CN101616926A - 11-(4-aminophenyl)-19-removes pregnant-4,9 (10)-diene-3 of first, the pharmacologically acceptable salt of 20-derovatives - Google Patents

11-(4-aminophenyl)-19-removes pregnant-4,9 (10)-diene-3 of first, the pharmacologically acceptable salt of 20-derovatives Download PDF

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CN101616926A
CN101616926A CN200880002367A CN200880002367A CN101616926A CN 101616926 A CN101616926 A CN 101616926A CN 200880002367 A CN200880002367 A CN 200880002367A CN 200880002367 A CN200880002367 A CN 200880002367A CN 101616926 A CN101616926 A CN 101616926A
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J·波多尔斯基
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Abstract

The invention provides and comprise that 11-(4-aminophenyl)-19-removes pregnant-4,9 (10)-diene-3 of first, the composition with the stability improved of the pharmacologically acceptable salt of 20-derovatives.

Description

11-(4-aminophenyl)-19-removes pregnant-4,9 (10)-diene-3 of first, the pharmacologically acceptable salt of 20-derovatives
The field of the invention
[0001] generality of the present invention relate to the composition that comprises steroid and, especially, relate to and comprise the effectively anti-pregnant activity of having of 19-norprogesterone I derivative, minimum anti-suprarenal gland glucocorticoid activity and the composition of improved stability.The invention still further relates to the use method for compositions.
Background of the present invention
[0002] there have been many trials to prepare in the past few decades and had the active steroid of hormone antagonist.What It is generally accepted for some years is, anti-pregnant steroid has found extensive applicability in Population control, anti-simultaneously suprarenal gland glucocorticosteroid is in for example Cushing's syndrome and be produced as on other treatment of conditions on basis with the excessive endogenous of cortisone be extremely valuable.
[0003], it is desirable to some and have the compound that resists pregnant activity but do not have (or having minimum) anti-suprarenal gland glucocorticoid activity in order to practise contraception.Realize separating between anti-pregnant activity and the anti-suprarenal gland glucocorticoid activity though existing many trials improve the mifepristone structure, this target still realizes fully.Itself still needs to develop the new preparaton that comprises steroid in the prior art, this steroid has anti-pregnant activity and has minimum anti-suprarenal gland glucocorticoid activity concurrently.
[0004] United States Patent (USP) 6,861, and 415 and 6,900,193 (both are hereby incorporated by reference) openly has the novel cpd that anti-pregnant activity has minimum anti-suprarenal gland glucocorticoid activity concurrently.Compound is a steroid derivatives and specifically they are 19-norprogesterone I, as the 17-alpha-substitution-the 11-beta substitution-19-that 4-aryl and 21-replace goes the structurally-modified of first pregnadienedione, and is slightly soluble in water.Therefore, still need to develop the preparaton that comprises steroid derivatives in the prior art, this steroid derivatives has the stability and the improved bioavailability of raising.
General introduction of the present invention
[0005] the invention provides new preparaton with effectively anti-pregnant activity, minimum anti-suprarenal gland glucocorticoid activity and improved stability.
[0006] more particularly, the invention provides the composition of the pharmacologically acceptable salt that comprises compound with following formula I:
Figure A20088000236700061
In the formula:
R 1Be basic functionality, can form salt on it, it preferably includes nitrogen, and this group includes but not limited to ,-N (CH 3) 2,-NHCH 3,-NC 4H 8,-NC 5H 10,-NC 4H 8O ,-O (CH 2) 2N (CH 3) 2,-O (CH 2) 2NC 4H 8With-O (CH 2) 2NC 5H 10
R 2Be functional group, it includes but not limited to, hydrogen, halogen, alkyl; acyl group, hydroxyl, alkoxyl group (for example, methoxyl group, oxyethyl group; vinyl oxygen base, ethynyl oxygen base, the ring propoxy-, or the like); acyloxy (for example, methanoyl, acetoxyl group, propionyloxy; oenanthyl oxygen base, the glycine root, or the like), the alkyl carbonate; cyclopentyl propionyloxy (cypionyloxy), the S-alkyl ,-SCN, the S-acyl group and-OC (O) R 6, R wherein 6Be functional group, this functional group includes but not limited to, alkyl (for example, methyl, ethyl, or the like), alkoxyalkyl (for example ,-CH 2OCH 3) and alkoxyl group (OCH 3);
R 3Be functional group, this functional group includes but not limited to, alkyl (for example, methyl, methoxymethyl, or the like), hydroxyl, alkoxyl group (for example, methoxyl group, oxyethyl group, methoxy ethoxy, vinyl oxygen base, or the like), and acyloxy;
R 4Be functional group, this functional group includes but not limited to, hydrogen and alkyl; With X be functional group, this functional group includes but not limited to ,=O and=N-OR 5, R wherein 5Being selected from hydrogen and alkyl and precondition is to work as R 1Be-N (CH 3) 2The time, R 2Be methoxyl group, R 3Be acetoxyl group, R 4Be that methyl and X are=O, this salt is not HCl or HBr salt.
