CN1095382A - The new A of cyanines family ring steroide - Google Patents
The new A of cyanines family ring steroide Download PDFInfo
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- CN1095382A CN1095382A CN93109540A CN93109540A CN1095382A CN 1095382 A CN1095382 A CN 1095382A CN 93109540 A CN93109540 A CN 93109540A CN 93109540 A CN93109540 A CN 93109540A CN 1095382 A CN1095382 A CN 1095382A
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- 0 C[*-]c1ccc(C(CC2)C(CC3)C(CC4)[C@@]2(C)[C@]4C#N)c3c1 Chemical compound C[*-]c1ccc(C(CC2)C(CC3)C(CC4)[C@@]2(C)[C@]4C#N)c3c1 0.000 description 1
- PDSOIUHLYKBZLZ-VRSOYXCKSA-N C[C@](CC1)(C(CC2)C(CC3)C1c(cc1)c3cc1O)[C@H]2C#N Chemical compound C[C@](CC1)(C(CC2)C(CC3)C1c(cc1)c3cc1O)[C@H]2C#N PDSOIUHLYKBZLZ-VRSOYXCKSA-N 0.000 description 1
- DNXHEGUUPJUMQT-GUZDXLFXSA-N C[C@](CC1)(C(CC2)C(CCc3c4)C1c3ccc4O)C2=O Chemical compound C[C@](CC1)(C(CC2)C(CCc3c4)C1c3ccc4O)C2=O DNXHEGUUPJUMQT-GUZDXLFXSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
- C07J7/007—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
The present invention is that 17 α and 17 β-alkyl ketone-3-carboxyl aromatics A encircle the steroidal synthetic like thing, contain the pharmaceutical composition of these compounds, and use these compounds to suppress the also method of carbinol isozyme I and steroide 5-alpha-reductase isozyme 2 of steroide 5-α.Some intermediates and the method that is used to prepare these compounds have also been found.
Description
The present invention relates to some 17 new α-and 17 β-alkyl ketone-3-carboxyl aromatics A encircle steroide, the method that contains the pharmaceutical composition of these compounds and use these compounds inhibition steroid 5-5 alpha-reductases isozyme 1 and steroid 5-alpha-reductase isozyme 2.Also invent some new intermediate products and the technology that is used for preparing these compounds.
Undertaking the physical trait of distinguishing masculinity and femininity as the known steroid hormone class of male sex hormone.Produce that testis produces these hormones with maximum quantity in the androgenic several organs.Major control is exercised to androgenic generation level in the brain center.Cause that when control is invalid excessive male sex hormone then causes performance and the morbid state on a large amount of healths when producing.For example, acne vulgaris, seborrheic dermatitis, female hirsutism, male sex's alopecia areata, and all relevant such as the prostatosis of benign prostatauxe with the rising of male sex hormone level.In addition, the reduction of male sex hormone level has shown has therapeutic action to prostate cancer.
Testosterone is the main male sex hormone of testicular secretion, and is main male sex hormone steroide in male sex's protoplasma.Know that 5-α-reductive male sex hormone is an active hormones in the tissue that resembles prostate gland and sebiferous gland.Therefore, the round-robin testosterone plays incretogenous effect to dihydrotestosterone (DHT) and 5-α-reductive analogue thereof in these tissues rather than in its hetero-organization such as muscle and testis.Steroid 5-alpha-reductase is Triphosphopyridine nucleotide, reduced salt (NADPH) subordinate enzyme, and it can change into DHT with testosterone.This enzyme is obviously emphasized in the developmental importance of the male sex, because find to lack in the androgynism steroid 5-alpha-reductase of heredity.See Imperator-McGinley, people's such as J. article, (1979), steroid class journal of biological chemistry, 11:637-648.
A large amount of 3-carboxyl-female 1,3,5(10) triolefin 5-alpha reductase inhibitor is well known in the art.For example:
1.J.Steroid Biochem.Vol.34, Nos.1-6pp.571-575(1989), wherein people such as M.A.Levy has narrated the mechanism that reacts to each other between the steroid class of rat prostate steroid 5-alpha-reductase and 3-carboxyl-17 beta substitution;
2.J.Med.Chem.(1990) Vol.33, among the 937-942, people such as D.A.Holt disclose the new class steroid class of A cyclophane yl carboxylic acid;
3.TIPS(1989.12.) V.10, people such as B.W.Metcalf has narrated the effect of 5-alpha-reductase inhibitors in benign prostatauxe disease, male sex's alopecia areata and acne among the pp.491-495.
In addition, narrated one group of 3-carboxyl-female 1,3 in the U.S. Pat 4954446, the 5(10) compound of triolefin-17 beta substitution discloses the inhibitor that these compounds can be used as steroid 5-alpha-reductase.Yet there is not one piece of listed document open or hinted that arbitrary new 17 β-alkyl ketone-3-carboxyl aromatics A ring steroide of the present invention can be used as the practicality of both highly efficient depressors (double inhibitor) of steroid class-5-5 alpha-reductases isozyme 1 and steroid class-5-5 alpha-reductases isozyme 2.
The present invention relates to a kind of compound of logical formula I:
Z wherein be α-or
, and R wherein is C
1-20Straight or branched, saturated or unsaturated alkyl; Its pharmacologically acceptable salts, hydrate, solvate and ester.
The invention still further relates to a kind of be suppressed at simultaneously 5-5 alpha-reductases isozyme 1 and 5-5 alpha-reductases isozyme 2 active methods in the Mammals that comprises human body, this method comprises that the present invention with significant quantity suppresses 5-5 alpha-reductases compound to the treatment target administration.Another aspect of the present invention provides some and is used for preparing the new intermediate product of double inhibition 5-5 alpha-reductases compound of the present invention and new technology.Containing pharmaceutical carrier also comprises in the present invention with the pharmaceutical composition that is used for the compound of the inventive method.Comprise a kind of method that also has in the present invention with double inhibition 5-5 alpha-reductases compound of the present invention and other activeconstituents co-administereds.
The compounds of this invention, can suppress 5-5 alpha-reductases isozyme 1 and 5-5 alpha-reductases isozyme 2 both, it has following chemical formula I:
Wherein Z be α or
, and R wherein is C
1-20Straight or branched, saturated or unsaturated alkyl; And pharmacologically acceptable salts, hydrate, solvate and ester.
Be meant the double inhibitor of steroid 5-alpha-reductase with this compound herein.
The compound that preferably has logical formula II in the The compounds of this invention:
Wherein R is C
1-20Straight or branched, saturated or unsaturated alkyl; And pharmacologically acceptable salts, hydrate, solvate and ester.
The compound that preferably has formula III in the formula II compound of the present invention:
R wherein
2Be C
1-8Straight or branched, saturated or unsaturated alkyl; And pharmacologically acceptable salts, hydrate, solvate and ester.
Preferred compound is R wherein in the formula III compound
2Be methyl, ethyl, propyl group, 3-first butyl, sec.-propyl, normal-butyl, isobutyl-, 1-first propyl group, the tertiary butyl, amyl group, 1,1-dimethylpropyl, 2,2-dimethylpropyl, octyl group or 3,3-diformazan butyl.
Particularly preferred compound is R wherein in the formula III compound
2Be 1-first propyl group, normal-butyl, sec.-propyl, n-pentyl, 3-first butyl, 2,2-dimethylpropyl, the tertiary butyl, 1,1-dimethylpropyl, isobutyl-, n-octyl, tert-pentyl, n-propyl, methyl or 3,3-diformazan butyl.
Particularly preferred formula III compound is:
17 β-(isobutyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(hot carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(uncle's penta carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(2,2-diformazan third carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(third carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(first carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid and
17 β-(3,3-diformazan fourth carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid; And pharmacologically acceptable salts, hydrate, solvate and ester.
Term used herein " α " is to follow the standard chemical term, mean the next, perhaps corresponding substituting group be connected on paper plane below.
Term " β " is with following the standard chemical term in this article, mean upper, perhaps corresponding substituting group be connected on paper plane above.
