CN101248056A - Non-steroidal progesterone receptor modulators - Google Patents
Non-steroidal progesterone receptor modulators Download PDFInfo
- Publication number
- CN101248056A CN101248056A CNA2006800306699A CN200680030669A CN101248056A CN 101248056 A CN101248056 A CN 101248056A CN A2006800306699 A CNA2006800306699 A CN A2006800306699A CN 200680030669 A CN200680030669 A CN 200680030669A CN 101248056 A CN101248056 A CN 101248056A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkynyl
- group
- ethynyl
- alkyl
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- 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
-
- 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
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- 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
-
- 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
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
- Furan Compounds (AREA)
Abstract
This invention relates to nonsteroidal progesterone receptor modulators of general formula (I), a process for their production, the use of progesterone receptor modulators for the production of pharmaceutical agents as well as pharmaceutical compositions that contain these compounds. The compounds according to the invention are suitable for therapy and prophylaxis of gynecological diseases, such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhea, as well as for the therapy and prophylaxis of hormone-dependent tumors and for use for female birth control as well as for hormone replacement therapy.
Description
Technical field
The present invention relates to non-steroidal progesterone receptor modulators, its preparation method, progesterone receptor modulator in the preparation medicine application and the pharmaceutical composition that comprises these compounds.
Background technology
The steroid hormone progesterone is critically regulated the intravital reproductive process of female.During the menstrual cycle and in pregnancy the time, progesterone is by secretion in a large number in ovary or the placenta.By with estrogenic interaction, progesterone produces the periodical change of uterine mucosa (uterine endometrium) in the menstrual cycle.Under the influence of the high progesterone level after the ovulation, uterine mucosa is transformed into the state that allows embryo's (protoblast) implantation.When pregnancy, the function of the lax and maintenance decidua tissue of progesterone control myometrium.
It is also known that in addition progesterone suppresses endometrial propagation (K.Chwalisz, R.M.Brenner by the mitotic division that suppresses estrogen-mediated in the uterine cancer cell, U.Fuhrmann, H.Hess-Stumpp, W.Elger, Steroids65,2000,741-751).
Progesterone and the PgR vital role in pathophysiological processes also is known.PgR not only in uterus is detected in the film ectopic focus, and also is detected in the tumour of uterus, mammary gland and CNS.In addition, known leiomyoma of uterus is grown in the dependent mode of progesterone.
Progesterone is by carrying out with the interaction of the PgR of responsible cytological effect in reproductive organ and the effect in its hetero-organization.
Progesterone receptor modulator is pure agonist, or partially or completely suppresses the effect of progesterone.Therefore, these materials are defined as full agonist, partial agonist (SPRMS) and pure antagonist.
According to the ability that progesterone receptor modulator is used at the work that influences PgR, these compounds as the therapeutical agent of gynaecopathia and tumor disease and be used for obstetrics and Birth control on have suitable potentiality.
Pure progesterone receptor antagonists suppresses the effect of progesterone in PgR fully.They have ovulation character, and suppress the oestrogenic hormon effect in the film in uterus until the ability of complete atrophy.Therefore, they are particularly suitable for getting involved female growing process, for example after ovulation, be used to suppress implantation, when pregnancy, be used to increase the uterus to the reactive of prostaglandin(PG) or pitocin or be used to guarantee Cervical opening and softening (maturation) and make myometrium be ready for production fully.
In uterus film ectopic focus or have in the tumor tissues of PgR can expect that after using pure progesterone receptor antagonists described lysis is had favourable effect.If can be in addition realize inhibition to ovulation by progesterone receptor antagonists, then the illness for influence such as endometriosis or hysteromyoma produces the particularly advantageous part.When suppressing ovulation, a part of ovarian hormone forms and also is because reformed tissue on the pathology by the hormesis that this part hormone causes.
At first progesterone receptor antagonists RU 486 (being also referred to as Mi Feisi ketone) afterwards, the analogue that has different PgRs-antagonistic activity degree is in a large number arranged again.Though RU 486 also has the Antiglucocorticoid effect except that PgR-antagonist action, the key distinction of synthetic compound is the selectively acting higher than progesterone receptor antagonists afterwards.
By in the document as can be known, steroidal compounds such as onapristone or onapristone, it differentiates progesterone-receptor-antagonists effect and Antiglucocorticoid effect, has better centrifugation with respect to RU 486, in addition also known various its non-steroidal structure to the antagonist action of PgR that detected is [for example referring to S.A.Leonhardt and D.P.Edwards, Exp.Biol.Med.227:969-980 (2002); And R.Winneker, A.Fensome, J.E.Wrobel, Z.Zhang, P.Zhang, Seminars in Reproductive Medicine, Volume 23:46-57 (2005)].But compound known is compared with known steroidal structure and is only had medium antagonistic activity at present.The external activity tool of effective nonsteroidal compound is described as RU 486 active 10%.
The Antiglucocorticoid activity is that main treatment application is disadvantageous for wherein suppressing PgR.The Antiglucocorticoid activity causes unwished-for side effect when treating required dosage.This can hinder the termination of using or causing treating of the useful dosage of treatment.
Therefore, partly or completely reducing Antiglucocorticoid character is important requirement for the treatment of using progesterone receptor antagonists, particularly continues the disease of the treatment of several weeks or several months for needs.
Opposite with pure antagonist, PgR partial agonist (SPRMs) has residual agonist character, and the intensity of this character can have different degree.This makes these materials show potent PgR agonism (D.DeManno, W.Elger, R.Garg, R.Lee in special tract, B.Schneider, H.Hess-Stumpp, G.Schuber, K.Chwalisz, Steroids 68,2003,1019-1032).These organ specificities and isolating effect can be used for treating described disease.
Therefore, the non-steroidal progesterone receptor modulators that the purpose of this invention is to provide other.These compounds need have the Antiglucocorticoid effect of reduction, and thereby be suitable for treating and prevent such as endometriosis, hysteromyoma, dysfunction is hemorrhage and the gynaecopathia of dysmenorrhoea.In addition, compound according to the present invention is suitable for treatment and prevention of hormone dependent tumour, for example mammary gland, uterine endometrium, ovary and prostate cancer.Moreover compound of the present invention is suitable for women's birth control and female sex hormone replacement therapy.
Summary of the invention
According to the present invention, this purpose realizes by the nonsteroidal compound of following general formula I:
Wherein
R
1And R
2Represent hydrogen atom independently of each other, the C of straight chain or non-straight chain, side chain or non-side chain
1-C
5-alkyl also can form the ring of 3-7 unit altogether with the C atom in this chain,
R
3Represent group C ≡ C-R
a,
R
aRepresent hydrogen or choose the C that is replaced by K in one or more positions wantonly identical or differently
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or Heterocyclylalkyl, or choose aryl or the heteroaryl that is replaced by L in one or more positions wantonly identical or differently,
K is a cyano group, halogen, hydroxyl, nitro ,-C (O) R
b, CO
2R
b,-O-R
b,-S-R
b, SO
2NR
cR
d,-C (O)-NR
cR
d,-OC (O)-NR
cR
d, or-C=NOR
b-NR
cR
d, or choose wantonly in one or more positions identical or differently by M, choose the C that the Heterocyclylalkyl that replaced by L in one or more positions or aryl or heteroaryl replace wantonly
3-C
10-cycloalkyl,
L represents C
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
6-perfluoroalkyl, C
1-C
6-perfluoro alkoxy, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group, (CH
2)
p-C
3-C
10-cycloalkyl, (CH
2)
p-Heterocyclylalkyl, (CH
2)
pCN, (CH
2)
pHal, (CH
2)
pNO
2, (CH
2)
p-C
6-C
12-aryl, (CH
2)
p-heteroaryl ,-(CH
2)
pPO
3(R
b)
2,
-(CH
2)
pNR
cR
d,-(CH
2)
pNR
eCOR
b,-(CH
2)
pNR
eCSR
b,-(CH
2)
pNR
eS (O) R
b,-(CH
2)
pNR
eS (O)
2R
b,-(CH
2)
pNR
eCONR
cR
d,-(CH
2)
pNR
eCOOR
b,-(CH
2)
pNR
eC (NH) NR
cR
d,-(CH
2)
pNR
eCSNR
cR
d,-(CH
2)
pNR
eS (O) NR
cR
d,-(CH
2)
pNR
eS (O)
2NR
cR
d,-(CH
2)
pCOR
b,-(CH
2)
pCSR
b,-(CH
2)
pS (O) R
b,-(CH
2)
pS (O) is R (NH)
b,-(CH
2)
pS (O)
2R
b,-(CH
2)
pS (O)
2NR
cR
d,-(CH
2)
pSO
2OR
b,-(CH
2)
pCO
2R
b,-(CH
2)
pCONR
cR
d,-(CH
2)
pCSNR
cR
d,-(CH
2)
pOR
b,-(CH
2)
pSR
b,-(CH
2)
pCR
b(OH)-R
e,-(CH
2)
p-C=NOR
b,-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-or-(CH
2)
N+2-, wherein n=1 or 2, and end Sauerstoffatom and/or carbon atom are connected on the ring carbon atom of direct neighbor,
M represents C
1-C
6-alkyl or group-COR
b, CO
2R
b,-O-R
b, or-NR
cR
d,
Wherein
R
bRepresent hydrogen or C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, C
6-C
12-aryl or C
1-C
3-perfluoroalkyl, and
R
cAnd R
dRepresent hydrogen independently of each other, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, C
6-C
12-aryl, C (O) R
bOr hydroxyl, if wherein
R
cBe hydroxyl, R
dCan only be a hydrogen, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or C
6-C
12-aryl also can be opposite,
R
eRepresent hydrogen, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or C
6-C
12-aryl, and
P is the number of 0-6,
Perhaps
R
3Be group C=C-R
gR
h, wherein
R
gAnd R
hBe hydrogen independently of each other or choose the C that is replaced by X in one or more positions wantonly identical or differently
1-C
8-alkyl, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl, wherein
X is a cyano group, halogen, hydroxyl, nitro ,-C (O) R
b, CO
2R
b,-O-R
b,-C (O)-NR
cR
d,-NR
cR
d, R wherein
b, R
cAnd R
dHave aforesaid definition,
R
4aAnd R
4bRepresent hydrogen atom independently of each other, C
1-C
4-alkyl, C
2-C
4-thiazolinyl or form 3-6 unit ring with ring carbon atom,
A represents monocycle or bicyclic carbocyclic ring or heteroaromatic ring, and it is chosen wantonly in one or more positions and is replaced by following group: C
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
6-perfluoroalkyl, C
1-C
6-perfluoro alkoxy, C
1-C
6-alkoxy-C
1-C
6-alkyl, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group, (CH
2)
p-C
3-C
10-cycloalkyl, (CH
2)
p-Heterocyclylalkyl, (CH
2)
pCN, (CH
2)
pHal, (CH
2)
pNO
2, (CH
2)
p-C
6-C
12-aryl, (CH
2)
p-heteroaryl ,-(CH
2)
pPO
3(R
b)
2,-(CH
2)
pNR
cR
d,-(CH
2)
pNR
eCOR
b,-(CH
2)
pNR
eCSR
b,-(CH
2)
pNR
eS (O) R
b,-(CH
2)
pNR
eS (O)
2R
b,-(CH
2)
pNR
eCONR
cR
d,-(CH
2)
pNR
eCOOR
b,-(CH
2)
pNR
eC (NH) NR
cR
d,-(CH
2)
pNR
eCSNR
cR
d,-(CH
2)
pNR
eS (O) NR
cR
d,-(CH
2)
pNR
eS (O)
2NR
cR
d,-(CH
2)
pCOR
b,-(CH
2)
pCSR
b,-(CH
2)
pS (O) R
b,-(CH
2)
pS (O) is R (NH)
b,-(CH
2)
pS (O)
2R
b,-(CH
2)
pS (O)
2NR
cR
d,-(CH
2)
pSO
2OR
b,-(CH
2)
pCO
2R
b,-(CH
2)
pCONR
cR
d,-(CH
2)
pCSNR
cR
d,-(CH
2)
pOR
b,-(CH
2)
pSR
b,-(CH
2)
pCR
b(OH)-R
d,-(CH
2)
p-C=NOR
b,-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-or-(CH
2)
N+2-, wherein n=1 or 2, and end Sauerstoffatom and/or carbon atom are connected on the ring carbon atom of direct neighbor, or
A represents group-CO
2R
b, C (O) NR
cR
d, COR
b,
Perhaps
A represents thiazolinyl-CR
5=CR
6R
7, wherein
R
5, R
6And R
7Identical or different, and represent hydrogen atom independently of each other, halogen, aryl, or not replacement or partially or completely fluorizated C
1-C
5-alkyl, perhaps
A represents alkynyl-C ≡ CR
5, R wherein
5Have aforesaid definition, and
B represents carbonyl or group CH
2,
And the acceptable salt of pharmacology.
