MXPA99005771A - Meiosis regulating compounds - Google Patents
Meiosis regulating compoundsInfo
- Publication number
- MXPA99005771A MXPA99005771A MXPA/A/1999/005771A MX9905771A MXPA99005771A MX PA99005771 A MXPA99005771 A MX PA99005771A MX 9905771 A MX9905771 A MX 9905771A MX PA99005771 A MXPA99005771 A MX PA99005771A
- Authority
- MX
- Mexico
- Prior art keywords
- diol
- hydroxy
- hydrogen
- halogen
- cholestan
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 262
- 230000021121 meiosis Effects 0.000 title claims abstract description 57
- 230000001105 regulatory Effects 0.000 title claims abstract description 16
- 210000000287 oocyte Anatomy 0.000 claims abstract description 52
- 210000003794 male germ cell Anatomy 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 120
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 110
- 239000001257 hydrogen Substances 0.000 claims description 108
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 88
- 229910052736 halogen Inorganic materials 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 150000002367 halogens Chemical class 0.000 claims description 65
- 150000002431 hydrogen Chemical class 0.000 claims description 55
- 125000004043 oxo group Chemical group O=* 0.000 claims description 52
- 229910052799 carbon Inorganic materials 0.000 claims description 51
- -1 methylene, hydroxy, methoxy, acetoxy Chemical group 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 17
- 150000003432 sterols Chemical group 0.000 claims description 17
- 210000004602 germ cell Anatomy 0.000 claims description 16
- 235000003702 sterols Nutrition 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 210000004027 cells Anatomy 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 150000002009 diols Chemical class 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 5
- 230000018046 regulation of meiosis Effects 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 4
- NIJCHQWGAFQPFT-GYKMGIIDSA-N (8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-8,9,11,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 NIJCHQWGAFQPFT-GYKMGIIDSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-M succinate(1-) Chemical compound OC(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-M 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- LEVKXKUKAMIEMX-XWAVZNOASA-N (4S,5R,8S,9S,10R,13R,14S,17R)-4-hydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one Chemical compound O[C@@H]([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 LEVKXKUKAMIEMX-XWAVZNOASA-N 0.000 claims description 2
- CMNWLRQKTRKSQO-QWMOJLDXSA-N (6R)-2-hydroxy-6-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-one Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(=O)C(C)(C)O)C)[C@@]1(C)CC2 CMNWLRQKTRKSQO-QWMOJLDXSA-N 0.000 claims description 2
- QLSIXUFIFMZEEO-FNOPAARDSA-N (8S,9S,10R,13R,14S,17R)-3-chloro-10,13-dimethyl-17-[(2R)-6-methylhept-5-en-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene Chemical compound C1C=C2CC(Cl)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC=C(C)C)C)[C@@]1(C)CC2 QLSIXUFIFMZEEO-FNOPAARDSA-N 0.000 claims description 2
- 230000002381 testicular Effects 0.000 claims description 2
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- 239000011647 vitamin D3 Substances 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 6
- CBMYJHIOYJEBSB-YSZCXEEOSA-N 5α-Androstane-3β,17β-diol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 CBMYJHIOYJEBSB-YSZCXEEOSA-N 0.000 claims 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 3
- HONQRLPRSAESGO-JOSISPIVSA-N (6R)-6-[(3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-one Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]2(C)CC1 HONQRLPRSAESGO-JOSISPIVSA-N 0.000 claims 2
- QJAZTHBZCSAVQS-JOVRKVRASA-N (6R)-6-[(8S,9S,10R,13R,14S,17R)-3-chloro-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-one Chemical compound C1C=C2CC(Cl)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]1(C)CC2 QJAZTHBZCSAVQS-JOVRKVRASA-N 0.000 claims 2
- APRTUYUNMHTWBF-REEZCCHISA-N (8S,9S,10R,13R,14S,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCCC(C)(C)O)C)[C@@]1(C)CC2 APRTUYUNMHTWBF-REEZCCHISA-N 0.000 claims 2
- 125000004429 atoms Chemical group 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- YXNATFVXXASJRS-XXTBIHTDSA-N (3R,5R,6S,8S,9S,10R,13R,14S,17R)-17-[(2R)-5-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,6-diol Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCC(O)C(C)C)[C@@]2(C)CC1 YXNATFVXXASJRS-XXTBIHTDSA-N 0.000 claims 1
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Abstract
Certain compounds, structurally related to natural compounds which can be extracted i.a. from bull testes and from human follicular fluid, can be used for regulating the meiosis in ovocytes and in male germ cells.
