in vitro reaching in vitro fertilization.Liquid composition can comprise normally used other compositions in this area, and some of them as mentioned above.In addition, the form of can medicine pasting is provided for the composition of percutaneous dosing The compounds of this invention, and is provided for the composition of intranasal administration with the form of liquid or powder nasal mist.
The using dosage of The compounds of this invention can be definite by the doctor, and depend on multiple factor, as employed particular compound, route of administration and application target.Generally, composition of the present invention is prepared as follows: making active compound and liquid or solid ancillary component thorough mixing, then if necessary, is desirable formulation with formed product.
The compound that the present invention relates to general formula I is regulated being used in the maiotic medicine in preparation.Reduction division in compounds affect ovocyte of the present invention and the male sex-cell.It is many-sided can influencing maiotic prospect.According to the preferred embodiments of the invention, the compound of general formula I can be used for stimulating reduction division.According to another preferred embodiment of the present invention, the compound of general formula I can be used for stimulating people's reduction division.Therefore, the compound of general formula I can be used as novel fertility conditioning agent, and does not have present used contraceptive to somatic common adverse effect, and present contraceptive is based on oestrogenic hormon and/or progestogen.
Therefore, the present invention relates to the application of compound of Formula I in alleviating infertility female and male, particularly Mammals, especially people.Can not form the female of mature oocyte by delivering medicine to owing to self produce meiosis activating material deficiency, comprise the women, the reduction division inductive substance of general formula I can be used for treating the infertility among them.
The compound of general formula I also can be used for the artificial insemination program, the interior sperm injection of for example in vitro fertilization or kytoplasm.When carrying out when in vitro fertilization,, can reach better result if in the substratum of cultivating ovocyte, add compound of the present invention.When self meiosis activating material produces not enough and makes the male generation that comprises the male sex sterile, and when lacking the The mature sperm cell thus, administration compound of the present invention can be alleviated this problem.
Of the present invention aspect another in, that the compound of general formula I can be used as is female and male, Mammals, especially people's contraceptive particularly.When in female, being used as contraceptive, but administration reduction division inductive substance so that when ovocyte still is in the ovarian follicle of growth, before the ovulation peak that gonad-stimulating hormone takes place, the ovocyte mid-early maturity induce reduction division to restart.In the women, for example after a preceding ischomenia, a week induce maiotic restarting.When ovulation, the postmature ovocyte that is produced may be fertilized least.Normal menstrual cycle can not be affected.In this regard, be important to note that, the existence of reduction division inductive substance does not influence the biosynthesizing of progesterone in people's granulosa cell (somatocyte of ovarian follicle) through cultivating, yet the oestrogenic hormon and the progestogen that are used as hormonal contraceptive at present but can have a negative impact to the biosynthesizing of progesterone.
As the method for substitution of aforesaid method, administration can suppress maiotic The compounds of this invention, also can realize contraception in female, and making does not have mature oocyte to produce.Similarly, administration can suppress maiotic The compounds of this invention, can realize contraception in male, and making does not have the mature sperm cell to form.
In one aspect of the method, the present invention relates to compound of Formula I and be used for the application of synthesising biological imaging with the initiator of instrument material as instrument material or conduct, described instrument material is the binding mode that is used to differentiate described material.For example, the meiosis activating sterols that comprises fluorescent marker can be used for making active substance to develop in the chamber of the grown cell of wherein bringing into play biological function.This information can help to differentiate the binding mode of described material.
In yet another aspect, the present invention relates to regulate maiotic method, it comprises one or more compound of Formula I to the acceptor effective dosage of these regulating effects of needs.
In yet another aspect, the present invention relates to regulate the maiotic method in the Mammals sexual cell, it comprises to the sexual cell of these regulating effects of needs in vitro or one or more compound of Formula I of treated in vitro significant quantity.Sexual cell can be ovocyte or male sex-cell.
The route of administration that comprises the composition of The compounds of this invention can be any approach that effectively active compound is transported to the site of action place.
Therefore, with compound administration of the present invention during in Mammals, it normally provides with the form that comprises the pharmaceutical composition of acceptable carrier at least a compound of the present invention and the pharmacology.When orally using, these compositions are preferably capsule or tablet.
Be appreciated that by above description needed dosage regimen will depend on illness to be treated.Therefore,, can only be administered once being used for the treatment of when sterile, perhaps administration in the limited time, for example conceived until realizing.
When the contraceptive bian, compound of the present invention can be continuously or periodically administration.When being used as female contraceptive bian and being not successive administration, be important with respect to the administration time of ovulating.