Owing to there is asymmetric center, the compound of the general formula I according to the present invention can exist with different steric isomers.The steric isomer of racemoid and Individual existence is all gone up the part of theme of the present invention.
In addition, the present invention includes the pharmaceutical preparation that new compound, its preparation method, treatment as active constituents of medicine are used and comprised these novel substances.
Compound or the acceptable salt of its pharmacology according to general formula of the present invention (I) can be used in the preparation medicine, especially for the treatment and the prevention such as endometriosis, hysteromyoma, dysfunction is hemorrhage and the gynaecopathia of dysmenorrhoea.In addition, compound according to the present invention can be used in treatment and prevention of hormone dependent tumour, for example mammary gland, prostate gland and carcinoma of endometrium.
Compound or the acceptable salt of its pharmacology according to general formula of the present invention (I) can be used in women's birth control and female sex hormone replacement therapy.
The method for preparing the compound of this general formula (I) also is a theme of the present invention.By the selectivity addition reaction such as the organometallic compound of alkynyl lithium or halo alkynyl magnesium, substituent R
3Be introduced into ketone group.This directly or after carrying out extra modification produces according to general formula of the present invention (I) compound.
Compound according to the present invention is made by optionally organometallic compound being added to the ketone group amide compound, and the latter has description at for example WO 200375915 and WO 9854159.Described organometallic compound for example can be alkynyl lithium compound or halo alkynyl magnesium compound.These compounds for example are that the reaction by corresponding alkynes and butyllithium or Grignard compound prepares.Be similar to this, also can prepare corresponding organo-metallic alkenyl compound.In the case, described ketone group has significantly higher reactive behavior than amide group carbonyl or benzo [c] furanone, makes can realize the selectivity addition by selective reaction condition suitably.Scheme as an alternative is as R
3Alkynyl or the thiazolinyl introduced also can be modified subsequently.Modify for carrying out these, reaction well known by persons skilled in the art all is suitable, the catalytic reaction of for example oxidation, reduction, replacement, alkylation or palladium.The optional protecting group that exists can remove in the suitable time.
Nonsteroidal compound according to general formula I of the present invention has strong antagonist action or strong partial agonist effect to PgR.With respect to the bonding strength to PgR and glucocorticoid receptor, they have strong centrifugation.Known progesterone receptor antagonists such as mifepristone (RU 486), except PgR being had desirable binding affinity, have high affinity equally for glucocorticoid receptor, still the feature according to compound of the present invention is to have low glucocorticoid receptor associativity when having high PgR affinity.
Embodiment
Substituting group according to the compound of general formula I of the present invention has following implication respectively.
C
1-C
5-, C
1-C
6-or C
1-C
8-alkyl is defined as straight chain or non-straight chain, side chain or non-branched-chain alkyl.In the case, it for example is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2,2-dimethyl propyl, 3-methyl butyl, hexyl, heptyl or octyl group.
In the case, for R
aPreferably methyl, ethyl, n-propyl or normal-butyl and n-pentyl.
For R
1And R
2, methyl or ethyl are preferred.
According to the present invention, hydrogen is for R
4aAnd R
4bBe preferred.
Thiazolinyl is defined as straight chain or non-straight chain, side chain or non-branched-chain alkenyl.For the present invention, C
2-C
8-thiazolinyl for example is vinyl, allyl group, 3-butene-1-Ji or 2,3-dimethyl-2-propenyl.If aromatic compound A is by C
2-C
8-alkenyl substituted then is preferably vinyl.
Alkynyl is defined as straight chain or non-straight chain, side chain or non-alkynyl group.C
2-C
8-alkynyl for example can be ethynyl, proyl, butynyl, pentynyl, hexin base or octyne base.
For C
3-C
10-cycloalkyl for example is preferably cyclopropane, tetramethylene, pentamethylene and hexanaphthene, wherein is preferably cyclopropyl, cyclopentyl and cyclohexyl.
For R
a, K or L, Heterocyclylalkyl is defined as 3 to 8 yuan of Heterocyclylalkyls.The example of Heterocyclylalkyl is morpholine, tetrahydrofuran (THF), pyrans, piperazine, piperidines, tetramethyleneimine, oxyethane, trimethylene oxide, aziridine, dioxolane and dioxane.In the case, heteroatoms can be chemically any feasible position with respect to the position of tie point.
For example, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group can be methoxymethoxy, oxyethyl group methoxy base or 2-methoxy ethoxy.
For the present invention, group OR
bBe hydroxyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy, or n-pentyloxy, 2,2-dimethyl propoxy-or 3-methyl butoxy.Hydroxyl, methoxyl group and oxyethyl group are preferred.
For fluorizated C partially or completely
1-C
5-alkyl can be considered fluoridized abovementioned alkyl.Wherein main uncle's trifluoromethyl or pentafluoroethyl group, and partially fluorinated alkyl, for example 5,5,4,4-five fluorine amyl groups or 5,5,5,4,4,3,3-seven fluorine amyl groups.
Fluorine, chlorine, bromine or iodine atom can be represented halogen atom.Here be preferably fluorine, chlorine or bromine.
If R
1And R
2C atom in chain forms 3-7 unit ring, and then it for example is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.Cyclopropyl and cyclopentyl ring are preferred.
At substituted monocycle in a plurality of positions or two ring carbocyclic ring aromatic nucleus A is carbocyclic ring or heterocyclic aryl.
Under first kind of situation, it for example is a phenyl or naphthyl, is preferably phenyl.
For heterocyclic group, it can be the monocyclic heterocycles group, as thienyl, furyl, pyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thiazolyl, oxazolyl, furazan base, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl or tetrazyl, and with respect to all possible isomer of heteroatomic position.
For R
3, aryl is optional phenyl, 1-or the 2-naphthyl that replaces, wherein preferred phenyl.The example of heteroaryl is 2-, 3-or 4-pyridyl, 2-or 3-furyl, 2-or 3-thienyl, 2-or 3-pyrryl, 2-, 4-or 5-imidazolyl, pyrazinyl, 2-, 4-or 5-pyrimidyl or 3-or 4-pyridazinyl.
Group (CH
2)
pIn numerical value p can be the numerical value of 0-6, preferred 0-2." group " is defined as all and (CH according to the present invention
2)
pRelevant functional group.
If the compound (B=-CH of general formula I
2-) exist with the form of salt, this can be, for example, and hydrochloride, vitriol, nitrate, tartrate, Citrate trianion, fumarate, succinate or benzoate.
If compound according to the present invention exists with racemic mixture, they can be separated into pure, optically active form according to racemic modification method for splitting well-known to those skilled in the art.For example racemic mixture can itself be exactly optically active carrier substance (CHIRALPAK AD by chromatogram
(R)) on be separated into pure isomer.Also may be with the free hydroxyl of the racemic compound of optically active acid esters general formula I, and separate by fractional crystallization or the diastereomer ester that obtains by chromatographic separation, and following isolating ester of every kind of situation of saponification is to form optically pure isomer.As optically active acid, for example mandelic acid, camphorsulfonic acid or tartrate can be used.
Following compound and application thereof are preferred according to the present invention.
