CN1349422A

CN1349422A - Contraceptive compositions containing cyclic carbramates and amide derivatives

Info

Publication number: CN1349422A
Application number: CN 00807137
Authority: CN
Inventors: G·S·格拉布; A·A·桑蒂拉; A·Q·维耶; 张普文; A·芬森; J·E·弗罗贝尔; J·P·爱德华兹; T·K·琼斯; C·M·特格利; 智林
Original assignee: Ligand Pharmaceuticals Inc; American Home Products Corp
Current assignee: Wyeth LLC; Ligand Pharmaceuticals Inc
Priority date: 1999-05-04
Filing date: 2000-05-01
Publication date: 2002-05-15
Also published as: AU5125100A

Abstract

This invention relates to cyclic combination therapies and regimens utilizin g, in combination with progestins, estrogens, or both, substituted indoline derivative compounds which are antagonists of the progesterone receptor having general structure (I) wherein A and B are independent substituents selected from S, CH or N; provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B both equal N, on e N may be optionally substituted with a C1 to C6 alkyl group; R1 and R2 are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substitute d C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA; or R1 and R2 are fused to form optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring, the heterocyclic ring containing one to three heteroatoms selected from the group of O, S and N; or pharmaceutically useful salts thereof. These methods of treatment may be used for contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.

Description

The composition for contraception that contains cyclic carbramates and amide derivatives

Invention field

The present invention relates to administration therapeutic method with the agonist compounds of the progesterone receptor of progestogen, estrogen or the two coupling.

Background of invention

Intracellular receptor (IR) forms the relevant Gene regulation agent of a class formation, is called " ligand dependent transcription factor " (R.M.Evans, Science, 240,889,1988).Steroid receptor family is a subclass of IR family, comprises progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) (GR) and mineralcorticoid receptor (MR).

For PR natural hormone or part is the steroid Progesterone, but has also synthesized chemical compound such as medroxyprogesterone acetate or levonorgestrel as part.In case have part in the pericellular liquid, part is just by the passive film that diffuses through, and combines with IR and to produce the receptor/ligand complex.This complex transporte to cells nuclear combines with the specific gene that exists in the cell DNA then.In case be incorporated into DNA sequence, this complex is with regard to the proteinic generation of regulating mRNA and this gene code.

The chemical compound that is incorporated into IR and the effect of simulation natural hormone is called agonist, and the chemical compound of inhibitory hormone effect is called antagonist.Known PR antagonist (natural and synthetic) plays an important role in women's health.The PR antagonist is used for the birth control preparation, when especially having the ER agonist.The ER agonist is used for the treatment of the disease in menopause, but discovery is relevant with the proliferative effect of uterus (women who does not hysterectomize), will cause increasing the danger of ovarian cancer.Can reduce/remove this danger with the coupling of PR agonist.The PR antagonist also can be used for contraception.They can give (people such as Ulmann separately in this case, Ann.N.Y.Acad.Sci., 261,248,1995), also can with PR agonist coupling (people such as Kekkonen, Fertility and Sterility, 60,610,1993) or with part ER antagonist (as Tamoxifen Citrate) coupling (WO 96/19997 A1 on July 4th, 1996).

The PR antagonist also can be used for the treatment of hormonal dependent breast carcinoma (283, publisher: Birkhaeuser, Boston, Mass writes Vedeckis for people such as Horwitz, Horm.Cancer) and uterus carcinoma and ovarian cancer.The PR antagonist also can be used for treating non-pernicious chronic disease such as fibroma (people such as Murphy, J.Clin.Endo.Metab., 76,513,1993) and endometriosis (people such as Kettel, Fertility and Sterility, 56,402,1991).

The PR antagonist also can be used for hormone replacement therapy, treats postclimacteric patient (US5719136) with part ER antagonist (as Tamoxifen Citrate) coupling.PR antagonist such as mifepristone have demonstrated the effect that rodent ulcer is had skeleton protection, therefore can be used for treating relevant osteoporosis in menopause people such as (, Bone, 17,21,1995) Barengolts.Be presented in the hormonal dependent carcinoma of prostate model, PR antagonist (as mifepristone and onapristone) is effectively, shows that they can be used for treating this class disease of male people such as (, Ann.N.Y.Acad.Sci., 761,224,1995) Michna.

The chemical compound that people such as Jones (U.S. Patent No. 5,688,810) describe is a PR antagonist dihydroquinoline 1.

People such as Jones (U.S. Patent No. 5,693,646) have described the enol ether 2 as the PR part.

People such as Jones (U.S. Patent No. 5,696,127) have described the chemical compound 3 as the PR part.

People such as Zhi (J.Med.Chem., 41,291,1998). the lactone 4,5 and 6 as the PR antagonist has been described.

People such as Zhi have described the ether 7 (J.Med.Chem., 41,291,1998) as the PR antagonist.

People such as Combs disclose the amide 8 (J.Med.Chem., 38,4880,1995) as the PR part.

People such as Perlman have described the novel vitamin D analogues 9 (Tet.Letters, 35,2295,1994) as the PR part.

People such as Hamann have described PR antagonist 10 (Ann.N.Y.Acad.Sci., 761,383,1995).

People such as Chen have described PR antagonist 11 (people POI-37 such as Chen, 16 ^ThIht.Cong.Het.Chem., Montana, 1997).

People such as Kurihari have described PR ligand 12 (J.Antibiotics, 50,360,1997).

U.S. Patent No. 5,521,166 (Grubb) point out that cycle stage property (cyclophasic) hormonotherapy comprises gestation and progestogen, wherein progestogen give in gestation existence and non-existent replacing.Disclosed therapy also provides estrogenic use in 2-4 days processes, takes place hemorrhage with prevention.

Detailed Description Of The Invention

The invention provides the combined therapy and the dosage that utilize contraceptive and one or more progestogenic medicine couplings.The present invention also provides Therapeutic Method and the dosage with these contraceptives and progestogenic medicine and estrogen (as ethinylestradiol) coupling.

Can give mammal with these therapies and combination, to cause contraception or to treat and/or prevent secondary amenorrhea, hemorrhage of functional disorder, leiomyoma of uterus, endometriosis; Polycystic ovary syndrome, uterine mucosa, ovary, mammary gland, colon, prostatic cancer and adenocarcinoma.Other purposes of the present invention comprise the stimulation food intake.This paper is used for the treatment of and/or prevents the purposes of above-mentioned situation or disease to comprise, continuous administration or regular discontinuous using according to the present invention make that effective dose minimum or side effect or periodicity menses are minimum.

Contraception purposes of the present invention comprises, with gestation and estrogen or progestogen or both couplings, is applied to (preferred oral) women of child-bearing age together.These dosage regimens should be carried out 28 days continuously, did not use progestogen, estrogen or gestation during this cycle final.

In header cycle 14-24 day, progestogen in these combinations can give separately or unite estrogen to give, the progestin dosage scope that gives is equivalent to about 35-150 microgram levonorgestrel every day on progestogenic activity, preferable about 35-100 microgram levonorgestrel every day that is equivalent to.Beginning to give separately gestation the day in cycle of 14-24 between day or unite estrogen to give gestation, continue 1-11 day then.Gestation in these combinations can every day the dosage of about 2-50 microgram give, estrogen can every day the dosage of about 10-35 microgram give.In oral administration, contain the packing of 28 tablets of tablets or medicine box and will be included in and not give the placebo tablet that gestation or progestogen or estrogenic those days give.

In a preferable embodiment of the present invention, can 18-21 day of 28 diurnal periodicitys separately or associating estrogen give progestogen of the present invention, then separately or associating estrogen give gestation, continue 1-7 day.

The estrogen that uses in compositions of the present invention and the preparation is ethinylestradiol preferably.

Progestogenic medicine useful among the present invention includes, but are not limited to: levonorgestrel, norgestrel, desogestrel, 3-ketone desogestrel, norethindrone, gestodene, SH 420, norgestimate, husky progesterone difficult to understand (osaterone), acetic acid cyproterone, trimegestone (trimegestone), dienogest, spirorenone (drospirenone), nomegestrol or (17-deacetylation) norgestimate in the wrong.The preferable progestogen that are used for the present invention's combination are levonorgestrel, gestodene and trimegestone.

Of the present invention in 28 diurnal periodicitys oral medicine comprise that pro-gave the progestogenic medicine separately on the 21st, its daily dose is equivalent to the levonorgestrel of about 35-100 microgram on progestogenic activity.Be about 2-50 milligram gestation chemical compound of the present invention giving daily dose 22-24 day then, then in 25-28 not administration of day or give placebo.Best is, each relevant active component of daily dose is merged in the single daily dose unit of combination 28 diurnal periodicity unit every day, totally 28 day units.

In another program, (a day unit dose is equivalent to about 35-150 microgram levonorgestrel on progestogenic activity can to give the progestogenic medicine in preceding 21 days jointly, preferably be equivalent to about 35-100 microgram levonorgestrel) and estrogen (as ethinylestradiol, day about 10-35 microgram of unit dose scope).Can give the gestation of the about 2-50 milligram of daily dose after this as mentioned above in 22-24 day, then in 25-28 not administration of day or give placebo.

Other schemes in the scope of the invention comprise: give progestogenic medicine and estrogen uniting 1-21 day, described progestogenic medicine is preferably levonorgestrel, the progestogenic activity of its daily dose is equivalent to about 35-100 microgram levonorgestrel, and the daily dose scope of described estrogen (as ethinylestradiol) is about the 10-35 microgram.Then, give gestation (2-50 milligram/day) and estrogen (as ethinylestradiol, its daily dose is about 10-35 microgram) uniting 22-24 day.In 25-28 day, not administration or give placebo.

The present invention also comprises the medicine box or the packing of the pharmaceutical preparation that is designed for scheme of the present invention.These medicine boxs should be designed in 28 diurnal periodicitys oral administration every day, preferably every day oral administration once, and organize, to show the single part of oral formulations will taking in the every day of 28 diurnal periodicitys or the combination of oral formulations.Preferably, each medicine box is included in the oral tablet that will take specified every day, and preferably a slice oral tablet will contain the daily dose of the various combinations of indicating.