To further describe the present invention by following examples.Embodiment 1:4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3-ketone a) 4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone
At 4 of 6.40g, 4-dimethyl-5 α-cholestane-8 adds several particulate molecular sieves in N-methyl-morpholine of the 14-diene-3 β-pure and mild 4.03g-solution of N-oxide compound in the 32ml methylene dichloride, stirred the mixture then 5 minutes.At room temperature add the Tetrapropyl ammonium perruthenate of 408mg, and stir the black reaction mixture 1 hour of gained.After filtering on the celite, evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ethyl acetate, obtains 4 of 5.60g white solid, 4-dimethyl-5 α-cholestane-8,14-diene-3-ketone.
1H-NMR (CDCl
3): δ=0.83 (s, 3H, H-18); 0.87 (2x d, J=7Hz, 6H, H-26/27); 0.94 (d, J=7Hz, 3H, H-21); 1.07 (s, 3H); 1.12 (2x s, 6H); 2.55 (m, 2H); (5.41 s, 1H, H-15) b) 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3-ketone
Phenyl selenic anhydride with 1.75g under room temperature is added on 4 of 2.00g, and 4-dimethyl-5 α-cholestane-8 is in the 14-diene-solution of 3-ketone in the 30ml chlorobenzene.With reaction mixture be warmed to 100 ℃ totally 2 hours.Behind cooling and the evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ethyl acetate, obtains 0.85g buttery 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3-ketone.
1H-NMR (CDCl
3): δ=0.84 (s, 3H, H-18), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.96 (d, J=7Hz, 3H, H-21), 1.11 (s, 3H), 1.18 (s, 3H), 1.25 (s, 3H), 5.45 (s, 1H, H-15), 5.95 (d, J=10Hz, 1H, H-2), 7.33 (d, J=10Hz, 1H, H-1) embodiment 2:4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3 β-alcohol
At room temperature the sodium borohydride with 14mg is added on 4 of 73mg, and 4-dimethyl-5 α-cholestane-1,8 is in 14-triolefin-3-ketone and the suspension of 67mg seven water Cerium II Chlorides in methyl alcohol.Mixture stirred 4 hours, was poured in the water, used extracted with diethyl ether then.Separate organic layer, use the salt water washing, dry on anhydrous sodium sulphate, filter then.Behind the evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ether, obtains 4 of 43mg white solid, 4-dimethyl-5 α-cholestane-1,8,14-triolefin-3 β-alcohol.
1H-NMR (CDCl
3): δ=0.82 (s, 3H), 0.85 (s, 3H), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.96 (d, J=7Hz, 3H, H-21), 1.02 (s, 3H), 1.10 (s, 3H), 3.89 (m, 1H, H-3), 5.37 (s, 1H, H-15), 5.50 (dd, J=10Hz, 1Hz, 1H, H-1), 5.90 (d, J=10Hz, 2Hz, 1H, H-2) embodiment 3:5 α-cholestane-1,8,14-triolefin-3 β-pure a) 5 α-cholestane-8,14-diene-3 β-alcohol
As described in embodiment 1a, 5 α of 2.40g-cholestane-8,14-diene-3 β-alcohol is handled in the 13ml methylene dichloride with N-methyl-morpholine-N-oxide compound and the 111mg Tetrapropyl ammonium perruthenate of 1.11g.After the chromatographic separation, obtain the 5 α-cholestane-8 of white solid, 14-diene-3-ketone 1.81g.
1H-NMR (CDCl
3): δ=0.82 (s, 3H, H-18), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.94 (d, J=7Hz, 3H, H-21), 1.18 (s, 3H, H-19), 5.39 (s, 1H, H-15) b) 5 α-cholestane-1,8,14-triolefin-3-ketone
As described in embodiment 1b, 5 α of 1.81g-cholestane-8,14-diene-3-ketone is handled in the 29ml chlorobenzene with the phenyl selenic anhydride of 1.67g.After the chromatographic separation, obtain 0.53g buttery 5 α-cholestane-1,8,14-triolefin-3-ketone.
1H-NMR (CDCl
3): δ=0.84 (s, 3H, H-18), 0.86 (2x d, J=7Hz, 6H, H-26/27), 0.96 (d, J=7Hz, 3H, H-21), 1.20 (s, 3H, H-19), 5.43 (s, 1H, H-15), 5.91 (d, J=10Hz, 1H, H-2), 7.42 (d, J=10Hz, 1H, H-1) c) 5 α-cholestane-1,8,14-triolefin-3 β-alcohol
As described in embodiment 2,5 α of 150mg-cholestane-1,8,14-triolefin-3-ketone is handled with the sodium borohydride of 15mg and the seven water Cerium II Chlorides of 147mg.Obtain the 5 α-cholestane-1,8 of white solid after the chromatographic separation, 14-triolefin-3 β-pure 47mg.
