CN1839146A - New delta-15-d-homosteroid compounds having an androgenic effect - Google Patents

New delta-15-d-homosteroid compounds having an androgenic effect Download PDF

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CN1839146A
CN1839146A CNA2004800240122A CN200480024012A CN1839146A CN 1839146 A CN1839146 A CN 1839146A CN A2004800240122 A CNA2004800240122 A CN A2004800240122A CN 200480024012 A CN200480024012 A CN 200480024012A CN 1839146 A CN1839146 A CN 1839146A
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ketone
beta
height
hydroxy
diene
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拉尔夫·维尔瓦
斯文·林
京特·考夫曼
瓦尔特·埃尔格
比尔吉特·施奈德
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Bayer Pharma AG
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Schering AG
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
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Abstract

The invention relates to Delta<15>-D-homosteroids of general formula (I), methods for the production thereof, and pharmaceutical compositions containing said compounds. The inventive compounds of general formula (I) are provided with androgenic activity.

Description

Δ with androgenic effect 15-D-homosteroid
Technical field
The present invention relates to the Δ of general formula (I) 15-D-homosteroid, its preparation method, comprise the application in the medicine that the pharmaceutical composition of this compound and their preparations have androgenic effect.
Figure A20048002401200091
Background technology
Do not know at present the Δ of oestrane or androstane system as yet 15-D-homosteroid.But, disclose in the following document and had androgenic activity and the active Δ of antigonadotropic 16-D-homosteroid: people such as the 4th, 155, No. 918 United States Patent (USP)s and Avery, Steroids, 1990, Vol.55, pp.9-64.
Summary of the invention
The purpose of this invention is to provide other the compound with androgenic activity and technology on easy and prepare the method for these compounds effectively.
This purpose is the Δ by following general formula (I) 15-D-homosteroid is realized:
Figure A20048002401200092
Wherein
R 1Represent C 1-4-alkyl, and
R 2Representation hydroxy, group OC (O)-R 20, OC (O) NH-R 20Or OR 20, R wherein 20Represent C 1-12-alkyl, C 3-8-cycloalkyl, aryl or aryl-C 1-4-alkyl, these groups are optional to be substituted, and
R 3Represent hydrogen atom or C 1-6-alkyl, vinyl, ethynyl or C nF 2n+1Group, n=1,2,3 wherein, and
R 4Represent hydrogen atom,
Perhaps
R 2Represent hydrogen atom or C 1-6-Alkyl, vinyl, ethynyl or C nF 2n+1Group, n=1,2,3 wherein,
R 3Representation hydroxy, group OC (O)-R 20, OC (O) NH-R 20Or OR 20, R wherein 20Represent C 1-12-alkyl, C 3-8-cycloalkyl, aryl or aryl-C 1-4-alkyl, these groups are optional to be substituted, and
R 4Represent hydrogen atom,
Perhaps
R 2And R 3Represention oxygen atom together, and
R 4Represent hydrogen atom,
Perhaps
R 2Representation hydroxy, group OC (O)-R 20, OC (O) NH-R 20Or OR 20, R wherein 20Represent C 1-12-alkyl, C 3-8-cycloalkyl, aryl or aryl-C 1-4Alkyl, these groups are optional to be substituted, and
R 3And R 4Form two keys together, and
STEROID represents the steroid part ring system of formula A, B, C, D, E and F:
Figure A20048002401200111
Wherein in A and C in 1, can there be extra two keys in the 2-position, and in B in 9, can there be one or two extra two keys in 10-position and 11,12-position,
R 7Represent hydrogen atom, halogen atom, hydroxyl or C nF 2n+1Group, n=1,2,3 wherein,
X represention oxygen atom, two hydrogen atoms or oxyimino,
R 8Represent hydrogen atom, methyl or ethyl,
R 9Represent hydrogen atom or halogen atom or and R 10Represent two keys together,
R 10Represent hydrogen atom, hydroxyl, methyl or ethyl, perhaps with R 9Represent two keys together,
R 11Represent hydrogen atom, C 1-4-alkyl, itrile group, hydroxyl methylene radical or formyl radical,
R 12Represent hydrogen atom, C 1-4-alkyl or itrile group,
R 11And R 12, except that above-mentioned definition, represent methylene bridge together,
R 13Represent hydrogen atom or and R 7Represent two keys together,
R 16Represent hydrogen atom or and R 13Represent two keys together,
R 15Representation hydroxy, R 14And R 15Represent hydrogen atom or together the two keys of representative, [2,3c] oxadiazole ring, [3,2c] isoxazole ring or [3,2c] pyrazoles ring,
R 17Represent hydrogen atom or methyl,
Y represention oxygen atom or nitrogen-atoms,
R 4, R 7, R 8, R 11, R 12, R 13, R 14And R 15It can be to be in α-or β-position that the setback line at place is represented these substituting groups,
And acceptable salt on their pharmacology.
Compound according to the present invention has androgenic activity.
C 1-4-alkyl is the alkyl of straight or branched, its be preferably methyl, ethyl, n-propyl group, i-propyl group-, n-butyl, i-butyl or the tertiary butyl.
C 1-6-alkyl is the alkyl of straight or branched, it is preferably methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl-or tertiary butyl, n-amyl group, i-amyl group, n-hexyl, 2-methyl amyl, 3-methyl amyl, 2,2-dimethylbutyl or 2, the 3-dimethylbutyl.
C 1-12-alkyl is the alkyl of straight or branched, it is preferably methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, the tertiary butyl, n-amyl group, i-amyl group, n-hexyl, 2-methyl amyl, 3-methyl amyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, octyl group, nonyl, decyl or undecyl.
C 3-8-cycloalkyl is preferably monocycle or bicyclic groups, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Term aryl representative replaces or the unsubstituted aryl that preferably has 6-15 carbon atom, and the phenyl of phenyl, replacement for example is as halogenophenyl or nitrophenyl, perhaps naphthyl.
Term aryl-C 1-4-The alkyl that alkyl is preferably replaced by aryl, they preferably have 7-15 carbon atom altogether, and wherein said aryl and/or alkyl can have other substituting group, for example are preferably halogen atom, hydroxyl, methoxyl group or itrile group.Particularly preferred aryl is the substituted benzyl that does not have replacement or aromaticity, as benzyl or halogeno-benzyl.
The term halogen atom is represented fluorine, chlorine, bromine or iodine atom.