Description
REGULATORY COMPOUNDS OF THE EIOSIS
FIELD OF THE INVENTION
The present invention relates to pharmacologically active compounds and their use as medicaments. More particularly it has been found that the sterol derivatives described herein can be used to regulate meiosis.
BACKGROUND OF THE INVENTION
In L.F. Fieser and M. Fieser: Steroids; Reinhold Publishing Corporation, 1967, the compounds 5a-bromocholesterol-3/3, 6/3-diol are mentioned in the subject index; 7o.-bromocolestan-3/3, doi-diol; 7o.-bromocholesterol-3jS, 6/3-diol; 7o-bromocholesterol-3/3, 5a-diol-6-one; 7/3-bromocholesterol-33, 5c-diol-6-one; 38-bromocholesterol-2?! - ol; 5a-chlorocholesterol-3/3, 6o; -diol; 5-chlorocholesterol-33,63-diol; 6/3-chlorocholesterol-3/3, 5-diol; ? 7.9 (11) -cystetadiene-3/3, 6/3-diol; 7'9 (11) cholestadien-3/3, 6/3-diol, cholestan-2o;, 3o-diol; cholestan-2ai, 33-diol; cholestan-23, 3o-diol; cholestan-2/3, 3/3-diol; cholestan-3a-, 4a-diol; cholestan-3a !, 4/3-diol; cholestan-3 / ?, 4? -diol; cholestan-3o-5o-diol; cholestan-3/3, 5a; -diol; cholestan-3β, 6?! -diol; cholestan-33, 6/3-diol; cholestan-3 / 322a; -diol; cholestan-3 / 3,22 / 3-diol; cholestan-3/3, 7Q, 8?! - riol; 5-cholesten-3/3, 4a-dio ?;
REF. 30458? S-cholesten-3 / 3,4 / 3-diol; 5-cholesten-33, 20ce-diol; ? s-cholesten-3/3, 22o! -diol; 5-cholesten-3/3, 22 / β-diol; 5-cholesten-3/3, 24a; -diol; ? s-cholesten-3 / 3,243-diol; 6-cholesten-3/3, 5o; -diol; ? 8 (1) -cholesterol-3β, 9?! -diol; ??: L-cholesten-3Q-, 24-diol; ? s-cholesten-33,6-diol-7-one; 5-cholesten-4a; -ol-3-one; ? s-cholesten-3/3, 4/3, 7a; -triol; coprostan-3a; 5/3-diol; coprostan-3/3, 5β-diol; coprostan-3/3, 6/3-diol; coprostan-4/3, 5 / d-diol-3-one and 20/3-hydroxy-20-isocholesterol. In the German patent application having publication No. 1,183,079, a process for preparing 4a-hydroxy-5a-cholestan-3-one is mentioned in Example 5. It is not established that this compound has another utility than as an intermediary. In the German patent application having publication No. 1,224,738, are mentioned in Examples 1-5, respectively, cholestan-3/3, 5a; -6j6-triol-3/3-hemisuccinate; cholestan-3/3, 5OÍ, 6/3-triol-3/3-hemisuccinate-6? -acetate; cholestan-3/3, 5o;, 6/3-triol-3/3-hemisuccinate-6/3-formate; cholestan-3/3, 5CÜ, 6β-triol-3j6-sulfate and cholestan-3/3, 5o-, 6/3-triol-3 / β-phosphate, respectively. It is mentioned that the compounds described in that document can be used for the treatment of arteriosclerosis. In the German patent application having publication No. 2,201,991 C2, a process for the preparation of insecticides such as 2/3, 3/3, 14a, 22 (R), 25-pentahydroxicolest-7-en-6- is described. ona The German patent application having publication No. 2,236,778 B2 relates to a novel insecticide, ie, colest-7-in-2/3, 3/3, 5/3, lio;, 14o;, 20 (R) , 22 (R) -heptahydroxy-6-one. In the German patent application having publication No. 2,409,971 B2, mention is made in the examples 1,1,2,3,3 and 6, respectively to 5,24-cholestadien-3/3-ol; 5-cholesten-3/3, 24, 25-triol-3/3-acetate, -5-cholesten-3/3, 24, 25-triol-3β, 24-diacetate; 5, 25-cholestadien-3/3-ol acetate; 5-cholesten-3/3, 25, 26-triol-3/3-acetate and 5-cholesten-3/3, 25, 26-triol. It is mentioned "that the compounds described in that document are valuable intermediates for the technical preparation of 24 to 25 (or 25 to 26) -dihydroxycholecalciferol. In the German patent application having publication No. 2,453,648 B2, colest-5c-an-3 / 3,6-diol is mentioned as intermediates in column 6; cholest-5/3-an-3/3, 6/3-diol; cholest-5o; -an-3,6-dione; cholest-5o; -an-6/3-ol-3-one and cholest-5o; -an-2Q! -bromo-6/3-ol-3-one. In the German patent application having publication No. 2,415,676, mention is made of cholestan-3 / ?, 25-diol-3 / d-acetate; cholestan-3/3, 5o;, 25-triol-3/3-acetate; cholestan- 3/3, 5o !, 25-triol; cholestan-5o;, 25-diol-3-one; cholest-4-en-25.