According to such scheme, medicine box can contain in a kind of 28 days:

A) be used for the progestogenic medicine of the 14-21 daily dose unit of phase I, its progestogenic activity is equivalent to about 35-150 microgram levonorgestrel, and preferably progestogenic activity is equivalent to about 35-100 microgram levonorgestrel;

B) be used for the gestation chemical compound of the present invention of a 1-11 daily dose unit of second stage, the gestation chemical compound that daily dose is about the 2-50 milligram is contained in each daily dose unit; With

C) optional, be used for acceptable oral placebo on the materia medica of cycle residue day of phase III, wherein do not give gestation, progestogen or estrogen.

The preferable embodiment of this medicine box can comprise:

A) be used for the progestogenic medicine of 21 daily dose units of phase I, its progestogenic activity is equivalent to about 35-150 microgram levonorgestrel, and preferably progestogenic activity is equivalent to about 35-100 microgram levonorgestrel;

B) be used for the gestation chemical compound of the present invention of 3 daily doses of second stage 22-24 day, the gestation chemical compound of the about 2-50 milligram of daily dose is contained in each daily dose unit; With

C) acceptable oral placebo on the materia medica of optional 4 daily dose units that are used for the phase III is used for 25-28 day.

Another kind of 28 diurnal periodicity packaging schemes of the present invention or medicine box comprise:

A) be used for the 18-21 of phase I and contain progestogenic medicine and estrogenic daily dose unit, the progestogenic activity of progestogenic medicine is equivalent to about 35-150 microgram levonorgestrel, preferably progestogenic activity is equivalent to about 35-100 microgram levonorgestrel, is about the 10-35 microgram as the daily dose scope of estrogenic ethinylestradiol; With

B) 1-7 the daily dose that have that is used for second stage is about the daily dose unit of the gestation chemical compound of the present invention of 2-50 milligram; With

C) optional, be used for acceptable oral placebo on the 28 diurnal periodicitys residue 0-9 materia medica of every day day, wherein do not give progestogenic medicine, estrogen or gestation.

A preferable embodiment of above-mentioned medicine box can comprise:

A) be used for the progestogenic medicine and the estrogen of 21 daily dose units of phase I, the progestogenic activity of progestogenic medicine is equivalent to about 35-150 microgram levonorgestrel, preferably be equivalent to about 35-100 microgram levonorgestrel, be about the 10-35 microgram as estrogenic ethinylestradiol daily dose scope; With

B) be used for the gestation of 3 daily dose units of second stage 22-24 day, give dosage its every day and be about the 2-50 milligram; With

C) optional, be used for acceptable oral placebo on the materia medica of 4 daily dose units of phase III 25-28 every day day.

Another kind of 28 days packaging schemes of the present invention or medicine box comprise:

A) be used for the 18-21 daily dose unit of phase I, constituent parts contains progestogenic medicine of the present invention and ethinylestradiol, the daily dose of progestogenic medicine is equivalent to about 35-150 microgram levonorgestrel on progestogenic activity, preferably be equivalent to about 35-100 microgram levonorgestrel, ethinylestradiol daily dose scope is about the 10-35 microgram; With

B) be used for the 1-7 daily dose unit of second stage, the gestation of the present invention of the about 2-50 milligram of concentration and the concentration ethinylestradiol for about 10-35 microgram is contained in each daily dose unit; With

A preferable embodiment of above-mentioned packing or medicine box comprises:

A) be used for 21 daily dose units of phase I, constituent parts contains progestogenic medicine of the present invention and ethinylestradiol, the daily dose of progestogenic medicine is equivalent to about 35-150 microgram, the progestogenic activity of preferably about 35-100 microgram levonorgestrel, and the daily dose scope of ethinylestradiol is about 10-35 microgram; With

B) be used for 3 daily dose units of second stage 22-24 day, each dosage unit contains the gestation of the present invention of the about 2-50 milligram of concentration and the ethinylestradiol of the about 10-35 microgram of concentration; With

In above-mentioned each scheme and medicine box, preferably, the daily dose of each active constituents of medicine is fixed in the stage in each specific administration in the scheme.Should also be understood that described daily dose unit gives with described order, is second and the phase III successively after the phase I.For consistent with each scheme, it also is preferable that medicine box contains the described placebo that used last several days of cycle.In addition, each packing or medicine box should contain acceptable packing on the materia medica, and it has the sign corresponding to 28 diurnal periodicity every days, as known in the art the blister package of tape label or be with graduated administrator packing.

In this article, term contraceptive, gestation and progesterone receptor antagonist should be understood to synonym.Similarly, progestogen, progestogenic medicine and progesterone receptor agonist are understood as and have identical active chemical compound.

These dosages can be regulated, so that best therapeutic response to be provided.For example,, but give every kind of composition with several dosage that separate every day, or increase or reduce dosage in proportion according to the treatment situation.In the description of this paper, so-called " daily dose unit " also can be included in the dosage unit that separately give in the process every day in cycle.

The chemical compound of the present invention that can be used as the contraceptive in medicine box described herein, method and the scheme is those chemical compounds or its pharmaceutically acceptable salt with formula 1:

Wherein:

A and B respectively are the substituent groups that is selected from S, CH or N;

Condition is when A is S, and B is CH or N; Condition is

When B was S, A was CH or N;

With A and B can not be CH simultaneously;

With when A and B are N, a N can be randomly by C ₁-C ₆Alkyl replaces;

R ¹And R ²Respectively be to be selected from following substituent group: H, C ₁-C ₆The C of alkyl, replacement ₁-C ₆Alkyl, C ₂-C ₆The C of alkenyl, replacement ₂-C ₆Alkenyl, C ₂-C ₆The C of alkynyl, replacement ₂-C ₆Alkynyl, C ₃-C ₈The C of cycloalkyl, replacement ₃-C ₈The heterocycle of the aryl of cycloalkyl, aryl, replacement, heterocycle, replacement, COR ^AOr NR ^BCOR ^A

Or R ¹And R ²Condense formation:

A) the optional 3-8 unit spirocyclane basic ring that replaces preferably is a 3-6 unit spirocyclane basic ring; Or

B) the optional 3-8 unit volution alkene basic ring that replaces preferably is a 3-6 unit volution alkene basic ring; Or

C) choose the 3-8 unit volution that replaces wantonly, contain 1-3 hetero atom that is selected from O, S and N, preferably for containing 1-3 the first volution of heteroatomic 3-6;

R ^ABe H, C ₁-C ₃The C of alkyl, replacement ₁-C ₃The aryl of alkyl, aryl, replacement, C ₁-C ₃The C of alkoxyl, replacement ₁-C ₃Alkoxyl, C ₁-C ₃Aminoalkyl or the C that replaces ₁-C ₃Aminoalkyl;

R ^BBe H, C ₁-C ₃Alkyl or the C that replaces ₁-C ₃Alkyl;

R ³Be H, OH, NH ₂, C ₁-C ₆The C of alkyl, replacement ₁-C ₆Alkyl, C ₃-C ₆The C of alkenyl, replacement ₁-C ₆Alkenyl, alkynyl or the alkynyl, the COR that replace ^C

R ^CBe H, C ₁-C ₃The C of alkyl, replacement ₁-C ₃The aryl of alkyl, aryl, replacement, C ₁-C ₃The C of alkoxyl, replacement ₁-C ₃Alkoxyl, C ₁-C ₃Aminoalkyl or the C that replaces ₁-C ₃Aminoalkyl;

R ⁴Be the trisubstituted benzene ring that contains substituent X, Y and Z as follows:

X is selected from halogen, CN, C ₁-C ₃The C of alkyl, replacement ₁-C ₃Alkyl, C ₁-C ₃The C of alkoxyl, replacement ₁-C ₃Alkoxyl, C ₁-C ₃The C of alkylthio group, replacement ₁-C ₃Alkylthio group, C ₁-C ₃The C of aminoalkyl, replacement ₁-C ₃Aminoalkyl, NO ₂, C ₁-C ₃Perfluoroalkyl, contain 1-3 heteroatomic 5 or 6 yuan of heterocycles, COR ^D, OCOR ^D, or NR ^ECOR ^D

R ^DBe H, C ₁-C ₃The C of alkyl, replacement ₁-C ₃The aryl of alkyl, aryl, replacement, C ₁-C ₃The C of alkoxyl, replacement ₁-C ₃Alkoxyl, C ₁-C ₃Aminoalkyl or the C that replaces ₁-C ₃Aminoalkyl;

R ^EBe H, C ₁-C ₃Alkyl or the C that replaces ₁-C ₃Alkyl;

Y and Z are selected from following substituent group: H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl, C ₁-C ₃Alkyl or C ₁-C ₃Alkylthio group;

Or

R ⁴Be 5 or 6 yuan of rings, contain 1,2 or 3 and be selected from following hetero atom O, S, SO, SO ₂Or NR ⁵, and contain individual following substituent group: H, halogen, CN, the NO of respectively being selected from of 1-2 ₂, and C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl, C ₁-C ₃Aminoalkyl, COR ^F, or NR ^GCOR ^F

R ^FBe H, C ₁-C ₃The C of alkyl, replacement ₁-C ₃The aryl of alkyl, aryl, replacement, C ₁-C ₃The C of alkoxyl, replacement ₁-C ₃Alkoxyl, C ₁-C ₃Aminoalkyl or the C that replaces ₁-C ₃Aminoalkyl;

R ^GBe H, C ₁-C ₃Alkyl or the C that replaces ₁-C ₃Alkyl;

R ⁵Be H or C ₁-C ₃Alkyl;

W is O or chemical bond.