If STEROID represents the steroid ring system of segment bounds A, then R 7Preferred hydrogen atom, chlorine atom, bromine atoms, hydroxyl or trifluoromethyl, the R of representing 10Preferred hydrogen atom, hydroxyl or methyl, the R of representing 9Preferred hydrogen atom or fluorine atom, the R of representing 8Preferred hydrogen atom or the methyl represented, wherein preferred especially this methyl.
If STEROID represents the steroid ring system of segment bounds B, then R 7Preferably represent hydrogen atom, chlorine atom, bromine atoms or hydroxyl or trifluoromethyl, and R 8Preferred hydrogen atom or the methyl represented, wherein preferred especially this methyl.
If STEROID represents the steroid ring system of segment bounds C, then R 7Preferably represent hydrogen atom, chlorine atom, bromine atoms or hydroxyl or trifluoromethyl, and R 11, R 12The preferred hydrogen atom of representing.In addition, 1, two keys of 2-position are preferred.For R 17, be preferably H or CH equally 3
If STEROID represents the steroid ring system of segment bounds D, then R 7Preferred hydrogen atom, chlorine atom, bromine atoms or hydroxyl or trifluoromethyl, the R of representing 8Preferred hydrogen atom or the methyl represented, wherein special preferable methyl, R 13And R 7Preferably represent two keys together, and the preferred represention oxygen atom of Y.
If STEROID represents the steroid ring system of segment bounds E, then R 8Preferred hydrogen atom or the methyl represented, wherein special preferable methyl, R 12The preferred hydrogen atom, R represented 13And R 16Preferably represent hydrogen atom or represent two keys, R together 15Preferred representation hydroxy, perhaps R under the various situations 14And R 15Preferably represent [3,2c] pyrazoles ring together.
If STEROID represents the steroid ring system of segment bounds F, then R 11The preferred C that represents 1-4-alkyl or itrile group.
R 1Preferred represent methylidene or ethyl, wherein preferred especially this methyl.
R 2Preferred representation hydroxy, methanoyl, acetoxyl group, propionyloxy, butyryl acyloxy, [(trans-4-butyl cyclohexyl) carbonyl] oxygen base, phenyl propionyl oxygen base, isobutyryl oxygen base, heptyl oxygen base, undecyl oxygen base or phenyl amino ketonic oxygen base wherein are preferably this hydroxyl especially.
R 3Preferred represent methylidene, trifluoromethyl, ethyl, pentafluoroethyl group or ethynyl, wherein special preferable methyl, ethyl, trifluoromethyl and pentafluoroethyl group.
R 4The preferred hydrogen atom of representing.
Particularly preferred Δ 15-D-homosteroid is as follows:
1) 17a beta-hydroxy-D-height-androstane-4,15-diene-3-ketone,
2) 17a β, 4-dihydroxyl-D-height-androstane-4,15-diene-3-ketone,
3) 17a beta-hydroxy-4-chloro-D-height-androstane-4,15-diene-3-ketone,
4) 17a beta-hydroxy-4-bromo-D-height-androstane-4,15-diene-3-ketone,
5) 17a beta-hydroxy-4-trifluoromethyl-D-height-androstane-4,15-diene-3-ketone,
6) 17a β, 11 beta-dihydroxyies-D-height-androstane-4,15-diene-3-ketone,
7) 17a β, 11 beta-dihydroxyies-D-height-9 α-fluoro-androstane-4,15-diene-3-ketone,
8) 17a beta-hydroxy-D-height-androstane-1,4,15-triolefin-3-ketone,
9) 17a beta-hydroxy-D-height-4-chloro-androstane-1,4,15-triolefin-3-ketone,
10) 17a β, 4-dihydroxyl-D-height-androstane-1,4,15-triolefin-3-ketone,
11) 17a beta-hydroxy-7 Alpha-Methyls-D-height-androstane-1,4,15-triolefin-3-ketone,
12) 17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-androstane-1 ,-4,15-triolefin-3-ketone,
13) 17a beta-hydroxyl-17 alpha-methyl-androstane-4,15-diene-3-ketone,
14) 17a beta-hydroxyl-17 a α-trifluoromethyl-7 Alpha-Methyls-androstane-4,15-diene-3-ketone,
15) 17a β, 4-dihydroxyl-17a α-trifluoromethyl-androstane-4,1-5-diene-3-ketone,
16) 17a beta-hydroxyl-17 a α-trifluoromethyl-4-chloro-androstane-4,15-diene-3-ketone,
17) 17a beta-hydroxy-7 Alpha-Methyls-D-height-androstane-4,15-diene-3--ketone,
18) 17a beta-hydroxyl-17 alpha-pentafluoroethyl group-androstane-4,15-diene-3-ketone,
19) 17a beta-hydroxy-D-height-female-4,15-diene-3-ketone,
20) 17a β, 4-dihydroxyl-D-height-female-4,15-diene-3-ketone,
21) 17a beta-hydroxy-4-chloro-D-height-female-4,15-diene-3-ketone,
22) 17a beta-hydroxy-4-bromo-D-height-female-4,15-diene-3-ketone,
23) 17a beta-hydroxy-4-trifluoromethyl-D-height-female-4,15-diene-3-ketone,
24) 17a beta-hydroxyl-17 a Alpha-Methyl-D-height-female-4,15-diene-3-ketone,
25) 17a beta-hydroxyl-17 a Alpha-Methyl-4-chloro-D-height-female-4,15-diene-3-ketone,
26) 17a Alpha-hydroxy-17a α-trifluoromethyl-D-height-female-4,15-diene-3-ketone,
27) 17a beta-hydroxyl-17 a α-pentafluoroethyl group-D-height-female-4,15-diene-3-ketone,
28) 17a beta-hydroxy-7 Alpha-Methyls-D-height-female-4,15-diene-3-ketone,
29) 17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-female-4,15-diene-3-ketone,
30) 17a beta-hydroxy-D-height-female-1,4,15-triolefin-3-ketone,
31) 17a beta-hydroxy-D-height-4-chloro-is female-1,4,15-triolefin-3-ketone,
32) 17a β, 4-dihydroxyl-D-height-female-1,4,15-triolefin-3-ketone,
33) 17a beta-hydroxy-7 Alpha-Methyls-D-height-female-1,4,15-triolefin-3-ketone,
34) 17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-female-1,4,15-triolefin-3-ketone,
35) 13-ethyl-17a beta-hydroxy-D-height-gona-4,15-diene-3-ketone,
36) 13-ethyl-17a beta-hydroxy-4-chloro-D-height-gona-4,15-diene-3-ketone,
37) 13-ethyl-17a beta-hydroxy-7 Alpha-Methyls-D-height-gona-4,15-diene-3-ketone,
38) 13-ethyl-17a beta-hydroxyl-17 alpha-methyl D-Gao-gona-4,15-diene-3-ketone,
39) 13-ethyl-17a beta-hydroxyl-17 alpha-methyl-4-chloro-D-height-gona-4,15-diene-3-ketone,
40) 13-ethyl-17a beta-hydroxy-D-height-gona-1,4,15-triolefin-3-ketone,
41) 13-ethyl-17a beta-hydroxy-4-chloro-D-height-gona-1,4,15-triolefin-3-ketone,
42) 13-ethyl-17a beta-hydroxy-7 Alpha-Methyls-D-height-gona-1,4,15-triolefin-3-ketone,
43) 13-ethyl-17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-gona-1,4,15-triolefin-3-ketone,
44) 17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone,
45) 2-oxa--17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone,
46) 17a beta-hydroxy-D-height-5 α-androstane-1,15-diene-3-ketone,
47) 2-hydroxyl methylene radical-17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone.