[0008] composition can have effectively anti-pregnant activity, minimum anti-suprarenal gland glucocorticoid activity is arranged, and have improved stability concurrently.Therefore, composition can be suitable for human endocrine disease or the medium-term and long-term use of other treatment of conditions in steroid class sensitive organization.The particular disorder of treatment includes, but not limited to endometriosis, dysmenorrhoea, leiomyoma of uterus, fibroid, meningioma and metastatic mammary cancer.Other application includes, but not limited to contraception, comprising inducing of emergent postcoital contraception and uterine cervix slaking.
[0009] also provides the purposes of any present composition in the preparation of medicine, this medicine is used for steroid class sensitive organization human endocrine disease or other treatment of conditions described here, these illnesss include but not limited to, endometriosis, dysmenorrhoea, leiomyoma of uterus, fibroid, meningioma and metastatic mammary cancer.
Detailed description of the present invention
[0010] provide composition, it comprises the steroid derivatives of following formula I:
Figure A20088000236700071
[0011] in formula I, R 1Be basic functionality, can form salt on it, it preferably includes nitrogen, and this group includes but not limited to ,-N (CH 3) 2,-NHCH 3,-NC 4H 8,-NC 5H 10,-NC 4H 8O ,-O (CH 2) 2N (CH 3) 2,-O (CH 2) 2NC 4H 8With-O (CH 2) 2NC 5H 10
R 2Be functional group, it includes but not limited to, hydrogen, halogen, alkyl; acyl group, hydroxyl, alkoxyl group (for example, methoxyl group, oxyethyl group; vinyl oxygen base, ethynyl oxygen base, the ring propoxy-, or the like); acyloxy (for example, methanoyl, acetoxyl group, propionyloxy; oenanthyl oxygen base, the glycine root, or the like), the alkyl carbonate; the cyclopentyl propionyloxy, the S-alkyl ,-SCN, the S-acyl group and-OC (O) R 6, R wherein 6Be functional group, this functional group includes but not limited to, alkyl (for example, methyl, ethyl, or the like), alkoxyalkyl (for example ,-CH 2OCH 3) and alkoxyl group (OCH 3);
R 3Be functional group, this functional group includes but not limited to, alkyl, hydroxyl, alkoxyl group and acyloxy;
R 4Be functional group, this functional group includes but not limited to, hydrogen and alkyl; With X be functional group, this functional group includes but not limited to ,=O and=N-OR 5, R wherein 5Being selected from hydrogen and alkyl and precondition is to work as R 1Be-N (CH 3) 2The time, R 2Be methoxyl group, R 3Be acetoxyl group, R 4Be that methyl and X are=O, this salt is not HCl or HBr salt.
[0012] therefore, composition of the present invention comprises the compound of general formula I, and this compound can form salt when compound and suitable acid-respons.Preferably, to be included in the 11 β positions that are positioned at compound (be R to the compound of general formula I 1The position) goes up the basic functionality that connects for 4 of the phenyl on; Yet the compound of Formula I that is included in the basic functionality that connects on any position is in the scope of the present invention, as long as can make the salt of compound.Except basic functionality listed above, R 1Other suitable basic functionality of (forming salt on it) comprises, without limits, and methylamine, dimethyl amine, ethylamine, diethylamide, ethylmethylamine, isopropylamine, diisopropylamine, n-butylamine, thanomin, diethanolamine, Mono Methyl Ethanol Amine, Yi Bingchunan, diisopropanolamine (DIPA), ethylenimine, quadrol, pyridine and morpholine functional group.
[0013] this term " alkyl " refers to have the branching of 1-12 carbon atom, nonbranched monovalence alkyl.When this alkyl had 1-6 carbon atom, it was called as " low alkyl group ".Representative alkyl comprises, for example, methyl, ethyl, n-propyl, sec.-propyl, 2-propenyl (or allyl group), normal-butyl, the tertiary butyl, isobutyl-(or 2-methyl-propyl), or the like.Here the term alkyl of Shi Yonging comprises " alkyl of replacement ".The alkyl that replaces is meant the alkyl that further contains one or more functional groups, as low alkyl group, aryl, aralkyl, acyl group, halogen (that is, and alkyl halide, for example, CF 3), the alkyl of hydroxyl (for example, methylol), amino, alkylamino, acyl amino, acyloxy, alkoxyl group (for example, methoxymethyl), sulfydryl or the like.These groups can be connected on any carbon atom of low alkyl group structure division.
