CN101248066A - Non-steroidal progesterone receptor modulators - Google Patents
Non-steroidal progesterone receptor modulators Download PDFInfo
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- CN101248066A CN101248066A CNA2006800308707A CN200680030870A CN101248066A CN 101248066 A CN101248066 A CN 101248066A CN A2006800308707 A CNA2006800308707 A CN A2006800308707A CN 200680030870 A CN200680030870 A CN 200680030870A CN 101248066 A CN101248066 A CN 101248066A
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Abstract
The present invention relates to non-steroidal progesterone receptor modulators of the general formula (I), a process for their preparation, the use of the progesterone receptor modulators for producing medicaments, and pharmaceutical compositions comprising these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional (bleeding )and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.
Description
Technical field
The present invention relates to non-steroidal progesterone receptor modulators, their preparation method, described progesterone receptor modulator in the preparation medicine application and comprise the pharmaceutical composition of these compounds.
Background technology
The steroid hormone Progesterone is being controlled reproductive process in conclusive mode in women's body.In menstrual cycle and pregnant process, Progesterone is secreted in a large number by ovary and placenta respectively.Progesterone and oestrogenic hormon are worked in coordination with the periodical change that causes uterine mucosa (uterine endometrium) in the menstrual cycle process.The Progesterone level affects uterine mucosa that raises after ovulation is to be translated into the state that allows embryo's (blastocyst) implantation.In pregnant process, Progesterone is being controlled the lax of myometrium and is being kept the function of decidua tissue.
Also known Progesterone by the mitotic division that suppresses the mediation of uterine cancer cell inner estrogen suppress endometrial hyperplasia (K.Chwalisz, R.M.Brenner, U.Fuhrmann, H.Hess-Stumpp, W.Elger, Steroids 65,2000,741-751).
Also known Progesterone and progesterone receptor have vital role in pathophysiological processes.Not only in uterus in the film ectopic focus, and in hysteroma, mastadenoma and CNS knurl, detected progesterone receptor.Also known leiomyoma of uterus relies on the Progesterone growth.
Progesterone is by bringing into play it in sexual organ tissue and other in-house effect with the interaction of the progesterone receptor that causes cytosis.
Progesterone receptor modulator is full agonist or the effect that suppresses Progesterone partially or completely.In view of the above, material is defined as full agonist, partial agonist (SPRMs) and pure antagonist.
Influence the ability of progesterone receptor effect according to progesterone receptor modulator, these compounds have as being used for gynaecology and tumour indication and being used for obstetrics and the obvious potentiality of the therapeutical agent of Birth control.
Pure Progesterone receptor antagonist suppresses the effect of Progesterone to progesterone receptor fully.They have ovulation and suppress the ability of oestrogenic hormon to endometrial effect, up to complete atrophy.Therefore their suitable especially being used for disturb the female reproduction process as after ovulating in pregnant process, to prevent implantation, improving the reactivity of uterus, or reach opening and softening (" maturation ") of uterine neck, and to induce myometrium be to shrink to carry out adequate preparation to prostaglandin(PG) or pitocin.
In endometriosis focus of being furnished with progesterone receptor and tumor tissues, pathology affair had beneficial effect after being desirably in the pure Progesterone receptor antagonist of administration.If can realize extraly that by the progesterone receptor antagonist ovulation suppresses, then influencing pathological state such as endometriosis or leiomyoma of uterus may be special advantage.Ovulation suppresses also can to reduce the generation of some ovarian hormones, and therefore reduces the hormesis of the tissue that pathology have been changed that is derived from this part.
The progesterone receptor antagonist RU486 (being mifepristone) that first is described has a large amount of analogues, these analogues to have the progesterone receptor antagonistic activity of varying strength afterwards.Although RU486 also shows the Antiglucocorticoid effect except that the progesterone receptor antagonistic action, the synthetic compound merited attention especially because of its effect that has more optionally as the progesterone receptor antagonist afterwards.
(they are well-known owing to compare with RU486 that progesterone receptor antagonistic action and Antiglucocorticoid effect are separated better) also known multiple non-steroidal structure from document except steroidal compounds such as onapristone (onapristone) or Lilopristone (lilopristone), described non-steroidal structure to the antagonistic action of progesterone receptor just under study for action [referring to for example 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)].Yet up to the present disclosed compound is compared with known steroidal structure only has medium antagonistic activity.It is reported that the external activity of effective nonsteroidal compound is RU486 active 10%.
It is disadvantageous that the Antiglucocorticoid activity is used treatment, and is the center of treatment to the inhibition of progesterone receptor.The Antiglucocorticoid activity can cause deleterious side effect under the essential dosage of treatment.The interruption that this may hinder the required dosage of drug treatment or cause treating.
Therefore partially or completely reducing of Antiglucocorticoid character is the important prerequisite of using the progesterone receptor antagonist for treating, and be especially all the more so for those indications that need the continued treatment a few weeks or months.
Opposite with pure antagonist, part progesterone receptor agonist (SPRMs) shows the remaining exciting character that intensity may be different.This causes these materials to show potential agonism (D.DeManno, W.Elger, R.Garg, R.Lee to progesterone receptor in some tract, B.Schneider, H.Hess-Stumpp, G.Schuber, K.Chwalisz, Steroids 68,2003,1019-1032).This organ specificity and the effect that is separated may have the treatment benefit for described indication.
Summary of the invention
Therefore the purpose of this invention is to provide other non-steroidal progesterone receptor modulators.These compounds will have the Antiglucocorticoid effect of reduction and therefore be fit to treatment and prevention gynecological diseases such as endometriosis, leiomyoma of uterus, hemorrhage of functional disorder and dysmenorrhoea.Compound of the present invention also will be fit to treatment and prevention of hormone dependent tumour, for example mammary cancer, carcinoma of endometrium, ovarian cancer and prostate cancer.Described compound also will be suitable for female fertility control and female hormone alternative medicine.
According to the present invention, realize described purpose by nonsteroidal compound and pharmacologically acceptable salts thereof that general formula I is provided:
Wherein:
R
1And R
2Be hydrogen atom mutually independently of each other, the C of linear or non-linear, side chain or straight chain
1-C
5-alkyl, they also form with the C atom of chain has the ring of 3-7 unit altogether,
R
3Be group C ≡ C-R
a, wherein:
R
aBe hydrogen or the optional C that is replaced one or many by identical or different K
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, Heterocyclylalkyl or optional by the aryl or the heteroaryl of identical or different L replacement one or many,
K be 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,-C=NOR
b-NR
cR
dOr C
3-C
10-cycloalkyl, optional by the Heterocyclylalkyl of identical or different M replacement one or many or optional by the aryl or the heteroaryl of L replacement one or many,
L is 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
eCONRR
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
b,-(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 is 1 or 2, and terminal Sauerstoffatom and/or carbon atom directly link to each other with adjacent ring carbon atom,
M is C
1-C
6-alkyl or group-COR
b, CO
2R
b,-O-R
bOr-NR
cR
d, wherein:
R
bBe 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
dBe hydrogen, C independently of each other
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, then R
dCan only be 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, vice versa and
R
eBe 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 can be the numeral of 0-6,
Perhaps
R
3Be group C=C-R
gR
h, wherein:
R
gAnd R
hBe hydrogen or the optional C that is replaced one or many by identical or different X independently of each other
1-C
8-alkyl, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl, wherein:
X be 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
dImplication as mentioned above and
R
4Be hydrogen atom, methyl or ethyl or fluorizated C partially or completely
1-C
3-alkyl,
A is monocycle or bicyclic carbocyclic or heterocycle aromatic ring, and it can be chosen wantonly by 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-replace one or many, wherein n is 1 or 2, and terminal Sauerstoffatom and/or carbon atom directly link to each other with adjacent ring carbon atom, perhaps
A is group-CO
2R
b, C (O) NR
cR
d, COR
b, perhaps
A is thiazolinyl-CR
5=CR
6R
7, wherein
R
5, R
6And R
7Identical or different, and be hydrogen atom, halogen atom, aryl or not replacement or partially or completely fluorizated C independently of each other
1-C
5-alkyl, perhaps
A is alkynyl-C ≡ CR
5, R wherein
5Implication as mentioned above and
B is carbonyl or CH
2Group.
Owing to there is asymmetric center, the The compounds of this invention of general formula I can exist with different stereoisomer forms.Racemic modification and independent steric isomer all belong to theme of the present invention.
The present invention also comprises as the novel cpd of active pharmaceutical composition, its preparation, its therepic use and comprises the pharmaceutical dosage form of described novel substance.
The compounds of this invention or its pharmacologically acceptable salts of general formula (I) can be used to prepare medicine, especially for treatment and prevention gynecological diseases such as endometriosis, leiomyoma of uterus, hemorrhage of functional disorder and dysmenorrhoea.Compound of the present invention can also be used for the treatment of and prevention of hormone dependent tumour such as mammary cancer, prostate cancer and carcinoma of endometrium.
The The compounds of this invention of general formula (I) or its pharmacologically acceptable salts are suitable for female fertility control or are used for the female hormone alternative medicine.
The invention still further relates to the method for the compound that is used to prepare general formula (I).Selectivity addition reaction by organometallic compound such as alkynyl lithium or halo alkynyl magnesium is with substituent R
3Be incorporated on the ketone group.This is direct or further modifying the The compounds of this invention that the back produces general formula (I).
Prepare compound of the present invention on the keto-amide by organometallic compound is optionally added to, it is described among 199B1, WO 200375915 and the WO 9854159 in for example disclosed specification sheets US 2002/0077356, US 6,323.Described organometallic compound can be for example alkynyl lithium or halo alkynyl magnesium compound.These compounds are by for example producing suitable alkynes and butyllithium or the reaction of Grignard compound.Also can prepare corresponding organo-metallic alkenyl compound similarly.In this case, the reactivity of ketone group is apparently higher than amidocarbonylation (amide carbonyl) and benzoxazinone (benzoxazinone), thereby realized the selectivity addition under the reaction conditions of suitably selecting.Perhaps, can further modify in the back as R
3Alkynyl or the thiazolinyl introduced.The reaction pair technician who is fit to these modifications is known, for example oxidation, reduction, replacement, alkanisation, the catalytic reaction of palladium.Eliminate any blocking group that exists at reasonable time.