Another object of the present invention is the Δ that simply and effectively prepares general formula (I) on technology 15The method of-D-homosteroid.
In this regard, the compound of general formula (II) (people such as M.A.Avery, Steroids, 1990,55,59-64; People such as A.Furst, 1976, the 3,984, No. 476 United States Patent (USP)s) be known,
Figure A20048002401200151
R wherein 1Have aforesaid definition with STEROID,
Acid as tosic acid in the presence of, react with acetylizing agent in accordance with known methods, for example acetate pseudoallyl ester (Hosoda; H. wait people, Chem.Phar.Bull., 23; 1975,3141-3145), diacetyl oxide (Rasmusson, G.H.; Arth, G.E., Steroids; 22,1973,107-111) etc.; to form the dienol acetic ester, use such as NaBH then 4Reductive agent reduce, obtain corresponding 17a beta-hydroxy-D-height-Δ 15-steroide.
When preparation has the general formula I I compound of part-structure A-F, can use known steroid parent.
For example, can use following steroid parent:
For steroid parent A: hero-4-alkene-3,17-diketone and dehydroepiandrosterone.
For steroid parent B: oestrone, 7 Alpha-Methyl oestrone.
For steroid parent C, D or E: epiandrosterone.
For steroid parent F: the 5 α-hero-2-alkene-17-ketone (the 3rd, 098, No. 851 United States Patent (USP)s) that is obtained from epiandrosterone.
The functional group that part-structure comprised that is used for the parent material of steroid parent A-F can randomly protect according to method known to those skilled in the art.
Therefore, the ketone group in the parent material of part-structure A-F can be protected with the form of ketal or sulfo-acetal according to method known to those skilled in the art.In part-structure A-F, introduce substituent R 7-R 15Can form D-height-Δ according to method known to those skilled in the art 15Before-the ring compound and carry out afterwards.
The acceptable salt of pharmacology for the compound of Formula I that forms the present invention, hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid can be considered as mineral acid, and acetate, propionic acid, toxilic acid, fumaric acid, succsinic acid, phenylformic acid, xitix, oxalic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, oxysuccinic acid, amygdalic acid, styracin and methylsulfonic acid can be considered as organic acid.
As shown in the following Table 1, compound according to the present invention has androgenic activity.
Table 1: compare the relative binding affinity/RBA of androgen receptor with testosterone and Methyltrienolone
Compound RBA％
Testosterone 35
R1881(Methyltrienolone) 100
17a beta-hydroxy-D-height-androstane-4,15-diene-3-ketone 12
17a beta-hydroxy-D-height-female-4,15-diene-3-ketone 25
17a beta-hydroxy-7 Alpha-Methyls-D-height is female-4, and 16-diene-3-ketone is described in Steroids, and 1990,55, among the 59-64, it is the male sex hormone with antigonadotropic character.But 17a beta-hydroxy-7 Alpha-Methyls-D-height is female-4, and 16-diene-3-ketone only shows 2% slight receptor binding affinity (reference DHT=100%) to androgen receptor.
Outside being enough to be all beyond one's expectations and surprisingly, according to Δ of the present invention 15-D-homosteroid shows significantly higher binding affinity to androgen receptor.Female-4 with 17a beta-hydroxy-7 Alpha-Methyls-D-height, (Steroids 1990,55,59-64) compare, and they are in conjunction with Δ for 16-diene-3-ketone 15The high compound of-D-is greater than 12% (reference DHT=100%) to androgen receptor.Therefore, carry and being illustrated in according to Δ of the present invention 15It is female-4 that the adjusting of androgenic activity is different from 17a beta-hydroxy-7 Alpha-Methyls-D-height in the-D-homosteroid, and 16-diene-3-ketone (Steroids, 1990,55,59-64)
In compound according to the present invention, these test results provide many possibilities to hormone disease such as endometriosis, mammary cancer or the hypogonadism of bringing out in the Birth control of masculinity and femininity, Hormone Replacement Therapy (HRT) in the masculinity and femininity or the treatment masculinity and femininity.
Therefore, the Δ that comprises at least a general formula (I) that also provides of the present invention 15The assistant agent that-D-homosteroid and optional pharmacology are compatible and the pharmaceutical composition of carrier, and the application of this compound in treatment or useful in preparing drug formulations, for example treatment of aforementioned clinical symptom.
These pharmaceutical compositions and medicine can pass through oral cavity, rectum, vagina, subcutaneous, through skin, vein or intramuscular administration.Remove conventional carrier and/or the thinner thing that uses, they comprise the compound of at least a general formula I.
Medicine of the present invention has proper dosage, and it is to make with the conventional solid that uses or liquid vehicle or thinner and the pharmaceutical adjuvant that uses corresponding to the routine of desirable form of medication according to known method.Preferred preparation is the distribution formulation that is suitable for oral administration.These distribute formulations is for example tablet, diaphragm, coating tablet, capsule, pill, powder, solution or suspensoid and other long-acting dosage forms.
Certainly, also can consider non-gastrointestinal preparation such as injection liquid.In addition, said preparation also can be suppository and the medicine that is used for vagina administration.
Corresponding tablet for example can be prepared as follows: described activeconstituents is mixed with known assistant agent, inert diluent for example, as glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, polyvinylpyrrolidone, disintegrating agent such as W-Gum or alginic acid, tackiness agent such as starch or gelatin, lubricant such as Magnesium Stearate or talcum, and/or be used to realize material such as carboxyl polymethylene, carboxymethyl cellulose, acetate phthalic acid Mierocrystalline cellulose or the polyvinyl acetate base ester of long-acting.This tablet also can be formed by a plurality of layers.