The biology of The compounds of this invention characterizes
The evaluation of progesterone receptor modulator can be undertaken by using simple method, test procedure well known by persons skilled in the art.Whether for this purpose, for example, compound to be tested is being used for the test macro incubation of PgR with progestogen, detect the effect that progesterone mediates in this test macro in the presence of conditioning agent then and be changed.
According to the material of general formula I of the present invention according to measuring with drag.
PgR is in conjunction with experiment
The measurement of receptor binding affinity
Receptor binding affinity is by the specificity bonded
3Hormone of H-mark (tracer) and compound to be tested are measured the competitiveness combination of the acceptor in the cytosol that is obtained by the animal target organ.In the case, search out the saturated and molecular balance of acceptor.
The compound to be tested that described tracer and concentration raise gradually (competition thing) is with the cytosol part that comprises acceptor incubation 18 hours under 0-4 ℃.Behind charcoal-dextran suspensoid separation tracer, the tracer part of the receptors bind when measuring each concentration is then by concentration sequential determination IC
50IC as reference material and compound to be tested
50The merchant (x100%) of value calculates relative mole binding affinity (RBA) (RBA=100% of reference material).
For described acceptor type, select following incubation conditions.
PgR:
The uterine cell colloidal sol of the rabbit of estradiol sensitization (estradiol-primed), comprise the TED damping fluid of 250mmol sucrose (Tris/HCl of 20mmol, pH 7.4; The ethylene diaminetetraacetic acid of 1mmol, the dithiothreitol (DTT) of 2mmol) middle homogenizing, store down at-30 ℃.Tracer:
3H-ORG 2058,5nmol; Reference material: progesterone.
Glucocorticoid receptor:
Through the thymocyte colloidal sol of adrenoprival rat, thymus gland stores down at-30 ℃, damping fluid: TED.Tracer:
3The H-dexamethasone, 20nmol; Reference material: dexamethasone.
Compound of Formula I according to the present invention to the receptor relative binding affinity (RBA value) of PgR with respect to progesterone between 3-100%.On glucocorticoid receptor, this RBA value with respect to dexamethasone in the scope of 3-30%.
Compound according to the present invention has high-affinity to PgR, but glucocorticoid receptor is had low affinity.
The antagonistic action of PgR PR-B
The trans-activation experiment is carried out described in WO 02/054064.
The agonism of PgR PR-B
The trans-activation experiment is carried out (Fuhrmann, U. as described in people such as Fuhrmann; Hess-Stump, H.; Cleve, A.; Neef, G.; Schwede, W.; Hoffmann, J.; Fritzemeier, K.-H., Chwalisz, K.; Journal ofMedicinal Chem., 43,26,2000,5010-5016).
Dosage
For application according to the present invention, but described progesterone receptor modulator per os, enteron aisle, parenteral route or transdermal administration.
Usually, in animal, if The compounds of this invention every day dosage at 1 μ g in the 500mg scope, then can expect satisfied result during above-mentioned disease in treatment.
Hemorrhage and when being used for Birth control and Hormone Replacement Therapy in treatment endometriosis, hysteromyoma and dysfunction, depend on patient's age and situation, suitable dose according to compound of the present invention is μ g to500mg every days 50, and wherein required every day, dosage can disposable or administration several times.
In treatment during mammary cancer, be 10mg-1000mg every day according to the dosage range of compound of the present invention.
Can be based on the prescription of the pharmaceutical preparation of this new compound in mode well known in the art, undertaken by the form of medication that expectation was processed and changed into to activeconstituents with the material of the vehicle that is generally used for Galenic formula, filler, influence degraded, wedding agent, wetting agent, lubricant, absorption agent, thinner, correctives, tinting material etc.In this case, referring to Remington ' s Pharmaceutical Science, the 15th edition, Mack PublishngCompany, East Pennsylvania (1980).
For oral administration, especially tablet, film tablet, coated tablet, capsule, pill, powder, granule, lozenge, suspensoid, emulsion or solution all are fit to.
For parenteral introduction, injection and infusion preparation are possible.
For intra-articular injection, the crystal suspensoid of available corresponding preparation.
For intramuscularly, used water and oily injection solution or suspension and corresponding depot formulation.
For rectal administration, described new compound can use to carry out whole body and topical therapeutic with the form of suppository, capsule, solution (for example form of enema) and ointment.
In addition, also comprise the preparation that is used for vagina administration.
For the pulmonary administration of new compound, this compound can use with aerosol and inhalation form.
For transdermal administration, it is feasible that medicine pastes.For topical application, gel, ointment, salve, ointment, paste, powder, emulsion and tincture formulation are possible.In the dosage of the compound of these preparation formula ofs I should the scope at 0.01%-20% to realize enough pharmacological actions.
Corresponding tablet can for example prepare by mixed active composition and known assistant agent, and described assistant agent for example is an inert diluent, as glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, polyvinylpyrrolidone; Disintegrating agent is as W-Gum or alginic acid; Tackiness agent is as starch or gelatin; Lubricant is as Magnesium Stearate or talcum; And/or the material of realization slow releasing function, as carboxyl polymethylene, carboxymethyl cellulose, Cellacefate or polyvinyl acetate.This tablet also can be formed by a plurality of layers.
Therefore, coated tablet can be prepared as follows: with normally used material in the tablet coating label of the method manufacturing that is similar to tablet is carried out dressing, described material for example is polyvinylpyrrolidone or shellac, Sudan Gum-arabic, talcum, titanium dioxide or sugar.In the case, the coated tablet shell also can be formed by a plurality of layers, wherein can use at the assistant agent described in the tablet.
Solution or suspensoid according to compound of Formula I of the present invention can comprise extra taste improving agent, as asccharin, cyclamate or sugar, and seasonings, as vanilla or orange extract.In addition, they can comprise suspension aids, as Xylo-Mucine, or sanitas, as the p-hydroxy benzoate.
The capsule that comprises compound of Formula I can for example be prepared as follows: the compound of general formula I and inert support such as lactose or sorbyl alcohol mix, and encapsulate is in gelatine capsule then.
Suitable suppository can be equipped with by for example mixing to draw with the carrier that provides for this purpose such as neutral fat or polyoxyethylene glycol or derivatives thereof.
Compound or the acceptable salt of its pharmacology according to general formula of the present invention (I) can be used to prepare medicine based on their antagonistic action or partial agonist effect, especially for the treatment and the prevention such as endometriosis, hysteromyoma, dysfunction is hemorrhage and the gynaecopathia of dysmenorrhoea.In addition, compound according to the present invention can be used for hormone antagonist irregular, causes menstruation, and induces fertility separately or with prostaglandin(PG) and/or pitocin.
In addition, compound or the acceptable salt of its pharmacology according to general formula of the present invention (I) is suitable for preparing female contraceptive agent (also referring to WO 93/23020, WO 93/21927).
Moreover, can be used from the female hormone replacement therapy separately or with selective estrogen receptor modulators (SERM) according to the compound or the acceptable salt of its pharmacology of general formula of the present invention (I).
In addition, above-claimed cpd has antiproliferative effect in hormone-dependent tumor.Therefore, they are suitable for treating the hormonal dependent cancer, for example mammary gland, prostate cancer or carcinoma of endometrium.
In a roentgenism x and two roentgenism ies, all can be used for treating the hormonal dependent cancer according to compound of the present invention or the acceptable salt of its pharmacology, particularly after the tamoxifen failure.
The compound of the general formula (I) with antagonistic action or partial agonist effect according to the present invention or the acceptable salt of its pharmacology also can be united use with compound with estrogenic antagonist (estrogen receptor antagon or aromatase inhibitor) or selective estrogen receptor modulators (SERM), are used to prepare the pharmaceutical preparation for the treatment of hormone-dependent tumor.For treatment endometriosis or hysteromyoma, can unite use with SERM or estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) according to compound of the present invention.When the treatment hormone-dependent tumor, described progesterone receptor modulator and estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) or SERM administration simultaneously or order administration.When the order administration, preferably at first described estrogen antagonist of administration (estrogen receptor antagon or aromatase inhibitor) or SERM, and then the described progesterone receptor modulator of administration.
In the case, when uniting use, for example can consider following estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) or SERM with non-steroidal progesterone receptor modulators according to the present invention:
Tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-five fluorine amyl groups) sulfinyl]-amyl group oxygen base } phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepta alkene-2-alcohol (WO 00/03979); ICI 182780 (7 α-[9-(4,4,5,5-five fluorine amyl group sulfinyls) nonyl] female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3); 11 β-fluoro-7 α-[5-(methyl { 3-[(4,4,5,5,5-five fluorine amyl groups) sulfane base]-propyl group } amino) amyl group] female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3 (WO98/07740); 11 β-fluoro-7 α-{ 5-[methyl (7,7,8,8,9,9,10,10,10-nine fluorine decyls) amino] amyl group } is female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3 (WO 99/33855); 11 β-fluoro-17 Alpha-Methyls-7 α-{ 5-[methyl-(8,8,9,9,9-five fluorine nonyls) amino] amyl group } is female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3 (WO 03/045972); Clomiphene; Raloxifene and other estrogen antagonist active compound, and aromatase inhibitor are as the stubborn assistant of method, formestane, letrozole, Anastrozole or Atamestane.
At last, the invention still further relates to compound of Formula I, optional application in the preparation medicine with estrogen antagonist or SERM.
The invention still further relates to and comprise at least a pharmaceutical composition according to compound of the present invention, the optional form for the compatible salt of pharmacology/pharmacology of this compound can comprise or not contain compatible assistant agent of pharmacology and/or carrier.
These pharmaceutical compositions and medicine per os, rectum, vagina, subcutaneous, through skin, intravenously or intramuscular administration.Except that carrier and/or thinner commonly used, they comprise at least a according to compound of the present invention.
Medicine of the present invention makes with the conventional solid that uses or liquid vehicle or thinner and corresponding to the pharmacy auxiliary agent commonly used of desirable administration type in accordance with known methods.Preferred preparation is the distribution formulation that is suitable for oral administration.These distribute formulation for example is tablet, film tablet, coated tablet, capsule, pill, powder, solution or suspensoid or other storage storehouse formulations.
Comprise at least a pharmaceutical composition preferred oral administration according to compound of the present invention.