[0014] this term " alkoxyl group " can refer to-the OR group, and wherein R is a low alkyl group, the low alkyl group of replacement, aryl, the aryl of replacement, the aralkyl of aralkyl or replacement.Suitable alkoxyl group comprises, methoxyl group for example, and oxyethyl group, phenoxy group, tert.-butoxy (for example, methoxy ethoxy, methoxymethoxy, or the like), or the like.
[0015] this term " acyloxy " can refer to the organic radical that forms from organic acid of removing by hydrogen.This organic radical can be further by one or more functional groups such as alkyl, aryl, and aralkyl, acyl group, halogen, amino, mercaptan, hydroxyl, alkoxyl group or the like replaces.The example of the organic group of this type of replacement be the glycine root (for example ,-OC (O) CH 2NH 2).Suitable acyloxy comprises, for example, and acetoxyl group, that is, and CH 3COO-, it can form from acetate, methanoyl, that is, H (CO) O-, it can form from formic acid, and the cyclopentyl propionyloxy, and it can form from the 3-cyclopentanepropanoiacid acid.
[0016] term " halogen " refers to fluorine, bromine, chlorine and iodine atom.Term " hydroxyl " refers to group-OH.Term " acyl group " expression group-C (O) R, wherein R is the alkyl of defined here alkyl or replacement, the aryl of aryl or replacement.Term " aryl " refers to aromatic substituents, and it can be monocycle or condense together, that connect with covalent or be connected in many rings on common group such as ethylidene or the methylene moiety.Aromatic ring can comprise phenyl, naphthyl, and xenyl, diphenyl-methyl, 2,2-phenylbenzene-1-ethyl, and can contain heteroatoms, as thienyl, pyridyl and quinoxalinyl.This aryl also can be by halogen atom, or other group such as nitro, carboxyl, alkoxyl group, replacements such as phenoxy group.In addition, this aryl can be connected in other structure division (as the 2-pyridyl, 3-pyridyl and 4-pyridyl) in any position that is occupied by hydrogen atom in addition on aryl.
[0017] term " alkyl carbonate " can refer to group-OC (O) OR, and wherein R is defined here alkyl, substituted alkyl, aryl, or substituted aryl.
[0018] term " S-alkyl " can refer to group-SR, and wherein R is low alkyl group or replaces low alkyl group.Term " S-acyl group " refers to from the thioesters of the reaction formation of thiol group and acylating agent.Suitable S-acyl group comprises, for example S-ethanoyl, S-propionyl and S-pivaloyl group.The S-acyl group can refer to this type of thioesters, does not consider their preparation method.Term " N-oxime " and " N-alkyl oxime " refer to group=N-OR 5, R wherein 5For example be hydrogen (N-oxime) or alkyl (N-alkyl oxime).This oxime can be by cis-isomeride, and the mixture of trans-isomer(ide) and cis and trans-isomer(ide) is formed.
[0019] representative compounds within formula I comprises wherein R 1Be-N (CH 3) 2Those; R wherein 2Be those of hydrogen, halogen or alkoxyl group; R wherein 3Be those of acyloxy; R wherein 4Be those of alkyl (for example methyl and ethyl); And wherein X be=O and=N-OR 5, R wherein 5Be those of hydrogen or alkyl.Additional compound comprises wherein R 1Be-N (CH 3) 2, R 2Be halogen, R 3Be acyloxy, and R 4Be those of alkyl; R wherein for example 2Be F, Br or Cl, and R 4Be those of methyl.In being also included within is R wherein 1Be-N (CH 3) 2R 2It is alkyl; R 3It is acyloxy; R 4It is alkyl; With X be=compound of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2It is alkoxyl group; R 3It is acyloxy; R 4It is alkyl; With X be=compound of O.Additional compound is R wherein 2It is methoxy or ethoxy; And R 3Be those of acetoxyl group or methoxyl group.In being also included within is R wherein 1Be-N (CH 3) 2R 2It is hydroxyl; R 3It is acyloxy; R 4It is alkyl; With X be=compound of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2And R 3The both is an acyloxy; R 4It is alkyl; With X be=compound of O.Additional compound is R wherein 2And R 3The both is those compounds of acetoxyl group.In being also included within is R wherein 1Be-N (CH 3) 2R 2It is the S-acyl group; R 3Be hydroxyl or acyloxy; R 4It is alkyl; With X be=those compounds of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2It is the cyclopentyl propionyloxy; R 3It is acetoxyl group; R 4It is alkyl; With X be=those compounds of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2It is methoxyl group; R 3It is acetoxyl group; R 4It is alkyl; With X be=O and=N-OR 5, R wherein 5For example be hydrogen or alkyl (for example, methyl, ethyl, or the like), those compounds.In being also included within is R wherein 1Be-N (CH 3) 2R 2And R 3The both is an acetoxyl group; R 4It is alkyl; With X be=O and=N-OR 5, R wherein 5For example be hydrogen or alkyl (for example, methyl, ethyl, or the like), those compounds.