Therefore coating tablet can be prepared as follows: with normally used reagent in the tablet coating core that is similar to above-mentioned tablet and makes is carried out dressing, described reagent for example is polyvinylpyrrolidone or lac, gum arabic, talcum, titanium oxide or sugar.In the case, this coating tablet shell also can be made up of several layers, wherein can use the assistant agent of mentioning in the above-mentioned tablet.
The solution or the suspensoid that contain with good grounds compound of Formula I of the present invention also can comprise seasonings such as asccharin, cyclamate or sucrose, and sweetener such as vanilla or citrus extract.In addition, they can comprise suspension aids such as Xylo-Mucine, or sanitas such as p-Hydroxybenzoate.
The capsule that comprises compound of Formula I for example can be prepared as follows: the compound of general formula I is mixed with inert support, and as lactose or sorbyl alcohol, encapsulate is in gelatine capsule then.
Suitable suppository can be for example prepares by mixing with the carrier that is used for this purpose such as neutral fat or polyoxyethylene glycol or derivatives thereof.
Embodiment
Following examples are used to explain the present invention, rather than to the restriction of its scope.
Embodiment 1
17a beta-hydroxy-D-height is female-4,15-diene-3-ketone
Step 1
3-methoxyl group-17a-acetoxyl group-D-height is female-1,3,5 (10), 15, the 17-pentaene
3-methoxyl group-D-height of 4.0g is female-1,3,5 (10), and 16-tetraene-17a-ketone is dissolved in 40ml diacetyl oxide and the 40ml acetate pseudoallyl ester.After adding the tosic acid of 2.0g, heated 48 hours to 80 ℃.Then neutralize with saturated sodium bicarbonate solution.This material ethyl acetate extraction, organic phase is washed with saturated nacl aqueous solution, and is dry on sal epsom, filters, and evaporation concentration also carry out chromatographically pure system on silica gel.It is female-1,3,5 (10), 15 to obtain 3-methoxyl group-17a-acetoxyl group-D-height, the 17-pentaene.
1H-NMR(CDCl 3)：0.96(s，3H，H-18)，2.20(s，3H，OAc)，3.78(s，3H，OCH 3)，5.65-6.05(m，3H，H-15，H-16，H-17)
Step 2
3-methoxyl group-17a beta-hydroxy-D-height is female-1,3,5 (10), the 15-tetraene
With 6.5g-methoxyl group-D-height-female-1,3,5 (10), 15,17-pentaene-17a-yl acetate is dissolved among the THF of 150ml methyl alcohol and 75ml.When-20 ℃ are stirred down, the NaBH of portion-wise addition 5.0g 4, stirred then 3 hours.Evaporation concentration to 1/5 is added 250ml water then.Distill remaining organic solvent.Filter this material, wash with water, vacuum-drying carry out chromatographically pure system then on silica gel.
1H-NMR(CDCl 3)：0.81(s，3H，H-18)，3.64(m，1H，H-17a)，3.77(s，3H，OCH 3)，5.60-5.80(m，2H，H-1S，H-16)
Step 3
3-methoxyl group-17a beta-hydroxy-D-height is female-1,3,5 (10), the 15-triolefin
3-methoxyl group-17a beta-hydroxy-D-height of 5.0g is female-2,5 (10), and the 15-tetraene is dissolved in 1-methoxyl group-2-propyl alcohol of the THF of 35ml and 15ml, drops under-70 ℃ then in the solution of being made up of THF and the about 0.3g sodium of 100ml liquefied ammonia, 10ml.After the bleaching, interrupt the interpolation process, and add sodium again.After adding the Na of 2.5g, reaction is finished.Add the solid NH of 2.5ml Virahol and 8g 4Cl.In mild heat, ammonia is evaporated.After adding 250ml cold water, filter steroidal compounds, be washed with water to neutral and vacuum-drying.It is female-1,3,5 (10) to obtain 3-methoxyl group-17a beta-hydroxy-D-height, the 15-triolefin.
Step 4
17a beta-hydroxy-D-height is female-4,15-diene-3-ketone
3-methoxyl group-17a beta-hydroxy-D-height of 4.6g is female-1,3,5 (10), and the 15-triolefin is dissolved in the 150ml acetone.Under stirring at room, drip 5% hydrochloric acid soln of 8ml.After 1 hour, add the saturated NaHCO of 50ml 3Solution and 150ml water.Distill to very big degree acetone.Filter this material, wash with water, vacuum-drying carry out chromatographically pure system then on silica gel.It is female-4 to obtain 17a beta-hydroxy-D-height, 15-diene-3-ketone.
1H-NMR(CDCl 3)：0.84(s，3H，H-18)，3.57(m，1H，H-17a)，5.57-5.72(m，2H，H-15，H-16)，5.84(s，1H，H-4)
Embodiment 2
17a beta-hydroxy-D-Kaohsiung-4,15-diene-3-ketone
Step 1
3 β-acetoxyl group-17a-acetoxyl group-D-high androstane-5,15, the 17-triolefin
With 3 β-acetoxyl group-D-high androstane-5 of 6.0g, 16-diene-17a-ketone is dissolved in 70ml diacetyl oxide and the 70ml acetate pseudoallyl ester, behind the tosic acid of interpolation 4.0g, heats 48 hours to 80 ℃.Neutralize with saturated sodium bicarbonate solution.This material ethyl acetate extraction, organic phase is washed with saturated nacl aqueous solution, and is dry on sal epsom, filters, and evaporation concentration also carry out chromatographically pure system on silica gel.Obtain 3 β-acetoxyl group-17a-acetoxyl group-D-high androstane-5,15, the 17-triolefin.
1H-NMR(CDCl 3)：0.95(s，3H，H-18)，1.02(s，3H，H-19)，2.04(s，3H，OAc)，2.18(s，3H，OAc)，4.60(m，1H，H-3)，5.41(m，1H，H-6)，5.60-5.98(m，3H，H-15，H-16，H-17)
Step 2
3 β-acetoxyl group-17a beta-hydroxy-D-high androstane-5, the 15-diene
With 3 β of 5.0g, 17a-diacetoxy-D-Kaohsiung-4,15, the 17-triolefin is dissolved among the THF of 200ml methyl alcohol and 150ml.When-20 ℃ are stirred down, the NaBH of portion-wise addition 5.0g 4, and stirred 2 hours.Add the saturated ammonium chloride solution of 100ml.Distill organic solvent.After adding 250ml water, filter this material, wash with water, vacuum-drying also carry out chromatographically pure system on silica gel.Obtain 3 β-acetoxyl group-17a beta-hydroxy-D-high androstane-5, the 15-diene.