1H-NMR (CDCl
3): δ=0.82 (s, 3H, H-18), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.95 (d, J=7Hz, 3H, H-21), 1.07 (s, 3H, H-19), 4.33 (m, 1H, H-3), 5.37 (s, 1H, H-15), 5.56 (dd, J=10Hz, 1Hz, 1H, H-1), 6.09 (d, J=10Hz, 1H, H-2) embodiment 4:1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone
Diethyl cyaniding aluminum solutions (1M is in toluene) with 1.47ml under 0 ℃ is added on 4, and 4-dimethyl-5 α-cholestane-1,8 is in the 14-triolefin-solution of 3-ketone in the 5ml tetrahydrofuran (THF).Reaction mixture is warmed to room temperature, stirs then 1 hour.After adding the sodium hydroxide solution (1M) of 2.45ml under 0 ℃, dilute with water gained mixture is used extracted with diethyl ether then.Separate organic layer, use the salt water washing, dry on anhydrous sodium sulphate, filter then.Behind the evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ethyl acetate, obtains 1 alpha-cyano-4 of white solid, 4-dimethyl-5 α-cholestane-8,14-diene-3-ketone 110mg.
1H-NMR (CDCl
3): δ=0.86 (2x d, J=7Hz, 6H, H-26/27), 0.89 (s, 3H), 0.94 (d, J=7Hz, 3H, H-21), 1.12 (s, 3H), 1.15 (s, 3H), 1.20 (s, 3H), 2.86 (m, 1H, H-2), 3.29 (dd, J=7Hz, 5Hz, 1H, H-1), 5.49 (ps, 1H, H-15) embodiment 5:1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-pure and mild 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3 α-alcohol
As described in embodiment 5,1 alpha-cyano-4 of 95mg, 4-dimethyl-5 α-cholestane-8,14-diene-3-ketone is handled with the sodium borohydride of 33mg, obtain 1 alpha-cyano-4 of 30mg, 4-dimethyl-5 α-cholestane-8,1 alpha-cyano-4 of 14-diene-3 α-pure and mild 25mg, 4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol.1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol
1H-NMR (CDCl
3): δ=0.83 (s, 3H), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.94 (d, J=7Hz, 3H, H-21), 1.09 (s, 3H), 1.17 (s, 3H), 3.08 (m, 1H, H-1), 3.72 (bm, 1H, H-3), 5.43 (ps, 1H, H-15) 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3 α-alcohol
1H-NMR (CDCl
3): δ=0.87 (2x d, J=7Hz, 6H, H-26/27), 0.91 (s, 3H), 0.93 (d, J=7Hz, 3H, H-21), 1.08 (s, 3H), 1.15 (s, 3H), 1.28 (s, 3H), 2.92 (m, 1H, H-1), 3.57 (ps, 1H, H-3), 5.44 (ps, 1H, H-15) embodiment 6:(E)-4-[(3-oxo-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile
The 4-cyanobenzaldehyde of 64mg and the hanging drop of potassium hydroxide in 2ml ethanol of 27mg are added in 4, and 4-dimethyl-cholestane-8 is in the 14-diene-suspension of 3-ketone in 4ml ethanol.Reaction mixture stirred 20 hours, and dilute with water is used dichloromethane extraction then.Separate organic layer, use the salt water washing, dry on anhydrous sodium sulphate, filter then.Behind the evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ethyl acetate, obtains (E)-4-[(3-oxo-4 of 168mg white solid, 4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile.
1H-NMR (CDCl
3): δ=0.83 (s, 3H), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.93 (d, J=7Hz, 3H, H-21), 0.98 (s, 3H), 1.16 (s, 3H), 1.23 (s, 3H), 2.58 (d, J=17Hz, 1H, H-1), 3.10 (d, J=17Hz, 1H, H-1), 5.47 (ps, 1H, H-15), 7.42 (s, 1H, H-2 '), 7.53 (d, J=8Hz, 2H, fragrance), 7.68 (d, J=8Hz, 2H, fragrance) embodiment 7:(E)-4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile
As described in embodiment 2, (E)-4-[(3-oxo-4 of 156mg, 4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-and methyl] benzonitrile handles with the sodium borohydride of 12mg in the presence of 111mg seven water Cerium II Chlorides, form (E)-4-[(3 beta-hydroxy-4 of 93mg white solid, 4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile.