[0020] example compound 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-methoxyl group-19-of including, but not limited to have following structural formula removes pregnant-4,9 (10)-diene-3 of first, 20-diketone (CDB-4124):
Figure A20088000236700101
Precondition is that the salt of CDB-4124 is not HCl or HBr hydrochlorate.
[0021] another example compound is that 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-19-with following structural formula goes first pregnant-4,9-diene-3, and 20-diketone (CDB-2914):
Figure A20088000236700102
[0022] other example compound includes, but not limited to 17 α-acetoxyl group-21-chloro-11 β-(4-N, N-dimethylamino phenyl)-19-and goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-bromo-11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17-, 21-diacetyl-11 β-(4-N, N-dimethylamino phenyl) 19-go first pregnant-4,9-diene-3,20-diketone; 17 alpha-hydroxy-2 1-acetylthio-11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-acetylthio-11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-oxyethyl group-11 β-(4N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-methyl isophthalic acid 1 β-(4-N, N-dimethylamino-phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-methoxyl group-11 β-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-oxyethyl group-11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-(3 '-cyclopentyl propionyloxy), 11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-hydroxyl-11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α, 21-diacetyl-11 β-(4-N, N-dimethylamino phenyl) 9-go first pregnant-4,9-diene-3,20-diketone 3-oxime; 17 α-acetoxyl group-21-methoxyl group-11 β-(4-N, N-dimethylamino phenyl)-19-goes first pregnant-4,9-diene-3,2-diketone 3-oxime; 17 α-acetoxyl group-11 β-[4-(N-methylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone; With 17 α, 21-diacetyl-11 β-[4-(N-methylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone.
[0023] in being also included within be R wherein 1Be-N (CH 3) 2,-NC 4H 8,-NC 4H 10,-NC 4H 8O ,-O (CH 2) 2N (CH 3) 2,-O (CH 2) 2NC 4H 8,-O (CH 2) 2NC 3H 10With-O (CH 2) 2NC 5H 10Those compounds; R wherein 2Be hydrogen, alkoxyl group, alkoxyl group ,-SAc ,-SCN ,-OC (O) CH 2N (CH 3) 2And-OC (O) R 6, R wherein 6Be functional group, it includes but not limited to, and alkyl (for example ,-CH 2CH 3), alkoxy ester (for example ,-CH 2OMe) and alkoxyl group (for example ,-OCH 3), those compounds; R wherein 3Be alkyl, alkoxyl group, those of acyloxy and hydroxyl; R wherein 4Be those of alkyl (for example, methyl and ethyl); Wherein X be=O or=N-OR 5, R wherein 5Be hydrogen or alkyl, those compounds.Also R wherein preferably 1Be-N (CH 3) 2R 2Be hydrogen; R 3It is methoxymethyl; R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2Be hydrogen; R 3Be-OC (O) H ,-OC (O) CH 2CH 3Or-OC (O) C 6H 13R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-NC 4Hs ,-NC 5H 10, or-NC 4H 8O; R 2Be hydrogen; R 3It is acetoxyl group; R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-N (CH 3) 2Or-NC 5H 10R 2Be hydrogen; R 3It is methoxyl group; R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-NC 5H 10R 2And R 3The both is an acetoxyl group; R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-NC 5H 10Or-O (CH 2) 2N (CH 3) 2R 2It is methoxyl group; R 3It is acetoxyl group; R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2Be-OC (O) CH 2CH 3,-OC (O) OCH 3,-OC (O) OCH 2OCH 3,-OCH=CH 2,-OC (O) CH 2N (CH 3) 2Or-SCN; R 3It is acetoxyl group; R 4It is methyl; With X be=those of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2Be-OC (O) H; R 3Be-OC (O) H; R 4It is methyl; With X be=those compounds of O.In being also included within is R wherein 1Be-N (CH 3) 2R 2Be-OC (O) H; R 3It is hydroxyl; R 4It is methyl; With X be=compound of O.In being also included within is R wherein 1Be-NC 5H 10R 2Be hydrogen; R 3It is acetoxyl group; R 4It is methyl; With X be=N-OR 5, R wherein 5It is the compound of hydrogen.In being also included within is R wherein 1Be-N (CH 3) 2Or-NC 5H 10R 2Be hydrogen or methoxyl group; R 3It is methoxy or ethoxy; R 4It is methyl; With X be=N-OR 5, R wherein 5Be hydrogen, compound.