Step 3
3 β-acetoxyl group-D-high androstane-5,15-diene-17a beta-tetrahydro pyranyl ether
With 3 β-acetoxyl group-17a beta-hydroxy-D-high androstane-5 of 4.25g, the 15-diene is dissolved in the 75ml methylene dichloride.Under stirring at room, add the pyridine tosylate of 7.5ml dihydropyrane and 500mg in order.After 3 hours, use 10%NaHCO 3Solution and saturated NaCl solution washing, dry on sal epsom, filter and evaporation concentration.Obtain 3 β-acetoxyl group-D-high androstane-5,15-diene-17a beta-tetrahydro pyranyl ether.
Step 4
3 beta-hydroxies-D-high androstane-5,15-diene-17a beta-tetrahydro pyranyl ether
With 3 β-acetoxyl group-D-high androstane-5 of 5.2g, 15-diene-17a beta-tetrahydro pyranyl ether is dissolved among the THF of 175ml methyl alcohol and 125ml.In vigorous stirring, add the K of 7.5g 2CO 3With 2.5ml water.3.5 after hour, evaporation concentration is to about 1/6.Add 250ml water, filter this material, wash with water and vacuum-drying.Obtain 3 beta-hydroxies-D-high androstane-5,15-diene-17a beta-tetrahydro pyranyl ether.
Step 5
3-ketone group-D-high androstane-4,15-diene-17a beta-tetrahydro pyranyl ether
With 3 beta-hydroxies-D-high androstane-5 of 4.5g, 15-diene-17a beta-tetrahydro pyranyl ether is dissolved in the 125ml toluene under argon atmospher.Add the Al (O-iPr) of 1.6g 3After, heated 2.5 hours to 110 ℃.Under the room temperature, the 1M potassium sodium tartrate solution with 250ml washs 2 times respectively.Moisture phase extracts again with ethyl acetate subsequently.The organic phase that merges is washed with saturated nacl aqueous solution, and is dry on sal epsom, filter, and vacuum-evaporation concentrates.Obtain 3-ketone group-D-high androstane-4,15-diene-17a beta-tetrahydro pyranyl ether.
Step 6
17a Alpha-hydroxy-D-high androstane-4,15-diene-3-ketone
With 3-ketone group-D-high androstane-4 of 14g, 15-diene-17a beta-tetrahydro pyranyl ether crude product is dissolved in the 100ml acetone.Under the room temperature, drip 10% hydrochloric acid soln of 10ml.After 2 hours, add the 50ml sodium hydrogen carbonate solution.Evaporation reaction mixture is to about 1/3.Add 150ml water, the filtering-depositing material washes with water, and vacuum-drying carry out chromatographically pure system then on silica gel.Obtain 17a beta-hydroxy-D-high androstane-4,15-diene-3-ketone.
1H-NMR(CDCl 3)：0.82(s，3H，H-18)，1.20(s，3H，H-19)，3.54(m，1H，H-17a)，5.55-5.67(m，2H，H-15，H16)，5.74(s，1H，H-4)
Embodiment 3
17a beta-hydroxy-4-chloro-D-high androstane-4,15-diene-3-ketone
Step 1
17a beta-hydroxy-4 ξ, 5 ξ-epoxy group(ing)-D-Kaohsiung-15-alkene-3-ketone
With 17a beta-hydroxy-D-Kaohsiung-4 of 2.0g, 15-diene-3-ketone is dissolved in the 80ml methyl alcohol and at 0 ℃ and mixes with 20ml superoxol (35%) down.Under agitation add 10% sodium hydroxide solution of 4ml, stirred then 3 hours.The evaporation concentration reaction soln mixes with 50ml methylene dichloride and 25ml water then to 50ml, separates organic phase then.Concentrate thiosulfate solution with half and wash, drying also is evaporated to dried.The residue of gained is by 4 α, 5 α-or 4 β, the mixture of 5 beta epoxide things is formed, and not further pure system promptly is used for next step.
Step 2
17a beta-hydroxy-4-chloro-D-high androstane-4,15-diene-3-ketone
(step 1) is dissolved in the 300ml acetone, mixes with the concentrated hydrochloric acid of 17ml down at 0 ℃ then with the epoxide mixture of 1.93g.After 2 hours,, and evaporate acetone with the soda solution neutralization.The residue dichloromethane extraction.Organic extract carries out drying and evaporation concentration.After crystallization in the ethyl acetate, obtain 17a beta-hydroxy-4-chloro-D-high androstane-4,15-diene-3-ketone.
1H-NMR(COCL 3)：0.82(s，3H，H-18)，1.25(s，3H，H-19)，3.57(m，1H，H-17a)，5.64(m，2H，H-15，H-16)
Embodiment 4
17a beta-hydroxy-7 Alpha-Methyls-D-high androstane-4,15-diene-3-ketone
Step 1
17a beta-hydroxy-D-high androstane-4,6,15-triolefin-3-ketone
Make 17a beta-hydroxy-D-high androstane-4 of 2.5g in the 80ml trimethyl carbinol, 15-diene-3-ketone refluxed 30 minutes with the chloranil of 2.5g.Cooling also is evaporated to dried.Residue carry out chromatographically pure system on silica gel.
Step 2
17a beta-hydroxy-7 Alpha-Methyls-D-high androstane-4,15-diene-3-ketone
The THF of 100ml is added in the methyl iodate magnesium solution (being made in the 25ml Anaesthetie Ether by the magnesium of 1.75g and the methyl iodide of 5ml), is cooled to-5 ℃, add 0.35g cuprous chloride (I) then.Be cooled to-20 ℃, drip 17a beta-hydroxy-D-high androstane-4,6 of 1.3g then, the 15-triolefin-solution of 3-ketone in the THF of 20ml.After hour, it is poured onto in frozen water/2N sulfuric acid, and with 30ml dichloromethane extraction 3 times.Dry organic extract and evaporation concentration.Residue carry out chromatographically pure system on silica gel.For further pure system, by recrystallization in the ethyl acetate.