-ol-3-one and cholesta-4, 6-dien-25-ol-3-one, compounds III, IV, X, XI, XII and XIII, respectively. It is suggested that the compounds described in that document may be substantially stronger than vitamin D3. In the German patent application having publication No. 2,546,715 Al, a process is mentioned to prepare the;, 3 /? - dihydroxycholest-5-ene and the;, 3/3-dihydrocolest-6-ene in Example 1, (compounds V and II). It is suggested that the compounds described in that document are useful additives for food products and that they can be used in vitamin compositions. In the German patent application having publication No. 2,822,486 Al, 3CÜ, 6a-dihydroxy-5/3-cholestan-24-one are mentioned; 3o;, 6o;, 24-trihydroxy-5/3-cholestan; 3-chlorocholest-5, 24-diene; 3/3-hydroxycholest-5-en-24-one acetate and 3-chlorocolest-5-en-24-one in Examples 3, 4, 5a and 6c, and as the formula VII, respectively. It is mentioned that the compounds described in that document can be used as intermediates for the preparation of osterin, derivatives thereof and another active vitamin D. In the German patent application of the publication No. 3,241,172 Al, cholestan-25-fluoro-3 / 3,22 (S) -diol is mentioned; cholestan-25-chloro-3/3, 22 (S) -diol; cholestan-25-met il -3jS, 22-diol; cholestan-25-methyl-3/3, 22-diol-3-hydrogenbutanediolate and cholestan-25-methyl-3/3, 22-diol- £ > is-hydrogenbutanedioate in claims 2, 3, 5, 6 and 7, respectively. It is mentioned that the compounds described therein inhibit the activity of HMGCOA reductase and the formation of blood cholesterol. In the German patent application having publication No. 3,390,016 C2, a process for preparing the;, 25-dihydroxy- 26, 26, 26, 27, 27, 27-hexfluoro-5-ene-is described. It is mentioned that this compound can be easily converted into a compound having vitamin D3-like activity. In the Danish patent application having publication No. 123,767, a process for preparing 2/3, 3/3, 14a,, 22, 25-pentahydroxy-? 7-5 / 3-cholesten-6-one is mentioned. It is mentioned that the compounds described therein have an action on the central nervous system. • "'In the European patent application having publication No. 15,122 Bl, the compounds 25-hydroxy-3 / 3- [(tetrahydro-2H-pyran-2-yl) oxy] cholest-5-en- 24-one; 3/3 [(Tetrahydro-2H-pyran-2-yl) oxy] -colest-5-en-24-one; 25-hydroxy-24-oxolenes terol- 3/3 -acetate; terol -3 / 3-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3c ?, 6o;, 25-trihydroxy-24-oxo-5/3-cholestane; the, 25-dihydroxy-24- oxocholesterol; l -, 24, 25-trihydroxycholesterol, - 3/3-hydroxy-24-oxocholesterol-5, 7-diene; 3/3, 25-dihydroxy-24-oxocholesterol-5, 7-diene; 3/3 - hydroxy -24-oxo-cholesta-5, 7-diene; 3, 3-dihydroxy-24-oxocholesterol-5, 7-diene and lo;, 3jS, 25-trihydroxy-24-oxo-cholesta-5,7 -I think in the examples 1, 1, 4, 4, 5ii, 5 (1), 6i, 7, 7 (2), 8iii, 8iv, 8iv, 9iii and 9iv, respectively.It is mentioned that the compounds described in that document they are useful intermediaries convertible into active vitamin D. In the European patent application that has publication No. 63.6 78 Bl, compounds (24R) -3 / 3,24,25-trihydrocolest-5-ene are mentioned; (24RS) -3/3, 24,25-trihydroxicolest-5-en