Also can consider the preparation of parenteral administration, as injection liquid.
In addition, described formulation example as can more than be used for the suppository of vagina administration.
Following examples are used for explaining theme of the present invention in more detail, but never only limit to these embodiment.
Initial compounds 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-oxo propionyl amino } preparation of benzo [c] furanone is described among the patent WO 200375915, and 5-{3-[1-phenyl-cyclopropyl]-2-oxo propionyl amino } preparation of benzo [c] furanone is described among the WO 9854159.
Rac-5-{2-ethynyl-2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-propionyl amino } benzo [c] furanone
1
Ethynyl bromination magnesium (6ml, 0.5M tetrahydrofuran solution) is added into 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-oxo propionyl amino } in the ice-cold solution of benzo [c] furanone (632mg) in THF (4ml).Reaction soln was back to room temperature in 3 hours under argon gas.Then, this reaction mixture is poured in the ice-cold saturated ammonium chloride solution.Use ethyl acetate extraction.The organic phase that merges is washed with saturated nacl aqueous solution, and is dry on sodium sulfate then.The crude product of gained carry out chromatographically pure system on silica gel.Obtain the 2.2g product.
1H-NMR(ppm，CDCl
3，400MHz)：0.83(1H)，0.92-1.10(2H)，2.37(1H)，2.56(1H)，2.59(1H)，3.10(1H)，5.28(2H)，7.02(1H)，7.31(1H)，7.37(1H)，7.58(1H)，7.86(1H)，7.94(1H)，8.70(1H).
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-propynyl-propionyl amino } benzo [c] furanone
2
Be similar to embodiment 1, by 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino of 1-proyl magnesium bromide (the 0.5M tetrahydrofuran solution of 2ml) and 210mg]-4-methyl-2,3-benzoxazine-1-ketone obtains the product of 145mg.
1H-NMR(ppm，CDCl
3，400MHz)：0.86(1H)，0.90-1.05(3H)，1.72(3H)，2.35(1H)，2.49(1H)，2.96(1H)，5.27(2H)，7.03(1H)，7.30(1H)，7.36(1H)，7.58(1H)，7.85(1H)，7.98(1H)，8.73(1H).
(+)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-phenyl-propionyl amino benzo [c] furanone 3a and
(-)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(phenylacetylene base)-propionyl amino } benzo [c] furanone 3b
Under-78 ℃, n-Butyl Lithium (625 μ l, 1.6M hexane solution) is added in the solution of phenylacetylene in tetrahydrofuran (THF) of 110 μ l.Under this temperature, continue to stir 30 minutes, then Dropwise 5-{ 3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-oxo propionyl amino } benzo [c] furanone (210mg) solution in the 5ml tetrahydrofuran (THF).Then make it in about 3 hours time, get back to 23 ℃, and restir 10 hours.Reaction mixture is poured in the ice-cold saturated ammonium chloride solution.Use ethyl acetate extraction.The organic phase that merges is washed with saturated nacl aqueous solution, and is dry on sodium sulfate then.Crude product carry out chromatographically pure system on silica gel.(Chiralpak AD post, 250 * 10mm) are separated into enantiomorph 3a (46mg) and 3b (47mg) to the racemic mixture of gained by preparation property chirality HPLC.
3a and 3b:
1H-NMR(ppm，CDCl
3，300MHz)：0.88(1H)，0.95-1.11(3H)，2.46(1H)，2.65(1H)，3.10(1H)，5.27(2H)，7.00(1H)，7.24-7.42(7H)，7.61(1H)，7.84(1H)，7.98(1H)，8.80(1H).
3a：[α]
D 20：+12.9°(CHCl
3，1.06g/100ml；λ＝589nM)
3b：[α]
D 20：-14.4°(CHCl
3，1.03g100ml；λ＝589nM)
Be similar to embodiment 3, by 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-oxo propionyl amino } benzo [c] furanone and corresponding aryl ethane lithium make compound 4 and 5.
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-trifluoromethyl) ethynyl] propionyl amino } benzo [c] furanone
4
1H-NMR(ppm，CDCl
3，300MHz)：0.92(1H)，0.99-1.16(3H)，2.55(1H)，2.68(1H)，3.27(1H)，5.30(2H)，7.03(1H)，7.30-7.52(4H)，7.55-7.62(2H)，6.67(1H)，7.99(1H)，8.03(1H)，8.84(1H).
(+)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-trifluoromethyl) ethynyl] propionyl amino } benzo [c] furanone
4aAnd
(-)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-trifluoromethyl) ethynyl] propionyl amino } benzo [c] furanone 4b
At embodiment
4(post ChiralpakAD 250 * 10mm) is separated into enantiomorph to the middle racemic mixture of describing (150mg) with preparation property chirality HPLC
4a(51mg) and
4b(62mg).
4a：[α]
D 20：+6.3°(CHCl
3，1.07g/100ml；λ＝589nM)
4b：[α]
D 20：-5.3°(CHCl
3，1.09g100ml；λ＝589nM)
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-aminomethyl phenyl) ethynyl] propionyl amino } benzo [c] furanone
5
1H-NMR(ppm，CDCl
3，300MHz)：0.87(1H)，0.93-1.15(3H)，2.38(3H)，2.45(1H)，2.66(1H)，3.11(1H)，5.25(2H)，6.99(1H)，7.10(2H)，7.18-7.38(4H)，7.61(1H)，7.86(1H)，8.00(1H)，8.80(1H).
(+)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-aminomethyl phenyl) ethynyl] propionyl amino benzo [c] furanone 5a and
(-)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-aminomethyl phenyl) ethynyl] propionyl amino } benzo [c] furanone 5b
At embodiment
5(post ChiralpakAD 250 * 10mm) is separated into enantiomorph to the middle racemic mixture of describing (109mg) with preparation property chirality HPLC
5a(41mg) and
5b(28mg).
5a：[α]
D 20：+14.8°(CHCl
3，1.07g/100ml；λ＝589nM)
5b：[α]
D 20：-16.3°(CHCl
3，1.13g100ml；λ＝589nM)
Rac-5-{2-[(4-acetoxyl group phenyl) ethynyl]-2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-propionyl amino } benzo [c] furanone
6
Compound (104mg), triphenylphosphine (12.2mg), cupric iodide (8.9mg), 4-iodophenyl acetic ester (92mg), the suspension of acid chloride (5.3mg) in THF (5ml) and triethylamine (5ml) described among the embodiment 1 were reacted 1 hour down in 25 °.Then, it is poured in the saturated aqueous ammonium chloride solution.Use ethyl acetate extraction, water and saturated nacl aqueous solution washing then.The organic phase that merges is dry on sodium sulfate.Crude product obtains the 55mg product after carrying out the pure system of column chromatography on the silica gel.
1H-NMR(ppm，CDCl
3，400MHz)：0.88(1H)，0.95-1.10(3H)，2.29(3H)，2.45(1H)，2.63(1H)，3.17(1H)，5.29(2H)，6.97-7.07(3H)，7.28-7.37(4H)，7.60(1H)，7.84(1H)，7.98(1H)，8.80(1H).
Rac-5-{2-hydroxyl-2-[(4-hydroxy phenyl) ethynyl]-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-propionyl amino } benzo [c] furanone
7
The solution of compound (45mg) in 5ml methyl alcohol of describing in 6 is mixed with sodium bicarbonate (130mg).23 ℃ of following restir 2 hours.Reaction mixture dilutes with ethyl acetate, then with saturated nacl aqueous solution washing 2 times.After drying on the sodium sulfate, crude product carries out the pure system of column chromatography on silica gel, obtain the 38mg product.
1H-NMR(ppm，CDCl
3，300MHz)：0.87(1H)，0.92-1.11(3H)，2.43(1H)，2.64(1H)，3.11(1H)，5.27(2H)，5.67(1H)，6.73(2H)，6.98(1H)，7.14(2H)，7.28-7.38(2H)，7.60(1H)，7.85(1H)，7.97(1H)，8.84(1H).
The rac-5-{2-[(4-carboxyl phenyl) ethynyl]-2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-propionyl amino } benzo [c] furanone
8
Be similar to embodiment 6, prepare compound 8 by compound and the 4-iodo-benzoic acid described among the embodiment 1.
1H-NMR(ppm，CDCl
3/MeOD(5％)，400MHz)：0.82(1H)，0.89-1.05(3H)，2.37(1H)，2.65(1H)，5.24(2H)，6.97(1H)，7.35(1H)，7.44(2H)，7.50-7.65(2H)，7.72(1H)，7.80(1H)，7.92(2H).
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(pentyne-1-yl)-propionyl amino } benzo [c] furanone
9
The solution of 1-pentyne (0.94ml) in THF (9ml) is in-78 ℃ of following and nBuLi (0.6ml, 1.6M hexane solution) mixing.Stirred 30 minutes down at-78 ℃, add 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl then]-2-oxo propionyl amino } solution of benzo [c] furanone (200mg) in the 3ml tetrahydrofuran (THF).In 3 hours time, make it be back to 23 ℃, and under this temperature restir 10 hours.Reaction mixture is poured in the ice-cold saturated ammonium chloride solution.Use ethyl acetate extraction.The organic phase that merges is washed with saturated nacl aqueous solution, and is dry on sodium sulfate then.Crude product carry out chromatographically pure system on silica gel, obtain the 130mg product.
1H-NMR(ppm，CDCl
3，400MHz)：0.82(1H)，0.92-1.07(6H)，1.45(2H)，2.08(2H)，2.30(1H)，2.53(1H)，2.83(1H)，5.27(2H)，7.02(1H)，7.29(1H)，7.36(1H)，7.57(1H)，7.84(1H)，7.96(1H)，8.72(1H).
(+)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(pentyne-1-yl)-propionyl amino benzo [c] furanone 9a and
(-)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(pentyne-1-yl)-propionyl amino } benzo [c] furanone 9b
At embodiment
9(post ChiralpakAD 250 * 10mm) is separated into enantiomorph to the middle racemic mixture of describing (120mg) with preparation property chirality HPLC
9a(46mg) and
9b(47mg).