1H-NMR(CDCl 3)：0.77(d，J＝7Hz，3H，H-7Me)，0.83(s，3H，H-18)，1.20(s，3H，H-19)，3.57(m，1H，H-17a)，5.63(m，2H，H-15，H-16)，5.74(s，1H，H-4)
Embodiment 5
17a beta-hydroxy-4-chloro-D-height is female-4,15-diene-3-ketone
Step 1
17a beta-hydroxy-4 ξ, 5 ξ-epoxy group(ing)-D-height is female-15-alkene-3-ketone
Be similar to 17a beta-hydroxy-4 ξ, 5 ξ-epoxy group(ing)-D-Kaohsiung-15-alkene-3-ketone is prepared.The residue of gained is by 4 α, 5 α-or 4 β, the mixture of 5 beta epoxide things is formed, and not further pure system promptly is used for next step.
Step 2
17a beta-hydroxy-4-chloro-D-height is female-4,15-diene-3-ketone
Be similar to 17 beta-hydroxyl-17 alphas-trifluoromethyl-4-chloro-hero-4-alkene-3-ketone, by 17a beta-hydroxy-4-chloro-D-high androstane-4,15-diene-3-ketone is prepared.
1H-NMR(CDCl 3)：0.84(s，3H，H-18)，3.57(m，1H，H-17a)，5.58-5.70(m，2H，H-15，H-16)
Embodiment 6
17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone
Step 1
3 β-17a-diacetoxy-D-height-5 α-androstane-15, the 17-diene
With 3 β-acetoxyl group-D-high androstane-5 of 14.5g, 16-diene-17a-ketone is dissolved in 200ml diacetyl oxide and the 200ml acetate pseudoallyl ester.After adding the tosic acid of 5.0g, refluxed 16 hours.This material ethyl acetate extraction, organic phase is washed with saturated nacl aqueous solution, and dry on sal epsom, filters, and evaporation concentration carry out chromatographically pure system then on silica gel.Obtain 3 β-acetoxyl group-17a-acetoxyl group-D-height-5a-androstane-15, the 17-diene.
1H-NMR(CDCl 3)：0.82(s，3H，H-18)，0.92(s，3H，H-19)，2.02(s，3H，Oac)，2.17(s，3H，＝Ac)，4.68(m，1H，H-3)，5.60-5.92(m，3H，H-15，H-16，H-17)
Step 2
3 β-acetoxyl group-17a beta-hydroxy-D-height-5 α-androstane-15-alkene
With 3 β of 8.5g, 17a-diacetoxy-D-height-5 α-androstane-15, the 17-diene is dissolved among the THF of 360ml methyl alcohol and 270ml.When-20 ℃ are stirred down, the NaBH of portion-wise addition 6.75g 4, and under 0 ℃, stirred 2 hours.Add the saturated NH of 200ml 4Cl solution, and under 0 ℃, stirred 2 hours.Add the saturated NH of 200ml 4Cl solution.Distill organic solvent.After adding 100ml water, filter this material, wash with water, vacuum-drying carry out chromatographically pure system then on silica gel.Obtain 3 β-acetoxyl group-17 α beta-hydroxy-D-height-5 α-hero-15-alkene.
1H-NMR(CDCl 3)：0.76(s，3H，H-18)，0.83(s，3H，H-19)，2.02(s，3H，OAc)，3.53(m，1H，17a-H)，4.69(m，1H，H-3)，5.60-5.65(m，2H，H-15，H-16)
Step 3
3 β-acetoxyl group-D-height-5 α-hero-15-alkene-17a beta-tetrahydro pyranyl ether
3 β-acetoxyl group-17-ab-hydroxyl-D-height-5a-hero-15-alkene of 7.60g is dissolved in the 135ml methylene dichloride.Under stirring at room, add 13.5ml dihydropyrane and 900mg pyridine tosylate in order.After 3 hours, use 10%NaHCO 3Solution and saturated NaCl solution washing, dry on sal epsom, filter and evaporation concentration.Obtain 3 β-acetoxyl group-D-high androstane-5,15-diene-17a beta-tetrahydro pyranyl ether.
Step 4
3 beta-hydroxies-D-height-5 α-hero-15-alkene-17a beta-tetrahydro pyranyl ether
3 β-acetoxyl group-D-height-5 α-hero-15-alkene-17a beta-tetrahydro pyranyl ether of 12.0g is dissolved among the THF of 150ml methyl alcohol and 100ml.Under the vigorous stirring, add the K of 15g 2CO 3With 5ml water.3.5 after hour, evaporation concentration washes with water and vacuum-drying to about 1/6.Obtain 3 beta-hydroxies-D-height-5 α-hero-15-alkene-17a beta-tetrahydro pyranyl ether.
Step 5
3-ketone group-D-height-5 α-hero-15-alkene-17a beta-tetrahydro pyranyl ether
3 beta-hydroxies-D-height-5 α-hero-15-alkene-17-a beta-tetrahydro pyranyl ether with 9.2g under argon atmospher is dissolved in the 200ml toluene.Add the Al (O-iPr) of 3.0g 3After, heated 1.5 hours to 110 ℃.Under the room temperature, the 1M potassium sodium tartrate solution with 250ml washs 2 times respectively.Containing the water hydration extracts again with ethyl acetate.The organic phase that merges is washed with saturated nacl aqueous solution, and is dry on sal epsom, and filtering also, vacuum-evaporation concentrates.Obtain 3-ketone group-D-height-5 α-hero-15-alkene-17a beta-tetrahydro pyranyl ether.
Step 6
17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone
3-ketone group-D-height-5 α-hero-15-alkene-17-a beta-tetrahydro pyranyl ether crude product of 15.7g is dissolved in the 100ml acetone.Under the room temperature, drip 10% hydrochloric acid of 10ml.After 2 hours, add the saturated NaHCO of 50ml 3Solution.The evaporation concentration reaction mixture is to about 1/3.Add 150ml water, and filter out sedimentary material, wash with water, vacuum-drying also carry out chromatographically pure system on silica gel.Obtain 17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone.
1H-NMR(CDCl 3)：0.76(s，3H，H-18)，1.02(s，3H，H-19)，3.53(m，1H，H-17a)，5.57-5.65(m，2H，H-15，H16)
Embodiment 7
2-hydroxyl methylene radical-17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone
Under shielding gas, 17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone of 2.1g is introduced in the 80ml toluene, added NaOH and the 4.0ml ethyl formate of 2.1g.After 1 hour, drip 2ml methyl alcohol.Add 50ml water, carry out acidifying with 5N HCl then.Use ethyl acetate extraction.Organic phase NaHCO 3Solution washing, dry on sal epsom, filter and evaporation concentration.On silica gel, carry out chromatographically pure system.Obtain 2-hydroxyl methylene radical-17-a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone.