Term used herein " alkyl " and derivative thereof and full carbochain all are to contain 1 C to n carbon atom unless otherwise
1-nThe carbochain of straight or branched.The example that is used in this paper and is " alkyl " and derivative thereof comprises: methyl, ethyl, propyl group, 3-first butyl, sec.-propyl, normal-butyl, isobutyl-, 1-first propyl group, the tertiary butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, n-octyl, tert-pentyl and 3,3-diformazan butyl.
Term used herein " disposal " means prevention or treatment.
Term used herein " isobutyl-" means-CH
2CH(CH
3)
2
Term used herein " metal catalyzed coupling reaction " mean with prepared 3-fluoroform sulphonate or 3-fluoro sulfonate in suitable organic solvent with alkali, metal catalyst and coupling agent react; The preferred toluene of solvent, dimethyl formamide or THF(tetrahydrofuran (THF)); Alkali preferred tertiary amine alkali such as triethylamine, pyridine, or Tributylamine, phosphine be such as two (diphenylphosphino) alkane, and be preferred 1, two (diphenylphosphino) propane of 3-or three adjacent toluene phosphines, or C
1-6Alkyl alcohol; Preferred palladium catalyst of metal catalyst such as acid chloride (II), Palladous chloride (II), or two (triphenyl phosphine) acid chloride II.
Term used herein " coupling agent " means a kind of compound, and it can generate carboxylic acid substituent with the aromatic base reaction, and carbon monoxide is a preferred coupling agent, can produce desired carboxylic acid group when it is added in the metal catalyzed coupling reaction as described herein.
Formula I and formula IV compound all can be included in the pharmaceutical composition of the present invention, and can be used in the inventive method.The all carboxylic acid group's of existence parts all can adopt the acceptable ester of pharmacy, methyl for example, and ethyl, the ester of pivalyl oxygen methyl etc., and known in this fieldly improve solubleness or hydrolysis properties so that as continuing to discharge or those esters of preparation prodrug.
Term used herein " alpha-receptor antagonistic ", be considered to known class α-androgenic gland (andrenergic) receptor antagonist drug compound, such as people such as Lafferty described in the US4963547, it can be used to dispose the blood vessel imbalance as diabetes, cardiovascular disorder, the too high disease of benign prostatauxe and intraocular pressure.
Preferred α-androgenic gland the receptor antagonist that is used in the present composition and the method comprises amsulosin, terazosin , Kui Evil piperazine, alfuzosin, WY-21901, Prazosin and 7-chloro-2-ethyl-3,4,5,6-tetrahydrochysene-4-thiotolene is [4,3,2-ef] [3]-benzazepines also.
Term used herein " amsolosin " means compound and salt thereof, hydrate and the solvate of following structural formula.
Amsulosin chemically is called (-)-(R)-5-[2-[[2-(O)-ethoxy phenoxy group) ethyl] amino] propyl group]-the 2-methoxybenzenesulphoismide.
Amsulosin is disclosed among the US4703063, and claimedly in US4987125 disposes the purposes of rudimentary urinary tract dysfunction with it.
Term used herein " terazosin " means compound and salt thereof, hydrate and the solvate of following structure.
Terazosin chemically is called 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-[(tetrahydrochysene-2-furoyl base) carbonyl] piperazine.Terazosin is disclosed among the US4251532.
Term used herein " quinoline Evil piperazine " means compound and salt thereof, hydrate and the solvate of following structure.
“ Kui Evil piperazine " chemically be called 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-[(2,3-dihydro-1,4-benzodioxan-2-yl) carbonyl]-piperazine.
Kui Evil piperazine is open in US4188390.
Term used herein " alfuzosin " means compound and salt thereof, hydrate and the solvate of following structure.
Alfuzosin chemically is called N-[3-[(4-amino-6,7-dimethoxy-2-quinazolyl) methylamino-] propyl group] tetrahydrochysene-2-furoylamide.
Alfuzosin is disclosed among the US4315007.
Term used herein " WY-21901 " means compound and salt thereof, hydrate and the solvate of following structure.
" WY-21901 " chemically is called the N-[[1-[2-(1H-indol-3-yl) ethyl]-the 4-[pyridyl] benzamide.
WY-21901 is disclosed among the SU3527761.
Term used herein " Prazosin " means compound and salt thereof, hydrate and the solvate of following structure.
" Prazosin " chemically is called 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-the 4-(2-furyl carbonyl) piperazine.
Prazosin is disclosed among the US3511836.
Term used herein " 7-chloro-2-ethyl-3,4,5,6-tetrahydrochysene-4-thiotolene be [4,3,2-ef]-[3] benzazepines also " means compound and salt thereof, hydrate and the solvate of following structure.
7-chloro-2-ethyl-3,4,5,6-tetrahydrochysene-4-thiotolene also [4,3,2-ef]-[3]-benzazepines are disclosed among the US5006521.In addition, all compounds that are disclosed among the US5006521 with α-androgenic gland receptor antagonist all are preferred α used herein-androgenic gland receptor antagonists.
Those skilled in the art can easily determine except that this paper refer in particular to compound whether be the α-androgenic gland receptor antagonist that utilizes the described test of Lafferty I..Therefore all these compounds all are included within the scope of used herein term " α-androgenic gland receptor antagonist ".
Term used herein " U-10858 " means the compound of following structure, and U-10858 chemically is called 2,4-pyrimidinediamine, 6-(1-piperidyl)-, the 3-oxide compound.U-10858 is at Rogaine
In be active ingredients, Rogaine
Usually to promote hair growth to sell, on sale in the Upjohn company of Michigan state Kalamazoo with partially coated solution.
Term used herein " testosterone inhibitor " is considered to a compounds, can be steroid or on-steroidal, it can prevent from male sex hormone is changed into oestrogenic hormon, described in people WO92/18132 such as Gormley, people such as Gormley disclose the purposes of testosterone inhibitor, can dispose benign prostatauxe disease when it is used in combination with the 5-alpha-reductase inhibitors.
The preferred testosterone inhibitor that is used for the present composition and method is 4-(5,6,7, the 8-imidazolidine is pyrimidine-5-yl also-[1,5-α]) benzonitrile (fadrazole).Fadrazole is disclosed among the US4728645.In addition, being disclosed in all compounds that have the testosterone inhibitor activity among people's such as Gormley the WO92/18132 all is preferred testosterone inhibitor used herein.
When 5-5 alpha-reductases double inhibitor as herein described and other activeconstituents or ingredients are used together, said 5-alpha-reductase inhibitors can with said other activeconstituents or ingredients co-administered.
Term used herein " co-administered and derivative thereof " means, as described herein, both can the administration simultaneously of 5-5 alpha-reductases compound and other activeconstituentss or ingredients will be suppressed, can separate any way administration that accompanies again, activeconstituents such as other known compound of disposing following disease: acne vulgaris, seborrheic dermatitis, female hirsutism, male sex's alopecia areata, benign prostatauxe or prostate cancer, or can unite the known compound of use with the 5-alpha-reductase inhibitors.If not the while administration, this compound is preferably each other with approaching tight time administration.Moreover, if compound with the same dose form administration, for example a kind of compound is a topical and other plants the compound oral administration, this all without a doubt.
The new compound of formula II of the present invention can be prepared by the estrone with following structural formula known and that be easy to get by the diagram of following scheme 1-4 and the method for embodiment, and perhaps the 17 β-carboxylic acid analogue by estrone prepares, and it is also known and be easy to get.
The scheme I illustrates preparation formula II compound, is at J.Chem.Soc.(C according to people such as Baldwin from compound (a) inhibition and generation compound (b) in the scheme I), 1968, the method steps described in the 2283-2289.
Then compound (b) is stirred with alkali (preferred sodium hydroxide) in appropriate organic solvent (particular methanol), acidifying subsequently obtains compound (c).And then compound (c) is handled with Grignard reagent, according to following described, perhaps used lithium reagent in suitable organic solvent (preferred tetrahydrofuran (THF) or ether solvent), preferred reflux temperature is handled and is obtained formula (d) compound.