The nonsteroidal compound of the present invention of general formula I has strong antagonistic action or strong part agonism to progesterone receptor.Aspect the bonding strength of progesterone receptor and glucocorticoid receptor, their show the separation of strong effect.Although known progesterone receptor antagonist such as mifepristone (RU486) also show the high-affinity to glucocorticoid receptor beyond the high binding affinity to the expectation of progesterone receptor, compound of the present invention obviously has extremely low glucocorticoid receptor combination when having high progesterone receptor avidity.
In each case, the substituting group that is defined as each group in the The compounds of this invention of general formula I can have following meanings:
C
1-C
5-, C
1-C
6-and C
1-C
8-alkyl refers to linear or non-linear, the alkyl of side chain or straight chain.The 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.
Preferred here R
aBe methyl, ethyl, n-propyl or normal-butyl and n-pentyl.
Preferred R
1And R
2Be methyl or ethyl.
Thiazolinyl refers to linear or non-linear, the thiazolinyl of side chain or straight chain.In the present invention, C
2-C
8The example of-thiazolinyl is as follows: vinyl, allyl group, 3-butene-1-Ji or 2,3-dimethyl-2-propenyl.If aromatic systems A is by C
2-C
8-alkenyl substituted, then this thiazolinyl is preferably vinyl.
Alkynyl refers to linear or non-linear, the alkynyl of side chain or straight chain.C
2-C
8-alkynyl will be preferably ethynyl or proyl for for example ethynyl, proyl, butynyl, pentynyl, hexin base and octyne base.
The C that can mention
3-C
10The example of-cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Be preferably cyclopropyl, cyclopentyl and cyclohexyl.
At R
a, the Heterocyclylalkyl in K and the L implication refers to 3-8 unit Heterocyclylalkyl.The example of Heterocyclylalkyl is morpholinyl, tetrahydrofuran base, pyranyl, piperazinyl, piperidyl, pyrrolidyl, Oxyranyle, oxetanyl, aziridinyl (aziridinyl), dioxolane base and dioxane base.Here, heteroatoms can be any chemically possible position with respect to the position of tie point.
C
1-C
6-alkoxy-C
1-C
6The possible example of-alkoxyl group is methoxymethoxy, oxyethyl group methoxy base or 2-methoxy ethoxy.
In the present invention, group OR
bBe hydroxyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy or n-pentyloxy, 2,2-dimethyl propoxy-or 3-methyl butoxy.Be preferably hydroxyl, methoxyl group and oxyethyl group.
Be suitable as partially or completely fluorizated C
1-C
5-alkyl is fluoridized abovementioned alkyl.Wherein, preferred especially trifluoromethyl or pentafluoroethyl group and partially fluorinated alkyl, for example 5,5,5,4,4-five fluorine amyl groups or 5,5,5,4,4,3,3-seven fluorine amyl groups.
Halogen atom can be fluorine, chlorine, bromine or iodine atom.Here preferred fluorine, chlorine or bromine.
If R
1And R
2Form 3-7 unit ring with the C atom of chain, then this ring can be for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.Preferred cyclopropyl and cyclopentyl ring.
Can be substituted more than once monocycle or bicyclic carbocyclic aromatic ring A is carbocyclic ring or heterocyclic aryl.
In the previous case, it is preferably phenyl for for example phenyl or naphthyl.
May as heterocyclic group for example the monocyclic heterocycles group be for example thienyl, furyl, pyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thiazolyl, oxazolyl, furazan base (furazanyl), pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazyl, particularly about all possible isomer of heteroatoms position.
Under the situation of aryl, R
3Refer to optional phenyl, 1-or the 2-naphthyl that replaces, 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.
(CH
2)
pThe digital p of group can be 0 to 6 numeral, is preferably 0 to 2." group " refers in the present invention by (CH
2)
pAll functional groups of expression.
Compound (B=-CH at general formula I
2-) be under the situation of salt form, this salt may be for example form of hydrochloride, vitriol, nitrate, tartrate, Citrate trianion, fumarate, succinate or benzoate.
If compound of the present invention is the form of racemic mixture, then can they be split as pure optically-active form by the racemic modification method for splitting that the technician knows.For example, can pass through at active solid support material (CHIRALPAK AD itself
) on chromatography with the isomer of racemic mixture separation Cheng Chun.Also may separate the diastereomer ester that obtains by splitting crystallization or chromatography, and in each case the isolating ester of institute is hydrolyzed into optically pure isomer with opticity acid with the free hydroxyl group esterification on the racemic compound of general formula I.May be as opticity acid be for example amygdalic acid, camphorsulfonic acid or tartrate.
Compound that the present invention preferably enumerates below and uses thereof:
The biological property of The compounds of this invention
Can differentiate progesterone receptor modulator by simple method known to the skilled and testing sequence.May for example whether test-compound be changed by the effect of Progesterone mediation in the presence of conditioning agent in this experimental system at test system incubation that is used for progesterone receptor and check with Progesterone for this reason.
The material of the present invention of test general formula I in following model:
The progesterone receptor binding analysis
The affine force measurement of receptors bind
In from the cytosol of animal target organ by the specificity combination
3Hormone of H mark (tracer agent) and the test-compound competitive binding assay receptors bind avidity on acceptor.In this case, target is the saturated and molecular balance of acceptor.
Partly the test-compound (competitor) of tracer agent and cumulative concentration is total to incubation 18h at 0-4 ℃ with the cytosol that comprises acceptor.After removing unconjugated tracer agent with carbon-dextran suspension, measure the tracer content of the receptors bind of each concentration, measure IC by concentration series
50Mole binding affinity (RBA) is calculated as the IC of reference material and test-compound relatively
50The ratio of value (x 100%) (RBA=100% of reference material).
For acceptor type has been selected following incubation conditions:
Progesterone receptor:
The uterine cell colloidal sol of (estrodiol-primed) rabbit that estradiol causes, the TED damping fluid (20mM Tris/HCl, pH 7.4; 1mM edetate, 2mM dithiothreitol (DTT)) in 250mM sucrose homogenizing; Store down at-30 ℃.Tracer agent:
3H-ORG 2058,5nM; Reference material: Progesterone.
Glucocorticoid receptor:
From the thymocyte colloidal sol of the rat that adrenalectomizes, thymus gland is stored down at-30 ℃; Damping fluid: TED.Tracer agent:
3The H-dexamethasone, 20nM; Reference material: dexamethasone.
With respect to Progesterone, the The compounds of this invention of general formula (I) is between 3 to 100% to the receptor relative binding affinity (RBA value) of progesterone receptor.With respect to dexamethasone, to the RBA value of glucocorticoid receptor in 3 to 30% scope.
Therefore compound of the present invention has high-affinity to progesterone receptor, but glucocorticoid receptor is only had low-affinity.
Antagonism to the PR-B progesterone receptor
Carry out the trans-activation analysis according to WO 02/054064 is described.
Excitement to the PR-B progesterone receptor
According to (Fuhrmann U., Hess-Stump H., Cleve A. such as Fuhrmann, Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., Chwalisz K., Journal ofMedicinal Chem, 43,26,2000,5010-5016) describedly carry out the trans-activation analysis.
| Numbering | Antagonistic activity | Agonist activity | ||
| IC 50[nM] | Validity [%] | EC 50[nM] | Validity [%] | |
| 5 | 0,2 | 86 | 0,2 | 10 |
| 14 | 6 | 53 | 7 | 35 |
| 16 | 0,7 | 82 | 0,5 | 13 |
| 17b | 0,03 | 88 | n.b. | 7 |
| 18 | 0,2 | 89 | n.b. | 8 |
| 24 | 2 | 100 | 0 | |
| 35 | 2 | 100 | 0 | |
Dosage
For application of the present invention, progesterone receptor modulator can be oral, enteron aisle, parenteral or transdermal administration.
When every day, dosage covered the scope of 1 μ g to 500mg The compounds of this invention, be expected at usually and obtain satisfied result in the treatment of the above-mentioned indication of this paper.
When being used for the treatment of endometriosis, leiomyoma of uterus and hemorrhage of functional disorder and being used for Birth control and being used for Hormone Replacement Therapy, The compounds of this invention is μ g to 500mg every days 50 in the intravital suitable dose of people, according to patient's age and physique, may give essential dosage every day by the single or multiple administration.
The dosage range that The compounds of this invention is used for the treatment of mammary cancer is 10mg to 1000mg every day.
By the medicament production of following known way preparation: handle activeconstituents and be used for carrier substance, the weighting agent of pharmaceutical technology, the material that influences disintegration, tackiness agent, wetting agent, lubricant, sorbent material, thinner, odor mask, tinting material etc., and be converted into the form of medication of expectation based on described novel cpd.This part content can be with reference to Remington ' s Pharmaceutical Sciences, the 15th edition, Mack Publishing Company, Easton, Pennsylvania (1980).
What be particularly suitable for oral administration is tablet, film coated tablet, sugar coated tablet, capsule, pill, powder, granule, lozenge, suspension agent, emulsion or solution.
Preparation for injection and transfusion can be used for parenteral admin.
Suitably prepd crystal suspension agent can be used for intra-articular injection (intraarticular injection).
Water-based and oily injection can be used for intramuscular injection with solution or suspension agent with corresponding depot formulation.
For the rectal administration that is used for whole body and topical therapeutic, described novel cpd can use with suppository, capsule, the solution form of enema (for example with) and the form of ointment.
In addition, compositions for vaginal use also can be used as preparation.
For the pulmonary administration of described novel cpd, they can use with the form of aerosol and inhalation.