[0024] example compound also includes, but not limited to 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-methoxyl group-19-and removes pregnant-4,9 (10)-diene-3 of first, 20-diketone; 17 alpha-formyloxies-11 β-[4-(N, N-diethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-propionyloxy-11 β-[4-(N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-oenanthyl Oxy-1 1 β-[4-(N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone; 17 alpha-methoxymethyl base-11 β-[4-N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-(4-N-pyrrolidino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-(4-N-piperidino-(1-position only) phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-(4-N-morpholino phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-methoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-methoxyl group-11 β-(4-N-pyridine subbase phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α, 21-diacetyl-11 β-(4-N-pyridine subbase phenyl)-19-go first pregnant-4,9-diene-3,20-diketone; 17 α, 21-dimethoxy-11 β-[4-(N, N-dimethylamino) phenyl]-19-go first pregnant-4,9-diene-3,20-diketone; 17 α, 21-dimethoxy-11 β-(4-N-pyrrolidino phenyl)-19-go first pregnant-4,9-diene-3,20-diketone; 17 α, 21-dimethoxy-11 β-(4-N-pyridine subbase phenyl) 19-go first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-4-[2 '-(N, N-dimethylamino) oxyethyl group] phenyl }-21-methoxyl group-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α, 21-two methanoyies-11 β-[4-(N, N-dimethylamino) phenyl]-19-go first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-propionyloxy-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-(2 '-methoxyl group ethanoyl) Oxy-1 9-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-21-hydroxyl-11 β-[4-(N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone-21-methyl carbonic; 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-(1 '-vinyl oxygen base)-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-(2 '-N, N-dimethylamino) acetoxyl group-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-thiocyanate ion-19-goes first pregnant-4,9-diene-3,20-diketone; 17 α-acetoxyl group-11 β-(4-N-pyridine subbase phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone 3-oxime; 17 α-methoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone 3-oxime; 17 α-methoxyl group-11 β-(4-N-pyridine subbase phenyl)-19-goes first pregnant-4,9-diene-3,20-diketone 3-oxime; With 17 α, 21-dimethoxy-11 β-[4-(N, N-dimethylamino) phenyl]-19-goes first pregnant-4,9-diene-3,20-diketone 3-oxime.
[0025] when the compound with general formula I presents the form of salt,, the stability of compound can improve significantly.Composition is provided, and it comprises the pharmacologically acceptable salt and the optional pharmaceutically useful carrier of compound of Formula I.
[0026] in practice, the use of salt form is equivalent to the use of free alkali form inherently.Correspondingly, the acid that is suitable for preparing this salt comprises, preferably, when combining, produce those acid of pharmacologically acceptable salt with free alkali, this pharmacologically acceptable salt is such salt: its negatively charged ion is nontoxic to the patient in the drug dose of this salt, and the useful effect of drugs of these compounds of free alkali form is not damaged by anionic side effect like this.The compound of general formula I can be regenerated from salt by the application or the modification of currently known methods.For example, compound can be by using alkali, and for example sodium hydrogen carbonate solution handles the acid-adducting salt regeneration from them.
[0027] this salt can preparation on the spot in the final separation of the compound of general formula I and purification process, or the purification compound by free alkali form reacts individually and separates formed salt with appropriate organic or mineral acid and prepares.Exemplary salt comprises hydrobromate, halogenide, hydrochloride, vitriol, hydrosulfate, phosphoric acid salt, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, lauroleate, borate, benzoate, lactic acid salt, tosylate, Citrate trianion, maleate, fumarate, succinate, tartrate, naphthoate (napthylate), mesylate, gluceptate, Lactobionate, lauryl sulfonate etc. (referring to, for example, S.M.Berge, et a1., " Pharmaceutical Salts ", J.Pharm.Sci., 66:1-19,1977, their content is hereby incorporated by reference).For example, by being dissolved in, free alkali contains in suitable aqueous acid or water-alcohol solution or other suitable solvent also by the evaporating solns separated salt, or the reaction in organic solvent by free alkali and acid, prepare this salt, the direct separation of this salt maybe can be by the concentrated acquisition of solution under latter instance.
[0028] term " pharmaceutically acceptable medicine " refers to the nontoxic relatively inorganic or organic acid adduct of compound of Formula I.
[0029] provide composition, it comprises the pharmacologically acceptable salt of compound of Formula I.Can be contemplated that the salt of compound of Formula I will have the stability of raising for this compound of the free alkali form of equivalent under the same conditions.Therefore can be contemplated that composition of the present invention has the tolerance to chemical modification of raising.For the same compound of the free alkali form of equivalent under the same conditions, the stability of the pharmacologically acceptable salt of compound of Formula I can strengthen at least 1,5,10,15,20,25,30,35,40,45,50,60,70,80,90,100,150,200,300,400,500,600,700,800,900, or 1000% or higher.