9a：[α]
D 20：+10.9°(CHCl
3，1.01g/100ml；λ＝589nM)
9b：[α]
D 20：-10.6°(CHCl
3，1.08g100ml；λ＝589nM)
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(hexin-1-yl)-propionyl amino } benzo [c] furanone
10
Be similar to embodiment 9 synthetic compounds 10.
1H-NMR(ppm，CDCl
3，400MHz)：0.80-1.06(7H)，1.30-1.50(2H)，1.59(2H)，2.10(2H)，2.30(1H)，2.52(1H)，2.82(1H)，5.28(2H)，7.02(1H)，7.30(1H)，7.36(1H)，7.57(1H)，7.84(1H)，7.95(1H)，8.72(1H).
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-hydroxyl) butine-1-yl]-propionyl amino } benzo [c] furanone
11
Steps A: make 4-(t-butyldimethylsilyl oxygen base) fourth-1-alkynes (175mg), nBuLi (0.59ml; 1.6M hexane solution) and 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-oxo propionyl amino-benzo [c] furanone (200mg) is similar among the embodiment 9 method of describing and reacts in tetrahydrofuran (THF), obtain the product of 165mg.
Step B: the product (160mg) that obtains in the steps A is dissolved in the 5ml tetrahydrofuran (THF).Under 0 ℃, add the 1M tetrabutyl ammonium fluoride tetrahydrofuran solution of 270 μ l, and stirred 1 hour down, then 23 ℃ of following restir 2 hours at 0 ℃.This reaction mixture is poured in the saturated sodium bicarbonate aqueous solution.With ethyl acetate extraction for several times.The organic phase that merges is washed with saturated nacl aqueous solution, and dry on sodium sulfate.After carry out chromatographically pure system on the silica gel, obtain the 77mg product.
1H-NMR(ppm，CDCl
3，400MHz)：0.83(1H)，0.90-1.03(3H)，2.20-2.40(3H)，2.50(1H)，3.39(1H)，3.68(2H)，5.25(2H)，7.01(1H)，7.32(2H)，7.57(1H)，7.82(1H)，7.93(1H)，8.91(1H).
Be similar to embodiment 11, by 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-oxo propionyl amino } benzo [c] furanone prepares compound 12 and 13:
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(5-hydroxyl) pentyne-1-yl]-propionyl amino } benzo [c] furanone
12
1H-NMR(ppm，CDCl
3，400MHz)：0.83(1H)，0.90-1.03(3H)，1.70(2H)，2.24(2H)，2.33(1H)，2.50(1H)，3.09(1H)，3.71(2H)，5.26(2H)，7.02(1H)，7.35(2H)，7.57(1H)，7.83(1H)，7.97(1H)，8.82(1H).
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(3-hydroxyl) propine-1-yl]-propionyl amino } benzo [c] furanone
13
1H-NMR(ppm，CDCl
3，400MHz)：0.84(1H)，0.90-1.03(3H)，2.37(1H)，2.52(1H)，3.25(1H)，4.17(2H)，5.27(2H)，7.02(1H)，7.30-7.40(2H)，7.58(1H)，7.83(1H)，7.91(1H)，8.77(1H).
(+)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(3-hydroxyl) propine-1-yl]-propionyl amino benzo [c] furanone 13a and
(-)-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(3-hydroxyl) propine-1-yl]-propionyl amino } benzo [c] furanone 13b
At embodiment
13(post ChiralpakAD 250 * 10mm) is separated into enantiomorph to the middle racemic mixture of describing (80mg) with preparation property chirality HPLC
13a(35mg) and
13b(37mg).
13a：[α]
D 20：+28.3°(CHCl
3，1.01g/100ml；λ＝589nM)
13b：[α]
D 20：-29.3°(CHCl
3，1.08g100ml；λ＝589nM)
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-the 2-[(4-hydroxy-3-methyl) butine-1-yl]-propionyl amino } benzo [c] furanone
14
Steps A: be similar to embodiment 11; make 5-{3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl of 300mg]-2-oxo propionyl amino } tertiary butyl-(1 of benzo [c] furanone and 282mg; 1-dimethyl Propargyl-oxygen base)-and the dimethylsilane reaction, obtain the 15mg product A.
Step B:70mg obtains compound dissolution in the 1ml methylene dichloride in steps A.At 0 ℃ of trifluoroacetic acid (20% dichloromethane solution) that adds 650 μ l down, and under 0 ℃, stirred 3.5 hours.Then vacuum-evaporation is extremely done, and residue carries out the pure system of column chromatography on silica gel.Obtain the 27mg product.
1H-NMR(ppm，CDCl
3，400MHz)：0.82(1H)，0.90-1.00(2H)，1.04(1H)，1.47(6H)，2.28(1H)，2.58(1H)，3.08(1H)，5.27(2H)，7.03(1H)，7.30(1H)，7.36(1H)，7.59(1H)，7.83(1H)，7.91(1H)，8.78(1H).
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(2-(tertiary butyl carboxyl) acetylene-1-yl)-propionyl amino } benzo [c] furanone
15
Be similar to embodiment 9 synthetic compounds 15.
1H-NMR(ppm，CDCl
3，400MHz)：0.87(1H)，0.93-1.05(3H)，1.46(9H)，2.42(1H)，2.59(1H)，3.39(1H)，5.28(2H)，7.03(1H)，7.30-7.42(2H)，7.57(1H)，7.85(1H)，7.92(1H)，8.68(1H).
Rac-5-{2-hydroxyl-3-[1-(2-fluoro-5-trifluoromethyl)-cyclopropyl]-2-(2-carboxyl acetylene-1-yl)-propionyl amino } benzo [c] furanone
16
The compound dissolution that 50mg describes in embodiment 15 is in the 5ml methylene dichloride.Add the trifluoroacetic acid of 100 μ l, then 23 ℃ of following restir 12 hours.Vacuum-evaporation is to dried, and residue carries out pure system by the column chromatography on the silica gel.Obtain the 36mg product.
1H-NMR(ppm，DMSO-D
6，300MHz)：0.48(1H)，0.78(1H)，0.86(1H)，1.09(1H)，1.73(1H)，2.89(1H)，5.27(2H)，6.62(1H)，7.13(1H)，7.31(1H)，7.41(1H)，7.53(1H)，7.62(1H)，7.68(1H)，9.85(1H).
Be similar to embodiment 3, by 5-{3-[1-phenyl-cyclopropyl]-2-oxo propionyl amino } benzo [c] furanone prepares compound 17.
Rac-5-{2-hydroxyl-3-[1-phenyl-cyclopropyl]-2-(phenyl-ethynyl) propionyl amino }-benzo [c] furanone
17
1H-NMR(ppm，CDCl
3，400MHz)：0.78(1H)，0.90(1H)，1.10-1.21(2H)，2.38(1H)，2.72(1H)，2.77(1H)，5.28(2H)，7.18(1H)，7.25-7.42(6H)，7.41-7.52(4H)，7.82(1H)，8.06(1H)，8.79(1H).
Claims (according to the modification of the 19th of treaty)
The statement of PCT treaty the 19th (1) bar
According to the 19th of PCT treaty, the applicant submits following claims at this and replaces page or leaf:
Claim 1 and claim 12-16 do not change,
Claim 2-11 revises according to the written comment of International Searching Authority, with " preferably " speech of wherein existing of deletion,
Claim 17 is rewritten, what is claimed is at first medicinal to show this,
Claim 18-25 makes amendment, with the relation between explanation and the claim 1-13, and has deleted claim 26.
The applicant guarantees, known to it, does not introduce fresh content without permission in the modification of being carried out in the application to the greatest extent.