In suitable organic solvent (preferred methylene dichloride), compound (d) and alkali (preferred 2,5-di-t-butyl-3-methyl-pyridine) are cooled to-20 to 20 ℃, preferred 0 ℃, reacting with the preferred trifluoromethanesulfanhydride anhydride of three alkyl halide sulphonic acid anhydrides generates compound (e).
Compound (e) is prepared compound (f) in the metal catalyst linked reaction.Preferably compound (f) is dissolved in the diformamide (DMF) the preferred triethylamine of organic bases, preferred two (diphenyl phosphine) propane of phosphine, the preferred acid chloride of palladium (II) compound (II), C
1-6Alkanol (C
1-6Alkane OH), add carbon monoxide (CO) subsequently, compound (f) reacts with suitable alkali (preferred salt of wormwood) then, and acidifying obtains compound (g) again.
The scheme II
Scheme (II) diagram preparation compound (II).Raw material is formula (d) compound in the scheme (II), and it is by described the making of scheme (I).
According to used scheme (II), formula (d) compound and alkali (preferred 2,5-di-t-butyl-3-methyl-pyridine) in appropriate organic solvent (preferred methylene dichloride), be cooled to-20 to 20 ℃, preferred 0 ℃, then with fluorosulfonic anhydride reacting generating compound (h).Compound (h) can make compound (f) in metal catalyzed coupling reaction.Compound (h) is preferably in the diformamide (DMF), the preferred triethylamine of organic bases, preferred two (diphenyl phosphine) propane of phosphine, the preferred acid chloride of palladium (II) compound (II), C
1-6Alkanol (C
1-6Alkane OH), add carbon monoxide (CO) subsequently.With compound (f) and suitable alkali, preferred salt of wormwood reacts, and obtains compound (g) after the acidifying afterwards.
The scheme III
Scheme (III) illustrates and generates the formula II compound.Used R in the scheme (III)
1Be CF
3O
2SO-or FO
2SO-.In used scheme (III) alkylation process (step C), preferably in tetrahydrofuran (THF) with pyridyl thioesters and LiR or XMgR(X=Cl, Br) Grignard reagent react (hereinafter chat and) generate required product, the preferred bromination isobutyl-of Grignard reagent magnesium, chlorination n-octyl magnesium, chlorination tert-pentyl magnesium or bromination 2,2-dimethyl propyl magnesium, preferred 17 β of product-(isobutyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid, 17 β-(hot carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid, 17 β-(uncle's penta carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid, or 17 β-(2,2-dimethyl propylene carbonyl)-female 1,3,5(10)-and the 3-carboxylic acid, can in one or two step, generate this product respectively.
In route 1,3-alcohol acid (i) can be changed into 3-fluoroform sulphonate or 3-fluoro sulfonate derivative (j) (steps A), method is in appropriate organic solvent approximately-20 to 20 ℃ preferred 0 ℃ the time, in the preferred methylene dichloride, with (i) trifluoromethanesulfanhydride anhydride or fluorosulfonic anhydride and a kind of amine alkaline purification, amine alkali is such as pyridine, and is preferred 2,5-di-t-butyl-3-picoline.
Preparation active ester (k) (step B) is at appropriate organic solvent solution, in preferred tetrahydrofuran (THF)/toluene in room temperature with (j) with 2,2-dithio pyridyl and triphenyl phosphine processing 8-14 hour.
Preparation 17-acyl derivative (l) (step C) can be in tetrahydrofuran (THF) or ether solvent in approximately-50 to-70 ℃ of temperature will (k) with hereinafter chat and Grignard reagent processing 1-16 hour.
Preparation 3-alkyl ester (f) (step D) can be handled (l) 1-16 hour under the carbonylation condition when about room temperature, be preferably in the solution that the CO (carbon monoxide converter) gas bubbling is fed the suitable organic solvent of (l), the solvent particular methanol, this solution contains palladium acetate catalyst, triphenyl phosphine and level Four organic amine, the preferred triethylamine of this amine.Subsequently compound (f) and suitable alkali such as salt of wormwood are reacted, acidifying afterwards obtains compound (g).
Also available step G prepares compound (g), method is that (l) handled under the carbonylation condition, preferred carbon monoxide bubbling feeds (l) solution of (preferred DMSO) in suitable Non-alchoholic solvents, and this solution contains palladium catalyst, preferred acid chloride (II), also contain 1, two (diphenyl phosphine) ferrocene (DPPF) of 1-; Preferably react with the preferred potassium acetate of a kind of alkali at elevated temperatures afterwards.
Route 2 comprises: utilize above-mentioned steps A that raw material steroid acid (i) is changed into 3-fluoroform sulphonate or 3-fluoro sulfonate derivative (j); D changes into (m) with (j) carbonyl with step; Generate active 2-pyridyl thioesters (n) with step B; Generate 17-acyl compounds (f) with step C; Reach the end product (g) that becomes 3-acid with step F hydrolysis 3-ester.
Route 3 comprises: with above-mentioned steps B raw material acid (i) is changed into active ester (o); Make (o) reaction generate 17-acyl compounds (d) with above-mentioned steps C; With above-mentioned steps A (d) changed into 3-fluoroform sulphonate or 3-fluoro sulfonate derivative (l); But D changes into end product (g) with above-mentioned step F with (l) subsequently with above-mentioned steps G above-mentioned steps.
The scheme IV
The scheme IV illustrates production II compound.
In the used scheme IV alkylation process (preparation formula (s) compound), preferably in tetrahydrofuran (THF) with carbon aldehyde and LiR or XMgR(X=Cl, Br) Grignard reagent (hereinafter described) reacts, generate desired product with one or two step respectively, the preferred bromopropyl magnesium of Grignard reagent, methylmagnesium-bromide or 3,3-diformazan dibutyl magnesium, preferred product is 17 β-(third carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid, 17 β-(first carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid, 17 β-(3,3-diformazan fourth carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid.
Raw material in the scheme IV is formula (c) compound of scheme I preparation.
In the used scheme IV, with formula (c) compound and alkali (preferred 2,5-di-t-butyl-3-picoline) in appropriate organic solvent, be cooled to-20 to 20 ℃ in (preferred methylene dichloride), preferred 0 ℃, then with three halosulfonic acid acid anhydrides (preferred trifluoromethanesulfanhydride anhydride) reacting generating compound (p).
Preparation formula (q) compound can carry out metal catalyzed coupling reaction with formula (p) compound.Preferably formula (p) compound is dissolved in the diformamide (DMF) the preferred triethylamine of organic bases, preferred two (diphenyl phosphine) propane of phosphine, the preferred acid chloride of palladium (II) compound (II), C
1-6Alkyl alcohol (C
1-C
6Alkane OH), add carbon monoxide (CO) subsequently.Formula (q) compound can with reductive agent, preferred diisobutylaluminium hydride production (r) compound that reacts.
Preparation formula (s) compound can get final product in approximately-50 to-70 ℃ of temperature formula (r) compound being handled with Grignard reagent (described in the scheme III) or lithium reagent in tetrahydrofuran (THF) or ether solvent in 1-16 hour.
With formula (s) but compound oxidation preparation formula (g) compound.Said oxidation is preferably used Jones reagent or is crossed the ruthenic acid tetrapropylammonium, uses sodium-chlor subsequently.
(the R here is C to prepare the Grignard reagent that is included in the scope of the present invention used XMgR type in all substances
1-20Straight or branched, saturated or unsaturated alkyl) all be easy to get, or those skilled in the art can easily make.
Preparation Z is that the formula I compound in the α position can be undertaken by following general method by the compound that contains corresponding β bit substituent.
General method A
Surpassing 100 ℃ of temperature, preferably under reflux temperature, in 17 β steroid double inhibition 5 compound stirred solutions of the replacement of the logical formula II in suitable solvent (preferred ethylene glycol or methyl-sulphoxide), add alkali, for example oxyhydroxide or alkoxide alkali, preferred sodium hydroxide, after separating and collecting, then obtain corresponding α steric isomer.