[0030] Wen Dingxing canonical parameter is the storage time, and it is defined as for some time, estimates to remain within the shelf life of approval at this section period Chinese traditional medicine product.Accelerated test can be carried out 6 months time under 40 ℃ and 75% relative humidity.Under these conditions, the change with initial analysis value about 5% drug level Comparatively speaking is considered to significant.Can be contemplated that for the same combination of the same compound that comprises free alkali form under the same conditions, comprise that the composition exhibiting of the pharmacologically acceptable salt of compound of Formula I goes out the storage time of raising.
[0031] stability of here using refers to that after the storage interval under the predetermined temperature and humidity condition, the activeconstituents in the detection composition (that is, compound of Formula I typically undertaken by HPLC by) ability.Though HPLC is preferred, the method for chemical modification that can the identified activity composition and/or any detection of active composition of change in concentration can be used.
[0032] also provides to react and form the method that pharmacologically acceptable salt improves the stability of compound of Formula I by this compound and appropriate acid.
[0033] composition can have effectively anti-pregnant activity and minimum anti-suprarenal gland glucocorticoid activity, has improved stability concurrently, and it is oral that this makes that these compositions are suitable for.
[0034] composition can be advantageously used in, especially, and the antagonism endogenous progesterone; Induce menses; The treatment endometriosis; The treatment dysmenorrhoea; Treatment endocrine hormone dependent tumors; The treatment meningioma; The treatment leiomyoma of uterus; The treatment fibroid; Suppress endometrial proliferation; Induced parturition; The slaking of elicitor uterine neck is used for hormonotherapy; Practise contraception with being used for.
[0035] has anti-pregnant active composition and also embody the effect of feature in the antagonism progesterone.Itself, composition can be particularly useful for the control of the hormone irregularity in the menstrual cycle, is used to control endometriosis and dysmenorrhoea; Be used to induce menses.In addition, composition can produce among the impaired in addition women of ability individually or provides the method for hormonotherapy in combination with estrogen substance the postmenopausal women or at ovarian hormone.
[0036] in addition, composition can be used in the control of fertility in the whole reproductive cycle.For long-term contraception, composition can be continuously or periodically according to dosed administration.In addition, composition can be particularly useful as postcoital contraceptives, is used to cause the uterus to conflict and implants implantation and be used as " January once " contraception medicament.
[0037] the important use of another of composition is that they slow down hormone-dependent tumor and/or the ability of the growth of tumor that exists in hormone responsiveness tissue.This type of tumour includes, but not limited to nephroncus, mammary cancer, and carcinoma of endometrium, ovarian cancer, and tumor of prostate, for example, to have the cancer that PgR is a feature.In addition, this type of tumour comprises meningioma.Other purposes of composition comprises the treatment of the fibrocystic disease in breast and uterus.
[0038] composition can be applied to the Mammals of any homoiothermy, as the people, and household pet, and farming animals.Household pet comprises dog, cat, or the like.Farming animals comprise ox, horse, and pig, sheep, goat, or the like.
[0039] can combine the amount of the activeconstituents of producing single formulation with the solid support material of the best will be according to the disease that will treat, and mammal species and concrete mode of administration change.For example, unitary dose can be included in activeconstituents or the activeconstituents between 0.001 and 0.5 gram between restraining for 0.1 milligram and 1.Yet any concrete patient's given dose level will depend on multiple factor, comprising the activity of the particular compound of being tested; The age of the individuality for the treatment of, body weight, general health, sex and diet; Time of administration and approach; Excretory speed; The other medicines of administration in advance; And the severity of the disease specific for the treatment of.
[0040] composition can be by the whole bag of tricks administration.For example, composition can be with solution, suspension, emulsion, tablet (comprising sublingual tablet and intrabuccal tablet), soft gelatin capsule (comprising the solution that in soft gelatin capsule, uses), water-based or oil suspension, emulsion, pill, lozenge, lozenge, tablet, the form oral administration of syrup or elixir.
[0041] composition also can come administration or come administration via intramuscularly and intravenous injection as implant that comprises SILASTIC and biodegradable implant.
[0042] composition can contain and is selected from sweeting agent, seasonings, one or more reagent in tinting material and the sanitas.Contain activeconstituents and with those tablets that its blended is suitable for the nontoxic pharmaceutically acceptable vehicle of tablet manufacturing be acceptable.These vehicle can be, for example, inert diluent, as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate, granulating agent and disintegrating agent, as W-Gum, or alginic acid; Binding agent, as starch, gelatin or Sudan Gum-arabic; And lubricant, as Magnesium Stearate, stearic acid and talcum.Tablet can be uncoated or, additionally, they can be by currently known methods coated with postponing disintegration and the absorption in gi tract and provide lasting effect in the long time.For example, time lag agent such as glyceryl monostearate or glycerol disterate base ester can use separately or with wax.