1. the compound of general formula I,
Wherein
R
1And R
2Represent hydrogen atom independently of each other, the C of straight chain or non-straight chain, side chain or non-side chain
1-C
5-alkyl also can form the ring of 3-7 unit altogether with the C atom in this chain,
R
3Represent group C ≡ C-R
a, wherein
R
aRepresent hydrogen or choose the C that is replaced by K in one or more positions wantonly identical or differently
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or Heterocyclylalkyl, or choose aryl or the heteroaryl that is replaced by L in one or more positions wantonly identical or differently,
K is a cyano group, halogen, hydroxyl, nitro ,-C (O) R
b, CO
2R
b,-O-R
b,-S-R
b, SO
2NR
cR
d,-C (O)-NR
cR
d,-OC (O)-NR
cR
d, or-C=NOR
b-NR
cR
d, or choose wantonly in one or more positions identical or differently by M, choose the C that the Heterocyclylalkyl that replaced by L in one or more positions or aryl or heteroaryl replace wantonly
3-C
10-cycloalkyl,
L represents C
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
6-perfluoroalkyl, C
1-C
6-perfluoro alkoxy, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group, (CH
2)
p-C
3-C
10-cycloalkyl, (CH
2)
p-Heterocyclylalkyl, (CH
2)
pCN, (CH
2)
pHal, (CH
2)
pNO
2, (CH
2)
p-C
6-C
12-aryl, (CH
2)
p-heteroaryl ,-(CH
2)
pPO
3(R
b)
2,-(CH
2)
pNR
cR
d,-(CH
2)
pNR
eCOR
b,-(CH
2)
pNR
eCSR
b,-(CH
2)
pNR
eS (O) R
b,-(CH
2)
pNR
eS (O)
2R
b,-(CH
2)
pNR
eCONR
cR
d,-(CH
2)
pNR
eCOOR
b,-(CH
2)
pNR
eC (NH) NR
cR
d,-(CH
2)
pNR
eCSNR
cR
d,-(CH
2)
pNR
eS (O) NR
cR
d,-(CH
2)
pNR
eS (O)
2NR
cR
d,-(CH
2)
pCOR
b,-(CH
2)
pCSR
b,-(CH
2)
pS (O) R
b,-(CH
2)
pS (O) is R (NH)
b,-(CH
2)
pS (O)
2R
b,-(CH
2)
pS (O)
2NR
cR
d,-(CH
2)
pSO
2OR
b,-(CH
2)
pCO
2R
b,-(CH
2)
pCONR
cR
d,-(CH
2)
pCSNR
cR
d,-(CH
2)
pOR
b,-(CH
2)
pSR
b,-(CH
2)
pCR
b(OH)-R
e,-(CH
2)
p-C=NOR
b,-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-or-(CH
2)
N+2-, wherein n=1 or 2, and end Sauerstoffatom and/or carbon atom are connected on the ring carbon atom of direct neighbor,
M represents C
1-C
6-alkyl or group-COR
b, CO
2R
b,-O-R
b, or-NR
cR
d, wherein
R
bRepresent hydrogen or C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, C
6-C
12-aryl or C
1-C
3-perfluoroalkyl, and
R
cAnd R
dRepresent hydrogen independently of each other, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, C
6-C
12-aryl, C (O) R
bOr hydroxyl, if wherein
R
cBe hydroxyl, R
dCan only be a hydrogen, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or C
6-C
12-aryl also can be opposite,
R
eRepresent hydrogen, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or C
6-C
12-aryl, and
P is the number of 0-6,
Perhaps
R
3Be group C=C-R
gR
h, wherein
R
gAnd R
hBe hydrogen independently of each other or choose the C that is replaced by X in one or more positions wantonly identical or differently
1-C
8-alkyl, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl, wherein
X is a cyano group, halogen, hydroxyl, nitro ,-C (O) R
b, CO
2R
b,-O-R
b,-C (O)-NR
cR
d,-NR
cR
d, R wherein
b, R
cAnd R
cHave aforesaid definition,
R
4aAnd R
4bRepresent hydrogen atom independently of each other, C
1-C
4-alkyl, C
2-C
4-thiazolinyl or form 3-6 unit ring with ring carbon atom,
A represents monocycle or bicyclic carbocyclic ring or heteroaromatic ring, and it is chosen wantonly in one or more positions and is replaced by following group: C
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
6-perfluoroalkyl, C
1-C
6-perfluoro alkoxy, C
1-C
6-alkoxy-C
1-C
6-alkyl, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group, (CH
2)
p-C
3-C
10-cycloalkyl, (CH
2)
p-Heterocyclylalkyl, (CH
2)
pCN, (CH
2)
pHal, (CH
2)
pNO
2, (CH
2)
p-C
6-C
12-aryl, (CH
2)
p-heteroaryl ,-(CH
2)
pPO
3(R
b)
2,-(CH
2)
pNR
cR
d,-(CH
2)
pNR
eCOR
b,-(CH
2)
pNR
eCSR
b,-(CH
2)
pNR
eS (O) R
b,-(CH
2)
pNR
eS (O)
2R
b,-(CH
2)
pNR
eCONR
cR
d,-(CH
2)
pNR
eCOOR
b,-(CH
2)
pNR
eC (NH) NR
cR
d,-(CH
2)
pNR
eCSNR
cR
d,-(CH
2)
pNR
eS (O) NR
cR
d,-(CH
2)
pNR
eS (O)
2NR
cR
d,-(CH
2)
pCOR
b,-(CH
2)
pCSR
b,-(CH
2)
pS (O) R
b,-(CH
2)
pS (O) is R (NH)
b,-(CH
2)
pS (O)
2R
b,-(CH
2)
pS (O)
2NR
cR
d,-(CH
2)
pSO
2OR
b,-(CH
2)
pCO
2R
b,-(CH
2)
pCONR
cR
d,-(CH
2)
pCSNR
cR
d,-(CH
2)
pOR
b,-(CH
2)
pSR
b,-(CH
2)
pCR
b(OH)-R
d,-(CH
2)
p-C=NOR
b,-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-or-(CH
2)
N+2-, wherein n=1 or 2, and end Sauerstoffatom and/or carbon atom are connected on the ring carbon atom of direct neighbor, or
A represents group-CO
2R
b, C (O) NR
cR
d, COR
b,
Perhaps
A represents thiazolinyl-CR
5=CR
6R
7, wherein
R
5, R
6And R
7Identical or different, and represent hydrogen atom independently of each other, halogen atom, aryl, or not replacement or partially or completely fluorizated C
1-C
5-alkyl, perhaps
A represents alkynyl-C ≡ CR
5, R wherein
5Have aforesaid definition, and
B represents carbonyl or group CH
2,
And the acceptable salt of pharmacology.
2. according to the compound of claim 1, R wherein
1And R
2Be hydrogen atom, methyl or ethyl.
3. according to the compound of claim 1, R wherein
1And R
2Carbon atom in chain forms 3-7 unit ring altogether.
4. according to the compound of one of claim 1-3, R wherein
3Represent thiazolinyl, alkynyl, aromatic yl polysulfide yl, heteroaryl alkynyl, cycloalkyl alkynyl or Heterocyclylalkyl alkynyl.
5. according to the compound of one of aforementioned claim, R wherein
3Represent vinyl; ethynyl; proyl; butynyl; pentynyl; the hexin base; the heptyne base; the octyne base; the hydroxypropyn base; the hydroxyl butynyl; 3-hydroxy-3-methyl butynyl; the hydroxyl pentynyl; the carboxyl proyl; tertiary butyl carboxyl proyl; the phenylacetylene base; (hydroxy phenyl) ethynyl; (p-methoxy-phenyl) ethynyl; (dimethylaminophenyl) ethynyl; (aminomethyl phenyl) ethynyl; (cyano-phenyl) ethynyl; (trifluoromethyl) ethynyl; (phenylbenzene) ethynyl; (nitrophenyl) ethynyl; (tert-butyl-phenyl) ethynyl; (acetylphenyl) ethynyl; (acetoxyl group phenyl) ethynyl; (carboxyl phenyl) ethynyl or benzyl ethynyl.
6. according to the compound of one of aforementioned claim, wherein A is an aromatic nucleus.
7. according to the compound of one of aforementioned claim, wherein A is a phenyl or naphthyl.
8. according to the compound of claim 7, wherein A is unsubstituted phenyl or chooses wantonly at the substituted phenyl in one or more positions.
9. compound according to Claim 8, wherein said phenyl replaces by one or two halogen atom or by trifluoromethyl.
10. according to the compound of claim 9, wherein said halogen atom is chlorine and/or fluorine.
11. according to the compound of one of claim 1-8, wherein A is-O-(CH
2)
n-O-or-O-(CH
2)
n-CH
2The benzyl ring of-replacement, wherein the ring carbon atom of corresponding direct neighbor links together.
12. according to the compound of one of aforementioned claim, wherein R
4aAnd R
4bBe respectively hydrogen atom independently of each other.
14. according to the compound of one of claim 1-12, it is:
14. pharmaceutical composition, it comprises at least a compound of Formula I and compatible assistant agent and/or the carrier of pharmacology according to one of claim 1-13, and randomly comprises at least a extra activeconstituents.
15. according to the pharmaceutical composition of claim 14, wherein said extra activeconstituents is SERM (selective estrogen receptor modulators), aromatase inhibitor, estrogen antagonist or prostaglandin(PG).
16. according to the pharmaceutical composition of claim 14, wherein said activeconstituents is a tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-five fluorine amyl groups) sulfinyl]-amyl group oxygen base } phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepta alkene-2-alcohol; ICI 182 780 (7 α-[9-(4,4,5,5-five fluorine amyl group sulfinyls) nonyl] female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3); 11 β-fluoro-7 α-[5-(methyl { 3-[(4,4,5,5,5-five fluorine amyl groups) sulfane base]-propyl group } amino) amyl group] female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3; 11 β-fluoro-7 α-{ 5-[methyl (7,7,8,8,9,9,10,10,10-nine fluorine decyls) amino] amyl group } is female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3; 11 β-fluoro-17 Alpha-Methyls-7 α-{ 5-[methyl-(8,8,9,9,9-five fluorine nonyls) amino] amyl group } is female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3; Clomiphene; Raloxifene; The stubborn assistant of method; Formestane; Letrozole; Anastrozole or Atamestane.
17. according to the compound of one of claim 1-13, it is used to prepare medicine.
18. according to the compound of one of claim 1-13 preparation be used for the treatment of and prevent such as endometriosis, hysteromyoma, dysfunction is hemorrhage and the medicine of the gynaecopathia of dysmenorrhoea in application.
19. be used for the treatment of application in the medicine with the prevention of hormone dependent tumour in preparation according to the compound of one of claim 1-13.
20. be used for the treatment of application in the medicine with Breast Cancer Prevention in preparation according to the compound of one of claim 1-13.
21. be used for the treatment of and prevent application in the medicine of carcinoma of endometrium in preparation according to the compound of one of claim 1-13.
22. be used for the treatment of and prevent application in the medicine of ovarian cancer in preparation according to the compound of one of claim 1-13.
23. be used for the treatment of and prevent application in the medicine of prostate cancer in preparation according to the compound of one of claim 1-13.
24. the application of compound in the medicine that preparation female sex hormone alternative medicine is used according to one of claim 1-13.
25. be used for the application of the medicine of women's birth control in preparation according to the compound of one of claim 1-13.