Be identified for carrying out the suitable solvent of steric isomer, when initial double inhibition 5 alpha-reductases 17 'beta ' steroids contain (for example) and carry out nucleophyllic chemical adsorption reactive activity substituting group or active unsaturated link(age), methyl-sulphoxide or other nonactive high boiling solvents are preferred, and when the activity of the substituting group of initial double inhibition 5 alpha-reductases 17 'beta ' steroids or arbitrary unsaturated link(age) is unworthy considering, but spent glycol or other active high boiling solvents.
Lead to the reduzate of formula I ketone, the secondary alcohol that leads to formula IV and pharmacy acceptable salt, hydrate, solvate and ester also within the scope of the invention,
Y is α or β in the formula
Wherein R is C
1-20Straight or branched, saturated or unsaturated alkyl.
In the above-mentioned ketone reduzate of the present invention preferably wherein
Substituting group is at the secondary alcohol of β position.
Particularly preferably be 17 β-(1-hydroxyethyl)-female 1,3 in the above-mentioned ketone reduzate of the present invention, 5(10) triolefin-3-carboxylic acid and 17 β-(1-hydroxyl butyl)-female 1,3,5(10) triolefin-3-carboxylic acid.
Preparing these compounds can be with receiving the conventional sodium borohydride reductive method that R goes up carbonyl, does not reduce the stereomeric of 17 bit substituents or the A that do not reduce ring or aromatics A intra-annular carbonyl simultaneously.
This borohydride reduction can be carried out under room temperature to 50 ℃ temperature in for example water or methanol aqueous solution, and separates and purifying with ordinary method.These compounds can be active as 5-alpha-reductase double inhibitor.
Used term " intensification " means and is higher than 25 ℃ in this paper and the claim, is preferably reflux temperature.
Used term " solvent " or " suitable solvent " mean these solvents in this paper and the claim: methylene dichloride, ethylene dichloride, chloroform, ethylene glycol, tetracol phenixin, tetrahydrofuran (THF) (THF), ether, toluene, ethyl acetate, methyl-sulphoxide (DMSO), N, N '-dimethyl-N, N '-propylidene urea, N-methyl-alpha-pyrrolidone, methyl alcohol, Virahol, diformamide (DMF), hexane, water, pyridine, quinoline or ethanol.
Pharmacy acceptable salt, hydrate and the solvate of logical formula I and logical formula IV can make with the known suitable method of present technique field ordinary skill philtrum person.
When preparation logical formula I compound of the present invention, the intermediate of synthetic new general formula (V):
R is C in the formula
1-20Straight or branched, saturated or unsaturated alkyl, R
4It is the fluorine sulfonyloxy.
Also preferred new logical formula VI intermediate in the logical formula I compound of synthetic the present invention:
R wherein
2As the definition in the logical formula II.
The compound of the logical formula II of preparation and the selection process of pharmacy acceptable salt, hydrate, solvate and ester thereof,
(R is C in the formula
1-20Straight or branched, saturated or unsaturation alkyl)
This technology comprises general formula
(R as above defines in the formula)
Compound with fluorosulfonic anhydride and alkali (preferred 2, the 5-tertiary butyl-3-methyl-pyridine) in solvent (preferred methylene dichloride) reaction with the formation general formula
(the R definition as above in the formula)
Compound, there is being the linked reaction that coupling agent (preferred carbon monoxide) carries out this compound metal catalytic down subsequently, then, if it is suitable, then at random be hydrolyzed and lead to the formula II compound, and then at random form its pharmacy acceptable salt, hydrate, solvate or ester to form.
Because the pharmaceutically active compound of the present invention active double inhibitor that is effective steroide 5-alpha-reductase, thereby it has in the purposes of disposing aspect disease and the pathological state, and it is active and produce required result of treatment wherein to reduce DHT.These diseases and pathological state comprise acne vulgaris, seborrheic dermatitis, female hirsutism, male sex's alopecia areata, prostatosis such as benign prostatauxe and prostate cancer.
For the effectiveness of checking inhibition human body 5, carry out the following step.
Be used as the preparation of the membrane granule in recombinant chou steroid class 5 alpha-reductase isozyme 1 source
With Dounce glass-glass hand homogenizer (Kontes Glass Co., Vineland, N.J.) will contain Chinese hamster ovary (CHO) cell (Anderss of the recombinant chou human body steroid class 5 alpha-reductase isozyme 1 of expression, S, Deng people Nature354,159-161(1991) homogenizing in the 20mM potassium phosphate buffer (pH6.5) (buffer A) that contains 0.33M sucrose, 1mM dithiothreitol (DTT) and 50 μ m NADPH.By centrifugation (100,000 * g, in 4 ℃ 60 minutes) and isolate membrane granule and resuspending in the 20mM potassium phosphate buffer (pH6.5) (buffer B) that contains 20% glycerine, 1mM dithiothreitol (DTT) and 50 μ m NADPH.With this suspended particle solvent in-80 ℃ of preservations.
Be used as the preparation of the prostate gland membrane granule in steroid class 5 isozyme 2 sources
Refrigerated human body prostate gland melted and cut (Brinkmann Polytron Sybron Corp., Westbury, New York) into pieces.With Sonifier(Branson Sonic Power Co.) with this solution sonication 3-5 minute, hand homogenizing in the Dounce hand homogenizer then.By 4 ℃ of down different centrifugations: 600 or 1000xg20 minute and 140,000 * g 60 minutes and obtain the prostate gland particle.By 140, the above-mentioned damping fluid washing that the pellet that the 000xg centrifugation obtains is doubly measured with the 5-10 of tissue volume and in 140,000xg centrifugation.The gained pellet is suspended in the buffer B and with this particle suspension in-80 ℃ of storages.
Be used as the preparation of the membrane granule in recombinant chou steroid class 5-alpha-reductase isozyme 2 sources
Chinese hamster ovary (CHO) cell homogenizing in the 20mM potassium phosphate buffer (pH6.5) (buffer A) that contains 0.33M sucrose, 1mM dithiothreitol (DTT) and 50 μ M NADPH that will contain the recombinant chou human body steroid class 5-alpha-reductase isozyme 2 of expression with the Dounce hand homogenizer.With centrifugation (100,000xg, in 4 ℃ 60 minutes) and isolate membrane granule and resuspending in containing 20% glycerine, in 1mM dithiothreitol (DTT) and the 50 μ M NADPH20mM potassium phosphate buffers (pH6.5) (buffer B).With this suspension particle solution in-80 ℃ of preservations until use.
The analysis of enzymic activity and inhibitor effectiveness
With constant in ethanol [
14C] potential inhibitor in ethanol of testosterone and variable places test tube and be concentrated into drying under vacuum, in each test tube, add damping fluid, 10 μ l(reorganization isozyme 1 or isozyme 2) or the isozyme 2 that obtains by the human body prostata tissue of 20 μ l() 10mM NADPH and the steroid class 5 alpha-reductase goods of aliquots containig so that final volume is 0.5ml.The recombinant protein sample that is expressed in the Chinese hamster ovary celI that is used for 50mM phosphate buffered saline buffer (pH7.5) is analyzed human body steroid class 5 isozyme 1, and human body prostate gland particle suspension liquid and/or the recombinant protein of expressing in Chinese hamster ovary celI in 50mM nitrate damping fluid (pH5.0) are analyzed isozyme 2.
Be that 37 ℃ are cultivated this solution 20 or after 30 minutes, should react chilling by adding the 4ml ethyl acetate, every part of testosterone of 0.25 μ mol, 5 α-dihydrotestosterone, dihydroandrosterone and androstanedione are as carrier.Organic layer moved in second test tube and in Speed Vae be evaporated to drying.Resistates is dissolved in the 40 μ l chloroforms, and (Si 250F-PA Baker Chemical) carries out Blot experiment and use acetone in 20 * 20cm has each groove of silica gel tlc plate of groove: chloroform (1: 9) develops the color twice.With BIOSCAN Imaging Scanner(Bioscan Inc., Washington D.C.) determine radiological chemistry content in enzyme substrate and the product band (band).Calculate the resulting radiolabeled percentage ratio that changes into product, determine the activity of enzyme therefrom.When carrying out all cultivating processes, make the enzyme substrate (testosterone) that is consumed be no more than 20%.