Chemical compound or its pharmaceutically acceptable salt that those formulas I is arranged in the preferred gestation chemical compound of the present invention, wherein:

Condition is when A is S, and B is CH or N; Condition is

When B was S, A was CH or N;

With A and B can not be CH simultaneously;

With when A and B are N, a N can be randomly by C ₁-C ₆Alkyl replaces;

R ¹Be H, C ₁-C ₆The C of alkyl, replacement ₁-C ₆Alkyl, C ₃-C ₈The C of cycloalkyl, replacement ₃-C ₈The heterocycle of the aryl of cycloalkyl, aryl, replacement, heterocycle, replacement, COR ^A, or NR ^BCOR ^A

R ²Be H, C ₁-C ₆The C of alkyl, replacement ₁-C ₆Alkyl, C ₂-C ₆The C of alkenyl, replacement ₂-C ₆Alkenyl, C ₂-C ₆The C of alkynyl, replacement ₂-C ₆Alkynyl, C ₃-C ₈The C of cycloalkyl, replacement ₃-C ₈The heterocycle of the aryl of cycloalkyl, aryl, replacement, heterocycle, replacement, COR ^A, or NR ^BCOR ^A

Or R ¹And R ²Condense formation:

A) the optional 3-8 unit spirocyclane basic ring that replaces; Or

B) the optional 3-8 unit volution alkene basic ring that replaces; Or

C) the optional 3-8 unit volution that replaces contains 1-3 hetero atom that is selected from O, S and N;

R ^BBe H, C ₁-C ₃Alkyl or the C that replaces ₁-C ₃Alkyl;

R ^CBe H, C ₁-C ₄The C of alkyl, replacement ₁-C ₄The aryl of alkyl, aryl, replacement, C ₁-C ₄The C of alkoxyl, replacement ₁-C ₄Alkoxyl, C ₁-C ₄Aminoalkyl or the C that replaces ₁-C ₄Aminoalkyl;

X is selected from halogen, CN, C ₁-C ₃The C of alkyl, replacement ₁-C ₃Alkyl, C ₁-C ₃The C of alkoxyl, replacement ₁-C ₃Alkoxyl, C ₁-C ₃The C of alkylthio group, replacement ₁-C ₃Alkylthio group, C ₁-C ₃The C of aminoalkyl, replacement ₁-C ₃Aminoalkyl, NO ₂, C ₁-C ₃Perfluoroalkyl, contain 1-3 heteroatomic 5 yuan of heterocycles, COR ^D, OCOR ^D, or NR ^ECOR ^D

R ^EBe H, C ₁-C ₃Alkyl or the C that replaces ₁-C ₃Alkyl;

R ⁴Be 5 or 6 yuan of rings, contain 1,2 or 3 and be selected from following hetero atom O, S, SO, SO ₂Or NR ⁵, and contain individual following substituent group: H, halogen, CN, the NO of respectively being selected from of 1-2 ₂, and C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl;

R ⁵Be H or C ₁-C ₃Alkyl;

W is O or chemical bond.

Chemical compound or its pharmaceutically acceptable salt that other preferred progesterone receptor antagonisies are those formulas I, wherein:

Condition is when A is S, and B is CH or N; With

When B was S, A was CH or N; With

A and B can not be CH simultaneously;

R ¹=R ²And be selected from: C ₁-C ₃The C of alkyl, replacement ₁-C ₃Alkyl, by R ¹And R ²Condense the spiro cycloalkyl group that the 3-6 unit spirane structure of formation is constituted;

R ³Be H, OH, NH ₂, C ₁-C ₆The C of alkyl, replacement ₁-C ₆Alkyl or COR ^C

R ^CBe H, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl;

R ⁴Be the disubstituted benzenes ring that contains substituent X and Y as follows:

X is selected from following group, comprising: halogen, CN, C ₁-C ₃Alkoxyl, C ₁-C ₃Alkyl, NO ₂, C ₁-C ₃Perfluoroalkyl, contain 1-3 heteroatomic 5 yuan of heterocycles or C ₁-C ₃Alkylthio group;

Y is the following substituent group of 4 ' or 5 ' be selected from, and comprising: H, halogen, CN, NO ₂, C ₁-C ₃Alkoxyl, C ₁-C ₄Alkyl, C ₁-C ₃Alkylthio group;

Or

R ⁴Be 5 yuan of rings of following structure

U is O, S or NR ⁵,

R ⁵Be H or C ₁-C ₃Alkyl or C ₁-C ₄CO ₂Alkyl;

X ' is selected from following group: halogen, CN, NO ₂, C ₁-C ₃Alkyl or C ₁-C ₃Alkoxyl;

Y ' is: H or C ₁-C ₄Alkyl;

Or

R ⁴Be 6 yuan of rings of following structure:

X ¹Be N or CX ²

X ²Be halogen, CN or NO ₂

W is O or chemical bond.

Chemical compound of the present invention can contain asymmetric carbon atom, and chemical compounds more of the present invention can contain one or more asymmetric centers, and therefore optical isomer and diastereomer can be arranged.Though formula I, II and III do not show with spatial chemistry, the present invention includes this type of optical isomer and diastereomer; And racemic and enantiomer-pure R and S stereoisomer that disassemble; And other mixture of R and S stereoisomer and their pharmaceutically acceptable salts.

Term used herein " alkyl " refers to straight chain and the saturated aliphatic hydrocarbon group that contains 1-8 carbon atom of side chain, is preferably and contains 1-6 carbon atom; " alkenyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon-carbon double bond and 2-8 carbon atom, preferably contains 1-6 carbon atom; " alkynyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon carbon triple bond and 2-8 carbon atom, preferably contains 2-6 carbon atom.

Term " alkyl of replacement ", " alkenyl of replacement " and " alkynyl of replacement " refer to by one or more are selected from abovementioned alkyl, alkenyl and alkynyl that following substituent group replaces at least: halogen, CN, OH, NO ₂, amino, aryl, heterocycle, the aryl of replacement, the heterocycle of replacement, alkoxyl, aryloxy group, the alkoxyl of replacement, alkyl-carbonyl, alkyl carboxyl, alkyl amino, arylthio.These substituent groups can be connected on any carbon atom of alkyl, alkenyl or alkynyl group, but condition is this stable chemical part that connects and composes.

The term of this paper " aryl " refers to aromatic systems, can be monocycle or many aromatic rings condensed or that link together, thereby condenses or at least one part of connecting ring forms conjugated virtue system.Aromatic yl group can comprise (but being not restricted to): phenyl, naphthyl, xenyl, anthryl, tetralyl, phenanthryl.

Term " aryl of replacement " refers to be selected from the above-mentioned aryl that following group replaces by one or more: halogen, CN, OH, NO ₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyl, aryloxy group, replacement alkoxyl, alkyl-carbonyl, alkyl carboxyl, alkyl amino or arylthio.

Term used herein " heterocycle " refers to stable 4-to 7-unit monocycle or stable multi-ring heterocycle, can be saturated, part is undersaturated or undersaturated, and by carbon atom be selected from a following 1-4 hetero atom and constitute: N, O and S atom.N and S atom can be oxidized.Heterocycle also can comprise any multi-ring, and wherein arbitrary above-mentioned heterocycle can condense in aromatic ring.This heterocycle can be connected in any hetero atom or carbon atom, but the structure that is generated must be chemically stable.These heterocycles comprise as oxolane, piperidyl, piperazinyl, 2-oxo-piperidine base, azepines base, pyrrolidinyl, imidazole radicals, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indyl, quinolyl, thienyl, furyl, benzofuranyl, benzothienyl, thio-morpholinyl, thio-morpholinyl sulfoxide and isoquinolyl.

Term used herein " heterocycle of replacement " refers to have following one or more substituent above-mentioned heterocycle: halogen, CN, OH, NO ₂, amino, alkyl, replacement alkenyl, alkynyl, alkoxyl, aryloxy group, alkoxyl, alkyl-carbonyl, alkyl carboxyl, alkyl amino or the arylthio of replacement of alkyl, cycloalkyl, alkenyl, replacement.Term used herein " alkoxyl " refers to the OR group, and wherein R is the alkyl of alkyl or replacement.The term of this paper " aryloxy group " refers to the OR group, and wherein R is the aryl of aryl or replacement.The term of this paper " alkyl-carbonyl " refers to the RCO group, and wherein R is the alkyl of alkyl or replacement.The term of this paper " alkyl carboxyl " refers to the COOR group, and wherein R is the alkyl of alkyl or replacement.Term " aminoalkyl " refers to secondary amine and tertiary amine, and wherein the alkyl of alkyl or replacement can be identical or different, and junction point be on nitrogen-atoms.Term used herein " alkylthio group " refers to the SR group, and wherein R is the alkyl of alkyl or replacement.Term " halogen " refers to Cl, Br, F and I element.

Can be by following flow preparation gestation chemical compound of the present invention:

The cyclic carbramates derivant

The method for preparing the thiphene ring carbamate derivatives

A. following flow process 1 has been described the method for synthesizing thiofuran cyclic carbramates chemical compound:

Flow process 1

So can be by the list of references flow process that comprises Gewald reaction (see " Comprehenisve HeterocyclicChemistry II; 1982-1995 literature review; people such as A.R.Katritsky the 2nd volume; the 639th page) preparation aminothiophene ester 2; promptly in the methanol that refluxes, suitably the aromatics acetaldehyde that replaces reacts (flow process 1) with sulfur and malonic methyl ester nitrile.2-amino group and suitable chloro-formate or carbonate reaction generate the amine of protecting 3.This can be by allowing 2 (to realize as methylchloroformate, ethyl chloroformate, allyl chlorocarbonate, 2-(trimethyl silyl) ethyl chloroformate or Bis(tert-butoxycarbonyl)oxide with chloro-formate or carbonic acid ester derivative in solvent (as benzene,toluene,xylene, dichloromethane, oxolane or pyridine).Can be under inert atmosphere (nitrogen or argon), 0 ℃ is carried out this reaction to the solvent refluxing temperature, and may need to exist alkali (as 4-dimethylaminopyridine, triethylamine, pyridine or diisopropylethylamine).Under the inert atmosphere (nitrogen or argon); 0 ℃ of suitable temperature to the solvent refluxing temperature; allow amino-compound 3 reactions of organometallic reagent (as Grignard reagent, alkyl or aryl zincon, alkyl or aryl lithium reagent) and protection in the atent solvent (as oxolane, diethyl ether), can generate the tertiary alcohol 4.Then chemical compound 4 is placed alkali condition to allow the ring closure obtain cyclic carbramates derivant 5.Appropriate condition comprises: handle 4 with alkali (as potassium hydroxide) in appropriate solvent (as the tetrahydrofuran solution of ethanol or potassium tert-butoxide).Can be under inert atmosphere (nitrogen or argon), 0 ℃ of reflux temperature to solvent carries out this reaction.