Patch can be used for transdermal administration, and the preparation of gelifying agent, ointment, fatty ointments, ointment, paste, applying medicinal powder, emulsion and tincture form can supply topical application.In order to reach enough pharmacotoxicological effects, the dosage of the compound of general formula I in these preparations should be 0.01%-20%.
Can the corresponding tablet of for example following acquisition: with activeconstituents and known vehicle, for example inert diluent such as dextrose, sugar, sorbyl alcohol, N.F,USP MANNITOL, Polyvinylpyrolidone (PVP), disintegrating agent such as W-Gum or alginic acid, tackiness agent such as starch or gelatin, lubricant such as Magnesium Stearate or talcum and/or for example carboxyvinyl polymer, carboxymethyl cellulose, rhodia phthalic ester or the polyvinyl acetate that are used to realize storing the storehouse effect mix.Described tablet can also be made up of multilayer.
Correspondingly, coating tablet can will prepare with the core dressing for preparing with mode the tablet class as Polyvinylpyrolidone (PVP) or shellac, gum arabic, talcum, titanium dioxide or sugar by using composition commonly used in the tablet coating.In this case, tablet coating layer (covering) can also be made up of multilayer, may use the above-mentioned vehicle that is used for tablet.
The solution of the The compounds of this invention of general formula I or suspension agent can also comprise odorant (taste-improving agent) as asccharin, cyclamate or sugar and for example seasonings such as Vanillin or orange extract.They can also comprise suspending vehicle (suspending excipient) as Xylo-Mucine or sanitas such as p-Hydroxybenzoate.
The capsule that comprises the compound of general formula I can be by for example with the compound of general formula I and inert support such as lactose or sorbyl alcohol mixes and it is encapsulated in the gelatine capsule prepares.
Suitable suppository can prepare by for example mixing with the carrier that is used for suppository such as neutral fat or polyoxyethylene glycol or derivative.
Because the The compounds of this invention of general formula (I) or the antagonism or the PAA of its pharmacologically acceptable salts, they can be used to prepare medicine, especially for the medicine of treatment and prevention gynecological diseases such as endometriosis, leiomyoma of uterus, hemorrhage of functional disorder and dysmenorrhoea.They can also be used to resist hormonal imbalance to induce menstruation, reach separately or make up with induced parturition with prostaglandin(PG) and/or pitocin.
The The compounds of this invention of general formula (I) or its pharmacologically acceptable salts also are suitable for preparing female contraception product (also referring to WO 93/23020, WO 93/21927).
Compound of the present invention or its pharmacologically acceptable salts also can be separately or are used in combination with selective estrogen receptor modulators (SERM) and are used for the female hormone alternative medicine.
In addition, described compound has antiproliferative effect to hormone-dependent tumor.Therefore they are suitable for treating hormonal dependent cancer such as mammary cancer, prostate cancer and carcinoma of endometrium.
Compound of the present invention or its pharmacologically acceptable salts may be used to treat the hormonal dependent cancer in first-line treatment and second line treatment, particularly after tamoxifen is invalid.
Have the The compounds of this invention of general formula (I) of antagonism or PAA or its pharmacologically acceptable salts can also with have the combination of active compound of estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) or selective estrogen receptor modulators (SERM) and be used to prepare the medicament production that is used for the treatment of hormone-dependent tumor.Compound of the present invention can also be used for the treatment of endometriosis or leiomyoma of uterus with SERM or estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) combination.In treatment during hormone-dependent tumor, can provide simultaneously or administration progesterone receptor modulator and estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) or SERM successively.Under the situation of administration successively, preferably at first administration estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) or SERM, administration progesterone receptor modulator then.
In this connection; be fit to non-steroidal progesterone receptor modulators combination of the present invention be for example following estrogen antagonist (estrogen receptor antagon or aromatase inhibitor) or SERM: tamoxifen; 5-(4-{5-[(RS)-(4; 4; 5; 5; 5-five fluorine amyl groups) sulfinyl] pentyloxy } phenyl)-6-phenyl-8; 9-dihydro-7H-benzocyclohepta alkene-2-alcohol (WO 00/03979); (7 α-[9-(4 for ICI 182 780; 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 (sulphanyl)] 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 } 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 } female-1,3; 5 (10)-triolefins-3; 17-isoallopregnane-3 (WO 03/045972); Clomiphene (clomifen); raloxifene (raloxifen) and have active other compound of estrogen antagonist and aromatase inhibitor such as fadrozole (fadrozole); formestane (formestane); letrozole (letrozole); Anastrozole (anastrozole) or Atamestane (atamestane).
At last, the invention still further relates to the application of compound in the preparation medicine of general formula I, randomly use with estrogen antagonist or SERM.
The invention still further relates to pharmaceutical composition, described pharmaceutical composition comprises at least a compound of the present invention, randomly is the acceptable salt form of pharmacy/pharmacology, does not contain or uses with acceptable vehicle of pharmacy and/or carrier.
That these pharmaceutical compositions and medicine can be used for is oral, rectum, vagina, subcutaneous, through skin, intravenously or muscle administration.Except the carrier and/or thinner of routine, they also comprise at least a compound of the present invention.
Medicine of the present invention is with proper dosage and known mode, and vehicle commonly used in the conventional solid of the mode of administration that use is suitable for expecting or liquid vehicle or thinner and the pharmaceutical technology prepares.Preferred preparation is made up of the dosage that is suitable for oral administration.The example of described formulation is tablet, film coated tablet, sugar coated tablet, capsule, pill, powder, solution or suspension agent or other reservoir type.
Comprise the pharmaceutical composition preferred oral administration of at least a The compounds of this invention.
Parenteral formulation also is suitable as the injection solution agent.Other preparation that can also mention is for example suppository and compositions for vaginal use.
Embodiment
The following example is used to illustrate in greater detail subject content of the present invention, is not to limit it.
Initial compounds 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone; 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone and 6-{3-[1-(2-chloro-phenyl-) cyclopentyl]-2-oxo propionyl amino }-4-methyl-2; being prepared among the patent US 2002/0077356 of 3-benzoxazine-1-ketone described; compound 6-[4-(2; 3-dihydro-7-benzofuryl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; the 3-benzoxazinone is in United States Patent (USP) 6; 323; describe among the 199B1 (embodiment 87 wherein); compound 6-(4-methyl-4-phenyl-2-oxo pentanoyl amino)-4-methyl-2; 3-benzoxazine-1-ketone is described in patent WO 199854159; compound 6-[3-[1-(2-fluoro-5-trifluoromethyl) cyclopropyl]-2-oxo propionyl amino]-4-methyl-2,3-benzoxazine-1-ketone is described in patent WO 200375915.
General method
1-(benzo [1,3] dioxy cyclopentenes-4-yl)-1-methyl ethanol
Under room temperature (RT) and argon, 57.2ml methyl magnesium chlorine solution (3M THF solution) is added in the 375ml THF solution of 25.5g 4-ethanoyl benzo [1,3] dioxole.Mixture is at room temperature stirred 16h and add in ice/2N hydrochloric acid.Use ethyl acetate extraction then, water and salt water washing organic phase and dry (Na
2SO
4).Obtain 27.89g 1-[benzo (1,3) Dioxol-4-yl]-the 1-methyl ethanol, it is brown oil.
1H-NMR(CDCl
3，ppm)＝1.6(s，6H)，5.95(s，2H)，6.76(dd，1H)，6.82(t，1H)，6.91(dd，1H)
4-(benzo [1,3] Dioxol-4-yl)-4-methyl 2-oxopentanoic acid
Under-70 ℃, 47ml tin chloride (IV) is added in the 200ml dichloromethane solution of 9.5g 1-(benzo [1,3] Dioxol-4-yl)-1-methyl ethanol and 14.2g 2-trimethylsiloxy ethyl propenoate.After 15 minutes, solution is added in the solution of potassium carbonate.After with the diethyl ether extraction, organic phase washes organic phase with water, dry and evaporation.
At room temperature, 14.4g 4-(benzo [1,3] the Dioxol-4-yl)-4-methyl-2-oxopentanoic acid ethyl ester that obtains was by this method stirred 10 hours with 150ml 1M sodium hydroxide and 300ml methyl alcohol.Remove methyl alcohol then in a vacuum, extract rest solution with diethyl ether.Water extracts with the 1M hcl acidifying and with diethyl ether.Dry and evaporation obtains 11.1g 4-(benzo [1,3] Dioxol-4-yl)-4-methyl-2-oxopentanoic acid, and it is an xanchromatic oil.
MS(ei)m/e：M
+＝251
6-[4-(benzo [1,3] Dioxol-4-yl)-4-methyl-2-oxo pentanoyl amino]-4-methyl 2,3-benzoxazine 1-ketone
10g 4-(benzo [1,3] Dioxol-4-yl)-4-methyl-2-oxopentanoic acid is dissolved in the 125ml N,N-DIMETHYLACETAMIDE, under-0 ℃ and argon, adds the 3.5ml thionyl chloride.After stirring 20 minutes under-3 to+3 ℃, add 7.6g 6-amino-4-methyl-2,3-benzoxazine-1-ketone (WO00/32584).Mixture is at room temperature stirred 96 hours, and after adding entry, use ethyl acetate extraction, organic phase to wash with water and dry (Na
2SO
4); evaporating solvent also carries out the silica gel chromatography purifying with hexane/ethyl acetate (100: 0 → 60: 40) to crude product; obtain 6.56g 6-[4-(benzo [1; 3] Dioxol-4-yl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone, it is the light brown solid.