[0043] oral preparaton also can exist as hard capsule, wherein for example lime carbonate, calcium phosphate or kaolin blending of activeconstituents and inert solid diluent, or as soft gelatin capsule existence, wherein activeconstituents and water or oily medium such as peanut oil, whiteruss or mixed with olive oil.
[0044] waterborne suspension can contain active material and be suitable for making the vehicle of waterborne suspension with its blended.This type of vehicle comprises suspension agent, as Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, Tragacanth and Sudan Gum-arabic, and dispersion or wetting agent, as natural phospholipid (for example, Yelkin TTS), the condensation product of oxyalkylene and lipid acid (for example, the polyoxyethylene stearate), () condensation product for example, 17 ethyleneoxy group hexadecanols, oxyethane and the partial ester that forms from lipid acid and hexitol are (for example for oxyethane and long chain aliphatic, the polyoxyethylene sorbitol monooleate) condensation product, or the condensation product of oxyethane and the partial ester (for example polyoxyethylene sorbitan monooleate) that forms from lipid acid and hexitol acid anhydrides.Waterborne suspension also can contain one or more sanitass such as ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl, one or more tinting materials, and one or more seasoningss and one or more sweeting agents, as sucrose, aspartame or asccharin.
[0045] oil suspension can be by being suspended in activeconstituents vegetables oil such as peanut oil, sweet oil, and sesame oil or Oleum Cocois, or in mineral oil such as whiteruss, prepare.This oil suspension can contain thickening material, as beeswax, paraffinum durum or cetyl alcohol.Sweeting agent can be added provide can be oral preparation.These compositions can be protected by the interpolation of antioxidant such as xitix.
[0046] is adapted to pass through and adds water and prepare the dispersible powders agent of waterborne suspension and particulate and can mix with dispersion agent, suspension agent and/or wetting agent and one or more sanitas from activeconstituents and prepare.Suitable dispersion agent or wetting agent and suspension agent for example are above those disclosed.Additional vehicle, for example sweeting agent, seasonings and toner also can exist.
[0047] this pharmaceutical composition also can present the form of emulsion oil-in-water.Oil phase can be vegetables oil such as sweet oil or peanut oil, mineral oil such as whiteruss, or these mixture.Suitable emulsifying agent comprises natural gum such as Sudan Gum-arabic and Tragacanth, natural phospholipid such as soybean lecithin, ester or partial ester from lipid acid and the formation of hexitol acid anhydrides, as dehydrating sorbitol monooleate, and the condensation product of these partial esters and oxyethane such as polyoxyethylene dehydrating sorbitol monooleate.This emulsion also can contain sweeting agent and seasonings.
[0048] syrup and the elixir enough sweeting agents of energy such as glycerine, Sorbitol Powder or sucrose are prepared.This type of preparaton can also contain negative catalyst, sanitas, seasonings or tinting material.
[0049] this pharmaceutical composition can present the form of aseptic injectable formulation, as aseptic injectable water-based and oily suspensions.This suspension can be prepared by using those suitable dispersion agents or wetting agent and above-mentioned suspension agent.This aseptic injectable preparation also can be can accept the thinner of (parenterally-acceptable) or aseptic injectable solution or the suspension in the solvent at nontoxic parenteral, as the solution of 1,3 butylene glycol.The acceptable vehicle that can use and solvent are water and Ringers solution (Ringer ' s solution), isotonic sodium chloride solution.In addition, aseptic fixed oil can be used as solvent or suspension medium.For this purpose, the fixed oil of any gentleness can be used, comprising synthetic glyceryl monoacetate or diglyceride.In addition, lipid acid such as oleic acid can similarly be used for the preparation of injectable agent.
[0050] compound also can be with the suppository form administration of the rectal administration that is used for medicine.These compositions can prepare by medicine and suitable non-irritating mixed with excipients, and it is solid at normal temperatures but is liquid and therefore fusing and discharge medicine in rectum under rectal temperature.This type of material is theobroma oil and polyoxyethylene glycol.
[0051] they also can by in the nose, intraocular, intravaginal and intrarectal approach come administration, comprising suppository, insufflation, powder agent and aerosol.
[0052] can be by the compound of topical routes as medicated sound, solution, suspension, emulsion, gelifying agent, creme, ointment, paste, jelly, paint, powder and aerosol come administration.
[0053] the present invention utilizes following specific but non-restrictive example to describe in more detail.
Embodiment 1. preparatons of the present invention can be prepared as tablet.