1H-NMR (CDCl
3): δ=0.75 (s, 3H), 0.80 (s, 3H) .0.85 (s, 3H), 0.87 (2xd, J=7Hz, 6H, H-26/27), 0.92 (d, J=7Hz, 3H, H-21), 1.18 (s, 3H), 3.02 (d, J=17Hz, 1H, H-1), 3.94 (m, 1H, H-3), 5.40 (ps, 1H, H-15), 6.78 (s, 1H, H-2 '), (7.37 d, J=8Hz, 2H, fragrance), (7.64 d, J=8Hz, 2H, fragrance) embodiment 8:(E)-N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-and methyl] phenyl] methyl] a) (E)-2-(4-amino methyl-phenyl)-methylene radical-4 of decoylamide, 4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol
Make the lithium aluminum hydride of 27mg and (E)-4-[(3 beta-hydroxy-4 of 74mg, 4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile refluxed 4 hours in the tetrahydrofuran (THF) of 6ml.After the cooling, as reaction mixture as described in the embodiment 3b.Use the ethyl acetate crystallization, obtain (E)-2-(4-amino methyl-phenyl)-methylene radical-4 of 26mg white solid, 4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol.
1H-NMR (CDCl
3): δ=0.77 (s, 3H), 0.82 (s, 3H), 0.86 (2x d, J=7Hz, 6H, H-26/27), 0.89 (s, 3H), 0.92 (d, J=7Hz, 3H, H-21), 1.18 (s, 3H), 3.15 (d, J=17Hz, 1H, H-1), 3.86 (s, 2H, Ar-CH
2-N), 3.92 (ps, 1H, H-3), 5.38 (ps, 1H, H-15), 6.72 (s, 1H, H-2 '), 7.26 (m, 4H, fragrance) b) (E)-and N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl] decoylamide
The solution of N-hydroxy-succinamide base octanoate in the 1ml dimethyl formamide of 8.6mg is added into 21mg (E)-2-(4-amino methyl-phenyl)-methylene radical-4 under room temperature, 4-dimethyl-5 α-cholestane-8 is in the 14-diene-3 β-solution of alcohol in the 4ml dimethyl formamide.Reaction mixture stirred 20 hours, and dilute with water is used ethyl acetate extraction then.
Separate organic layer, wash with water, dry on anhydrous sodium sulphate, filter then.Obtain (E)-N-[[4-[(3 beta-hydroxy-4 of 21mg white solid behind the evaporating solvent, 4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl] decoylamide.
1H-NMR (CDCl
3): δ=0.77 (s, 3H), 0.82 (s, 3H), 0.86 (2x d, J=7Hz, 6H, H-26/27), 0.89 (s, 3H), 0.92 (d, J=7Hz, 3H, H-21), 1.18 (s, 3H), 3.12 (d, J=17Hz, 1H, H-1), 3.92 (ps, 1H, H-3), 4.44 (d, J=5Hz, 2H, Ar-CH
2-N), 5.37 (ps, 1H, H-15), 5.76 (t, J=5Hz, 1H, NH), 6.72 (s, 1H, H-2 '), 7.24 (m, 4H, fragrance) embodiment 9:(E)-and N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl]-5-(4,4-two fluoro-5,7-dimethyl-4-boron-3a, 4a-diaza-s-indacen-3-yl) valeramide
5.0mg 5-(4,4-two fluoro-5,7-dimethyl-4-boron-3a, 4a-diaza-s-indacen-3-yl) solution of valeric acid succinimido ester in the 0.5ml dimethyl formamide is added into (E)-2-(4-amino methyl-phenyl)-methylene radical-4 of 8.9g under room temperature, 4-dimethyl-5 α-cholestane-8 is in the 14-diene-3 β-solution of alcohol in the 2ml dimethyl formamide.Reaction mixture stirred 44 hours, and dilute with water is used ethyl acetate extraction then.Separate organic layer, wash with water, dry on anhydrous sodium sulphate, filter then.Behind the evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ethyl acetate, obtain (E)-N-[[4-[(3 beta-hydroxy-4 of 6.5mg, 4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-and methyl] phenyl] methyl]-5-(4,4-two fluoro-5,7-dimethyl-4-boron-3a, 4a-diaza-s-indacen-3-yl) valeramide.