Fusing point=165-166 ℃, MS (ei) m/e:M
+=409
Synthesis example
(-)-6-{2-[2-(2,3-(methylene radical dioxy base) phenyl)-2-methyl-propyl]-2-hydroxyl suffering-3-alkynes acyl group }-4-methyl-2,3-benzoxazine-1-ketone
1(+)-6-{2-[2-(2,3-(methylene radical dioxy base) phenyl)-2-methyl-propyl]-2-hydroxyl suffering-3-alkynes acyl group }-4-methyl-2,3-benzoxazine-1-ketone
2
Under-78 ℃, nBuLi (0.7ml, 1.6M hexane solution) is added in THF (4ml) solution of 1-hexin (0.5ml).Mixture is stirred 20min down at-78 ℃, adds 6-[4-(benzo [1,3] Dioxol-4-yl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2,3-benzoxazine-1-ketone (192mg), mixture stirs 4h down at-78 ℃.Add water then, and make mixture reach room temperature.Use ethyl acetate extraction; wash with saturated nacl aqueous solution; obtain the 82mg white foam with dried over sodium sulfate and by the silica gel column chromatography purifying; then by preparation chirality HPLC (Chiralpak AD 250 * 10mm; elutriant: acetonitrile/water 55/45 volume ratio; flow velocity 4.7ml/min; 40 ℃ of temperature; retention time: 12.2min (+)-enantiomer; 15.7min (-)-mapping allosome) be translated into compound (-)-6-{2-[2-(2; 3-(methylene radical dioxy base) phenyl)-the 2-methyl-propyl]-2-hydroxyl suffering-3-alkynes acyl group }-4-methyl-2; 3-benzoxazine-1-ketone (embodiment 1) and (+)-6-{2-[2-(2; 3-(methylene radical dioxy base) phenyl)-the 2-methyl-propyl]-2-hydroxyl suffering-3-alkynes acyl group }-4-methyl-2,3-benzoxazine-1-ketone (embodiment 2).
1H-NMR(ppm，CDCl
3，400MHz)：0.91(t，J＝7.2Hz，3H，CH3)，1.32-1.49(m，4H)，1.55(s，3H)，1.58(s，3H)，2.17(t，J＝7.2Hz，2H)，2.56(s，3H，CH3)，2.59(d，J＝14.4Hz，1H)，2.74(d，J＝14.8Hz，1H)，2.80(s，1H，OH)，5.94-5.96(m，2H)，6.46-6.49(m，1H)，6.64(t，J＝7.8Hz，1H)，7.47-7.49(m，1H)，8.25-8.28(m，1H)，8.76(s，1H，NH).C
28H
30N
2O
6(490.6)：
Racemize-6-{2-[2-(2-chloro-5-fluorophenyl)-2-methyl-propyl]-2,7-dihydroxy heptyl-3-alkynes acyl group }-4-methyl-2,3-benzoxazine-1-ketone
3
Steps A: described according to embodiment 1; under-78 ℃, make 5-(t-butyldimethylsilyloxy base) penta-1-alkynes (531mg), nBuLi (0.7ml; 1.6M hexane solution) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone (207mg) reaction obtains colourless oil (86mg) behind silica gel column chromatography.
Step B: under room temperature and argon, in THF (3ml), stir the oil (3h) of gained.Add water,, use dried over sodium sulfate then with ethyl acetate extraction and with the saturated brine washing.Obtain title compound by the silica gel column chromatography purifying, be white foam (43mg).
1H-NMR(ppm，CDCl
3，400MHz)：1.58(s，3H，Me)，1.59(s，3H，Me)，1.71-1.74(m，2H，CH
2)，2.2-2.3(m，2H)，2.56(s，3H，CH
3)，2.75(d，J＝15.2Hz，1H，CH)，2.92(d，J＝14.8Hz，1H，CH)，3.26(s，1H，OH)，3.74-3.78(m，2H)，6.67-6.78(m，1H)，7.09-7.19(m，2H)，7.66-7.69(m，2H)，8.20-8.21(m，1H)，8.27-8.29(m，1H)，8.99(s，1H，NH).C
26H
26ClFN
2O
5(501.0)：LC-MS：m/z＝501[M+H
+].
Racemize-6-{2-[2-(2-chloro-5-fluorophenyl)-2-methyl-propyl]-2-hydroxyl suffering-3-alkynes acyl group }-4-methyl-2,3-benzoxazine-1-ketone
4
Described according to embodiment 1; under-78 ℃, make 1-hexin (0.6ml), nBuLi (0.7ml; 1.6M hexane solution) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone (207mg) reaction, the oil that behind silica gel column chromatography and preparative thin layer chromatography, obtains gluing (12mg).
1H-NMR(ppm，CDCl
3，400MHz)：0.90(t，J＝7.2Hz，3H，Me)，1.32-1.47(m，4H)，1.57(s，3H，Me)，1.62(s，3H，Me)，2.13(t，J＝7.2Hz，CH
2C≡C)，2.56(s，3H，Me)，2.81-2.95(m，3H)，6.68-6.71(m，1H)，7.11-7.17(m，2H)，7.56-7.58(m，1H)，8.21(d，J＝2.0Hz，1H)，8.29(d，J＝12.6Hz，1H)，8.73(br.s.，1H，NH).C
27H
28ClFN
2O
4(499.0)：LC-MS：m/z＝499[M+H
+].
Racemize-6-{2-[(2-chloro-phenyl-) cyclopentyl] methyl-2-hydroxy-4-phenyl fourth-3-alkynes acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
5
Under-78 ℃ with phenylacetyl lithium (lithiumphenylacetylide) (0.65ml; 1M THF solution) add 6-{3-[1-(2-chloro-phenyl-)-cyclopentyl to]-2-oxo propionyl amino }-4-methyl-2; in 3-benzoxazine-1-ketone (110mg), make it reach room temperature and under argon, spend the night.By embodiment 1 described arrangement the in order and silica gel column chromatography, after the oil pump drying, obtain title compound, it is foam (54mg).1H-NMR (ppm, CDCl
3, 400MHz): 1.59-1.85 (m, 5H), 2.18-2.35 (m, 3H), 2.54 (s, 3H, Me), 2.7-3.09 (3H), 6.94-7.58 (m, 10H), 8.18 (d, J=1.1Hz), 8.25 (d, J=8.6Hz, 1H), 8.81 (br.s., 1H, NH) .C
31H
27ClN
2O
4(526.0): HPLCMS:m/z=526[M], purity 97%.
6-{2-[2-(2,3-dihydro-7-benzofuryl)-2-methyl-propyl]-2-hydroxyl-3-octyne acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
6
Described according to embodiment 1; under-78 ℃, make 1-hexin (0.4ml), nBuLi (0.7ml; 1.6M hexane solution) and 6-[4-(2; 3-dihydro-7-benzofuryl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone (99.5mg) reacts in THF (3ml), obtains solidified water white oil (42mg) after silica gel column chromatography and vacuum-drying.1H NMR(ppm，CDCl
3，400MHz)：0.89(t，J＝7.2Hz，3H，Me)，1.35-1.56(m，10H)，2.14-2.18(m，2H)，2.56(s，3H，Me)，2.66(d，J＝14.8Hz，1H)，2.73(d，J＝14.8Hz，1H)，3.0-3.2(m，2H)，3.27(s，1H)，4.57(t，J＝9.3Hz，2H)，6.75(t，J＝7.5Hz，1H)，6.95(d，J＝6.3Hz，1H)，7.05(d，J＝7.8Hz，1H)，7.50-7.52(m，1H)，8.23-8.29(m，2H)，8.78(br.s.，NH).C
29H
32ClN
2O
5(488)：LC-MS：m/z＝489[M+H
+].
Racemize-6-{4-(2-chloro-4-fluorophenyl)-2-hydroxyl-2-[(4-hydroxy phenyl) ethynyl]-4-methylpent acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
7
Steps A: the compound (57.8mg), triphenylphosphine (6.8mg), cupric iodide (5mg), 4-iodophenyl acetate (4-iodophenyl acetate) that makes embodiment 10 (51mg), THF (1ml) solution of 5mg acid chloride and the suspension of triethylamine (3ml) reacts 1h under ultrasonic bath and argon.Add saturated aqueous ammonium chloride, then with ethyl acetate extraction and water and salt water washing.Use dried over sodium sulfate, concentrate then and by the silica gel column chromatography purifying.Obtain white solid (46.7mg).
Step B: will under room temperature and argon, stir 6h from the suspension of the compound (46.7mg) of steps A and the methanol solution of sodium bicarbonate (128mg).Add a blade tip sodium bicarbonate then, mixture is stirred spend the night.With the ethyl acetate dilution, add water, and separate phase, use ethyl acetate extraction then.With the organic phase that the salt water washing merges, use dried over sodium sulfate, concentrate and carry out silica gel column chromatography, obtain title compound, its oil (29mg) for gluing.
1H-NMR(ppm，CDCl
3，400MHz)：1.63(s，3H，Me)，1.69(s，3H，Me)，2.56(s，3H，Me)，2.94-3.01(m，3H)，5.48(br.s，1H，OH)，6.74-6.77(m，2H)，6.84-6.93(m，2H)，7.21-7.25(m，2H)，7.43(dd，J＝9.0，6.1Hz，1H)，7.57-7.59(dd，J＝8.6，2.3Hz，1H)，8.22-8.23(m，1H)，8.31(d，J＝8.6Hz，1H)，8.80(br.s，1H，NH).C
29H
24ClFN
2O
5(534.98)：LC-MS：m/z＝535[M+H
+].
Racemize-6-{2-[2-(2-chloro-4-fluorophenyl)-2-methyl-propyl]-2-hydroxyl last of the ten Heavenly stems-3-alkynes acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
8
Described according to embodiment 1; under-78 ℃, make 1-octyne (0.4ml), nBuLi (0.6ml; 1.6M hexane solution) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone (110mg) reacts in THF (3ml), obtains white solid (25mg) behind silica gel column chromatography.
1H-NMR(ppm，CDCl
3，400MHz)：0.87(t，J＝7.0Hz，3H)，1.26-1.46(m，8H)，1.58(s，3H，Me)，1.63(s，3H，Me)，2.12(t，J＝7.0Hz，CH
2C≡C)，2.56(s，3H，Me)2.79-2.91(m，3H)，6.92-6.95(m，2H)，7.40(dd，J＝8.9，6.3Hz，1H)，7.53(dd，J＝8.6，1.9Hz，1H)，8.21(d，J＝1.9Hz，1H)，8.30(d，J＝8.6Hz，1H)，8.71(br.s.，1H，NH)；C
29H
32ClFN
2O
4(527.0)：LC-MS：m/z＝527[M+H
+].