Flow process 2

In addition, can remove under the condition of carbamic acid ester protecting group being suitable for, this group of removing in 4 obtains 6 (flow processs 2).Subsequently in suitable solvent (as oxolane, dichloromethane, benzene etc.), with 6 ring closure, also will obtain 5 with reagent (as phosgene, carbonyl dimidazoles or DMC dimethyl carbonate).

Flow process 3

In addition, also chemical compound 4 dehydrations can be obtained different acryloyl derivative 7 (flow process 3).The condition that is suitable for dewatering is for using reagent such as acetic anhydride, mesyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfchloride chloride or anhydride in solvent (as pyridine, oxolane, dichloromethane or benzene).Can be under inert atmosphere (nitrogen or argon), 0 ℃ is carried out this reaction to the solvent refluxing temperature, and may need to exist alkali (as 4-dimethylaminopyridine, triethylamine, pyridine or diisopropylethylamine).Contact with acid condition 7, will make the ring closure obtain 5.Appropriate condition is to use acid as p-methyl benzenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in appropriate solvent (as dichloromethane, benzene, toluene or oxolane).Can be under inert atmosphere (nitrogen or argon), 0 ℃ of reflux temperature to solvent carries out this reaction.

Flow process 4

Flow process 4 has shown and has prepared 5 another kind of method.Under the inert atmosphere (nitrogen or argon), 0 ℃ of suitable temperature to the solvent refluxing temperature uses organometallic reagent such as Grignard reagent, alkyl or aryl zincon, alkyl or aryl lithium reagent to handle above-mentioned chemical compound 8 (M.Sugiyama, T.Sakamoto in atent solvent (as oxolane, diethyl ether), K.Tabata, K.Endo, K.Ito, M.Kobayashi, H.Fukiumi, Chem.Pharm.Bull., 37 (8): 2091 (1989)), generate the tertiary alcohol 9.Chemical compound 9 can be placed alkali condition then, allow the ring closure generate cyclic carbramates derivant 10.Appropriate condition is included in the tetrahydrofuran solution of atent solvent such as ethanol or potassium tert-butoxide with alkali such as potassium hydroxide treatment 10.Can be under inert atmosphere (nitrogen or argon), 0 ℃ of reflux temperature to solvent carries out this reaction.Chemical compound 10 can be changed into the derivant 11 of bromination then.Appropriate condition is included in the solvent (as dichloromethane, oxolane or acetic acid) and handles with bromine or N-bromine butanimide.Can be under inert atmosphere (nitrogen or argon), 0 ℃ of reflux temperature to solvent carries out this reaction when having additive such as silica gel.With relief 11 and aryl or heteroaryl boric acid, boric anhydride or the reaction of trialkyl aryl stannane, generate required biaryl compound 5.Under the inert atmosphere (nitrogen or argon), 0 ℃-solvent refluxing temperature, in solvent such as acetone, ethanol, benzene, toluene or oxolane, exist palladium catalyst as four (triphenylphosphines) close-carry out this reaction when palladium (O) or acid chloride, also may need additive such as sodium carbonate, cesium fluoride or potassium phosphate.

Flow process 5

In addition, also can be in atent solvent (as oxolane), low temperature with reagent such as lithium alkylide or Lithamide. and 10 (flow process 5) reaction, changes into boric acid 12 (M=B (OH) down then under the effect of methyl borate. or triisopropyl borate ester ₂), or by changing into the aryl stannane with trimethyltin chloride or two (tin trimethyl).When having palladium catalyst (closing-palladium (0) or acid chloride) subsequently as four (triphenylphosphines), allow 12 with the reaction of aryl or heteroaryl bromine or iodine, may need additive such as sodium carbonate, cesium fluoride or potassium phosphate, convert it into required thiophene carbamate 5 then.

B. following flow process 6 has shown the method for synthesizing thiofuran cyclic carbramates chemical compound:

Flow process 6

Press flow process (" Comprehenisve Heterocyclic Chemistry II; 1982-1995 literature review; people such as A.R.Katritsky the 2nd volume; the 639th page) preparation aminothiophene chemical compound 15 (flow processs 6) of list of references; comprise N; the aromatics ketone 13 that the dinethylformamide solution-treated suitably replaces, generate chlorine cyano group alkene derivatives 14 with phosphorus oxychloride.Allow 14 with the methyl thioglycolate reaction that contains in the methanol of Feldalat NM, generate crucial aminothiophene carboxylate starting material.Allow 2-amino with suitable chloro-formate or carbonate reaction, generate protected amine 16.This can finish with 15 reactions with chloro-formate or carbonic acid ester derivative (as methylchloroformate, ethyl chloroformate, allyl chlorocarbonate, 2-(trimethyl silyl) ethyl chloroformate or Bis(tert-butoxycarbonyl)oxide) by in solvent (as benzene,toluene,xylene, dichloromethane, oxolane or pyridine).Can be under inert atmosphere (nitrogen or argon), 0 ℃-solvent refluxing temperature is carried out this reaction, also may need alkali such as 4-dimethylaminopyridine, triethylamine, pyridine or diisopropylethylamine.At inert atmosphere (nitrogen or argon), the proper temperature between 0 ℃-solvent refluxing temperature is handled the amino-compound of protecting 16 with organometallic reagent (as Grignard reagent, alkyl or aryl zincon, alkyl or aryl lithium reagent), generates the tertiary alcohol 17.Then chemical compound 17 is placed alkali condition, make the closed cyclic carbramates derivant 18 that generates of ring.The condition that is fit to is included in the solvent (as the tetrahydrofuran solution of ethanol or potassium tert-butoxide) and handles 4 with alkali (as potassium hydroxide).Can under inert atmosphere (nitrogen or argon), carry out this reaction in the reflux temperature of 0 ℃-solvent.

Flow process 7

In addition, also can remove under the condition of carbamic acid blocking group being suitable for, remove 17 carbamic acid blocking group, generate 19 (flow processs 7).In suitable solvent (as oxolane, dichloromethane, benzene etc.), handle 19 subsequently, make its closed loop generate 18 with reagent (as phosgene, carbonyl dimidazoles or DMC dimethyl carbonate).

Flow process 8

In addition, chemical compound 17 dehydrations are generated different acryloyl derivative 20 (flow process 8).The condition that is fit to dehydration is included in the solvent (as pyridine, oxolane, dichloromethane or benzene) with reagent such as acetic anhydride, mesyl chloride, paratoluensulfonyl chloride or trifluoromethanesulfchloride chloride or anhydride.To the solvent refluxing temperature, carry out this reaction at inert atmosphere (nitrogen or argon) 0, may need to exist alkali such as 4-dimethylaminopyridine, triethylamine, pyridine or diisopropylethylamine.Place acid condition with 20, make the ring closed loop generate 18.Appropriate condition is included in uses acid as p-methyl benzenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in the solvent (as dichloromethane, benzene, toluene or oxolane).Can carry out this reaction to the solvent refluxing temperature for following 0 ℃ at inert atmosphere (nitrogen or argon).

Flow process 9

Flow process 9 has shown other approach of synthetic 18.As H.Fukiumi, M.Sugiyama, T.Sakamoto, Chem.Pharm.Bull., 37 (5): 1197 (1989) is described, 0 ℃ of inert atmosphere (nitrogen or argon) proper temperature is handled above-mentioned chemical compound 21 with organometallic reagent (as Grignard reagent, alkyl or aryl zincon, alkyl or aryl lithium reagent) to the solvent refluxing temperature in atent solvent (oxolane, diethyl ether), generate the tertiary alcohol 22.Then chemical compound 22 is placed alkali condition, obtain cyclic carbramates derivant 23 with closed loop.Appropriate condition is included in the solvent (as the tetrahydrofuran solution of ethanol or potassium tert-butoxide) and handles 22 with alkali (as potassium hydroxide).Can be under inert atmosphere (nitrogen or argon), 0 ℃ to the solvent refluxing temperature, carries out this reaction.Then chemical compound 23 is changed into the derivant 24 of bromination.Appropriate condition is to handle with bromine or N-bromine butanimide in solvent (as dichloromethane, oxolane or acetic acid).Can be under inert atmosphere (nitrogen or argon), 0 ℃-solvent refluxing temperature is carried out this reaction when having additive (as silica gel).With aryl or heteroaryl boric acid, boric anhydride or trialkyl aryl stannane and 24 reactions, generate required biaryl compound 18 subsequently.Can be in inert atmosphere (nitrogen or argon) solvent (as acetone, ethanol, benzene, toluene or oxolane) 0 ℃ to the solvent refluxing temperature, carry out this reaction when having palladium catalyst (closing-palladium (O) or acid chloride), may need additive such as sodium carbonate, cesium fluoride or potassium phosphate as four (triphenylphosphines).

Flow process 10

In addition, also can in atent solvent (as oxolane),, under the effect of methyl borate. or triisopropyl borate ester, change into boric acid 25 (M=B (OH) then at low temperatures with lithium alkylide or lithium amide-treated 23 (flow process 10) ₂), or by changing into the aryl stannane with trimethyltin chloride or two (tin trimethyl) reaction.Exist palladium catalyst to react with aryl or heteroaryl bromine or iodine and 25 when (as closing-palladium (0) or acid chloride) subsequently as four (triphenylphosphines), may need additive (as sodium carbonate, cesium fluoride or potassium phosphate), change into required thiphene ring carbamate 18 then.

C. following flow process 11 has shown the method for synthesizing thiofuran sulfo-cyclic carbramates chemical compound 26 and 27:

Flow process 11

Phosphorus pentasulfide in the available backflow pyridine handles 5 and 18 respectively, directly obtains thiophenic sulfur for cyclic carbramates 26 and 27.In addition, the Lawesson reagent ([2,4-two (4-methoxyphenyl)-1,3-dithio-2,4-two phosphetane-2,4-disulphide]) that also can be used in the backflow pyridine handles 5 and 18 respectively, generates 26 and 27.