1H-NMR (CDCl
3): δ=0.77 (s, 3H), 0.82 (s, 3H), 0.86 (2x d, J=7Hz, 6H, H-26/27), 0.89 (s, 3H), 0.92 (d, J=7Hz, 3H, H-21), 1.19 (s, 3H), 2.25 (s, 3H, Ar-Me), 2.55 (s, 3H, Ar-Me), 3.12 (d, J=17Hz, 1H, H-1), 3.92 (ps, 1H, H-3), 4.44 (d, J=5Hz, 2H, Ar-CH
2-N), 5.37 (ps, 1H, H-15), 5.87 (m, 1H, NH), 6.09 (s, 1H, fragrance), (6.30 d, J=5Hz, 1H, fragrance), 6.70 (s, 1H, H-2 '), 6.90 (d, J=5Hz, 1H, fragrance), 7.24 (m, 4H, fragrance) embodiment 10:2 α-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-pure a) 2 α-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone
Under-70 ℃ with 4 of 200mg, 4-dimethyl-5 α-cholestane-8, the 14-diene-drips of solution of 3-ketone in the THF of 3ml be added in new system LDA solution (5.8ml, 1M) in.Solution stirring 1 hour is added the 3-iodo-propylene of 0.07ml then., reaction mixture is poured in the saturated ammonium chloride solution, and uses ethyl acetate extraction after 1 hour at 0 ℃ of following restir.Separate organic layer, use the salt water washing, dry on anhydrous sodium sulphate, filter then.Behind the evaporating solvent, residue carries out chromatographic separation with the mixture of hexane and ethyl acetate, obtains the 2 α-allyl group-4 of 160mg white solid, 4-dimethyl-5 α-cholestane-8,14-diene-3-ketone.
1H-NMR (CDCl
3): δ=0.82 (s, 3H), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.93 (d, J=7Hz, 3H, H-21), 1.10 (2x s, 6H), 1.30 (s, 3H), 2.60 (m, 1H, allyl group), 2.77 (m, 1H, allyl groups), 5.05 (m, 2H, allyl group), 5.38 (ps, 1H, H-15), 2 α-allyl group-4 (5.80 m, 1H, allyl group) b), 4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol
As described in embodiment 5,2 α of 160mg-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone is handled with the sodium borohydride of 55mg, obtains 2 α-allyl group-4 of 15mg, 4-dimethyl-5 α-cholestane-8,2 α-allyl group-4 of 14-diene-3 α-pure and mild 80mg, 4-dimethyl-5 α-cholestane-8,14-diene-3 β-pure 2 α-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol
1H-NMR (CDCl
3): δ=0.81 (s, 3H), 0.85 (s, 3H), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.94 (d, J=7Hz, 3H, H-21), 1.03 (s, 3H), 1.05 (s, 3H), 2.50 (m, 1H), 2.95 (d, J=11Hz, 1H, H-3), 5.06 (m, 2H, allyl group), 5.37 (ps, 1H, H-15), (5.89 m, 1H, allyl group) 2 α-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 α-alcohol
1H-NMR (CDCl
3): δ=0.82 (s, 3H), 0.87 (2x d, J=7Hz, 6H, H-26/27), 0.90 (s, 3H), 0.94 (d, J=7Hz, 3H, H-21), 1.00 (s, 3H), 1.05 (s, 3H), 3.36 (ps, 1H, H-3), 5.05 (m, 2H, allyl group), 5.35 (ps, 1H, H-15), 5.85 (m, 1H, allyl group) embodiment 11: test meiosis activating material animal in the ovocyte experiment
By immature body weight be 13-16 gram female mice (C57B1/6J * DBA/2J F1-hybridization, Bomholtgaard Denmark) obtains ovocyte, described mouse is raised under controlled illumination and temperature.Mouse is accepted gonad-stimulating hormone (Gonal F, Serono, Solna, the Sweden of peritoneal injection 0.2ml, comprise 20 IU FSH, perhaps, Puregon, Organon, Swords, Ireland comprises 20 IU FSH), by the neck dislocation animal is killed after 48 hours.The collection of ovocyte and cultivation
Separate ovary, use the manual ovarian follicle that destroys of a pair of No. 27 pins, under stereoscopic microscope, in Hx-substratum (as follows), separate ovocyte.Spheric ova nuda parent cell (NO) demonstrates complete germinal vesicle (GV), place it in α-minimum minimum medium (α-MEM, do not contain ribonucleoside, Gibco BRL, catalog number (Cat.No.) 22561) in, be added with the xanthoglobulin (Sigma of 3mM in this substratum, catalog number (Cat.No.) H-9377), human serum albumin (the HAS of 8mg/ml, State Serum Institute, Denmark), 0.23mM pyrubate (Sigma, catalog number (Cat.No.) S-8636), the glutamine of 2mM (Flow catalog number (Cat.No.) 16-801), the Streptomycin sulphate of the penicillin of 100IU/ml and 100 μ g/ml (Flow, catalog number (Cat.No.) 16-700).This substratum is called the Hx-substratum.Ovocyte drip washing 3 times in the Hx-substratum, (Nuncion cultivates in Denmark), comprises Hx-substratum and 35-45 ovocyte of 0.4ml in each hole at 4 well culture plates then.Contrast (the ovocyte 35-45 that cultivates in not adding the Hx-substratum of test compounds) carry out simultaneously with test media, and this test media has the testing compound of different concns.