Claims (26)
1. the compound of general formula I,
Wherein
R
1And R
2Represent hydrogen atom independently of each other, the C of straight chain or non-straight chain, side chain or non-side chain
1-C
5-alkyl also can form the ring of 3-7 unit altogether with the C atom in this chain,
R
3Represent group C ≡ C-R
a, wherein
R
aRepresent hydrogen or choose the C that is replaced by K in one or more positions wantonly identical or differently
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or Heterocyclylalkyl, or choose aryl or the heteroaryl that is replaced by L in one or more positions wantonly identical or differently,
K is a cyano group, halogen, hydroxyl, nitro ,-C (O) R
b, CO
2R
b,-O-R
b,-S-R
b, SO
2NR
cR
d,-C (O)-NR
cR
d,-OC (O)-NR
cR
d, or-C=NOR
b-NR
cR
d, or choose wantonly in one or more positions identical or differently by M, choose the C that the Heterocyclylalkyl that replaced by L in one or more positions or aryl or heteroaryl replace wantonly
3-C
10-cycloalkyl,
L represents C
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
6-perfluoroalkyl, C
1-C
6-perfluoro alkoxy, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group, (CH
2)
p-C
3-C
10-cycloalkyl, (CH
2)
p-Heterocyclylalkyl, (CH
2)
pCN, (CH
2)
pHal, (CH
2)
pNO
2, (CH
2)
p-C
6-C
12-aryl, (CH
2)
p-heteroaryl ,-(CH
2)
pPO
3(R
b)
2,
-(CH
2)
pNR
cR
d，-(CH
2)
pNR
eCOR
b，
-(CH
2)
pNR
eCSR
b，-(CH
2)
pNR
eS(O)R
b，
-(CH
2)
pNR
eS(O)
2R
b，-(CH
2)
pNR
eCONR
cR
d，
-(CH
2)
pNR
eCOOR
b，-(CH
2)
pNR
eC(NH)NR
cR
d，
-(CH
2)
pNR
eCSNR
cR
d，-(CH
2)
pNR
eS(O)NR
cR
d，
-(CH
2)
pNR
eS(O)
2NR
cR
d，-(CH
2)
pCOR
b，
-(CH
2)
pCSR
b，-(CH
2)
pS(O)R
b，
-(CH
2)
pS(O)(NH)R
b，-(CH
2)
pS(O)
2R
b，
-(CH
2)
pS(O)
2NR
cR
d，-(CH
2)
pSO
2OR
b，
-(CH
2)
pCO
2R
b，-(CH
2)
pCONR
cR
d，
-(CH
2)
pCSNR
cR
d，-(CH
2)
pOR
b，-(CH
2)
pSR
b，
-(CH
2)
pCR
b(OH)-R
e，-(CH
2)
p-C＝NOR
b，
-O-(CH
2)
n-O-,-O-(CH
2)
n-CH
2-,-O-CH=CH-or
-(CH
2)
N+2-, wherein n=1 or 2, and end Sauerstoffatom and/or carbon atom are connected on the ring carbon atom of direct neighbor,
M represents C
1-C
6-alkyl or group-COR
b, CO
2R
b,-O-R
b, or-NR
cR
d,
Wherein
R
bRepresent hydrogen or C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, C
6-C
12-aryl or C
1-C
3-perfluoroalkyl, and R
cAnd R
dRepresent hydrogen independently of each other, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, C
6-C
12-aryl, C (O) R
bOr hydroxyl, if wherein
R
cBe hydroxyl, R
dCan only be a hydrogen, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or C
6-C
12-aryl also can be opposite,
R
eRepresent hydrogen, C
1-C
6-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl or C
6-C
12-aryl, and
P is the number of 0-6,
Perhaps
R
3Be group C=C-R
gR
h, wherein
R
gAnd R
hBe hydrogen independently of each other or choose the C that is replaced by X in one or more positions wantonly identical or differently
1-C
8-alkyl, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl, wherein X is a cyano group, halogen, hydroxyl, nitro ,-C (O) R
b, CO
2R
b,-O-R
b,-C (O)-NR
cR
d,-NR
cR
d, R wherein
b, R
cAnd R
dHave aforesaid definition,
R
4aAnd R
4bRepresent hydrogen atom independently of each other, C
1-C
4-alkyl, C
2-C
4-thiazolinyl or form 3-6 unit ring with ring carbon atom,
A represents monocycle or bicyclic carbocyclic ring or heteroaromatic ring, and it is chosen wantonly in one or more positions and is replaced by following group: C
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
1-C
6-perfluoroalkyl, C
1-C
6-perfluoro alkoxy, C
1-C
6-alkoxy-C
1-C
6-alkyl, C
1-C
6-alkoxy-C
1-C
6-alkoxyl group, (CH
2)
p-C
3-C
10-cycloalkyl, (CH
2)
p-Heterocyclylalkyl, (CH
2)
pCN, (CH
2)
pHal, (CH
2)
pNO
2, (CH
2)
p-C
6-C
12-aryl, (CH
2)
p-heteroaryl ,-(CH
2)
pPO
3(R
b)
2,
-(CH
2)
pNR
cR
d，-(CH
2)
pNR
eCOR
b，-(CH
2)
pNR
eCSR
b，-(CH
2)
pNR
eS(O)R
b，
-(CH
2)
pNR
eS(O)
2R
b，-(CH
2)
pNR
eCONR
cR
d，-(CH
2)
pNR
eCOOR
b，
-(CH
2)
pNR
eC(NH)NR
cR
d，-(CH
2)
pNR
eCSNR
cR
d，-(CH
2)
pNR
eS(O)NR
cR
d，
-(CH
2)
pNR
eS(O)
2NR
cR
d，-(CH
2)
pCOR
b，-(CH
2)
pCSR
b，-(CH
2)
pS(O)R
b，
-(CH
2)
pS(O)(NH)R
b，-(CH
2)
pS(O)
2R
b，-(CH
2)
pS(O)
2NR
cR
d，-(CH
2)
pSO
2OR
b，
-(CH
2)
pCO
2R
b，-(CH
2)
pCONR
cR
d，-(CH
2)
pCSNR
cR
d，-(CH
2)
pOR
b，
-(CH
2)
pSR
b，-(CH
2)
pCR
b(OH)-R
d，-(CH
2)
p-C＝NOR
b，-O-(CH
2)
n-O-，
-O-(CH
2)
n-CH
2-,-O-CH=CH-or-(CH
2)
N+2-, wherein n=1 or 2, and end Sauerstoffatom and/or carbon atom are connected on the ring carbon atom of direct neighbor, or
A represents group-CO
2R
b, C (O) NR
cR
d, COR
b,
Perhaps
A represents thiazolinyl-CR
5=CR
6R
7, wherein
R
5, R
6And R
7Identical or different, and represent hydrogen atom independently of each other, halogen atom, aryl, or not replacement or partially or completely fluorizated C
1-C
5-alkyl, perhaps
A represents alkynyl-C ≡ CR
5, R wherein
5Have aforesaid definition, and
B represents carbonyl or group CH
2,
And the acceptable salt of pharmacology.
2. according to the compound of claim 1, R wherein
1And R
2Be preferably hydrogen atom, methyl or ethyl.
3. according to the compound of claim 1, R wherein
1And R
2Preferably the carbon atom in chain forms 3-7 unit ring altogether.
4. according to the compound of one of claim 1-3, R wherein
3Preferred thiazolinyl, alkynyl, aromatic yl polysulfide yl, heteroaryl alkynyl, cycloalkyl alkynyl or the Heterocyclylalkyl alkynyl represented.
5. according to the compound of one of aforementioned claim, R wherein
3The preferred vinyl of representing; ethynyl; proyl; butynyl; pentynyl; the hexin base; the heptyne base; the octyne base; the hydroxypropyn base; the hydroxyl butynyl; 3-hydroxy-3-methyl butynyl; the hydroxyl pentynyl; the carboxyl proyl; tertiary butyl carboxyl proyl; the phenylacetylene base; (hydroxy phenyl) ethynyl; (p-methoxy-phenyl) ethynyl; (dimethylaminophenyl) ethynyl; (aminomethyl phenyl) ethynyl; (cyano-phenyl) ethynyl; (trifluoromethyl) ethynyl; (phenylbenzene) ethynyl; (nitrophenyl) ethynyl; (tert-butyl-phenyl) ethynyl; (acetylphenyl) ethynyl; (acetoxyl group phenyl) ethynyl; (carboxyl phenyl) ethynyl or benzyl ethynyl.
6. according to the compound of one of aforementioned claim, wherein A is preferably aromatic nucleus.
7. according to the compound of one of aforementioned claim, wherein A is preferably phenyl or naphthyl.
8. according to the compound of claim 7, wherein A is preferably unsubstituted phenyl or chooses wantonly at the substituted phenyl in one or more positions.
9. compound according to Claim 8, wherein said phenyl preferably replaces by one or two halogen atom or by trifluoromethyl.
10. according to the compound of claim 9, wherein said halogen atom is preferably chlorine and/or fluorine.
11. according to the compound of one of claim 1-8, wherein A preferably-O-(CH
2)
n-O-or-O-(CH
2)
n-CH
2The benzyl ring of-replacement, wherein the ring carbon atom of corresponding direct neighbor links together.
12. according to the compound of one of aforementioned claim, wherein R
4aAnd R
4bBe respectively hydrogen atom independently of each other.
13. according to the compound of one of claim 1-12, it is:
14. pharmaceutical composition, it comprises at least a compound of Formula I and compatible assistant agent and/or the carrier of pharmacology according to one of claim 1-13, and randomly comprises at least a extra activeconstituents.
15. according to the pharmaceutical composition of claim 14, wherein said extra activeconstituents is SERM (selective estrogen receptor modulators), aromatase inhibitor, estrogen antagonist or prostaglandin(PG).
16. according to the pharmaceutical composition of claim 14, wherein said activeconstituents is a tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-five fluorine amyl groups) sulfinyl]-amyl group oxygen base } phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepta alkene-2-alcohol; ICI 182780 (7 α-[9-(4,4,5,5-five fluorine amyl group sulfinyls) nonyl] female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3); 11 β-fluoro-7 α-[5-(methyl { 3-[(4,4,5,5,5-five fluorine amyl groups) sulfane base]-propyl group } amino) amyl group] female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3; 11 β-fluoro-7 α-{ 5-[methyl (7,7,8,8,9,9,10,10,10-nine fluorine decyls) amino] amyl group } is female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3; 11 β-fluoro-17 Alpha-Methyls-7 α-{ 5-[methyl-(8,8,9,9,9-five fluorine nonyls) amino] amyl group } is female-1,3,5 (10)-triolefins-3,17-isoallopregnane-3; Clomiphene; Raloxifene; The stubborn assistant of method; Formestane; Letrozole; Anastrozole or Atamestane.
17. the application of compound in the preparation medicine according to one of claim 1-13.
18. according to the application of compound of claim 17, its be used to prepare the treatment and the prevention such as endometriosis, hysteromyoma, dysfunction is hemorrhage and the medicine of the gynaecopathia of dysmenorrhoea.
19. according to the application of compound of claim 17, it is the medicine that is used to prepare treatment and prevention of hormone dependent tumour.