Racemize-6-{2-[2-(2-chloro-4-fluorophenyl)-2-methyl-propyl]-2-hydroxyl-5-phenyl penta-3-alkynes acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
9
Described according to embodiment 1; under-78 ℃, make 3-phenyl-1-propine (0.17ml), nBuLi (0.51ml; 1.6M hexane solution) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone (140mg) reacts in THF (3ml), obtains white foam (116mg) after silica gel column chromatography and vacuum-drying.
1H-NMR(ppm，CDCl
3，400MHz)：1.59(s，3H，Me)，1.61(s，3H，Me)，2.55(s，3H，Me)，2.79-2.95(m，3H)，3.4-3.6(m，2H，CH
2C≡C)，6.8-6.93(m，2H)，7.23-7.42(m，7H)，8.15(d，J＝2.3Hz，1H)，8.27(d，J＝8.6Hz，1H)，8.64(br.s.，1H，NH).C
30H
26ClFN
2O
4(533.0)：LC-MS：m/z＝533[M+H
+].
Racemize-6-{4-(2-chloro-4-fluorophenyl)-2-ethynyl-2-hydroxy-4-methyl pentyne acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
10
Add ethynyl magnesium bromine (2.2ml, 0.5M THF solution) to 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2, in THF (4ml) the ice bath solution of 3-benzoxazine-1-ketone (208mg).Under argon, make reaction soln in 3h, reach room temperature.As putting in order as described in the embodiment 1 and carrying out silica gel column chromatography, after the oil pump drying, obtain title compound, it is foam (84mg).1H-NMR(ppm，CDCl
3，400MHz)：0.8-0.9(m，1H)，1-58(s，3H，Me)，1.65(s，3H，Me)，2.56-2.96(6H)，6.86-6.94(m，2H)，7.41(dd，J＝9.0，6.2Hz，1H)，7.56(dd，J＝8.6，1.9Hz，1H)，8.19(d，J＝1.9Hz，1H)，8.31(d，J＝8.6Hz，1H)，8.63(br.s.，1H，NH).
C
23H
20ClFN
2O
4(542.9)：LC-MS：m/z＝543[M+H
+].
Racemize-6-{4-(2-chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-vinyl-pentyne acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
11
Under-78 ℃ with vinyl magnesium bromine solutions (0.5ml; 1M THF solution) be expelled to 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; in THF (3ml) solution of 3-benzoxazine-1-ketone (103mg), make mixture reach room temperature and under argon, spend the night.Add aqueous ammonium chloride solution, wash with ethyl acetate extraction and with saturated nacl aqueous solution then.Use dried over sodium sulfate, concentrate in rotatory evaporator then and by the silica gel column chromatography purifying, obtain title compound, it is solidified oil (18mg).1H-NMR (ppm, CDCl
3, 400MHz, the signal of selection): 1.53 (s, 3H, Me), 1.57 (s, 3H, Me), 2.35 (s, 1H), 2.56 (s, 3H, Me), 2.74 (d, J=15.3Hz, 1H), 2.89 (d, J=15.3Hz, 1H), 5.15 (d, J=10.5Hz, 1H), 5.27 (d, J=17.6Hz, 1H), 6.10 (dd, J=17.2,10.6Hz, 1H), 6.81-6.86 (m, 1H).
Racemize-6-{4-(2-chloro-4-fluorophenyl)-2-hydroxyl-2-[(4-p-methoxy-phenyl) ethynyl]-4-methyl pentyne acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
12
Described according to embodiment 1; under-78 ℃, make 4-anisole ethyl-acetylene (0.4ml), nBuLi (0.6ml; 1.6M hexane solution) and 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2; 3-benzoxazine-1-ketone (110mg) reaction; obtain title compound behind silica gel column chromatography, it is white solid (44mg).
1H-NMR(ppm，CDCl
3，400MHz)：1.63(s，3H，Me)，1.69(s，3H，Me)，2.91-3.01(m，3H)，3.81(s，3H，Me)，6.81-6.94(m，3H)，7.25-7.29(m，3H)，7.43(dd，J＝8.4，6.3Hz，1H)，7.58(dd，J＝8.6，2.3Hz，1H)，8.24(d，J＝1.9Hz，1H)，8.31(d，J＝8.6Hz，1H)，8.79(br.s.，1H，NH).C
30H
26ClFN
2O
5(549.0)：LC-MS：m/z＝549[M+H
+].
Racemize-6-{4-(2-chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-(phenylacetylene base)-pentyne acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
13
Under-78 ℃, add phenylacetyl lithium (0.65ml, 1M THF solution) to 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxo pentanoyl amino]-4-methyl-2, under-78 ℃ and argon, stir 2.5h in 3-benzoxazine-1-ketone (136mg) and with mixture.According to embodiment 1 described arrangement the in order and silica gel column chromatography, after the oil pump drying, obtain title compound, it is white foam (102mg).
1H-NMR(ppm，CDCl
3，400MHz)：1.64(s，3H，Me)，1.70(s，3H，Me)，2.57(s，3H，Me)，2.92-3.03(m，3H)，6.82-6.86(m，1H)，6.91-6.93(m，1H)，7.30-7.36(m，5H)，7.44(dd，J＝9.0，6.2Hz，1H)，7.59(dd，J＝8.6，2.0Hz，1H)，8.23(d，J＝2.0Hz，1H)，8.31(d，J＝8.2Hz，1H)，8.79(br.s.，NH)；C
29H
24ClFN
2O
4(519.0)：HPLC-MS：m/z＝518[M].
Similar to Example 10, by 6-(4-methyl-4-phenyl-2-oxo pentanoyl amino)-4-methyl-2,3-benzoxazine-1-ketone and alkynyl magnesium stew in soy sauce are equipped with compound 14 and 15:
Racemize-6-[2-ethynyl-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
14
1H-NMR(ppm，CDCl
3，400MHz)：1.42(3H)，1.59(3H)，2.57(3H)，2.64(4H)，7.15(1H)，7.31(2H)，7.46(2H)，7.58(1H)，8.25(1H)，8.30(1H)，8.81(1H).
Racemize-6-[2-hydroxy-4-methyl-4-phenyl-2-propynyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
15
1H-NMR(ppm，CDCl
3，400MHz)：1.42(3H)，1.59(3H)，2.50-2.65(6H)，7.11(1H)，7.30(2H)，7.43(2H)，7.58(1H)，8.29(2H)，8.85(1H).
Similar to Example 1, by 6-(4-methyl-4-phenyl-2-oxo pentanoyl amino)-4-methyl-2,3-benzoxazine-1-ketone and corresponding aryl ethane lithium (lithium arylacetylide) preparation compound 15-28:
Racemize-6-[2-hydroxy-4-methyl-4-phenyl-2-(phenylacetylene base) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
16
1H-NMR(ppm，CDCl
3，300MHz)：1.47(3H)，1.65(3H)，2.57(3H)，2.62-2.78(3H)，7.15(1H)，7.27-7.37(5H)，7.40(2H)，7.50(2H)，7.59(1H)，8.29(2H)，8.90(1H).
(+)-6-[2-hydroxy-4-methyl-2-[(4-aminomethyl phenyl) ethynyl]-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
17aWith
(-)-6-[2-hydroxy-4-methyl-2-[(4-aminomethyl phenyl) ethynyl]-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone.
17b
1H-NMR(ppm，CDCl
3，300MHz)：1.48(3H)，1.64(3H)，2.36(3H)，2.57(3H)，2.60-2.80(3H)，7.08-7.20(3H)，7.30(4H)，7.49(2H)，7.60(1H)，8.29(2H)，8.90(1H).
16a：[α]
D 20：+28.4°(CHCl
3，1.03g/100ml；λ＝589nm)
16b：[α]
D 20：-28.6°(CHCl
3，1.01g/100ml；λ＝589nm)
Racemize-6-[2-hydroxyl-2-[(4-p-methoxy-phenyl) ethynyl]-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
18
1H-NMR(ppm，CDCl
3，300MHz)：1.47(3H)，1.63(3H)，2.56(3H)，2.60-2.78(3H)，3.80(3H)，6.81(2H)，7.13(1H)，7.25-7.38(4H)，7.48(2H)，7.60(1H)，8.28(2H)，8.89(1H).
(+)-6-[2-hydroxyl-2-[(4-p-methoxy-phenyl) ethynyl]-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
18aWith
(-)-6-[2-hydroxyl-2-[(4-p-methoxy-phenyl) ethynyl]-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
18b
(post: ChiralpakAD 250 * 10mm) is with embodiment by preparation chirality HPLC
18Described racemic mixture is separated into enantiomer
18aWith
18b
18a：[α]
D 20：+29.3°(CHCl
3，1.12g/100ml；λ＝589nM)
18b：[α]
D 20：-30.0°(CHCl
3，1.14g/100ml；λ＝589nM)
Racemize-6-[2-hydroxyl-2-[(4-(N, N-dimethylamino) phenyl) ethynyl]-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
19
1H-NMR(ppm，CDCl
3，400MHz)：1.48(3H)，1.62(3H)，2.57(3H)，2.60-2.75(3H)，2.98(6H)，6.58(2H)，7.12(1H)，7.23-7.38(4H)，7.48(2H)；7.57(1H)，8.28(2H)，8.90(1H).
Racemize-6-[2-hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
20
1H-NMR(ppm，CDCl
3，400MHz)：1.48(3H)，1.63(3H)，2.57(3H)，2.64-2.80(3H)，7.17(1H)，7.33(2H)，7.48(4H)，7.56(2H)，7.61(1H)，8.30(2H)，8.92(1H).