At 37 ℃, 100% humidity, 5%CO
2Cultivate under the conditions of air.Incubation time is 22-24 hour.The inspection of ovocyte
After incubation period finished, the inverted microscope counting that uses stereoscopic microscope or have a differential interference phase contrast equipment had the ovocyte of germinal vesicle (GV) or germinal vesicle fragment (GVB) and the quantity with ovocyte of polar body (PB).In test media, calculate the per-cent that has the ovocyte of PB in the ovocyte per-cent that has GVB in total ovocyte quantity and the total ovocyte quantity, and compare with control medium.Embodiment 12: test reduction division inhibitory substance in the ovocyte experiment
Use the same procedure of describing as among the embodiment 11 (on seeing), by obtaining germinal vesicle (GV) ovocyte in the immature female mice of handling through FSH.The drip washing 3 times in the Hx-substratum of exposed ovocyte (NO).Shown 4 in the past, 4-dimethyl-5 α-cholestane-8,14,24-triolefin-3 β-alcohol (FF-MAS) can be at the reduction division among the external evoked NO (Byskov, people such as A.G., Nature 374 (1995) 559-562).In 4 well culture plates (Nunclon, Denmark) in NO in the Hx-substratum, cultivate, be added with the FF-MAS of 5 μ M in this substratum, and with the test compounds co-cultivation of different concns, each hole comprises Hx-substratum and 35-45 ovocyte of 0.4ml.One over against always not carrying out simultaneously with test media according to (35-45 the ovocyte of cultivating in comprising the Hx-substratum of FF-MAS wherein do not add test compounds), is added with the compound to be tested of different concns in this test media.Carry out a negative contrast (the only 35-45 that in the Hx-substratum, a cultivates ovocyte) simultaneously in addition, with over against shining.The inspection of ovocyte
After incubation period finished, the inverted microscope counting that uses stereoscopic microscope or have a differential interference phase contrast equipment had the ovocyte of germinal vesicle (GV) or germinal vesicle fragment (GVB) and the quantity with ovocyte of polar body (PB).In test media, calculate the per-cent that has the ovocyte of PB in the ovocyte per-cent that has GVB in total ovocyte quantity and the total ovocyte quantity, and compare with control medium.Embodiment 13: test meiosis activating material in " experiment in vitro fertilization "
The ovocyte (CEO) of ovocyte (NkO) that obtains exposing in the ovarian follicle by immature (C57BL/6xDBA/2) F1 mouse (21-24 days ages) and accumulation (cumulus) sealing, described mouse are accepted 10 IU Pregnant Mare serogans (FSH activity) at preceding 48 hours i.p. of collection ovocyte.
Compile ovocyte (NkO and CEO), and cultivated about 20 hours in the α-MEM substratum of improvement, described substratum comprises xanthoglobulin (Hx-substratum) and the 1mg peptide sphaeroprotein/ml substratum of 3mM.Use two groups of ovocytes: (a) contrast ovocyte, in no Hx-substratum, cultivate (positive control group), and the ovocyte of (b) in comprising the Hx-substratum of test compounds, cultivating.After about 20 hours, show ovocyte simply washing in no Hx-substratum of germinal vesicle fragment (GVB), be transferred to then in the preprepared fertilization dish, this fertilization dish comprises the active sperm preparation that is obtained by the cauda epididymidis of male mice (cauda epididymis).Described dish is at specific gas condition (5%CO
2) and 37 ℃ under in the improvement α-MEM IVF-substratum in cultivate.Checked ovocyte in after fertilization 20-22 hour, to check the fertilization situation and to write down the quantity of 2-cell stage.Measure fertilization per-cent (=rate of fertilization) with the ovocyte that is separated into the 2-cell stage with respect to total fertilization quantity.Carry out each IVF-experiment with 50-200 GVB/PB ovocyte altogether.Calculating comprises in the group of test compounds and the ratio of rate of fertilization in the control group, and calculating thus stimulates coefficient.