The method for preparing the thiazole ring carbamate derivatives

The following method for preparing the thiazole ring carbamate compounds that shown:

Flow process 12

So, pressing document flow process B.Golankiewicz and P.Januszczyk, Tetrahedron, 41:5989 (1985) they are flow process 12 preparation thiazoles 28.With amine 28 and suitable chloro-formate or carbonate reaction, generate the amine 29 of protection.This can allow chemical compound 28 and chloro-formate or carbonic acid ester derivative (realize as methylchloroformate, ethyl chloroformate, allyl chlorocarbonate, 2-(trimethyl silyl) ethyl chloroformate or Bis(tert-butoxycarbonyl)oxide reaction by in solvent (as dichloromethane, THF, benzene, dimethylbenzene or pyridine).Can carry out this reaction in 0 ℃-solvent refluxing temperature of inert atmosphere (nitrogen or argon), may need to exist alkali such as 4-dimethylaminopyridine, triethylamine, pyridine or diisopropyl ester ethamine.Inert atmosphere (nitrogen or argon) following 0 ℃ to the proper temperature between the solvent refluxing temperature, with the reaction of the organometallic reagent (as Grignard reagent, alkyl or aryl zincon, alkyl or aryl lithium reagent) in chemical compound 29 and the atent solvent (as THF, ether), generate alcohol 30.Then chemical compound 30 is placed to make under the closed alkali condition of ring, generate cyclic carbramates derivant 31.Appropriate condition is included in the solvent (as ethanol) and handles chemical compound 30 with alkali (as potassium hydroxide).Under inert atmosphere (nitrogen or argon), 0 ℃ is carried out this reaction to the solvent refluxing temperature.

Flow process 13

In addition; as T.W.Greene and P.G.M.Wuts (at " blocking group in the organic synthesis "; second edition; Wiley-Interscience (1991)) described in; can be suitable for removing under the condition of carbamic acid ester protecting group; remove the carbamic acid ester protecting group of chemical compound 30, generate chemical compound 32.In appropriate solvent (as THF, dichloromethane, benzene etc.), use reagent (as phosgene, carbonyl dimidazoles or DMC dimethyl carbonate) with chemical compound 32 closed loops subsequently, also can generate chemical compound 31.

Flow process 14

In addition, if chemical compound 30 is tertiary alcohols, then its dehydration can be generated different acryloyl derivative 33 (flow process 3).The condition that is adapted to dewater is to use reagent such as acetic anhydride, mesyl chloride, paratoluensulfonyl chloride or trifluoromethanesulfchloride chloride or anhydride in solvent (as pyridine, THF, dichloromethane or benzene).Can carry out this reaction to the solvent refluxing temperature 0 ℃ of inert atmosphere (nitrogen or argon), may need to exist alkali such as 4-dimethylaminopyridine, triethylamine, pyridine or diisopropylethylamine.Chemical compound 33 is placed acid condition, make the ring closed loop generate chemical compound 31.Appropriate condition is to use acid as p-methyl benzenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in solvent (as dichloromethane, benzene, toluene or THF), and carries out this reaction in 0 ℃-solvent refluxing temperature of inert atmosphere (nitrogen or argon).

Flow process 15

Chemical compound 31 can be changed into bromide 34 in the flow process 15.The condition that is fit to is to contact with bromine or N-bromine butanimide in solvent (as dichloromethane, THF or acetic acid), to the solvent refluxing temperature, carries out this reaction 0 ℃ of inert atmosphere (nitrogen or argon) when having additive (as silica gel).With chemical compound 34 and aryl or heteroaryl boric acid, boric anhydride or the reaction of trialkyl aryl stannane, generate required biaryl compound 35 subsequently.Can be in solvent (as acetone, ethanol, benzene, toluene or THF) 0 ℃ of inert atmosphere (nitrogen or argon) to the solvent refluxing temperature, carry out this reaction when having palladium catalyst (closing-palladium (0) or acid chloride), also may need additive such as sodium carbonate, cesium fluoride or potassium phosphate as four (triphenylphosphines).

Flow process 16

In addition, also can handle chemical compound 31, under the effect of methyl borate. or triisopropyl borate ester, change into boric acid (M=B (OH) then at the reagent (as lithium alkylide or lithium amide) that low temperature is used in the atent solvent (as THF) ₂) 36, or under trimethyltin chloride or two (tin trimethyl) effect, changing into aryl stannane (flow process 16).Exist palladium catalyst to close-when palladium (0) or acid chloride, react subsequently, also may need additive such as sodium carbonate, cesium fluoride or potassium phosphate, thereby change into required chemical compound 35 with aryl or heteroaryl bromide or iodide as four (triphenylphosphines).

Amide derivatives

The method for preparing the amide thiophene derivant

Following flow process 17 has shown the method for preparing thiophene derivant:

Flow process 17

So amide 37 can be changed into carbamate (as t-butyl carbamate as described in preparation in the flow process 1 is during chemical compound 2).Ester hydrolysis 38 in the room temperature alkali condition (as Lithium hydrate in THF or methanol or sodium hydroxide) generates acid 39.Realize when (promptly have pure thionyl chloride or oxalyl chloride or thionyl chloride in solvent such as dichloromethane or oxalyl chloride, and contain the N of additive such as catalytic amount, dinethylformamide) that in standard conditions acid 39 changes into acid chloride 40.Then in atent solvent (as THF or dichloromethane) with chemical compound 40 and Azimethylene. or trimethyl silyl diazomethane reaction, when having silver oxide (I) then product diazo ketone 41 is reset, generate acid 42.Remove the condition (as acid condition) of protectiveness carbamate-functional at specificity and handle chemical compound 42 down, closed loop generates chemical compound 43 then.Inert atmosphere (nitrogen or argon) at-78 ℃ to the temperature between solvent boiling point, in solvent (as THF), alkali condition is (as existing N, N, N, butyl lithium during the N-tetra-methylenedimine) under,, generates alkylating derivant 44 with alkylating agent (as alkiodide, alkyl bromide, alkyl toluene sulphonic acid ester or alkyl methanesulfonates or dialkyl group iodide, dialkyl group bromide, dialkyl group tosylate or dialkyl group methanesulfonates) and chemical compound 43 reactions.

The method for preparing thiazole

Following flow process 18 has shown the method for preparing thiazole.

Flow process 18

Room temperature is in THF or methanol, and alkali condition (as sodium hydroxide or Lithium hydrate) ester hydrolysis 29 generates acid 45., realize acid 45 is changed into acid chloride 46 when (as having pure thionyl chloride or oxalyl chloride or thionyl chloride in solvent such as dichloromethane or oxalyl chloride, and containing the N of additive such as catalytic amount, dinethylformamide) in standard conditions.Then in atent solvent (THF or dichloromethane) with chemical compound 46 and Azimethylene. or three silicyl diazomethane reactions, when having silver oxide (I) then product diazo ketone 47 reset and generates acid 48.Remove the condition (as acid condition) of protectiveness carbamate-functional at specificity and handle chemical compound 48 down, closed loop generates heterocyclic compound 49 then.Inert atmosphere (nitrogen or argon) at-78 ℃ to the temperature between solvent boiling point, in solvent (as THF), alkali condition is (as existing N, N, N, butyl lithium during the N-tetra-methylenedimine) under,, generates alkylating heterocyclic compound 50 with alkylating agent (as alkiodide, alkyl bromide, alkyl toluene sulphonic acid ester or alkyl methanesulfonates or dialkyl group iodide, dialkyl group bromide, dialkyl group tosylate or dialkyl group methanesulfonates) and chemical compound 49 reactions.Chemical compound 50 can be changed into bromide 51 then.Suitable condition is to contact with bromine or N-bromine butanimide in the solvent (as dichloromethane, THF or acetic acid), inert atmosphere (nitrogen or argon) following 0 ℃ between the solvent refluxing temperature, carry out this reaction when having additive (as silica gel).With relief chemical compound 51 and aryl or heteroaryl boric acid, boric anhydride or the reaction of trialkyl aryl stannane, generate required biaryl compound 52.0 ℃ of inert atmosphere (nitrogen or argon) is between the solvent refluxing temperature, when having palladium catalyst (closing-palladium (0) or acid chloride) as four (triphenylphosphines), in solvent (as acetone, ethanol, benzene, toluene or THF), carry out this reaction, also may need additive such as sodium carbonate, cesium fluoride or potassium phosphate.Handle 52 with the phosphorus pentasulfide in the backflow pyridine and can directly obtain 40 thione derivatives-chemical compound 53.In addition, the Lawesson agent treated 52 in the also available backflow pyridine generates 53.

Gestation chemical compound in the present invention prescription can by pharmaceutically or the acceptable acid of physiology or the deutero-salt form of alkali use.These salt comprise the salt that (but being not restricted to) and following mineral acid form: example hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, organic acid then refer to acetic acid, oxalic acid, succinic acid and maleic acid.Other salt comprise the salt with alkali metal or alkaline-earth metal, as sodium, potassium, calcium or magnesium, with the form (when giving this form, can change into active part in vivo) of " prodrug " of ester, carbamate or other routines.

These Therapeutic Method can be used for contraception, or be used for the treatment of and/or prevent the method for secondary amenorrhea, hemorrhage of functional disorder, leiomyoma of uterus, endometriosis, polycystic ovary syndrome and uterine mucosa, ovary, mammary gland, colon and prostatic cancer and adenocarcinoma, or periodically menstrual bleeding or side effect minimize.Other purposes of the present invention comprise the stimulation food intake.

When blended chemical compound is used for such use; they can with one or more pharmaceutically acceptable carrier or mixed with excipients; as solvent, diluent etc., and can following form oral administration: tablet, capsule, dispersive powder, granule or suspension (containing 0.05-5% suspending agent according to appointment), syrup (containing sugar) and elixir (containing 20-50% ethanol according to appointment) etc. or carry out parenteral with sterile injectable solution or form of suspension (containing the 0.05-5% suspending agent of having an appointment in the medium waiting to ooze) just like 10-50%.These pharmaceutical preparatioies can contain just like with the blended about 25-90% active component of carrier, be about usually between 5%-60% (weight).

Can give these reactive compounds by oral and intravenous, intramuscular or subcutaneous route.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose and kaolin, and liquid carrier comprises: sterilized water, Polyethylene Glycol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami), as long as be adapted to the characteristic of active component and required form of medication.Normally used adjuvant comprises as flavoring agent, pigment, antiseptic and antioxidant such as vitamin E, vitamin C, BHT and BHA in pharmaceutical compositions.

From being easy to preparation and administration, preferred pharmaceutical composition is a solid-state composition, especially the capsule of tablet and hard filling or liquid filling.The oral administration of chemical compound is preferred.