(+)-6-[2-hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
20aWith
(-)-6-[2-hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
20b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
20Described racemic mixture is separated into enantiomer
20aWith
20b
20a：[α]
D 20：+19.9°(CHCl
3，1.05g/100ml；λ＝589nM)
20b：[α]
D 20：-20.4°(CHCl
3，1.01g/100ml；λ＝589nM)
Racemize-6-[2-[(4-cyano-phenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
21
1H-NMR(ppm，CDCl
3，400MHz)：1.50(3H)，1.62(3H)，2.57(3H)，2.63-2.82(3H)，7.18(1H)，7.35(2H)，7.48(4H)，7.55-7.68(2H)，7.62(1H)，8.30(2H)，8.94(1H).
(+)-6-[2-[(4-cyano-phenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
21a and
(-)-6-[2-[(4-cyano-phenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
21b
(post: ChiralpakAD 250 * 10mm) is with embodiment by preparation chirality HPLC
21Described racemic mixture is separated into enantiomer
21aWith
21b
21a：[α]
D 20：+26.6°(CHCl
3，1.12g/100ml；λ＝589nM)
21b：[α]
D 20：-26.8°(CHCl
3，1.02g/100ml；λ＝589nM)
Racemize-6-[2-hydroxy-4-methyl-4-phenyl-2-[(4-phenyl) ethynyl] the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
22
1H-NMR(ppm，CDCl
3，400MHz)：1.50(3H)，1.68(3H)，2.58(3H)，2.64-2.81(3H)，7.18(1H)，7.30-7.40(3H)，7.41-7.61(11H)，8.30(2H)，8.92(1H).
(+)-6-[2-hydroxy-4-methyl-4-phenyl-2-[(4-phenyl) ethynyl] the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
22aWith
(-)-6-[2-hydroxy-4-methyl-4-phenyl-2-[(4-phenyl) ethynyl] the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
22b
(post: ChiralpakAD 250 * 10mm) is separated into enantiomer with embodiment 22 described racemic mixtures by preparation chirality HPLC
22aWith
22b
22a：[α]
D 20：+38.4°(CHCl
3，1.06g/100ml；λ＝589nM)
22b：[α]
D 20：-30.6°(CHCl
3，1.12g/100ml；λ＝589nM)
Racemize-6-[2-hydroxy-4-methyl-4-phenyl-2-[(3-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
23
1H-NMR(ppm，CDCl
3，300MHz)：1.52(3H)，1.68(3H)，2.60(3H)，2.65-2.88(3H)，7.21(1H)，7.49(2H)，7.42-7.70(7H)，8.34(2H)，8.96(1H).
Racemize-6-[2-hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
24
1H-NMR(ppm，CDCl
3，600MHz)：1.52(3H)，1.65(3H)，2.62(3H)，2.69(1H)，2.78(1H)，2.91(1H)，7.11(1H)，7.32(3H)，7.51(3H)，7.57(2H)，7.70(1H)，8.20(1H)，8.45(1H)，8.75(1H).
(+)-6-[2-hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
24aWith
(-)-6-[2-hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethyl) ethynyl]-the pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
24b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
24Described racemic mixture is separated into enantiomer
24aWith
24b
24a：[α]
D 20：+21.3°(CHCl
3，1.00g/100ml；λ＝589nM)
24b：[α]
D 20：-19.4°(CHCl
3，1.00g/100ml；λ＝589nM)
Racemize-6-[2-hydroxy-4-methyl-2-[(4-nitrophenyl) ethynyl]-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
25
1H-NMR(ppm，CDCl
3，600MHz)：1.47(3H)，1.62(3H)，2.55(3H)，2.79(1H)，2.81(2H)，7.18(1H)，7.34(2H)，7.50(4H)，7.63(1H)，8.17(2H)，8.80(2H)，8.94(1H).
Racemize-6-[2-[[4-(1, the 1-dimethyl ethyl) phenyl] ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
26
1H-NMR(ppm，CDCl
3，300MHz)：1.32(9H)，1.51(3H)，1.68(3H)，2.62(3H)，2.65-2.82(3H)，7.18(1H)，7.30-7.40(6H)，7.52(2H)，7.63(1H)，8.32(2H)，8.93(1H).
Racemize-6-[2-hydroxy-4-methyl-2-[(3-aminomethyl phenyl) ethynyl]-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
27
1H-NMR(ppm，CDCl
3，400MHz)：1.47(3H)，1.63(3H)，2.30(3H)，2.58(3H)，2.62-2.80(3H)，7.12-7.26(5H)，7.32(2H)，7.50(2H)，7.60(1H)，8.30(2H)，8.90(1H).
Racemize-6-[2-hydroxy-4-methyl-2-[(2-aminomethyl phenyl) ethynyl]-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
28
1H-NMR(ppm，CDCl
3，300MHz)：1.47(3H)，1.65(3H)，2.38(3H)，2.58(3H)，2.62-2.80(3H)，7.08-7.42(7H)，7.49(2H)，7.60(1H)，8.22-8.36(2H)，8.90(1H).
Racemize-6-[2-(3,3-dimethyl butyrate alkynyl)-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
29
1H-NMR(ppm，CDCl
3，300MHz)：1.20(9H)，1.43(3H)，1.60(3H)，2.46(1H)，2.50-2.63(5H)，7.11(1H)，7.28(2H)，7.43(2H)，7.54(1H)，8.22(1H)，8.29(1H)，8.32(1H).
Similar to Example 7, by embodiment 13 described compounds and 4 ' the iodobenzene ethyl ketone prepares following compounds:
Racemize-6-[2-[(4-acetylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
30
1H-NMR(ppm，CDCl
3，300MHz)：1.48(3H)，1.63(3H)，2.56(3H)，2.60(3H)，2.63-2.82(3H)，7.18(1H)，7.33(2H)，7.40-7.56(4H)，7.62(1H)，7.90(2H)，8.30(2H)，8.93(1H).
(+)-6-[2-[(4-acetylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
30aWith
(-)-6-[2-[(4-acetylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
30b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
30Described racemic mixture is separated into enantiomer
30aWith
30b
30a：[α]
D 20：+31.3°(CHCl
3，1.09g/100ml；λ＝589nM)
30b：[α]
D 20：-28.4°(CHCl
3，1.09g/100ml；λ＝589nM)
Similar to Example 1, by 6.[3-[1-(2-fluoro-5-trifluoromethyl) cyclopropyl]-2-oxo propionyl amino]-4-methyl-2,3-benzoxazine-1-ketone prepares compound 30 and 31:
Racemize-6-[2-[(2-fluoro-5-trifluoromethyl) cyclopropyl methyl]-2-hydroxyl-4-(4-trifluoromethyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
31
1H-NMR(ppm，CDCl
3，400MHz)：0.90(1H)，1.00-1.15(3H)，2.51(1H)，2.55(3H)，2.68(1H)，3.18(1H)，7.01(1H)，7.30(1H)，7.41(2H)，7.56(2H)，7.63(1H)，7.68(1H)，8.19(1H)，8.31(1H)，8.98(1H).
(+)-6-[2-[(2-fluoro-5-trifluoromethyl) cyclopropyl methyl]-2-hydroxyl-4-(4-trifluoromethyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
31aWith
(-)-6-[2-[(2-fluoro-5-trifluoromethyl) cyclopropyl methyl]-2-hydroxyl-4-(4-trifluoromethyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
31b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
31Described racemic mixture is separated into enantiomer
31aWith
31b
31a：[α]
D 20：+2.3°(CHCl
3，1.00g/100ml；λ＝589nM)
31b：[α]
D 20：-1.9°(CHCl
3，1.00g/100ml；λ＝589nM)
Racemize-6-[2-[(2-fluoro-5-trifluoromethyl) cyclopropyl methyl]-2-hydroxyl-4-(4-aminomethyl phenyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
32
1H-NMR(ppm，CDCl
3，400MHz)：0.88(1H)，0.98-1.13(3H)，2.34(3H)，2.44(1H)，2.55(3H)，2.70(1H)，3.02(1H)，7.01(1H)，7.10(2H)，7.22(2H)，7.30(1H)，7.64(2H)，8.19(1H)，8.31(1H)，8.98(1H).
(+)-6-[2-[(2-fluoro-5-trifluoromethyl) cyclopropyl methyl]-2-hydroxyl-4-(4-aminomethyl phenyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
32aWith
(-)-6-[2-[(2-fluoro-5-trifluoromethyl) cyclopropyl methyl]-2-hydroxyl-4-(4-aminomethyl phenyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
32b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
32Described racemic mixture is separated into enantiomer
32aWith
32b
32a：[α]
D 20：+8.6°(CHCl
3，1.00g/100ml；λ＝589nM)
32b：[α]
D 20：-8.7°(CHCl
3，1.00g/100ml；λ＝589nM)
Similar to Example 7, by embodiment 14 described compounds and 3 '-phenyl-iodide ethyl ketone (3 '-iodacetophenon) prepares following compound:
Racemize-6-[2-[(3-acetylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
33
1H-NMR(ppm，CDCl
3，300MHz)：1.49(3H)，1.63(3H)，2.57(6H)，2.62-2.81(3H)，7.1681H)，7.28-7.70(7H)，7.90-8.00(2H)，8.30(2H)，8.94(1H).
Similar to Example 1, by 6-(4-methyl-4-phenyl-2-oxo pentanoyl amino)-4-methyl-2,3-benzoxazine-1-ketone and corresponding aryl ethane lithium prepare compound 34 and 35:
Racemize-6-[2-[(2, the 5-3,5-dimethylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
34
1H-NMR(ppm，CDCl
3，400MHz)：1.49(3H)，1.62(3H)，2.27(3H)，2.33(3H)，2.57(3H)，2.65-2.78(3H)，7.03(2H)，7.13(2H)，7.30(2H)，7.50(2H)，7.61(1H)，8.22(1H)，8.30(1H)，8.89(1H).