Table 1: maiotic activation in exposed mouse ovocyte
Hx=xanthoglobulin GV=germinal vesicle GVB=germinal vesicle fragment PB=polar body n=ovocyte quantity
| Compound | Ovocyte (n) | Activation (%) GVB+PB | ||
| ????GV | ????GVB | ????PB | ||
| Contrast (Hx) | ????39 | ????0 | ????1 | ????2.6 |
| ?10μM?FF-MA | ????5 | ????29 | ????4 | ????86.8 |
| 10 μ M 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3 β-alcohol | ????9 | ????18 | ????5 | ????71.9 |
Table 2: maiotic relative restraining effect in exposed mouse ovocyte
The Hx=xanthoglobulin, GV=germinal vesicle GVB=germinal vesicle fragment, PB=polar body n=ovocyte quantity
| Compound | Ovocyte (n) | Restraining effect (%) | ||
| ????GV | ????GVB | ????PB | ||
| Contrast (Hx) | ????34 | ????2 | ????0 | ????100 |
| 5μM?FF-MA | ????6 | ????28 | ????0 | ????0 |
| 5 μ M FF-MA+40 μ M, 1 α-cyano group-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone | ????38 | ????0 | ????0 | ????107 |
Table 3: maiotic relative restraining effect in exposed mouse ovocyte
The Hx=xanthoglobulin, GV=germinal vesicle GVB=germinal vesicle fragment, PB=polar body n=ovocyte quantity
| Compound | Ovocyte (n) | Restraining effect (%) | ||
| ????GV | ????GVB | ????PB | ||
| Contrast (Hx) | ????34 | ????2 | ????0 | ????100 |
| 5μM?FF-MA | ????6 | ????28 | ????0 | ????0 |
| 5 μ M FF-MA+10 μ M (E)-N-[[4-[(3 beta-hydroxies-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl] decoylamide | ????25 | ????13 | ????0 | ????63 |
Claims (14)
1, the compound of general formula I or its ester:
Wherein: R
1Represent hydrogen atom, C
2-C
6Alkyl, optional phenyl, cyano group, the CH that is substituted
2-NH-COR
1 ', perhaps with R
2Form another key together, wherein R
1 'Be C
1-C
8Alkyl or
The optional phenyl that is substituted; R
2Represent hydrogen atom, C
4-C
8Alkyl, C
3-C
6Thiazolinyl, C
1-C
6Hydroxyalkyl is with R
2 'One
Work forming the optional benzylidene that replaces, with R
2 'Form the hydroxyl methylene radical together, perhaps with R
1
Form another key together; R
2 'Represent hydrogen atom, with R
2Form the optional benzylidene that replaces together, perhaps with R
2Form together
The hydroxyl methylene radical; R
3Represent hydrogen atom or and R
3 'Form another key together; R
3 'Represent hydrogen atom or and R
3Form another key together; R
4Represent hydrogen atom or methyl; R
4 'Represent hydrogen atom or methyl; R
8With R
9Perhaps with R
14Form another key together; R
9Represent hydrogen atom or and R
8Form another key together; R
14Represent α-hydrogen atom or and R
8Form another key together, perhaps with R
15Form together
Another key; R
15Represent hydrogen atom or and R
14Form another key together; R
24Represent hydrogen atom or and R
25Form another key together; R
25Represent hydrogen atom or and R
24Form another key together.
Its condition is to be not included in 1 and 2 not adorned compound R of while
1=R
2=R
2 '=H.
2, compound as claimed in claim 1, wherein R
1Represent hydrogen atom, phenyl or and R
2Form another key together.
3, compound as claimed in claim 1 or 2, wherein R
2Represent C
4-C
8Alkyl, allyl group or and R
1Form another key.
4, compound as claimed in claim 1 or 2, wherein R
2And R
2 'The optional benzylidene that replaces of representative.
5, as the described compound of one of claim 1-4, it is: 2 α-allyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, (E)-2-benzylidene-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, 5 α-cholestane-1,8,14-triolefin-3 β-alcohol, 5 α-cholestane-1,8,14-triolefin-3-ketone, 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, 1 alpha-cyano-4,4-dimethyl-5 α-cholestane-8,14-diene-3-ketone, 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3 β-alcohol, 4,4-dimethyl-5 α-cholestane-1,8,14-triolefin-3-ketone, (E)-and 4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile; (E)-and N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl] decoylamide; (E)-and N-[[4-[(3 beta-hydroxy-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] phenyl] methyl]-5-(4,4-two fluoro-5,7-dimethyl-4-boron-3a, 4a-diaza-s-indacen-3-yl) valeramide; 2 alpha-hydroxymethyls-4,4-dimethyl-5 α-cholestane-8,14-diene-3 α-alcohol, 2 α-octyl group-4,4-dimethyl-5 α-cholestane-8,14-diene-3 β-alcohol, and (E)-4-[(3-oxo-4,4-dimethyl-5 α-cholestane-8,14-diene-2-subunit)-methyl] benzonitrile.
6, pharmaceutical composition, its comprise one or more as the described compound of Formula I of one of claim 1-5 as activeconstituents.
7, as the application of the described compound of Formula I of one of claim 1-5 in the preparation meiosis-regulating medicaments.
8, application as claimed in claim 7, it is to be used to prepare that treatment is female or male, the medicine of preferred people's infertility.
9, application as claimed in claim 7, it is to be used to prepare that treatment is female or male, preferred people's contraceptive.
10, as the application aspect the rate of fertilization of the described compound of Formula I of one of claim 1-5 in regulating artificial fertilization process.