But these reactive compounds are parenteral or intraperitoneal administration also.The solution or the suspension that also can in the water that suitably is mixed with surfactant (as hydroxypropyl cellulose), prepare these reactive compounds (free alkali or pharmaceutically acceptable salt).Also can in glycerol, liquid, Polyethylene Glycol and their mixture in oil, prepare dispersion liquid.Under common storage and service condition, contain antiseptic in these preparations to prevent growth of microorganism.

The medicament forms that is adapted to inject comprises aseptic aqueous solution or dispersion liquid and aseptic powder (being used for temporarily preparing aseptic injectable solution or dispersion liquid).In all situations, these forms must be aseptic and must be that fluid is to be easy to the use of syringe.Under manufacturing and condition of storage must be stable, and must be able to resist the pollution effect of microorganism (as antibacterial and fungus).Carrier can be solvent or disperse medium, contains just like water, ethanol (as glycerol, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetable oil.

Following non-limiting example has illustrated the preparation of The compounds of this invention 5.

Embodiment 1

6-(3-chlorphenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno [2,3-d] [1,3] oxazine-2-ketone

2-(3-benzyl chloride base) acetaldehyde

Anhydrous CH at the 3-chlorostyrene ₂Cl ₂(10.0g dropwise adds the Pb (OAc) that stirs in 25 ℃ of solution 72.15mmol) ₄(35.2g, trifluoroacetic acid 79.4mmol) (150ml) solution.Interpolation in 30 minutes finishes, and then stirs 30 minutes, and reaction is finished, and this mixture is toppled in the entry, and ether (3X) extracts, and uses saturated NaHCO ₃The organic layer that solution, water washing merge, dry (MgSO4) is concentrated into the 15ml volume, and is used for following reaction rapidly.

2-amino-5-(3-chloro-phenyl)-thiophene-3-carboxylate methyl ester

In the methanol solution of the crude aldehyde of above-mentioned preparation, add sulfur (2.55g, 79.44mmol), malonic methyl ester nitrile (7.88g, 79.44mmol) and morpholine (6.92g, mixture 79.44mmol) was with this reaction mixture refluxed 16 hours.The unreacted sulfur of elimination, evaporated filtrate obtains black residue.With this residue of ether extraction, use H ₂The O washing.From ether/hexane (1: 5) crystallization, obtain white crystal (3.85g, 14.3mmol, 50%), mp 85-87 °. ¹H NMR (DMSO-d ₆) δ 3.75 (s, 3H), 7.18-7.27 (m, 1H), 7.31-7.42 (m, 3H), 7.53 (s, 1H), 7.62 (s, 1H); MS (+APCI) m/z268 (M+H); C ₁₂H ₁₀ClNO ₂S analyzes straight: C, 53.83, H, 3.76, N, 5.23.Measured value: C, 53.57, H, 3.37, N, 5.00.

2-allyloxy carbonyl ammonia base-5-(3-chloro-phenyl)-thiophene-3-carboxylate methyl ester

Under the room temperature nitrogen, 2-amino-5-(3-chloro-phenyl)-thiophene-3-carboxylate methyl ester (2g, 7.5mmol) anhydrous 1, add in 2-dichloroethanes (50ml) solution allyl chlorocarbonate (1.6ml, 15.1mmol).This reactant mixture of reflux is 18 hours under the nitrogen, is cooled to room temperature, handles with saturated sodium bicarbonate aqueous solution (100ml).Separately organic layer is used dichloromethane (3 * 20ml) extraction water layers.Organic layer and dry (MgSO4) with salt water washing merging.Remove desolvate after, fast the silicagel column purification (hexane: ethyl acetate/7: 1) residue obtains being the inferior title compound (2.14g, 81%) of pale solid: ¹H-NMR (DMSO-d ₆) δ 10.2 (s, 1H), 7.73 (t, 1H, J=1.7Hz), 7.66 (s, 1H), 7.57 (dt, 1H, J=7.7,1.7Hz), 7.41 (t, 1H, J=7.7Hz), 7.34 (dt, 1H, J=6.8,1.6Hz), 6.01 (m, 1H), 5.41 (dd, 1H, J=7.3,1.6Hz), 5.29 (dd, 1H, J=10.5,1.3Hz), 4.74 (d, 2H, J=5.5Hz), 3.84 (s, 3H).C ₁₆H ₁₄ClNO ₄S assay value: C, 54.63, H, 4.01, N, 3.98.Measured value: C, 54.56, H, 3.92, N, 3.89.

Under the room temperature nitrogen, 2-allene oxygen base (allenoxy) carbonylamino-5-(3-chloro-phenyl)-thiophene-3-carboxylate methyl ester (0.1g, add in anhydrous THF solution 0.28mmol) methyl-magnesium-bromide (the 3.0M diethyl ether solution, 1.5ml, 4.5mmol).Room temperature nitrogen stirs after 20 minutes down, handles this reactant mixture with saline (10ml), adds 1N HCl solution (5ml) then.Add ethyl acetate (20ml), separately organic layer washs the MgSO4 drying with saline (5ml).Except that after desolvating, (silica gel, hexane: ethyl acetate/5: 1) purification residue, the methanol that obtains need not to be further purified and the qualitative next step that is directly used in the flash chromatography post.

Under the room temperature nitrogen, be stirred in the above-mentioned crude methanol in the ethanol, the mixture overnight of potassium hydroxide (excessive).Add cold this reaction solution of 1N HCl acidified aqueous solution then.Add ethyl acetate (20ml), separately organic layer washs with saline (5ml), dry (MgSO4).Remove desolvate after, (hexane: ethyl acetate/2: 1) purification residue obtains being the title compound (16mg, 19% liang of step) of pale solid: mp 149-150 ℃ to the silicagel column purification; ¹H-NMR (DMSO-d ₆) δ 10.69 (s, 1H), 7.64 (t, 1H, J=1.8Hz), 7.49 (s, 1H), 7.47 (dt, 1H, J=7.7,1.4Hz), 7.39 (t, 1H, J=7.8Hz), 7.29 (dt, 1H, J=7.8,1.3Hz), 1.61 (s, 6H).MS(EI)m/z?293/295(M ⁺)。C ₁₄H ₁₂ClNO ₂S assay value: C, 57.24, H, 4.12, N, 4.77.Measured value: C, 57.27, H, 4.25, N, 4.66.

Embodiment 2

6-(3-chlorphenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno [3,2-d] [1,3] oxazine-2-ketone

3-chloro-3-(3-chloro-phenyl)-acrylonitrile

POCl3 solution slowly is added in the dry DMF, for the time 20 minutes, and with temperature maintenance about 30 ℃.The anhydrous DMF solution of 3 '-chloracetophenone is added in the above-mentioned solution, allows reaction temperature rise to about 50 ℃.In this reaction solution, add the HCl azanol in batches, for the time 1 hour.Add 500ml volume water and form precipitation, stirred 1 hour, with B ü chner funnel collecting precipitation, H ₂The O washing, drying obtains yellow crystalline chemical compound, mp 60-62 ℃. ¹H NMR (DMSO-d ₆) δ 1.60 (s, 6H), 7.30 (d, 1H, J=8.41Hz), 7.41 (d, 1H, J=8.41Hz), 10.47 (s, 1H); MS (+APCI) m/z 213 (M+H); C ₉H ₉ClN ₂O ₂Assay value: C, 50.84, H, 4.27, N, 13.17.Measured value: C, 50.99, H, 4.28, N, 12.98

3-amino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester

The sodium grain is slowly dropped into methanol solution form NaOMe, when in methanol solution, adding the thiol methyl acetate then and being 20 minutes.Slowly add the methanol solution of 3-chloro-3-(3-chloro-phenyl)-acrylonitrile, refluxed then 1 hour.Reactant mixture is cooled to room temperature, this methanol is concentrated into 100ml, add 200ml water, stirred 30 minutes, collect yellow mercury oxide, wash several times with water, obtain 92-95 ℃ of yellow crystalline chemical compound mp. ¹H NMR (DMSO-d ₆) δ 1.60 (s, 6H), 7.30 (d, 1H, J=8.41Hz), 7.41 (d, 1H, J=8.41Hz), 10.47 (s, 1H); MS (+APCI) m/z 213 (M+H); C ₉H ₉ClN ₂O ₂Assay value: C, 50.84, H, 4.27, N, 13.17.Measured value: C, 50.99, H, 4.28, N, 12.98.

3-allyloxy carbonyl ammonia base-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester

(15g adds allyl chlorocarbonate (8.10g, toluene 67.2mmol) (5.0ml) solution, this reaction solution of reflux 3 hours in the solution of toluene 56.0mmol) (200ml) at 3-amino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester.Remove (strip down) toluene, collect crystal, obtain yellow crystals chemical compound, mp 101-103C with the ether/hexane washing. ¹H NMR (DMSO-d ₆) δ 3.85 (s, 3H), 4.68-4.71 (d, 2H, J=5.46Hz), 5.26-5.30 (dd, 1H, J=1.35,9.84Hz), 5.36-5.42 (dd, 1H, J=1.57,15.68Hz), 5.96 (m, 2H), 7.50-7.52 (m, 2H), and 7.67-7.71 (m, 1H), 7.79 (s, 1H), 8.10 (s, 1H); MS (+APCI) m/z 352 (M+H); C ₁₆H ₁₄ClNO ₄S assay value: C, 54.63, H, 4.01, N, 3.97.Measured value: C, 54.05, H, 4.17, N, 3.84.

[5-(3-chloro-phenyl)-2-(1-hydroxyl-1-methyl-ethyl)-thiene-3-yl-]-allyl carbamate

(5.3g in the solution of anhydrous THF (30ml) 15.1mmol), adds ether (20.1ml, 60.24mmol) solution of 3.0M MeMgI to room temperature at 3-allyloxy carbonyl ammonia base-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester.After 30 minutes, use H ₂Saturated NH is used in slowly cancellation reaction of O (10ml) ₄OH (100ml) handles, and ether (200ml) extracts, the salt water washing, and dry (MgSO4) concentrates and chromatography (hexane/ether, 1: 4): mp 60-61 ℃; ¹H NMR (DMSO-d ₆) δ 1.52 (s, 6H), 4.59-4.61 (d, 2H, J=5.35Hz), 5.22-5.36 (m, 2H), 5.91-6.04 (m, 2H), 7.33-7.67 (m, 5H), 8.89 (s, 1H); MS (EI) m/z 351/353 (M+H); C _L7H ₁₈ClNO ₃S assay value: C, 58.03, H, 5.16, N, 3.98.Measured value: C, 58.17, H, 5.16, N, 3.97.