Racemize-6-[2-[(2,4, the 5-trimethylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
35
1H-NMR(ppm，CDCl
3，400MHz)：1.47(3H)，1.64(3H)，2.18(3H)，2.21(3H)，2.30(3H)，2.56(3H)，2.65-2.77(3H)，6.93(1H)，7.12(2H)，7.30(2H)，7.48(2H)，7.59(1H)，8.22(1H)，8.29(1H)，8.90(1H).
(+)-6-[2-[(2,4, the 5-trimethylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
35aWith
(-)-6-[2-[(2,4, the 5-trimethylphenyl) ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
35b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
35Described racemic mixture is separated into enantiomer
35aWith
35b
35a：[α]
D 20：+30.6°(CHCl
3，0.97g/100ml；λ＝589nM)
35b：[α]
D 20：-28.0°(CHCl
3，0.96g/100ml；λ＝589nM)
Similar to Example 9, by 3-phenyl-1-propine, nBuLi and 6-(4-methyl-4-phenyl-2-oxo pentanoyl amino)-4-methyl-2,3-benzoxazine-1-ketone prepares following compound:
Racemize-6-{2-(2-phenyl)-2-methyl-propyl]-2-hydroxyl-5-phenyl penta-3-alkynes acyl amino }-4-methyl-2,3-benzoxazine-1-ketone
36
1H-NMR(ppm，CDCl
3，400MHz)：1.42(3H)，1.53(3H)，2.55-2.70(6H)，3.58(2H)，7.11(1H)，7.20-7.35(7H)，7.41(2H)，7.48(1H)，8.20(1H)，8.28(1H)，8.80(1H).
Similar to Example 1, by 6-(4-methyl-4-(2-chloro-6-fluorophenyl)-2-oxo pentanoyl amino)-4-methyl-2,3-benzoxazine-1-ketone and corresponding aryl ethane lithium prepare compound 37 and 38.
Racemize-6-[2-hydroxy-4-methyl-4-(2-chloro-6-fluorophenyl)-2-(4-aminomethyl phenyl-ethynyl) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
37
1H-NMR(ppm，CDCl
3，300MHz)：1.73(3H)，1.82(3H)，2.33(3H)，2.57(3H)，2.88-3.02(3H)，6.75-6.96(2H)，7.01(1H)，7.09(2H)，7.27(2H)，7.60(1H)，8.22-8.35(2H)，8.96(1H).
(+)-6-[2-hydroxy-4-methyl-4-(2-chloro-6-fluorophenyl)-2-(4-aminomethyl phenyl-ethynyl) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
37aWith
(-)-6-[2-hydroxy-4-methyl-4-(2-chloro-6-fluorophenyl)-2-(4-aminomethyl phenyl-ethynyl) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
37b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
37Described racemic mixture is separated into enantiomer
37aWith
37b
37a：[α]
D 20：+21.5°(CHCl
3，1.00g/100ml；λ＝589nM)
37b：[α]
D 20：-21.0°(CHCl
3，1.04g/100ml；λ＝589nM)
Racemize-6-[2-hydroxy-4-methyl-4-(2-chloro-6-fluorophenyl)-2-(4-(trifluoromethyl) phenyl-ethynyl) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
38
1H-NMR(ppm，CDCl
3，400MHz)：1.60(3H)，1.93(3H)，2.36(1H)，2.56-2.72(5H)，7.04(1H)，7.14(2H)，7.45(2H)，7.53(2H)，7.80(1H)，8.35-8.45(2H)，8.90(1H).
(+)-6-[2-hydroxy-4-methyl-4-(2-chloro-6-fluorophenyl)-2-(4-(trifluoromethyl) phenyl-ethynyl) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
38aWith
(-)-6-[2-hydroxy-4-methyl-4-(2-chloro-6-fluorophenyl)-2-(4-(trifluoromethyl) phenyl-ethynyl) pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
38b
(post: ChiralpakAD 250 * 10mm) is with embodiment by preparation chirality HPLC
38Described racemic mixture is separated into enantiomer
38aWith
38b
38a：[α]
D 20：+143.2°(CHCl
3，1.05g/100ml；λ＝589nM)
38b：[α]
D 20：-137.8°(CHCl
3，1.12g/100ml；λ＝589nM)
Similar to Example 1, by 6-(4-methyl-4-(2-chloro-phenyl-)-2-oxo pentanoyl amino)-4-methyl-2,3-benzoxazine-1-ketone and corresponding aryl ethane lithium prepare compound 39 and 40.
Racemize-6-[2-(2-chloro-phenyl-) cyclopropyl methyl]-2-hydroxyl-4-(4-aminomethyl phenyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
39
1H-NMR(ppm，CDCl
3，400MHz)：0.84(1H)，1.00(1H)，1.08-1.22(2H)，2.36(3H)，2.53(3H)，2.90(1H)，7.03-7.18(4H)，7.23-7.38(3H)，7.50(1H)，7.60(1H)，8.22(1H)，8.29(1H)，8.91(1H).
(+)-6-[2-(2-chloro-phenyl-) cyclopropyl methyl]-2-hydroxyl-4-(4-aminomethyl phenyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
39aWith
(-)-6-[2-(2-chloro-phenyl-) cyclopropyl methyl]-2-hydroxyl-4-(4-aminomethyl phenyl) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
39b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
39Described racemic mixture is separated into enantiomer
39aWith
39b
39a：[α]
D 20：+30.8°(CHCl
3，1.00g/100ml；λ＝589nM)
39b：[α]
D 20：-28.3°(CHCl
3，1.00g/100ml；λ＝589nM)
Racemize-6-[2-(2-chloro-phenyl-) cyclopropyl methyl]-2-hydroxyl-4-(4-three fluoro-aminomethyl phenyls) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
40
1H-NMR(ppm，CDCl
3，300MHz)：0.91(1H)，1.02(1H)，1.08-1.25(2H)，2.53(3H)，3.00(1H)，7.02-7.18(2H)，7.28(1H)，7.42-7.54(3H)，7.55-7.67(3H)，8.22(1H)，8.32(1H)，8.91(1H).
(+)-6-[2-(2-chloro-phenyl-) cyclopropyl methyl]-2-hydroxyl-4-(4-three fluoro-aminomethyl phenyls) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
40aWith
(-)-6-[2-(2-chloro-phenyl-) cyclopropyl methyl]-2-hydroxyl-4-(4-three fluoro-aminomethyl phenyls) fourth-3-alkynes acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
40b
(post: Chiralpak AD 250 * 10mm) is with embodiment by preparation chirality HPLC
40Described racemic mixture is separated into enantiomer
40aWith
40b
40a：[α]
D 20：+20.9°(CHCl
3，1.06g/100ml；λ＝589nM)
40b：[α]
D 20：-20.6°(CHCl
3，1.05g/100ml，λ＝589nM)
Racemize-6-[2-[[3-(1-hydroxyl-1-methylethyl) phenyl] ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
41
Dilute 3 moles of methyl magnesium chlorine solution of 59 μ l with the 1ml pure tetrahydrofuran.Solution is cooled to-70 ℃, adds the 0.5ml pure tetrahydrofuran solution of 30mg embodiment 33 described compounds.After stirring 2.5h under-70 ℃, mixture is poured in the saturated ammonium chloride solution.After with the ethyl acetate extraction mixture, wash the organic phase that merges and use dried over sodium sulfate with saturated sodium-chloride.After column chromatography, obtain the 16mg product.
1H-NMR(ppm，CDCl
3，400MHz)：1.46(3H)，1.53(6H)，1.62(3H)，1.80(1H)，2.55(3H)，2.65-2.90(3H)，7.12(1H)，7.30(3H)，7.40-7.52(3H)，7.53(1H)，7.60(1H)，8.27(2H)，8.95(1H).
Similar to Example 7, prepare following compound by embodiment 14 described compounds and 4-phenyl-iodide methyl alcohol:
Racemize-6-[2-[[4-(hydroxymethyl) phenyl] ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
42
1H-NMR(ppm，CDCl
3，300MHz)：1.47(3H)，1.60(3H)，1.80(1H)，2.57(3H)，2.62-2.83(3H)，4.68(2H)，7.13(1H)，7.25-7.43(6H)，7.48(2H)，7.59(1H)，8.25-8.32(2H)，8.91(1H).
Similar to Example 7, prepare following compound by embodiment 14 described compounds and 4-phenyl-iodide methyl alcohol:
Racemize-6-[2-[[3-(hydroxymethyl) phenyl] ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
43
1H-NMR(ppm，CDCl
3，400MHz)：1.48(3H)，1.62(3H)，1.79(1H)，2.57(3H)，2.62-2.80(3H)，4.68(2H)，7.15(1H)，7.25-7.39(5H)，7.40(1H)，7.49(2H)，7.60(1H)，8.29(2H)，8.91(1H).
Similar with embodiment 41, prepare following compound by embodiment 30 described compounds and methyl magnesium chlorine solution:
Racemize-6-[2-[[4-(1-hydroxyl-1-methylethyl) phenyl] ethynyl]-2-hydroxy-4-methyl-4-phenyl pentyne acyl amino]-4-methyl-2,3-benzoxazine-1-ketone
44
1H-NMR(ppm，CDCl
3，400MHz)：1.47(3H)，1.55(6H)，1.62(3H)，1.70(1H)，2.55(3H)，2.60-2.80(3H)，7.14(1H)，7.28-7.40(4H)，7.41(2H)，7.48(2H)，7.60(1H)，8.25-8.32(2H)，8.90(1H).