Experiment gained data machine are as calculated handled, graph of a relation draws the linear functional relation that they meet between inverse (1/ speed) by drawing enzymic activity and various inhibitor concentration, determine proximate inhibition constant (Ki is approximate) by Dixon analyser (Dixon, M, 1953).
(Levy, M.(1989), Biochmistry 29:2815-2824) can calculate the value that suppresses constant (Ki) according to currently known methods.
All compounds in the scope of the invention all are used for suppressing steroid class 5-alpha-reductase isozyme 1 and the steroid class 5-alpha-reductase isozyme 2 of Mammals (comprising the people), and these animals need this inhibition certainly.
Compound in the scope of the invention is tested and isozyme 1 is shown 15Ki(nM) to 180Ki(nM) active and isozyme 2 shown 0.5Ki(nM) to 30Ki(nM) activity.Compound particularly preferred and that be used for pharmaceutical composition of the present invention and the inventive method is in the The compounds of this invention:
17 β-(isobutyl-carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(tert-pentyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(2,2-dimethylpropyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(propyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(methyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(3,3-diformazan butyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(1-hydroxyethyl)-female 1,3,5(10) triolefin-3-carboxylic acid and
17 β-(1-hydroxyl butyl)-female 1,3,5(10) triolefin-3-carboxylic acid.
Pharmaceutical active compounds of the present invention is combined makes agent shape commonly used, is preferably capsule, tablet or injected articles.Can use solid-state or liquid pharmaceutical carrier.Solid-state carrier comprises starch, lactose, terra alba, terra alba, sucrose, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate and stearic acid.Liquid carrier comprises: syrup, peanut oil, sweet oil, salt solution and water.Similarly, this carrier or thinner can comprise any lasting h substance, and for example glyceryl monostearate or distearin can use separately or use with wax.The consumption of solid-state carrier can change in wide range, but the preferred about 25mg to 1g of per 1 unitary dose.When using liquid carrier, the form of these goods preferably is being syrup, elixir, emulsion, soft gelatin capsule, aseptic parenteral solution such as medicine administered by injection or the aqueous solution or anhydrous liquid suspended emulsion agent.
This pharmaceutical preparation can be routinely the pharmaceutical chemistry technology and make, this comprises mixing, granulation and compacting, comprises when needed that for tablet mixing, filling and dissolved constituent are to obtain the goods of required oral or stomach and intestine administration.
The dosage of the pharmaceutical active compounds of the present invention in the said medicine dose unit should be effective, non-to poison, is preferably the active compound of 0.1-1000mg/Kg, more preferably 1-100mg/Kg.When dispose to need suppressing the patient of steroid 5-alpha-reductase, preferred dosage is every day 1-6 time, oral or parenteral admin.Preferred parenteral admin mode comprises external application, rectal administration, transdermal (transdermally) administration, by injection and lasting input administration.Oral dosage units to the human body administration is preferably the active compound that contains 1-500mg, and oral administration preferably uses lower dosage.Yet ought be safe with at one's leisure for patient, also heavy dose be carried out parenteral admin.
Steroid class 5-alpha-reductase isozyme 1 and isozyme 2 active methods comprise to this inhibiting curee of needs and carry out administration with the The compounds of this invention of effective double inhibition amount in the inhibition of the present invention Mammals (comprising the people).
The present invention also provides logical formula I or logical formula IV compound to be used for the purposes of the medicine of double inhibition steroid class 5-alpha-reductase in preparation.
The present invention also provides the pharmaceutical composition that is used for the treatment of benign prostatauxe, and this pharmaceutical composition contains the compound and the pharmaceutically useful carrier of logical formula I or logical formula IV.
The present invention also provides the pharmaceutical composition that is used for the treatment of prostate cancer, and this pharmaceutical composition contains the compound and the pharmaceutically useful carrier of logical formula I or logical formula IV.
The method that the present invention also provides preparation to contain the pharmaceutical composition of pharmaceutically acceptable carrier or thinner and logical formula I or logical formula IV compound, this method comprise that the compound of logical formula I or logical formula IV combines with pharmaceutically useful carrier or thinner.
According to the present invention, when the The compounds of this invention administration, wish not produce unacceptable toxication.
In addition, pharmaceutical active compounds of the present invention can with other active ingredient co-administereds, other compounds of for example known treatment acne vulgaris, seborrheic dermatitis, female hirsutism, male sex's alopecia areata, benign prostatauxe or prostate cancer morbid state or the known compound that practicality is arranged when being used in combination with the 5-alpha reductase inhibitor.Particularly preferably be dual 5-alpha reductase inhibitor disclosed herein with the U-10858 administration that is used for the treatment of male sex's alopecia areata.Particularly preferably be dual 5-alpha reductase inhibitor disclosed herein with the alpha-receptor antagonist administration that is used for the treatment of benign prostatauxe.Dual 5-alpha reductase inhibitor preferably disclosed herein is with the testosterone inhibitor administration that is used for the treatment of benign prostatauxe.Dual 5-alpha reductase inhibitor preferably disclosed herein is with alpha-receptor antagonist that is used for the treatment of benign prostatauxe and the administration of testosterone inhibitor.
Do not need to be described in further detail.Believe that those skilled in the art passes through the above, can utilize the present invention to perfect degree.Therefore, following embodiment mainly is explanation the present invention, and does not limit the scope of the invention.
Embodiment 1-is corresponding to the scheme III
17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) S-(2-pyridyl)-and 3-hydroxyl-female 1,3,5(10) triolefin-17 β-3-dithionate.
In room temperature under nitrogen with 3-hydroxyl-female 1,3,5-(10) triolefin-17 β-carboxylic acid (0.11g, 0.37mmol), 2,2 '-pyridyl disulfide (0.163g, 0.74mmol), triphenylphosphine (0.19g, 0.74mmol) and the mixture of methylene dichloride (20ml) stirred 4 hours.With the gained solution concentration and residue is made chromatogram separate (silica gel is with 25% eluent ethyl acetate in hexane) and then obtain the solid title compound that is white in color, mp.195-196 ℃ (recrystallization from ethyl acetate-methyl alcohol).
(ⅱ) .17 β-isobutyl-carbonyl-3-hydroxyl-female 1,3,5(10) triolefin
In-78 ℃ bromination isobutyl-magnesium (2.3ml, 2M diethyl ether solution) is joined the S-(2-pyridyl in tetrahydrofuran (THF) (20ml) lentamente)-3-hydroxyl-female 1,3,5(10) (0.60g is 1.53mmol) in the solution for triolefin-17 β-dithionate.After 1 hour, use saturated NH
4The Cl aqueous solution is with the mixture chilling and use ethyl acetate extraction.Organic extract is also concentrated with salt water washing, drying.Residue is made chromatogram to be separated (silica gel is used for 15% eluent ethyl acetate of hexane) and obtains the foam thing.Then obtain white solid (0.27g) with the ether development.
(ⅲ) 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-fluoroform sulphonate.
To cold (0 ℃) 17 β-isobutyl-carbonyl-3-hydroxyl-female 1,3,5(10) triolefin (0.28g, 0.82mmol) and 2,6-two-tert-butyl-4-picoline (0.17g, 0.83mmol) dichloromethane solution (20ml) in slowly add trifluoromethanesulfanhydride anhydride (0.23g, 0.82mmol).Stirred gained solution 1 hour at 0 ℃, then in stirring at room 30 minutes.This reaction mixture is with rare HCl, water, rare NaHCO
3, salt water washing, dry and concentrate.The gained residue is made chromatogram and is separated the oily matter that (silica gel is with eluent ethyl acetate in 7% hexane) obtains 0.13mg.
(ⅳ) .17 β-isobutyl carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester.