1H-NMR(CDCl 3)：0.78(s，3H，H-18)，0.79(s，3H，H-19)，3.55(m，1H，H-17a)，5.55-5.67(m，2H，H-15，H16)，8.64(s，1H，＝CH(OH))，14.37(s，1H，＝CH(OH))

Claims (21)

1, the Δ of general formula (I) 15-D-homosteroid:
Wherein
R 1Represent C 1-4-alkyl, and
R 2Representation hydroxy, group OC (O)-R 20, OC (O) NH-R 20Or OR 20, R wherein 20Represent C 1-12-alkyl, C 3-8-cycloalkyl, aryl or aryl-C 1-4-alkyl, these groups are optional to be substituted,
And
R 3Represent hydrogen atom or C 1-6-alkyl, vinyl, ethynyl or C nF 2n+1Group, n=1,2,3 wherein, and
R 4Represent hydrogen atom,
Perhaps
R 2Represent hydrogen atom or C 1-6-alkyl, vinyl, ethynyl or C nF 2n+1Group, n=1,2,3 wherein,
R 3Representation hydroxy, group OC (O)-R 20, OC (O) NH-R 20Or OR 20, R wherein 20Represent C 1-12-alkyl, C 3-8-cycloalkyl, aryl or aryl-C 1-4-alkyl, these groups are optional to be substituted,
And
R 4Represent hydrogen atom,
Perhaps
R 2And R 3Represention oxygen atom together, and
R 4Represent hydrogen atom,
Perhaps
R 2Representation hydroxy, group OC (O)-R 20, OC (O) NH-R 20Or OR 20, R wherein 20Represent C 1-12-alkyl, C 3-8-cycloalkyl, aryl or aryl-C 1-4-alkyl, these groups are optional to be substituted,
And
R 3And R 4Form two keys together, and
STEROID represents the steroid ABC part ring system of formula A, B, C, D, E and F:
Figure A2004800240120003C1
Wherein in A and C in 1, can there be extra two keys in the 2-position, and in B in 9, can there be one or two extra two keys in 10-position and 11,12-position,
R 7Represent hydrogen atom, halogen atom, hydroxyl or C nF 2n+1Group, n=1,2,3 wherein,
X represention oxygen atom, two hydrogen atoms or oxyimino,
R 8Represent hydrogen atom, methyl or ethyl,
R 9Represent hydrogen atom or halogen atom, perhaps with R 10Represent two keys together,
R 10Represent hydrogen atom, hydroxyl, methyl or ethyl, perhaps with R 9Represent two keys together,
R 11Represent hydrogen atom, C 1-4-alkyl, itrile group, hydroxyl methylene radical or formyl radical,
R 12Represent hydrogen atom, C 1-4-alkyl or itrile group,
R 11And R 12, except that above-mentioned definition, represent methylene bridge together,
R 13Represent hydrogen atom or and R 7Represent two keys together,
R 16Represent hydrogen atom or and R 13Represent two keys together,
R 15Representation hydroxy, R 14And R 15Represent hydrogen atom or together the two keys of representative, [2,3c] oxadiazole ring,
[3,2c] isoxazole ring or [3,2c] pyrazoles ring,
R 17Represent hydrogen atom or methyl,
Y represention oxygen atom or nitrogen-atoms,
R 4, R 7, R 8, R 11, R 12, R 13, R 14And R 15It can be to be in α-or β-position that the setback line at place is represented these substituting groups.
2, compound as claimed in claim 1, wherein R 1Represent methylidene or ethyl.
3, compound as claimed in claim 1 or 2, wherein R 2Representation hydroxy, methanoyl, acetoxyl group, propionyloxy, butyryl acyloxy, [(trans-4-butyl cyclohexyl) carbonyl] oxygen base, phenyl propionyl oxygen base, isobutyryl oxygen base, heptyl oxygen base, undecyl oxygen base or phenyl amino ketonic oxygen base.
4, as the described compound of one of claim 1-3, wherein R 3Represent methylidene, trifluoromethyl, ethyl, pentafluoroethyl group or ethynyl.
5, as the described compound of one of claim 1-4, wherein R 4Represent hydrogen atom.
6, as the described compound of one of claim 1-5, wherein STEROID represents the steroid ring system of segment bounds A, wherein R 7Represent hydrogen atom, chlorine atom, bromine atoms, hydroxyl or trifluoromethyl, R 10Represent hydrogen atom, hydroxyl or methyl, R 9Represent hydrogen atom or fluorine atom, and R 8Represent hydrogen atom or methyl.
7, as the described compound of one of claim 1-5, wherein STEROID represents the steroid ring system of segment bounds B, wherein R 7Represent hydrogen atom, chlorine atom, bromine atoms, hydroxyl or trifluoromethyl, and R 8Represent hydrogen atom or methyl.
8, as the described compound of one of claim 1-5, wherein STEROID represents the steroid ring system of segment bounds C, wherein R 7Represent hydrogen atom, chlorine atom, bromine atoms or hydroxyl or trifluoromethyl, and R 11, R 12Represent hydrogen atom respectively, and two key is present in 1, the 2-position.
9, as the described compound of one of claim 1-5, wherein STEROID represents the steroid ring system of segment bounds D, wherein R 7Represent hydrogen atom, chlorine atom, bromine atoms or hydroxyl or trifluoromethyl, R 8Represent hydrogen atom or methyl, R 13And R 7Represent two keys together, and the Y represention oxygen atom.
10, as the described compound of one of claim 1-5, wherein STEROID represents the steroid ring system of segment bounds E, wherein R 8Represent hydrogen atom or methyl, R 12Represent hydrogen atom, R 13And R 16Represent hydrogen atom respectively or represent two keys, R together 15Representation hydroxy, perhaps R 14And R 15Represent [3,2c] pyrazoles ring together.
11, as the described compound of one of claim 1-5, wherein STEROID represents the steroid ring system of segment bounds F, wherein R 11Represent C 1-4-alkyl or itrile group.