Claims (25)
1. the compound of general formula I and pharmacologically acceptable salts thereof:
Wherein:
R
1And R
2Be hydrogen atom mutually independently of each other, the C of linear or non-linear, side chain or straight chain
1-C
5-alkyl, they also form with the C atom of chain has the ring of 3-7 unit altogether,
R
3Be group C ≡ C-R
a, wherein:
R
aBe hydrogen or the optional C that is replaced one or many by identical or different K
1-C
8-alkyl, C
2-C
8-thiazolinyl, C
2-C
8-alkynyl, C
3-C
10-cycloalkyl, Heterocyclylalkyl or optional by the aryl or the heteroaryl of identical or different L replacement one or many,
K be 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,-C=NOR
b-N
cR
dOr C
3-C
10-cycloalkyl, optional by the Heterocyclylalkyl of identical or different M replacement one or many or optional by the aryl or the heteroaryl of L replacement one or many,
L is 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
e(S (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 is 1 or 2, and terminal Sauerstoffatom and/or carbon atom directly link to each other with adjacent ring carbon atom,
M is C
1-C
6-alkyl or group-COR
b, CO
2R
b,-O-R
bOr-NR
cR
d, wherein:
R
bBe 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
dBe hydrogen, C independently of each other
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, then R
dCan only be 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, vice versa and
R
cBe 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 can be the numeral of 0-6,
Perhaps
R
3Be group C=C-R
gR
h, wherein:
R
gAnd R
hBe hydrogen or the optional C that is replaced one or many by identical or different X independently of each other
1-C
8-alkyl, C
2-C
8-thiazolinyl or C
2-C
8-alkynyl, wherein:
X be 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
dImplication as mentioned above and
R
4Be hydrogen atom, methyl or ethyl or fluorizated C partially or completely
1-C
3-alkyl,
A is monocycle or bicyclic carbocyclic or heterocycle aromatic ring, and it can be chosen wantonly by 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-replace one or many, wherein n is 1 or 2, and terminal Sauerstoffatom and/or carbon atom directly link to each other with adjacent ring carbon atom, perhaps
A is group-CO
2R
b, C (O) NR
cR
d, COR
b, perhaps
A is thiazolinyl-CR
5=CR
6R
7, wherein
R
5, R
6And R
7Identical or different, and be hydrogen atom, halogen atom, aryl or not replacement or partially or completely fluorizated C independently of each other
1-C
5-alkyl, perhaps
A is alkynyl-C ≡ CR
5, R wherein
5Implication as mentioned above and
B is carbonyl or CH
2Group.
2. compound as claimed in claim 1, wherein R
1And R
2Be preferably hydrogen atom, methyl or ethyl.
3. compound as claimed in claim 1, wherein R
1And R
2Preferably form and have the ring of 3-7 unit altogether with the C atom of chain.
4. as the described compound of claim 1 to 3, wherein R
3Be preferably thiazolinyl, alkynyl, aromatic yl polysulfide yl, heteroaryl alkynyl, cycloalkyl alkynyl, Heterocyclylalkyl alkynyl.
5. the described compound of one of claim, wherein R as described above
3Be preferably 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; (xenyl) ethynyl; (nitrophenyl) ethynyl; (tert-butyl-phenyl) ethynyl; (acetylphenyl) ethynyl; (acetoxyl group phenyl) ethynyl; (carboxyl phenyl) ethynyl or benzyl ethynyl.
6. the described compound of one of claim as described above, wherein A is preferably aromatic ring.
7. the described compound of one of claim as described above, wherein A is preferably phenyl or naphthyl.
8. compound as claimed in claim 7, wherein A is preferably unsubstituted or optional single the replacement or polysubstituted phenyl.
9. compound as claimed in claim 8, wherein said phenyl are preferably replaced by one or two halogen atom or a trifluoromethyl.
10. compound as claimed in claim 9, wherein said halogen atom is preferably chlorine and/or fluorine.
11. as the described compound of claim 1-8, wherein A is preferably by-O-(CH
2)
n-O-or-O-(CH
2)
n-CH
2The phenyl ring of-replacement wherein links to each other with the ring carbon atom of direct neighbor respectively.
12. the described compound of one of claim, wherein R as described above
4Be hydrogen atom, methyl or trifluoromethyl.
13. as the described compound of claim 1-5, that is:
14. pharmaceutical composition, described pharmaceutical composition comprise at least a compound as one of claim 1-13 described general formula I, and randomly at least a other activeconstituents and pharmaceutically suitable vehicle and/or carrier.
15. pharmaceutical composition as claimed in claim 14, wherein said other activeconstituents are SERM (selective estrogen receptor modulators), aromatase inhibitor, estrogen antagonist or prostaglandin(PG).
16. pharmaceutical composition as claimed in claim 14, wherein said activeconstituents can be tamoxifen; 5-(4-{5-[(RS)-(4,4; 5,5,5-five fluorine amyl groups) sulfinyl] pentyloxy } phenyl)-6-phenyl-8; 9-dihydro-7H-benzocyclohepta alkene-2-alcohol; (7 α-[9-(4,4,5 for ICI 182 780; 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) the 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 } 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 } female-1; 3,5 (10)-triolefins-3,17-isoallopregnane-3; Clomiphene; raloxifene; fadrozole; formestane; letrozole; Anastrozole or Atamestane.
17. as the application of the described compound of one of claim 1-13 in the preparation medicine.
18. compound as claimed in claim 17 is used for the treatment of and prevents application in the medicine of gynecological diseases such as endometriosis, leiomyoma of uterus, hemorrhage of functional disorder and dysmenorrhoea in preparation.
19. compound as claimed in claim 17 is used for the treatment of application in the medicine with the prevention of hormone dependent tumour in preparation.
20. compound as claimed in claim 17 is used for the treatment of application in the medicine with Breast Cancer Prevention in preparation.
21. compound as claimed in claim 17 is used for the treatment of and prevents application in the medicine of carcinoma of endometrium in preparation.
22. compound as claimed in claim 17 is used for the treatment of and prevents application in the medicine of ovarian cancer in preparation.
23. compound as claimed in claim 17 is used for the treatment of and prevents application in the medicine of prostate cancer in preparation.
24. compound as claimed in claim 17 is used for the application of the medicine of female hormone alternative medicine in preparation.
25. the application of compound as claimed in claim 17 in female fertility control.
26. be used for alkynyl lithium and halo alkynyl magnesium compound selectivity are added to method on the keto-amide.
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| 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 |
| JP2011519916A (en) * | 2008-07-02 | 2011-07-14 | ファーマコステック カンパニー リミテッド | Method for producing amide derivative |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19856475A1 (en) * | 1998-11-27 | 2000-05-31 | Schering Ag | Nonsteroidal anti-inflammatories |
| EP1344776A1 (en) * | 2002-03-11 | 2003-09-17 | Schering Aktiengesellschaft | 5- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -phtalide and 6- 2-hydroxy-3-[1-(3-trifluoromethylphenyl)-cyclopropyl]-propionylamino -4-methyl-2,3-benzoxazin-1-one derivatives with progesterone receptor modulating activity for use in fertility control, hormone replacement therapy and the treatment of gynecological disorders |
| BRPI0412231A (en) * | 2003-07-01 | 2006-08-22 | Schering Ag | heterocyclically substituted pentanol derivatives, processes for their preparation and application as inflammation inhibitors |
-
2005
- 2005-06-24 DE DE102005030292A patent/DE102005030292A1/en not_active Ceased
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2006
- 2006-06-22 AU AU2006261048A patent/AU2006261048A1/en not_active Abandoned
- 2006-06-22 CN CNA2006800308707A patent/CN101248066A/en active Pending
- 2006-06-22 EP EP06762404A patent/EP1902049A2/en not_active Withdrawn
- 2006-06-22 EA EA200702524A patent/EA200702524A1/en unknown
- 2006-06-22 JP JP2008517444A patent/JP2008543910A/en active Pending
- 2006-06-22 CA CA002611897A patent/CA2611897A1/en not_active Abandoned
- 2006-06-22 KR KR1020087001793A patent/KR20080030622A/en not_active Application Discontinuation
- 2006-06-22 WO PCT/EP2006/006531 patent/WO2006136461A2/en active Application Filing
- 2006-06-22 MX MX2008000072A patent/MX2008000072A/en not_active Application Discontinuation
- 2006-06-22 BR BRPI0611903-4A patent/BRPI0611903A2/en not_active Application Discontinuation
- 2006-06-23 TW TW095122742A patent/TW200740778A/en unknown
- 2006-06-26 UY UY29624A patent/UY29624A1/en not_active Application Discontinuation
- 2006-06-26 DO DO2006000148A patent/DOP2006000148A/en unknown
- 2006-06-26 PE PE2006000733A patent/PE20070125A1/en not_active Application Discontinuation
- 2006-06-27 AR ARP060102750A patent/AR054519A1/en unknown
- 2006-06-28 GT GT200600271A patent/GT200600271A/en unknown
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2007
- 2007-12-10 IL IL188021A patent/IL188021A0/en unknown
- 2007-12-17 CR CR9598A patent/CR9598A/en not_active Application Discontinuation
- 2007-12-21 EC EC2007008044A patent/ECSP078044A/en unknown
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2008
- 2008-01-23 NO NO20080440A patent/NO20080440L/en not_active Application Discontinuation
- 2008-01-23 ZA ZA200800690A patent/ZA200800690B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CR9598A (en) | 2008-04-09 |
| EP1902049A2 (en) | 2008-03-26 |
| PE20070125A1 (en) | 2007-02-14 |
| KR20080030622A (en) | 2008-04-04 |
| EA200702524A1 (en) | 2008-06-30 |
| BRPI0611903A2 (en) | 2010-10-05 |
| TW200740778A (en) | 2007-11-01 |
| JP2008543910A (en) | 2008-12-04 |
| NO20080440L (en) | 2008-03-25 |
| MX2008000072A (en) | 2008-03-24 |
| GT200600271A (en) | 2007-02-05 |
| ECSP078044A (en) | 2008-01-23 |
| WO2006136461A2 (en) | 2006-12-28 |
| WO2006136461A3 (en) | 2007-03-15 |
| DE102005030292A1 (en) | 2007-01-11 |
| DOP2006000148A (en) | 2007-07-15 |
| UY29624A1 (en) | 2007-01-31 |
| CA2611897A1 (en) | 2006-12-28 |
| IL188021A0 (en) | 2008-03-20 |
| ZA200800690B (en) | 2009-09-30 |
| AU2006261048A1 (en) | 2006-12-28 |
| AR054519A1 (en) | 2007-06-27 |
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