[0054] in order to obtain to be used to implement tablet of the present invention, following ingredients can be suppressed in tabletting machine together:
10.0mg the pharmacologically acceptable salt of CDB-4124
140.5mg lactose
69.5mg W-Gum
2.5mg the poly-N-vinyl pyrrolidone
2.0mg aerosol (aerosil)
0.5mg Magnesium Stearate
[0055] in order to obtain to be used to implement Oily preparation of the present invention, following ingredients can be mixed together and pack in the ampoule:
100.0mg the pharmacologically acceptable salt of CDB-4124
343.3mg Viscotrol C
608.6mg phenylformic acid benzyl ester
The perchlorate of embodiment 2.CDB-4124, mesylate and phosphatic formation
[0056] CDB-4124 is dissolved in the ethyl acetate of a acetone and five parts, gained solution is divided into five fractions.In each fraction, add the citric acid of enough molar weights, mandelic acid, perchloric acid, methylsulfonic acid or phosphoric acid are to produce the corresponding hydrochlorate of CDB-4124.Reaction mixture is about 20 ℃ of following stir abouts 2 hours, stirs 2 hours down being lower than 0 ℃ then.The gained solid is filtered off, then with cold ethyl acetate washing, and dry.
[0057] do not form Citrate trianion and amygdalate under these conditions.Perchloric acid, methylsulfonic acid and phosphoric acid steroid class salt all make (～90%) with good yield.Determine that immediately these sour steroid class salt are hygroscopic and need handle in the bag glove of nitrogen atmosphere is arranged.Use the recrystallization of all kinds of SOLVENTS system (for example ethanol/ether) to attempt but not success.Therefore believe that employed initial steroid (90% peak area purity) does not have sufficiently high purity, and perhaps owing to the difficulty of the recrystallization of hydrochlorate.
[0058] correspondingly, more the CDB-4124 of purity yield is used for the formation of the mesylate implemented by aforesaid program.This mesylate uses successfully recrystallize of acetone solvent system.

Claims (18)

1. the composition that comprises the pharmacologically acceptable salt of compound with following formula:
Figure A2008800023670002C1
Wherein:
R 1Be to be selected from-N (CH 3) 2,-NHCH 3,-NC 4H 8,-NC 5H 10With-NC 4H 8Basic functionality among the O;
R 2Be selected from hydrogen, halogen, alkyl, acyl group, hydroxyl, alkoxyl group, acyloxy, the alkyl carbonate, the cyclopentyl propionyloxy, the S-alkyl ,-SCN, the S-acyl group and-OC (O) R 6, R wherein 6Be selected from alkyl, alkoxy ester and alkoxyl group;
R 3Be selected from alkyl-alkoxyl group, alkoxyl group and acyloxy;
R 4Be selected from hydrogen and alkyl;
X is selected from=O and=N-OR 5, R wherein 5Be selected from hydrogen and alkyl;
Wherein this pharmacologically acceptable salt is compared the stability with raising with the free alkali of this compound of equivalent; With precondition is to work as R 1Be-N (CH 3) 2The time, R 2Be methoxyl group, R 3Be acetoxyl group, R 4Be that methyl and X are=O, this salt is not HCl or HBr salt.
2. the composition of claim 1, wherein this compound is that 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-19-removes pregnant-4,9 (10)-diene-3 of first, 20-diketone.
3. the composition of claim 1, wherein this compound is that 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino) phenyl]-21-methoxyl group-19-goes first pregnant-4,9-diene-3,20-diketone.
4. the composition of claim 1, wherein this compound has following structural formula:
Figure A2008800023670003C1
5. the composition of claim 1, wherein this compound has following structural formula:
Figure A2008800023670003C2
6. the composition of claim 5, wherein this salt is the perchlorate of this compound, mesylate or phosphoric acid salt.
7. the composition of claim 5, wherein this salt is mesylate.
8. produce the method for anti-pregnant effect in the patient, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
9. induce the method for menses in the patient, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
10. treat the method for endometriosis, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
11. the method for treatment dysmenorrhoea, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
12. the method for treatment endocrine hormone dependent tumors, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
13. the method for treatment meningioma, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
14. the method for treatment fibroid in the patient, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
15. suppress the method for endometrial proliferation in the patient, this method comprises uses the claim 1 of significant quantity or the composition of claim 6 to the patient.
16. the method for induced parturition, this method comprise the patient is used the claim 1 of significant quantity or the composition of claim 6.
17. method of contraception, this method comprise the patient is used the claim 1 of significant quantity or the composition of claim 6.
18. the method for postcoital contraception, this method comprise the patient is used the claim 1 of significant quantity or the composition of claim 6.
CN200880002367A 2007-01-17 2008-01-03 11-(4-aminophenyl)-19-removes pregnant-4,9 (10)-diene-3 of first, the pharmacologically acceptable salt of 20-derovatives Pending CN101616926A (en)

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EA200970692A1 (en) 2010-02-26
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AR064947A1 (en) 2009-05-06
WO2008088935A2 (en) 2008-07-24
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