12, as the described compound of one of claim 1-11, it is:
1) 17a beta-hydroxy-D-height-androstane-4,15-diene-3-ketone,
2) 17a β, 4-dihydroxyl-D-height-androstane-4,15-diene-3-ketone,
3) 17a beta-hydroxy-4-chloro-D-height-androstane-4,15-diene-3-ketone,
4) 17a beta-hydroxy-4-bromo-D-height-androstane-4,15-diene-3-ketone,
5) 17a beta-hydroxy-4-trifluoromethyl-D-height-androstane-4,15-diene-3-ketone,
6) 17a β, 11 beta-dihydroxyies-D-height-androstane-4,15-diene-3-ketone,
7) 17a β, 11 beta-dihydroxyies-D-height-9 α-fluoro-androstane-4,15-diene-3-ketone,
8) 17a beta-hydroxy-D-height-androstane-1,4,15-triolefin-3-ketone,
9) 17a beta-hydroxy-D-height-4-chloro-androstane-1,4,15-triolefin-3-ketone,
10) 17a β, 4-dihydroxyl-D-height-androstane-1,4,15-triolefin-3-ketone,
11) 17a beta-hydroxy-7 Alpha-Methyls-D-height-androstane-1,4,15-triolefin-3-ketone,
12) 17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-androstane-1 ,-4,15-triolefin-3-ketone,
13) 17a beta-hydroxyl-17 alpha-methyl-androstane-4,15-diene-3-ketone,
14) 17a beta-hydroxyl-17 a-trifluoromethyl-7 Alpha-Methyls-androstane-4,15-diene-3-ketone,
15) 17a β, 4-dihydroxyl-17a α-trifluoromethyl-androstane-4,1-5-diene-3-ketone,
16) 17a beta-hydroxyl-17 a α-trifluoromethyl-4-chloro-androstane-4,15-diene-3-ketone,
17) 17a beta-hydroxy-7 Alpha-Methyls-D-height-androstane-4,15-diene-3--ketone,
18) 17a beta-hydroxyl-17 alpha-pentafluoroethyl group-androstane-4,15-diene-3-ketone,
19) 17a beta-hydroxy-D-height-female-4,15-diene-3-ketone,
20) 17a β, 4-dihydroxyl-D-height-female-4,15-diene-3-ketone,
21) 17a beta-hydroxy-4-chloro-D-height-female-4,15-diene-3-ketone,
22) 17a beta-hydroxy-4-bromo-D-height-female-4,15-diene-3-ketone,
23) 17a beta-hydroxy-4-trifluoromethyl-D-height-female-4,15-diene-3-ketone,
24) 17a beta-hydroxyl-17 a Alpha-Methyl-D-height-female-4,15-diene-3-ketone,
25) 17a beta-hydroxyl-17 a Alpha-Methyl-4-chloro-D-height-female-4,15-diene-3-ketone,
26) 17a Alpha-hydroxy-17a α-trifluoromethyl-D-height-female-4,15-diene-3-ketone,
27) 17a beta-hydroxyl-17 a α-pentafluoroethyl group-D-height-female-4,15-diene-3-ketone,
28) 17a beta-hydroxy-7 Alpha-Methyls-D-height-female-4,15-diene-3-ketone,
29) 17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-female-4,15-diene-3-ketone,
30) 17a beta-hydroxy-D-height-female-1,4,15-triolefin-3-ketone,
31) 17a beta-hydroxy-D-height-4-chloro-is female-1,4,15-triolefin-3-ketone,
32) 17a β, 4-dihydroxyl-D-height-female-1,4,15-triolefin-3-ketone,
33) 17a beta-hydroxy-7 Alpha-Methyls-D-height-female-1,4,15-triolefin-3-ketone,
34) 17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-female-1,4,15-triolefin-3-ketone,
35) 13-ethyl-17a beta-hydroxy-D-height-gona-4,15-diene-3-ketone,
36) 13-ethyl-17a beta-hydroxy-4-chloro-D-height-gona-4,15-diene-3-ketone,
37) 13-ethyl-17a beta-hydroxy-7 Alpha-Methyls-D-height-gona-4,15-diene-3-ketone,
38) 13-ethyl-17a beta-hydroxyl-17 alpha-methyl D-Gao-gona-4,15-diene-3-ketone,
39) 13-ethyl-17a beta-hydroxyl-17 alpha-methyl-4-chloro-D-height-gona-4,15-diene-3-ketone,
40) 13-ethyl-17a beta-hydroxy-D-height-gona-1,4,15-triolefin-3-ketone,
41) 13-ethyl-17a beta-hydroxy-4-chloro-D-height-gona-1,4,15-triolefin-3-ketone,
42) 13-ethyl-17a beta-hydroxy-7 Alpha-Methyls-D-height-gona-1,4,15-triolefin-3-ketone,
43) 13-ethyl-17a beta-hydroxy-7 Alpha-Methyls-4-chloro-D-height-gona-1,4,15-triolefin-3-ketone,
44) 17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone,
45) 2-oxa--17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone,
46) 17a beta-hydroxy-D-height-5 α-androstane-1,15-diene-3-ketone, or
47) 2-hydroxyl methylene radical-17a beta-hydroxy-D-height-5 α-hero-15-alkene-3-ketone.
13, preparation is as the method for the described general formula of one of claim 1-12 (I) compound and the acceptable salt of pharmacology thereof,
The compound of general formula I I wherein
Figure A2004800240120007C2
R wherein 1Define with STEROID such as claim 1-12,
In the presence of acid,,, reduce with reductive agent then, obtain corresponding 17a beta-hydroxy-D-height-Δ to form the dienol acetic ester with the acetylizing agent reaction 15-steroide is introduced then as defined substituent R among the claim 1-12 1, R 2, R 3And R 4
14, method as claimed in claim 13, wherein when preparation has the general formula I I compound of part-structure A-F, use following steroid parent:
A: hero-4-alkene-3,17-diketone and dehydroepiandrosterone,
B: oestrone, 7 Alpha-Methyl oestrone,
C, D and E: epiandrosterone, and
F: the 5 α-hero-2-alkene-17-ketone that is obtained from epiandrosterone.
15, as claim 13 or 14 described methods, wherein contained functional group is protected in the part-structure of the parent material of steroid parent A-F.
16, method as claimed in claim 15, wherein the ketone group in the parent material of part-structure A-F is protected with the form of ketal or sulfo-acetal.
17, pharmaceutical composition, it comprises at least a as the described compound of one of claim 1-12.
18, be used for the application of medicine of the Hormone Replacement Therapy of masculinity and femininity in preparation as the described compound of one of claim 1-12.
19, be used for the application of medicine of the Birth control of masculinity and femininity in preparation as the described compound of one of claim 1-12.
20, be used for the treatment of application in the medicine of the disease that the hormone of masculinity and femininity brings out as the described compound of one of claim 1-12 in preparation.
21, application as claimed in claim 20, it is the medicine that preparation is used for the treatment of endometriosis, mammary cancer and hypogonadism.
CNA2004800240122A 2003-08-21 2004-08-19 New delta-15-d-homosteroid compounds having an androgenic effect Pending CN1839146A (en)

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US4155918A (en) * 1976-10-28 1979-05-22 Hoffmann-La Roche Inc. Novel D-homosteroids

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