20. according to the application of compound of claim 17, it is the medicine that is used to prepare treatment and Breast Cancer Prevention.
21. according to the application of compound of claim 17, it is the medicine that is used to prepare treatment and prevention carcinoma of endometrium.
22. according to the application of compound of claim 17, it is the medicine that is used to prepare treatment and prevention ovarian cancer.
23. according to the application of compound of claim 17, it is the medicine that is used to prepare treatment and prevention prostate cancer.
24. according to the application of compound of claim 17, it is to be used to prepare the medicine that the female sex hormone alternative medicine is used.
25. according to the application of compound of claim 17, it is to be used for women's birth control.
26. selectivity addition alkynyl lithium compound and halo alkynyl magnesium compound are to the method for ketone group acid amides.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005030294A DE102005030294A1 (en) | 2005-06-24 | 2005-06-24 | Nonsteroidal progesterone receptor modulators |
| DE102005030294.7 | 2005-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101248056A true CN101248056A (en) | 2008-08-20 |
Family
ID=36716643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800306699A Pending CN101248056A (en) | 2005-06-24 | 2006-06-22 | Non-steroidal progesterone receptor modulators |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1899315A1 (en) |
| JP (1) | JP2008543911A (en) |
| KR (1) | KR20080018275A (en) |
| CN (1) | CN101248056A (en) |
| AR (1) | AR057409A1 (en) |
| AU (1) | AU2006261049A1 (en) |
| BR (1) | BRPI0612305A2 (en) |
| CA (1) | CA2611900A1 (en) |
| CR (1) | CR9595A (en) |
| DE (1) | DE102005030294A1 (en) |
| DO (1) | DOP2006000150A (en) |
| EA (1) | EA200702604A1 (en) |
| EC (1) | ECSP078043A (en) |
| GT (1) | GT200600272A (en) |
| IL (1) | IL188022A0 (en) |
| MX (1) | MX2008000070A (en) |
| NO (1) | NO20080441L (en) |
| PE (1) | PE20070170A1 (en) |
| TW (1) | TW200738665A (en) |
| UY (1) | UY29626A1 (en) |
| WO (1) | WO2006136462A1 (en) |
| ZA (1) | ZA200800689B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UY30805A1 (en) * | 2006-12-21 | 2008-07-31 | Bayer Schering Pharma Ag | NON-STEROID MODULATORS OF PROGESTERONE RECEPTORS |
| DE102007032800A1 (en) * | 2007-07-10 | 2009-01-15 | Bayer Schering Pharma Aktiengesellschaft | Nonsteroidal progesterone receptor modulators |
| DE102007058747A1 (en) * | 2007-12-05 | 2009-06-10 | Bayer Schering Pharma Aktiengesellschaft | Nonsteroidal progesterone receptor modulators |
| TWI477276B (en) * | 2008-04-28 | 2015-03-21 | Repros Therapeutics Inc | Antiprogestin dosing regimens |
| US10328022B2 (en) | 2012-05-31 | 2019-06-25 | Repros Therapeutics Inc. | Formulations and methods for vaginal delivery of antiprogestins |
| WO2014070517A1 (en) | 2012-11-02 | 2014-05-08 | Repros Therapeutics Inc. | Methods and compositions for treating progesterone-dependent conditions |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19723722A1 (en) * | 1997-05-30 | 1998-12-10 | Schering Ag | Nonsteroidal progestogens |
| CN1353717A (en) * | 1999-05-04 | 2002-06-12 | 莱加制药公司 | Tetracyclic progesterone receptor modulator compounds and methods |
| US6358948B1 (en) * | 1999-05-04 | 2002-03-19 | American Home Products Corporation | Quinazolinone and benzoxazine derivatives as progesterone receptor modulators |
| AU2003202216A1 (en) * | 2002-01-14 | 2003-07-30 | Boehringer Ingelheim Pharmaceuticals, Inc. | Glucocorticoid mimetics, methods of making them, pharmaceutical formulations containing them and uses thereof |
| EP1482925B1 (en) * | 2002-03-11 | 2007-01-17 | Schering AG | 5-(2-hydroxy-3-'1-(3-trifluoromethylphenyl)-cyclopropl]-propionylamino)-phtalide and related compounds with progesterone receptor modulating activity for use in fertility control and hormone replacement therapy |
| DE10346939A1 (en) * | 2003-10-06 | 2005-05-19 | Schering Ag | New arylalkanol derivatives used for treating e.g. respiratory diseases, joint diseases, vascular inflammations, skin disorders, kidney and liver diseases and neurological diseases |
-
2005
- 2005-06-24 DE DE102005030294A patent/DE102005030294A1/en not_active Ceased
-
2006
- 2006-06-22 MX MX2008000070A patent/MX2008000070A/en not_active Application Discontinuation
- 2006-06-22 EA EA200702604A patent/EA200702604A1/en unknown
- 2006-06-22 JP JP2008517445A patent/JP2008543911A/en active Pending
- 2006-06-22 BR BRPI0612305-8A patent/BRPI0612305A2/en not_active Application Discontinuation
- 2006-06-22 EP EP06762405A patent/EP1899315A1/en not_active Withdrawn
- 2006-06-22 KR KR1020087001789A patent/KR20080018275A/en not_active Application Discontinuation
- 2006-06-22 AU AU2006261049A patent/AU2006261049A1/en not_active Abandoned
- 2006-06-22 CA CA002611900A patent/CA2611900A1/en not_active Abandoned
- 2006-06-22 WO PCT/EP2006/006532 patent/WO2006136462A1/en active Application Filing
- 2006-06-22 CN CNA2006800306699A patent/CN101248056A/en active Pending
- 2006-06-23 TW TW095122741A patent/TW200738665A/en unknown
- 2006-06-26 UY UY29626A patent/UY29626A1/en not_active Application Discontinuation
- 2006-06-26 DO DO2006000150A patent/DOP2006000150A/en unknown
- 2006-06-26 PE PE2006000732A patent/PE20070170A1/en not_active Application Discontinuation
- 2006-06-26 GT GT200600272A patent/GT200600272A/en unknown
- 2006-06-27 AR ARP060102752A patent/AR057409A1/en unknown
-
2007
- 2007-12-10 IL IL188022A patent/IL188022A0/en unknown
- 2007-12-14 CR CR9595A patent/CR9595A/en not_active Application Discontinuation
- 2007-12-21 EC EC2007008043A patent/ECSP078043A/en unknown
-
2008
- 2008-01-23 NO NO20080441A patent/NO20080441L/en not_active Application Discontinuation
- 2008-01-23 ZA ZA200800689A patent/ZA200800689B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2006261049A1 (en) | 2006-12-28 |
| EP1899315A1 (en) | 2008-03-19 |
| GT200600272A (en) | 2007-08-20 |
| DE102005030294A1 (en) | 2007-01-04 |
| BRPI0612305A2 (en) | 2010-11-03 |
| PE20070170A1 (en) | 2007-03-02 |
| DOP2006000150A (en) | 2006-12-31 |
| ECSP078043A (en) | 2008-01-23 |
| NO20080441L (en) | 2008-03-07 |
| AR057409A1 (en) | 2007-12-05 |
| UY29626A1 (en) | 2007-01-31 |
| JP2008543911A (en) | 2008-12-04 |
| MX2008000070A (en) | 2008-03-19 |
| KR20080018275A (en) | 2008-02-27 |
| TW200738665A (en) | 2007-10-16 |
| ZA200800689B (en) | 2009-07-29 |
| IL188022A0 (en) | 2008-03-20 |
| WO2006136462A1 (en) | 2006-12-28 |
| CA2611900A1 (en) | 2006-12-28 |
| CR9595A (en) | 2008-05-05 |
| EA200702604A1 (en) | 2008-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU749597B2 (en) | Novel anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use | |
| US7388006B2 (en) | Non-steroidal progesting | |
| CN101248056A (en) | Non-steroidal progesterone receptor modulators | |
| US9090583B2 (en) | Benzopyrone estrogen receptor regulator | |
| CN102834405B (en) | Progesterone receptor antagonists | |
| CN101360419A (en) | Chemical compounds | |
| CN102796160A (en) | 17ss-hsd1 and sts inhibitors | |
| NZ576927A (en) | Progesterone receptor antagonists | |
| JPH07502281A (en) | A novel 19-norsteroid having a thiocarbonate chain at the 11β position, its production method and intermediates thereof, its use as a drug and compositions | |
| JP3954386B2 (en) | 4-Fluoroalkyl-2H-benzopyran with antiestrogenic activity | |
| CN102471365B (en) | 17-hydroxy-17-pentafluorethyl female-4,9 (10)-diene 11-acetylenylbenzene radical derivative, its preparation method and the application in treatment illness thereof | |
| CN101248066A (en) | Non-steroidal progesterone receptor modulators | |
| Miller et al. | Targeting the estrogen receptor with SERMs | |
| Jin et al. | Synthesis and identification of novel 11β-aryl-4′, 5′-dihydrospiro [estra-4, 9-diene-17β, 4′-oxazole] analogs with dissociated antiprogesterone activities | |
| KR20040091727A (en) | 5-{(2-hydroxy-3-`1-(3-trifluoromethyl-phenyl)-cyclopropyl!-propionylamino}-phtalide and related compounds with progesterone receptor modulating activity for use in fertility control and hormone replacement therapy | |
| US7408060B2 (en) | Nonsteroidal progesterone receptor modulators | |
| JP4509380B2 (en) | Novel 17-halogenated-19-norsteroids, processes for their preparation and intermediates, their use as pharmaceuticals and pharmaceutical compositions containing them | |
| WO2009071252A1 (en) | Nonsteroidal progesterone receptor modulators | |
| WO2008077646A1 (en) | Non-steroidal progesterone receptor modulators | |
| US20090099147A1 (en) | Non-steroidal progesterone receptor modulators | |
| DE102007049630A1 (en) | New amide compounds used for therapy and/or prophylaxis of gynecological diseases e.g. endometriosis, for female fertility control and female hormone replacement therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1121152 Country of ref document: HK |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080820 |