11, be used for the application of synthesising biological imaging with the initiator of instrument material as the described compound of Formula I of one of claim 1-5 as instrument material or conduct, described instrument material is the binding mode that is used to differentiate described general formula compound.
12, the maiotic method of a kind of adjusting, it comprises to one or more of the acceptor effective dosage of these regulating effects of needs as the described compound of Formula I of one of claim 1-5.
13, a kind of maiotic method of regulating in the Mammals sexual cell, it comprise to the sexual cell of these regulating effects of needs in vitro or one or more of treated in vitro significant quantity as the described compound of Formula I of one of claim 1-5.
14, method as claimed in claim 13, wherein sexual cell is ovocyte or male sex-cell.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99250040.5 | 1999-02-10 | ||
| EP99250040 | 1999-02-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1368977A true CN1368977A (en) | 2002-09-11 |
Family
ID=8241140
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00803662A Pending CN1368977A (en) | 1999-02-10 | 2000-02-09 | Unsaturated cholestane derivatives and their use for preparation of meiosis regulating medicaments |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1150993A1 (en) |
| JP (1) | JP2002536456A (en) |
| KR (1) | KR20010101820A (en) |
| CN (1) | CN1368977A (en) |
| AU (1) | AU3279700A (en) |
| BR (1) | BR0008065A (en) |
| CA (1) | CA2359687A1 (en) |
| CZ (1) | CZ20012866A3 (en) |
| HU (1) | HUP0200280A2 (en) |
| IL (1) | IL143735A0 (en) |
| NO (1) | NO20013901D0 (en) |
| PL (1) | PL350557A1 (en) |
| SK (1) | SK11382001A3 (en) |
| WO (1) | WO2000047604A1 (en) |
| ZA (1) | ZA200107387B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5716777A (en) * | 1994-06-23 | 1998-02-10 | Novo Nordisk A/S | Regulation of meiosis using sterols |
| CZ279797A3 (en) * | 1995-03-06 | 1998-01-14 | Novo Nordisk A/S | Method of stimulating miosis of a germ cell and application of a compound causing accumulation of a substance activating endogenic miosis |
| BR9608968A (en) * | 1995-06-23 | 1999-06-29 | Novo Nordisk As | Compound and process for regulating meiosis in a mammalian germ cell |
| JP2001506656A (en) * | 1996-12-20 | 2001-05-22 | ノボ ノルディスク アクティーゼルスカブ | Meiotic regulatory compounds |
-
2000
- 2000-02-09 BR BR0008065-9A patent/BR0008065A/en not_active Application Discontinuation
- 2000-02-09 HU HU0200280A patent/HUP0200280A2/en unknown
- 2000-02-09 JP JP2000598521A patent/JP2002536456A/en active Pending
- 2000-02-09 WO PCT/EP2000/001074 patent/WO2000047604A1/en not_active Application Discontinuation
- 2000-02-09 CA CA002359687A patent/CA2359687A1/en not_active Abandoned
- 2000-02-09 SK SK1138-2001A patent/SK11382001A3/en unknown
- 2000-02-09 CZ CZ20012866A patent/CZ20012866A3/en unknown
- 2000-02-09 PL PL00350557A patent/PL350557A1/en not_active Application Discontinuation
- 2000-02-09 IL IL14373500A patent/IL143735A0/en unknown
- 2000-02-09 KR KR1020017009985A patent/KR20010101820A/en not_active Application Discontinuation
- 2000-02-09 AU AU32797/00A patent/AU3279700A/en not_active Abandoned
- 2000-02-09 CN CN00803662A patent/CN1368977A/en active Pending
- 2000-02-09 EP EP00910664A patent/EP1150993A1/en not_active Withdrawn
-
2001
- 2001-08-10 NO NO20013901A patent/NO20013901D0/en not_active Application Discontinuation
- 2001-09-06 ZA ZA200107387A patent/ZA200107387B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002536456A (en) | 2002-10-29 |
| AU3279700A (en) | 2000-08-29 |
| EP1150993A1 (en) | 2001-11-07 |
| WO2000047604A1 (en) | 2000-08-17 |
| NO20013901L (en) | 2001-08-10 |
| IL143735A0 (en) | 2002-04-21 |
| CZ20012866A3 (en) | 2002-01-16 |
| ZA200107387B (en) | 2002-12-06 |
| PL350557A1 (en) | 2002-12-16 |
| SK11382001A3 (en) | 2002-01-07 |
| BR0008065A (en) | 2001-11-06 |
| HUP0200280A2 (en) | 2002-07-29 |
| NO20013901D0 (en) | 2001-08-10 |
| CA2359687A1 (en) | 2000-08-17 |
| KR20010101820A (en) | 2001-11-14 |
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