(0.12g adds KO in anhydrous THF (5.0ml) solution 0.34mmol) at [5-(3-chloro-phenyl)-2-(1-hydroxyl-1-methyl-ethyl)-thiene-3-yl-]-allyl carbamate ^t(0.076g 0.068mmol), stirred 15 minutes Bu, used H ₂The O cancellation adds minute quantity MeOH crystallization then in solution.Collect white crystal, mp 123-125 ℃ with B ü chner funnel. ¹H NMR (DMSO-d ₆) δ 1.64 (s, 6H), 7.05 (s, 1H), 7.37-7.48 (m, 2H), 7.53-7.56 (s, 1H), 7.67-7.68 (m, 1H), 10.41 (s, 1H); MS (EI) m/z 293/295 (M+H); C ₁₇H ₁₈ClNO ₃S assay value: C, 57.24, H, 4.12, N, 4.77.Measured value: C, 56.93, H, 3.92, N, 4.97.

Embodiment 3 pharmacologys

As follows, the activity of usefulness PRE-luciferase experimental evaluation progestogen of the present invention in the CV-1 cell.Their scope of validity is 0.01nM-10 in vitro tests, 000nM.Arrive 30mg/kg for 1mg/kg in the in vivo test.

The purpose of this test is based on chemical compound influence to PRE-luciferase reporter activity in the CV-1 cell of personnel selection PR and PRE-luciferase plasmids cotransfection, determines the progestogenic or the anti-pregnant effect of chemical compound.Material used in this test is as follows:

A. culture medium: growth medium is as follows: contain 10% (v/v) hyclone (hot deactivation), 0.1mM MEM non essential amino acid, 100U/ml penicillin, 100mg/ml streptomycin and 2mM GlutaMax (GIBCO, DMEM BRL) (BioWhittaker).Test medium is as follows: contain the hyclone (heat inactivation) of 10% (v/v) activated carbon desorbing, MEM, 100U/ml penicillin, 100mg/ml streptomycin and the 2mM GlutaMax of 0.1mM MEM non essential amino acid (GIBCO, no phenol red DMEM (BioWhittaker) BRL).

B. the cultivation of cell, transfection, processing and luciferase test

The CV-1 cell stock solution is maintained in the growth medium.With 1.2 * 10 ⁷The calf thymus DNA that individual cell, 5mgpLEM plasmid (inserting hPR-B at Sph1 and BamH1 site), 10mgpGL3 plasmid (two PRE are arranged in the luciferase sequence upstream) and 50mg supersound process are crossed carries out cotransfection as carrier DNA (250ml).

In 260V and 1,000mF carries out electroporation with Biorad Gene Pulser II.Behind the electroporation, cell is resuspended to growth medium, and on 96 orifice plates, inoculates with 40,000 cells/well (200 μ l).After the overnight incubation, change culture medium into test medium.In test medium, handle these cells then with contrast or test compounds.When the 3nM Progesterone, measure the contraception activity of chemical compound.Handle after 24 hours, discard culture medium, (GIBCO BRL) washs these cells 3 times with D-PBS.Each hole adds 50 μ l cell lysis buffer solution, and (WI), dull and stereotyped (Lab LineInstrument Inc) goes up vibration 15 minutes at the titration oscillator plate for Promega, Madison.Measure the activity of luciferase with the luciferase reagent of Promega.

C. interpretation of result

Various processing repeat 4 times at least.Be matched with the variance and the non-linear dose response curve of agonist and antagonist pattern with the data analysis of logarithm conversion.Reduce the influence of outlier (outlier) with the Huber weighting method.With the numerical computations EC that converts again ₅₀Or IC ₅₀In two one-way analysises of variance and non-linear response analysis, and use JMP software (SAS Institute, Inc.).

D. control compound

Progesterone and trimegestone be progestogen in contrast, and RU486 is gestation in contrast.All control compounds are all tested in full dose response curve, and calculate EC ₅₀Or IC ₅₀Value.

The expectation EC of contrast progestogen in three independent studies of table 1. ₅₀, standard deviation (SE) and 95% confidence interval (CI)

EC ₅₀95%CI chemical compound experiment (nM) SE lower limit upper limit Progesterone 1 0.616 0.026 0.509 0.746

2 0.402 0.019 0.323 0.501

3 0.486 0.028 0.371 0.637Trimegeston 1 0.0075 0.0002?0.0066?0.0085

e

2 0.0081 0.0003?0.0070?0.0094

3 0.0067 0.0003?0.0055?0.0082

The expectation IC of gestation RU486 in three independent studies of table 2. ₅₀, standard deviation (SE) and 95% confidence interval (CI)

IC50 95%CI chemical compound experiment (nM) SE lower limit upper limit RU486 1 0.028 0.002 0.019 0.042

2 0.037 0.002 0.029 0.048

3 0.019 0.001 0.013 0.027

Progestogenic activity: compare with control vector, the chemical compound that makes the PRE-uciferase activity significantly increase (p＜0.05) is thought activated.

Anti-pregnant activity: the chemical compound that significantly reduces the activity (p＜0.05) of the inductive PRE-luciferase of 3nM Progesterone.

EC ₅₀: can increase PRE-uciferase activity maximum one half, compound concentrations (be defaulted as " nM ') and standard deviation.

IC ₅₀: can reduce the inductive PRE-uciferase activity of 3nM Progesterone maximum one half, compound concentrations (being defaulted as " nM ") and standard deviation.

This paper includes the publication of all references as a reference in.Though the present invention is described with preferred embodiment, be appreciated that not breaking away from spirit of the present invention can also do some improvement.These improvement are in the appended claim scope of the present invention 9.

Claims

1. A contraceptive method, characterized in that the method comprises giving women of childbearing age 28 consecutive days:

a) In the first stage, 14-24 daily dosage units of progestational agents are administered, the progestational activity of which is equivalent to 35-100 micrograms of levonorgestrel;

b) In the second stage, 1-11 daily dosage units of the anti-pregnancy compound of Formula 1 or a pharmaceutically acceptable salt thereof are given, and the daily dosage unit is 2-50 mg:

It is characterized in that, wherein:

A and B are each a substituent selected from S, CH or N;

The condition is that when A is S, B is CH or N; the condition is

When B is S, A is CH or N;

and A and B cannot be CH at the same time;

and when both A and B are N, one N may be optionally substituted by C ₁ -C ₆ alkyl;

_Each of R _and R is a substituent selected from the group consisting of H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, Heterocycle, substituted heterocycle, ^CORA or NR ^B ^CORA ;

Or ^R1 and ^R2 are fused to form:

a) an optionally substituted 3-8 membered spirocycloalkyl ring; or

b) an optionally substituted 3-8 membered spiroalkenyl ring; or

c) optionally substituted 3-8 membered spirocycles containing 1-3 heteroatoms selected from O, S and N;

R ^A is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy , C ₁ -C ₃ aminoalkyl, or substituted C ₁ -C ₃ aminoalkyl;

R ^B is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, substituted C ₁ -C ₆ alkenyl, alkynyl , or substituted alkynyl, ^CORC ;

R ^C is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy , C ₁ -C ₃ aminoalkyl, or substituted C ₁ -C ₃ aminoalkyl;

^R4 is a trisubstituted benzene ring containing substituents X, Y and Z as shown below:

X is selected from halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ Alkylthio, substituted C ₁ -C ₃ alkylthio, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, containing 1 - a 5- or 6-membered heterocyclic ring with 3 heteroatoms, ^CORD , OCOR ^D , or NR ^E ^CORD ;

R ^D is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy , C ₁ -C ₃ aminoalkyl, or substituted C ₁ -C ₃ aminoalkyl;

R ^E is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

Each of Y and Z is a substituent selected from H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkylthio;

or

R ⁴ is a 5 or 6 membered ring containing 1, 2 or 3 heteroatoms selected from O, S, SO, SO ₂ or NR ⁵ , and the 5 or 6 membered ring optionally contains 1-2 Substituents each selected from the group consisting of H, halogen, CN, NO ₂ , and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ aminoalkyl, ^CORF , or NR ^G ^CORF ;

R ^F is H, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, aryl, substituted aryl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy , C ₁ -C ₃ aminoalkyl, or substituted C ₁ -C ₃ aminoalkyl;

R ^G is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

R ⁵ is H or C ₁ -C ₃ alkyl;

W is O or a chemical bond;

c) Optionally, administer a pharmaceutically acceptable oral placebo for the third phase of the remaining days of 28 consecutive days, the total number of daily dosage units of the first, second and third phases being equal to 28, where no Give an antiprogestin, progestin, or estrogen.

2. The method as claimed in claim 1, characterized in that, the progestational drug is levonorgestrel, and the antiprogestin is a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable Accepted salts where:

A and B are each a substituent selected from S, CH or N;

The condition is that when A is S, B is CH or N;

and when B is S, A is CH or N;

and A and B cannot be CH at the same time;

R ¹ is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl , heterocycle, substituted heterocycle, ^CORA , or NR ^B ^CORA ;

R ² is H, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , substituted C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, substituted C ₃ -C ₈ cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, ^CORA , or NR ^B ^CORA ;

Or ^R1 and ^R2 are fused to form:

a) an optionally substituted 3-8 membered spirocycloalkyl ring; or

b) an optionally substituted 3-8 membered spiroalkenyl ring; or

R ^B is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

R ^C is H, C ₁ -C ₄ alkyl, substituted C ₁ -C ₄ alkyl, aryl, substituted aryl, C ₁ -C ₄ alkoxy, substituted C ₁ -C ₄ alkoxy , C ₁ -C ₄ aminoalkyl, or substituted C ₁ -C ₄ aminoalkyl;

X is selected from halogen, CN, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted C ₁ -C ₃ alkoxy, C ₁ -C ₃ Alkylthio, substituted C ₁ -C ₃ alkylthio, C ₁ -C ₃ aminoalkyl, substituted C ₁ -C ₃ aminoalkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, containing 1 - a 5-membered heterocyclic ring of 3 heteroatoms, ^CORD , OCOR ^D , or NR ^E ^CORD ;

R ^E is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

or

R ⁴ is a 5 or 6 membered ring containing 1, 2 or 3 heteroatoms selected from O, S, SO, SO ₂ or NR ⁵ , and the 5 or 6 membered ring is optionally surrounded by 1-2 each Substituents selected from the following substituents: H, halogen, CN, NO ₂ , amino, and C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy;

R ⁵ is H or C ₁ -C ₃ alkyl;

W is O or a chemical bond.