Under CO atmosphere with 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-fluoroform sulphonate (0.13g, 0.28mmol), acid chloride (II) (4.2mg, 0.0187mmol), 1,3-two (diphenylphosphino) propane (dppp, 7.5mg, 0.0182mmol), triethylamine (0.08mL), methyl alcohol (0.6mL), 1,2-ethylene dichloride (0.32mL) and mixture DMSO(1mL) are in 70-75 ℃ of heated overnight.This refrigerative reaction mixture is then with methylene dichloride dilution, water, rare HCl, rare NaHCO
3, the salt water washing, dry and concentrate.Residue chromatographic separation (silica gel is with the eluent ethyl acetate in 10% hexane) is got the title compound of 70mg.
(ⅴ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
With 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester (70mg, 0.18mmol), K
2CO
3(0.12g, 0.87mmol), water (1.5mL) and methyl alcohol (10mL) is in the heated overnight down that refluxes.Concentrate this reaction mixture then.The residue dilute with water is with rare HCl acidifying and use ethyl acetate extraction.This organic extract also concentrates with salt water washing, drying.With this title compound of HPLC purifying, mp.202-206 ℃.
Embodiment 2-is corresponding to the scheme III
17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-fluoro sulfonate
0 ℃ will be in methylene dichloride 17 β-isobutyl-carbonyl-female 1,3,5(10) solution is with 2 for triolefin-3-alcohol (press embodiment 1(ⅰ-ⅱ) prepared), 5-di-t-butyl-3-methyl-pyridine is handled, and handles with fluorosulfonic anhydride after 10 minutes.Stirred the gained mixture 2 hours, and diluted with methylene dichloride then.The saturated NaHCO of this organic layer
3MgSO is used in the aqueous solution and salt water washing
4Drying also is concentrated into dried.Chromatographic separation output title compound on silica gel.
(ⅱ) 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester
Under carbon monoxide atmosphere in 80 ℃ with 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-fluoro sulfonate, 1, two (diphenylphosphino) propane of 3-, bis(acetato)palladium, triethylamine, methyl alcohol, DMSO and 1, the mixture heating up of 2-methylene dichloride and violent stirring 5 hours.After being cooled to room temperature, with methylene dichloride dilution gained mixture.This organic phase water thoroughly washs, dry (MgSO
4) and be evaporated to dried.The silica gel chromatography separation obtains title compound.
(ⅲ) 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
With 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester, K
2CO
3, water and methyl alcohol and mixture heating up refluxed 5 hours.Under reduced pressure volatile matter is removed then, this residue dilute with water with the acidifying of rare HCl water liquid, and extracts with EtOAc.With organic extract water and salt water washing, drying, and evaporation then obtain title compound.
Embodiment 3-is corresponding to the scheme III
17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) 3-(trifluoro-methanesulfonyl oxy)-and female 1,3,5(10) triolefin-17 β-carboxylic acid
3-hydroxyl that will be in methylene dichloride-female 1,3,5(10) triolefin-17 β-carboxylic acid, 2, the solution of 6-two-tertiary butyl-4-picoline and trifluoromethanesulfanhydride anhydride stirred 20 hours at 5 ℃.Organic solvent is steamed.Resistates is dissolved in the tetrahydrofuran (THF) water (99.5: 0.5) with the 4-Dimethylamino pyridine, uses hcl acidifying, and arrangement obtains title compound routinely subsequently.
(ⅱ) .S-(2-pyridyl)-the 3-(trifluoro-methanesulfonyl oxy)-female 1,3,5(10) triolefin-17 β-dithionate
Under nitrogen, stir the 3-(trifluoro-methanesulfonyl oxy)-female 1,3,5(10) triolefin-17 β-carboxylic acid, triphenylphosphine and 2,2 '-toluene solution of pyridyl disulfide 20 hours.Concentrate this reaction mixture, residue directly by silica gel, is evaporated suitable cut and obtains title compound.
(ⅲ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-fluoroform sulphonate
To the S-(2-pyridyl)-the 3-(trifluoro-methanesulfonyl oxy)-female 1,3,5(10) in the tetrahydrofuran solution of triolefin-17 β-dithionate in approximately-50 ℃ add bromination isobutyl-magnesium.Reaction mixture is warmed to-10 ℃ approximately, dilutes with saturated aqueous ammonium chloride.Separate with column chromatography subsequently and carry out routine separation filing and obtain title compound.
(ⅳ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester
With 17 β-isobutyl-carbonyl-female 1,3,5(10) the solution violent stirring of triolefin-3-fluoroform sulphonate, triphenylphosphine, acid chloride (II), triethylamine, methyl alcohol and diformamide is 20 hours under carbon monoxide atmosphere.Separate with column chromatography subsequently and carry out routine separation arrangement output title compound.
(ⅴ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
With 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester, K
2CO
3, water and methanol mixture reflux 5 hours.Conventional arrangement then produces title compound after the acidifying.
Embodiment 4-is corresponding to the scheme III
17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) .3-(fluorine sulfonyloxy)-and female 1,3,5(10) triolefin-17 β-carboxylic acid
In 5 ℃ with 3-hydroxyl-female 1,3,5(10) triolefin-17 β carboxylic acid, 2, the dichloromethane solution of 6-two-tertiary butyl-4-picoline and fluorosulfonic anhydride stirred 20 hours, with aqueous hydrochloric acid and water washing reaction mixture.Concentrate organic phase, use then output title compound of column chromatography separating purification gained resistates.
(ⅱ) .S-(2-pyridyl)-3-(fluorine sulfonyloxy)-female 1,3,5(10) triolefin-17 β-carbothioic acid ester
Under nitrogen with 3-(fluorine sulfonyloxy)-female 1,3,5(10) triolefin-17 β-carboxylic acid, triphenylphosphine and 2,2 '-toluene solution of pyridyl disulfide stirred 20 hours.Concentrated reaction mixture directly by silica gel, evaporates then output title compound of suitable cut with resistates.
(ⅲ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-fluosulfonic acid ester
Approximately under-50 ℃ to the S-(2-pyridyl)-3-(fluorine sulfonyloxy)-female 1,3,5(10) add bromination isobutyl-magnesium in the tetrahydrofuran solution of triolefin-17 β-thiosulfonate.Reaction mixture is warmed to approximately-10 ℃ and dilute with saturated aqueous ammonium chloride.Put then output title compound in order with separating with conventional column chromatography.
(ⅳ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester
With 17 β-isobutyl-carbonyl-female 1,3,5(10) the solution violent stirring of triolefin-3-fluoro sulfonate, triphenylphosphine, acid chloride (II), triethylamine, methyl alcohol and diformamide is 20 hours under carbon monoxide atmosphere.Separate with conventional column chromatography subsequently and put then output title compound in order.
(ⅴ) .17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
With 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylate methyl ester, K
2CO
3, water and carbinol mixture reflux 5 hours.Put after the acidifying then output title compound routinely in order.
Embodiment 5-is corresponding to the scheme III
17 β-octyl group carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) .17 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-trifluoro sulfonate
According to embodiment 1(ⅰ-ⅲ), usefulness chlorination n-octyl magnesium replaces bromination isobutyl-magnesium in step (ⅱ), makes this title compound.
(ⅱ) .17 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
With 17 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-fluoroform sulphonate (0.38g, 0.7mmol), potassium acetate (0.27g), bis(acetato)palladium (II) (0.008g, 0036mmol), 1,1 '-two (diphenylphosphino) ferrocene (dppf, 0.08g, 0.14mmol) at DMSO(15ml) in mixture blew 2 minutes with carbon monoxide, and stir under CO balloon atmosphere at 60 ℃ and to spend the night.This reaction mixture dilute with water is with the 0.5N hcl acidifying and use dichloromethane extraction.This organic layer washes with water, dry (MgSO
4) and vaporising under vacuum.Resistates is done chromatogram separation (silica gel is with 20% ethyl acetate in the hexane, 10% acetate wash-out) and is then obtained solid, develops then output title compound with methyl alcohol-acetonitrile: 0.22g(73%), and mp.175 ℃.
Embodiment 6-is corresponding to the scheme III
17 β-(uncle's penta carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ). Trifluoromethyl-1 7 β-(tert-pentyl carbonyl)-female 1,3,5(10) triolefin-3-sulfonate
According to embodiment 1(ⅰ-ⅲ), in step (ⅱ), replace bromination isobutyl-magnesium to make this title compound with chlorination tert-pentyl magnesium.
(ⅱ .17 β-(uncle's penta carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
According to embodiment 5(ⅱ), with embodiment 6(ⅰ) Trifluoromethyl-1 7 β-(tert-pentyl carbonyl)-female 1,3 of making, 5(10) triolefin-3-sulfonate replaces Trifluoromethyl-1 7 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-sulfonate, thus make this title compound.mp.199-200℃。
Embodiment 7-is corresponding to the scheme III
17 β-(2,2-dimethylpropyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ). Trifluoromethyl-1 7 β-(2,2-dimethylpropyl carbonyl)-female 1,3,5(10) triolefin-3-sulfonate
According to embodiment 1(ⅰ-ⅲ) in step (ⅱ) with 2,2-dimethylpropyl magnesium bromide replaces bromination isobutyl-magnesium and makes this title compound.
(ⅱ) .17 β-(2,2-dimethylpropyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
According to embodiment 5(ⅱ), with embodiment 1(ⅰ) in Trifluoromethyl-1 7 β-(2 that make, 2-dimethylpropyl carbonyl)-female 1,3,5(10) triolefin-3-sulfonate replaces Trifluoromethyl-1 7 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-sulfonate, thus make this title compound.mp.210℃。
Embodiment 8-is corresponding to the scheme IV
17 β-(propyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) 17 beta-cyanos-female 1,3,5(10) triolefin-3-mesylate
This title compound is known, and can be by people such as Baldwin (J.Chem.Soc.(c), 1968, and method 2283-2289) is made by estrone.
(ⅱ) 17 beta-cyanos-female 1,3,5(10) triolefin-3-alcohol
Will be in 17 beta-cyanos in the methyl alcohol (100mL)-female 1,3,5(10) triolefin-3-mesylate (10g) drips of solution be added in the NaOH solution (42mL 20% 1: the 1MeOH-aqueous solution).With gained mixture heating up to 40 ℃, be incubated 24 hours, afterwards, mixture is chilled to 0 ℃, water (350ml) dilution is with rare HCl acidifying.The gained white depositions washes with water by isolated by vacuum filtration, and dry under vacuum.Recrystallization then obtains title compound from acetonitrile, mp.249-250 ℃ (decomposition).
(ⅲ) 17 beta-cyanos-female 1,3,5(10) triolefin-3-fluoroform sulphonate
With 17 beta-cyanos-female 1,3,5(10) (4.2g and 2,6-di-t-butyl-4-picoline (3.6g) is dissolved in the 50ml methylene dichloride triolefin-3-alcohol.In this mixture of stirring at room 30 minutes.Add trifluoromethanesulfanhydride anhydride (triflic anhydride) (4.2mL), and then stirred this mixture 40 minutes, use 50mlCH
2Cl
2Dilution, filtration, concentrated, and on silica gel, make chromatogram and separate.With 20% eluent ethyl acetate in hexane, output 5.3g(87%) title compound, mp.115-117 ℃.
(ⅳ) .17 beta-cyano-female 1,3,5(10) triolefin-3-carboxylate methyl ester
To 17 beta-cyanos in 77ml DMSO-female 1,3,5(10) add 7ml triethylamine, 0.35 acid chloride, two (diphenylphosphino) propane and 1 of 0.64g, 2-ethylene dichloride (26ml) in the solution of triolefin-3-alcohol (10g) and 5ml MeOH.With the carbon monoxide bubbling by this solution and with reaction mixture in 75 ℃ at 1atm CO(balloon) stir down and spend the night.With this mixture of EtOAc wash-out, and wash (3 *) with water, dry and concentrate.Resistates is made chromatogram separate the title compound that (silica gel is used for the 10%EtOAc wash-out of hexane) then obtains 4.5g, mp.161-163 ℃.
(ⅴ) .3-methylol-female 1,3,5(10) triolefin-17 β-carbonyl aldehyde
With 17 beta-cyanos-female 1,3,5(10) triolefin-3-carboxylate methyl ester (0.8g) is dissolved in the 30ml toluene, and uses DIBAL(6ml, 1M) handle, under argon gas in this mixture of stirring at room 2.5 hours.Then this mixture is poured into 50ml5%H
2SO
4In and stir this mixture 1 hour, filter, dry and concentrate.Resistates is made chromatogram separates, be used for the 20%EtOAc wash-out of hexane) then obtain the title compound of 424mg, mp.146-150 ℃.
(ⅵ) .17 β-(1-hydroxyl butyl)-female 1,3,5(10) triolefin-3-methylol
With 3-methylol-female 1,3,5(10) triolefin-17 β-carbonyl aldehyde (75mg is in 2ml THF) solution join lentamente bromination propyl group magnesium solution (2ml, 1.6M) in.In this mixture of stirring at room 2 hours.
Use saturated NH
4The Cl aqueous solution is this mixture chilling, and uses CH
2Cl
2Extraction.Organism is also concentrated with salt water washing, drying.The gained resistates is made chromatogram to be separated (silica gel is used for 30% eluent ethyl acetate of hexane) and obtains the 57mg title compound.
(ⅶ) .17 β-(propyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
With 17 β-(1-hydroxyl butyl)-female 1,3,5(10) triolefin-3-methylol (57mg) is dissolved in the acetone (5ml) and uses the Jones agent treated.Stir this mixture 1 hour, and used 2-propyl alcohol chilling then, use CH
2Cl
2Extraction and with chromatographic separation (silica gel is used for the 30%etase wash-out of the adding 0.5%HOAc of the hexane) title compound of output 47mg then, mp.211-213 ℃.
Embodiment 9-is corresponding to the scheme IV
17 β-(methyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
According to embodiment 8(ⅰ)-(ⅶ), replace bromination propyl group magnesium (in step (ⅵ)) and make this title compound, mp.199-202 ℃ with methylmagnesium-bromide.
Embodiment 10-is corresponding to the scheme IV
17 β-(3,3-diformazan butyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid
According to embodiment 8(ⅰ)-(ⅶ), with 3,3-diformazan dibutyl magnesium muriate replaces bromination propyl group magnesium and makes this title compound, mp.252-255 ℃ in step (ⅵ).
Embodiment 11-is corresponding to the scheme IV
17 β-[1-(R, S)-hydroxyethyl]-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ). use NaBH
4Handle 17 β-(methyl carbonyl) in methyl alcohol-female 1,3,5(10) triolefin-3-carboxylic acid (6mg) (making among the embodiment 9) solution.This mixture is warming up to 45 ℃ and stir and to spend the night.Remove solvent by rotary evaporation, be dissolved in the methylene dichloride resistates and filtration.With preparative thin layer chromatography purifying title compound (1.6mg), mp.202-204 ℃.
(ⅱ) isolation technique by easy realization obtains pure (R) and (S) configuration, and this is known to present technique field personnel.
Embodiment 12-is corresponding to the scheme IV
17 β-[1-(R, S)-hydroxyl butyl]-female 1,3,5(10) triolefin-3-carboxylic acid
(ⅰ) according to embodiment 11, with embodiment 8(ⅰ)-17 β-(propyl group carbonyl)-female 1,3 of (ⅶ) making, 5(10) triolefin-3-carboxylic acid replaces 17 β-(methyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid and make this title compound, mp.208-211 ℃.
(ⅱ) isolation technique by easy realization makes pure (R) and (S) configuration, and this is known for present technique field personnel.
Embodiment 13
By sieving, mix and be filled into the medicinal preparation for oral administration shape for preparing the logical formula I compound of administration in the hard gelatin capsule, the ratio of each component is listed in the table I.