3. The method as claimed in claim 1, characterized in that, the progestational drug is levonorgestrel, and the antiprogestin is a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable Accepted salts where:

A and B are each a substituent selected from S, CH or N;

The condition is that when A is S, B is CH or N;

and when B is S, A is CH or N;

and A and B cannot be CH at the same time;

R ¹ = R ² and is selected from: C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, or spirocycloalkyl composed of 3-6 membered spiro ring formed by the fusion of R ¹ and R ² ;

R ³ is H, OH, NH ₂ , C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, or ^CORC ;

R ^C is H, C ₁ -C ₄ alkyl, or C ₁ -C ₄ alkoxy;

^R4 is a disubstituted benzene ring containing substituents X and Y as shown below:

X is a group selected from the group consisting of: halogen, CN, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, NO ₂ , C ₁ -C ₃ perfluoroalkyl, containing 1-3 A heteroatomic 5-membered heterocyclic ring, or a C ₁ -C ₃ alkylthio group;

Y is a substituent at the 4' or 5' position selected from the group consisting of: H, halogen, CN, NO ₂ , C ₁ -C ₃ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₃ Alkylthio;

or

R ⁴ is a 5-membered ring with the following structure

U is O, S, or NR ⁵ ,

R ⁵ is H, or C ₁ -C ₃ alkyl, or C ₁ -C ₄ CO ₂ alkyl;

X' is a group selected from the group consisting of halogen, CN, NO ₂ , C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

Y' is: H or C ₁ -C ₄ alkyl;

or

R ⁴ is a 6-membered ring of the following structure:

^X1 is N or ^CX2 ;

X ² is halogen, CN, or NO ₂ ;

W is O or a chemical bond.

4. The method as claimed in claim 1, characterized in that, the progestational drug is levonorgestrel, and the antiprogestogen is a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable of salt, of which:

R ¹ = R ² and is selected from: C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, or spirocycloalkyl consisting of R ¹ and R ² fused to form a 3-6 membered spiro ring ;

And A, B, R ³ , R ^C , R ⁴ , X, Y, U, R ⁵ , X', Y', X ¹ , X ² , R ⁶ , R ⁷ , R ⁸ , R ⁹ and W are as in the right as defined in Requirement 3.

5. The method as claimed in claim 1, characterized in that, the progestational drug is levonorgestrel, and the antiprogestogen is a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable of salt, of which:

R ¹ and R ² are fused to form a 3-6 membered spiro ring;

6. A contraceptive method, characterized in that the method comprises giving women of childbearing age 28 consecutive days:

b) In the second stage, 1-11 daily dosage units of the anti-pregnancy compound of the following formula or a pharmaceutically acceptable salt thereof are administered, and the daily dosage unit is 2-50 mg:

Or ^R1 and ^R2 are fused to form:

a) a 3-6 membered spirocycloalkyl ring; or

b) a 3-6 membered spiro alkenyl ring; or

R ^B is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

RE is H, C ₁ -C ₃ alkyl, or substituted C ₁ -C ₃ alkyl;

7. The method of claim 1, wherein the antiprogestin compound is 6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H- Thieno[2,3-d][1,3]-oxazin-2-one, or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1, wherein the progestational drug is selected from the group consisting of: levonorgestrel, norgestrel, desogestrel, 3-ketone desogestrel, norethindrone ketone, gestodene, norethindrone acetate, norgestimate, oxagestrol, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestone or (17- deacetyl) norgestimate.

9. The method according to claim 1, characterized in that, the method comprises giving a continuous 28-day cycle to women of childbearing age as follows:

a) 21 daily dosage units of a progestational drug for the first phase, the progestational activity of the progestational drug is equivalent to 35-150 micrograms of levonorgestrel;

b) 3 daily dosage units of the antiprogestogenic compound of claim 1 for the second phase, each daily dosage unit containing a daily dose of 2-50 mg of the antiprogestogenic compound; and

c) Optionally administer 4 daily dosage units of a pharmaceutically acceptable oral placebo on each day after the first and second phases of the 28-day cycle.

10. A contraceptive method, characterized in that the method comprises giving women of childbearing age the following substances within 28 consecutive days:

a) In the first phase, 18-21 daily dose units of progestational agents and ethinyl estradiol are given, the progestational activity of the progestational drugs is equivalent to the daily dose of 35-150 micrograms of levonorgestrel, ethinyl estradiol in the range of 10-35 micrograms; and

b) the second stage, administering 1-7 daily dose units of the antiprogestin of claim 1, the daily dose of which is 2-50 mg; and

c) Optionally administer a pharmaceutically acceptable oral placebo on each remaining day of the 28 consecutive days.

11. The method according to claim 10, wherein the method comprises administering the following substances to women of childbearing age within 28 consecutive days:

a) In the first phase, 21 daily dose units of a progestational drug and ethinyl estradiol are administered, the progestational activity of the progestational drug is equivalent to 35-100 micrograms of levonorgestrel, and the daily dose of ethinyl estradiol ranges from 10 -35 micrograms; and

b) the second stage, administering 3 daily dose units of the antiprogestogen according to claim 1, the daily dose being 2-50 mg; and

c) An optional third phase, administering 4 daily dosage units of a pharmaceutically acceptable oral placebo.

12. A method of contraception, characterized in that said method comprises giving women of childbearing age the following substances during 28 consecutive days:

a) In the first phase, 18-21 daily dosage units of the progestational drug and ethinyl estradiol are administered, the daily dose of the progestational drug is equivalent in progestational activity to 35-150 micrograms of levonorgestrel, ethinyl estradiol Alcohol daily dose ranges from 10-35 micrograms; and

b) a second phase, administering 1-7 daily dosage units, each daily dosage unit containing the antiprogestin of claim 1 at a concentration of 2-50 mg and ethinyl estradiol at a concentration of 10-35 micrograms; and

c) An optional third phase, administering daily dosage units of pharmaceutically acceptable oral placebo, for a total of 28 daily dosage units.

13. The method of claim 12, wherein the method comprises administering the following substances to women of childbearing age during 28 consecutive days:

a) In the first phase, 21 daily dosage units are administered, each daily dosage unit containing a progestational drug and ethinyl estradiol, the daily dose of the progestational drug is equivalent in progestational activity to 35-100 micrograms of levonorgestrel , the daily dose of ethinyl estradiol ranges from 10-35 micrograms; and

b) second phase, administering 3 daily dosage units, each containing the antiprogestin of claim 1 at a concentration of 2-50 mg and ethinyl estradiol at a concentration of 10-35 micrograms; and

14. A pharmaceutically available kit suitable for oral administration, characterized in that said medicine comprises:

a) 14-21 daily dosage units of a progestational drug for the first phase, the progestational activity of the progestational drug is equivalent to 35-150 micrograms of levonorgestrel;

b) 1 to 11 daily dosage units of the antiprogestogenic compound of claim 1 for the second phase, each daily dosage unit containing a daily dose of 2 to 50 mg of the antiprogestogenic compound; and

c) daily dosage units of pharmaceutically acceptable oral placebo for the third phase;

Wherein the total number of daily dosage units of the first phase, the second phase and the third phase is equal to 28.

15. The pharmaceutically available kit suitable for oral administration as claimed in claim 14, wherein said kit comprises:

c) 4 daily dosage units of pharmaceutically acceptable oral placebo for the third period.

16. A pharmaceutical kit suitable for daily oral administration, characterized in that the kit comprises:

a) 18-21 daily dosage units of progestational drug and ethinyl estradiol for the first phase, the progestational activity of progestational drug is equivalent to the daily dose of 35-150 micrograms levonorgestrel, ethinyl estradiol Doses range from 10-35 micrograms; and

b) 1-7 daily dosage units of the antiprogestogenic compound of claim 1 for the second phase, in a daily dosage of 2-50 mg; and

c) 0-9 daily dosage units of pharmaceutically acceptable oral placebo for Phase III;

Wherein the total number of daily dosage units in the first phase, the second phase and the third phase is equal to 28.

17. The pharmaceutical kit suitable for daily oral administration as claimed in claim 16, wherein said kit comprises:

a) 21 daily dosage units of a progestational drug and ethinyl estradiol for the first phase, the progestational activity of the progestational drug is equivalent to 35-150 micrograms of levonorgestrel, the daily dose range of ethinyl estradiol 10-35 micrograms; and

b) 3 daily dosage units of the antiprogestin of claim 1 for the second phase, in a daily dosage of 2-50 mg; and

18. A pharmaceutical kit suitable for daily oral administration, characterized in that the kit comprises:

a) 18-21 daily dosage units for the first phase, each daily dosage unit containing a progestational drug and ethinyl estradiol, the daily dose of the progestational drug is equivalent in progestational activity to 35-150 micrograms of levonin norgestimate, ethinyl estradiol in a daily dose range of 10-35 micrograms;

b) 1-7 daily dosage units for the second phase, each daily dosage unit containing the antiprogestin of claim 1 at a concentration of 2-50 mg and ethinyl estradiol at a concentration of 10-35 micrograms ;and

19. The pharmaceutical kit suitable for daily oral administration according to claim 18, wherein said kit comprises:

a) 21 daily dosage units for the first phase, each daily dosage unit containing a progestational drug and ethinyl estradiol, the daily dose of the progestational drug is equivalent in progestational activity to 35-150 micrograms of levonorgestrel Ketones, the daily dose of ethinyl estradiol ranges from 10-35 micrograms;

b) 3 daily dosage units for the second phase, each daily dosage unit containing the antiprogestin of claim 1 at a concentration of 2-50 mg and ethinyl estradiol at a concentration of 10-35 micrograms; and