The table I
Component concentration
Triolefin-3-carboxylic acid 50mg
Magnesium Stearate 5mg
Lactose 75mg
Embodiment 14
With sucrose, terra alba and the logical formula I compound of the II that is listed in the table below, with listed ratio and 10% gelatin solution granulation.With wet granular sieve, drying, mix with starch, talcum and stearic acid, sieve and be pressed into tablet.
The table II
Component concentration
17 β-isobutyl-carbonyl-female 1,3,
5 (10) triolefins-3-carboxylic acid 100mg
Terra alba 150mg
Sucrose 20mg
Starch 10mg
Talcum 5mg
Stearic acid 3mg
Embodiment 15
With 17 β-isobutyl-carbonyl-female 1,3,5(10) triolefin-3-carboxylic acid (75mg) is scattered in and then makes injected articles in the 25ml physiological saline.
Although top described the preferred embodiments of the present invention that illustrated,, be, the present invention is not limited in these explanations disclosed herein, and the institute that is done in claims changes all within the scope of the invention. with being to be understood that
Claims (18)
3, the compound of claim 2 and pharmacologically acceptable salts thereof, hydrate, solvate and ester, wherein R
2Be methyl, ethyl, propyl group, 3-first butyl, isobutyl-, normal-butyl, isobutyl-, 1-first propyl group, the tertiary butyl, amyl group, 1,1-dimethylpropyl, 2,2-dimethylpropyl, octyl group or 3,3-diformazan butyl.
5, a kind of compound that is selected from following thing group:
17 β-(isobutyl-carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(octyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(tert-pentyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(2,2-dimethylpropyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(propyl group carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(methyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(3,3-diformazan butyl carbonyl)-female 1,3,5(10) triolefin-3-carboxylic acid,
17 β-(1-hydroxyethyl)-female 1,3,5(10) triolefin-3-carboxylic acid and
17 β-(hydroxyl butyl)-female 1,3,5(10) triolefin-3-carboxylic acid.
6, a kind of pharmaceutical composition that contains arbitrary compound and pharmaceutical acceptable carrier among the claim 1-5.
7, any compound is used for the treatment of among the claim 1-5.
8, any compound among the claim 1-5 is used in as steroide 5-alpha reductase inhibitor and is used in the pharmaceutical preparation.
9, any compound among the claim 1-5 is used for reducing the pharmaceutical preparation of prostate gland size.
10, any compound among the claim 1-5 is used for disposing the pharmaceutical preparation of prostate cancer.
12, any compound and alpha-receptor antagonist compound are as the using method of active treatment material in the claim 1 to 5, and this method comprises any compound among the claim 1-5 and the administration or the administration simultaneously of order separately of alpha-receptor antagonist compound.
13, any compound and the alpha-receptor antagonist compound in pharmaceutical preparation are in the using method that is used for disposing benign prostatauxe among the claim 1-5, and this method comprises any compound and the administration or the administration simultaneously of order separately of α receptor antagonist compounds among the claim 1-5.
14, any compound and U-10858 (minoxidil) are as active treatment material using method among the claim 1-5, and this method comprises the administration or the administration simultaneously of order separately of any compound and U-10858 among the claim 1-5.
15, any compound and the U-10858 in pharmaceutical preparation are in the using method that is used for disposing male sex's alopecia areata among the claim 1-5, and this method comprises the administration or the administration simultaneously of order separately of any compound and U-10858 among the claim 1-5.
16, a kind of intermediate of following general formula:
R is C in the formula
1-20Straight or branched, saturated or unsaturated alkyl.
17, a kind of method for preparing logical formula II compound and pharmacologically acceptable salts, hydrate, solvate and ester,
R is C in the formula
1-20Straight or branched, saturated or unsaturated alkyl, this method comprise or
(ⅰ) compound of the following general formula of oxidation
(the R definition is as mentioned above in the formula), perhaps
(ⅱ) react at the compound that has under the suitable coupling agent in metal catalyzed coupling reaction with following general formula,
(R as mentioned above in the formula)
Preferred coupling agent is a carbon monoxide, subsequently, if suitable, the reaction that can at random be hydrolyzed, perhaps
(ⅲ) compound of the following general formula of hydrolysis
(R is as mentioned above in the formula), perhaps
(ⅳ) react at the compound that has under the coupling agent (preferred carbon monoxide) in metal catalyzed coupling reaction with following general formula,
(R as mentioned above in the formula)
Subsequently, if suitable, the reaction that can at random be hydrolyzed, and
At random form its pharmacologically acceptable salts, hydrate, solvate or ester afterwards.
18, among the claim 1-5 any compound in the purposes of the pharmaceutical preparation that is used for suppressing steroide 5-alpha-reductase.
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GB929213835A GB9213835D0 (en) | 1992-06-30 | 1992-06-30 | Compounds |
GB9213835.3 | 1992-06-30 |
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Family
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KR (1) | KR950702118A (en) |
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AP (1) | AP412A (en) |
AU (1) | AU4545993A (en) |
BG (1) | BG99313A (en) |
BR (1) | BR9306748A (en) |
CA (1) | CA2138956A1 (en) |
CZ (1) | CZ334694A3 (en) |
FI (1) | FI946189A0 (en) |
GB (1) | GB9213835D0 (en) |
HU (1) | HUT69409A (en) |
IL (1) | IL106158A0 (en) |
MA (1) | MA22927A1 (en) |
MX (1) | MX9303970A (en) |
NO (1) | NO945074L (en) |
OA (1) | OA10122A (en) |
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US5925774A (en) * | 1991-01-07 | 1999-07-20 | Pherin Corporation | Estrenes for inducing hypothalamic effects |
AU676478B2 (en) * | 1992-05-20 | 1997-03-13 | Merck & Co., Inc. | New delta-17 and delta-20 olefinic and saturated 17beta- substituted-4-aza-5alpha-androstan-3-ones as 5alpha- reductase inhibitors |
US5543417A (en) * | 1994-10-21 | 1996-08-06 | Merck & Co., Inc. | Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents |
GB201102913D0 (en) | 2011-02-18 | 2011-04-06 | Univ Birmingham | Novel therapeutic |
JP2015129095A (en) | 2013-12-19 | 2015-07-16 | ロレアル | composition |
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US4954446A (en) * | 1988-05-25 | 1990-09-04 | Smithkline Beecham Corporation | Aromatic steroid 5-α-reductase inhibitors |
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CN114805462A (en) * | 2018-02-11 | 2022-07-29 | 江苏豪森药业集团有限公司 | Steroid derivative regulator and preparation method and application thereof |
CN114805462B (en) * | 2018-02-11 | 2024-06-18 | 江苏豪森药业集团有限公司 | Steroid derivative regulator and preparation method and application thereof |
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MA22927A1 (en) | 1994-04-01 |
HUT69409A (en) | 1995-09-28 |
CA2138956A1 (en) | 1994-01-06 |
FI946189A (en) | 1994-12-30 |
EP0651643A4 (en) | 1995-10-04 |
RU94046378A (en) | 1996-10-10 |
JPH08500821A (en) | 1996-01-30 |
SK159994A3 (en) | 1996-01-10 |
AU4545993A (en) | 1994-01-24 |
BR9306748A (en) | 1998-12-08 |
MX9303970A (en) | 1994-04-29 |
BG99313A (en) | 1995-09-29 |
AP412A (en) | 1995-09-29 |
EP0651643A1 (en) | 1995-05-10 |
WO1994000125A1 (en) | 1994-01-06 |
IL106158A0 (en) | 1993-10-20 |
NO945074L (en) | 1995-02-16 |
SI9300350A (en) | 1993-12-31 |
ZA934645B (en) | 1994-01-25 |
CZ334694A3 (en) | 1995-10-18 |
KR950702118A (en) | 1995-06-19 |
AP9300542A0 (en) | 1993-07-31 |
GB9213835D0 (en) | 1992-08-12 |
FI946189A0 (en) | 1994-12-30 |
OA10122A (en) | 1996-12-18 |
NO945074D0 (en) | 1994-12-29 |
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