and (24R) -Iß, 3 / 3,24, 25-tetrahydroxycholest-5-ene in examples le, 3e and 4f, respectively. It is mentioned that the compounds described in that document can be used as intermediates in the preparation of vitamin D3 derivatives. In the European patent application having publication No. 322.036 Al, the compounds 4,4-dimethyl-24-methylene-3 / 3- sulf oxy-12a; -acetoxicolesta-8, 14-dien-2o; / 3-diol; 4,4-dimethyl-24-methylene-3/3-sulfooxi-12a; -acetoxycholest-8-en-2o-, 11/3-diol; 4, 4-dimethyl-24-methylene-12o-acetoxycholesta-8,14-diene-2a;, 3/3, ll / 3-triol; 4, 48-dimethyl-24-methylene-12a; -acetoxy-cholesta-8, 14-diene-3/3, 11/3-diol; 4, 4-dimethyl-24-methylene-12a; -acetoxycholest-8-en-2o;, 3β, 11/3-triol; 4, 4-dimethyl-24-methylene-12 [beta] -acetoxicolest-8-en-3/3, 11/3, 12 [beta] -diol; 4, 4-dimethyl-24-methylenecholest-8-en-2, 3/3, 11/3, 12th; -tetraol; 4, 4-dimethyl-24-methylene-3/3-sulfo-oxoles-8, 14-diene-2o-, 11/3, 12a-riol; 4,4-dimethyl-24-methylenecholesterol-8, 14-dien-2?!, 3/3, 11/8, 12a; -tetraol; 4,4-dimethyl-24-methylene-3/3-sulfooxi-12o; -acetoxicolest-8-en-2-ol-lione and mono (4,4-dimethyl-24-methylene-12?! -acetoxicolesta-8,14-dien-2o;, ll / 3-diol) -3ß- succinate in Tables I (1 + 2), II (5-9) and III (11-14). It is mentioned that the compounds described in that document are anti-inflammatory. In the European patent application having the publication No. 349,869 A2, the compounds lo;, 3/3-dihydroxicolest-5-ene and lo;, 3/3, 24-trihydroxycholest-5-ene are mentioned in Examples 1 and 2, respectively. It is mentioned that this last compound is useful for the production of Ice, 24-dihydroxy-vitamin D3. In the United Kingdom patent application having publication No. 2,089,810 A, there is mentioned cholesta-5, 7-dien-3 / 3,23 (R), 25-triol and cholesta-5, 7-dien-3/3 , 23 (S), 25-triol in Example 1. It is mentioned that the compounds described in that document can find application as a substitute for 25-hydroxy vitamin D3 in various therapeutic applications. In the Norwegian patent application having publication No. 144,264, there is mentioned;, 3/3-dihydroxy-cholest-5-ene and lo;, 3/3, 25-trihydroxycholest-5-ene in Examples 1 and 3 , respectively. It is mentioned that the compounds described in that document can be used within the veterinary field. In the Swedish patent application having publication No. 314,978, a process is used in which? 7-cholesten-2/3, 3/3-diol-6-one is used as starting material (for the preparation of? 7- coprosten-2/3, 33, 14o; -triol-6-one) and is described in Example 3. The latter compound is active against metamorphosis hormones in insecticides. In the Swedish patent application having the publication No. 330,883, 2/3, 3/3, 14o, 22 (R), 25-pentahydroxy-? 7-5 / 3-cholesten-6-one and 2 are mentioned. / 3, 3/3, 14o;, 22 (S), 25-pentahydroxy-? 7-5 / 3-cholesten-6-one in Examples 4 and 5, respectively. It is mentioned that the compounds described herein have valuable pharmacological properties, however, none is specified. In the Swedish patent application, which has the publication No. 430,508, mention is made of colest-5-in-33, 22 (R, S), 25-triol; cholest-5-en-25-fluoro-3/3, 22 (R, S) -diol; cholest-5-en-25-fluoro-22 (R, S) -ol-3/3-semisuccinate; cholest-5-en-25-chloro-3/3, 22-diol and cholest-5-en-25-chloro-22-ol-3/3-hemisuccinate in Examples 5, 8, 9, 11 and 12, respectively. It is mentioned that the compounds described in that document have pharmaceutical activities, for example they inhibit (HMG-CoA) reductase. In the United States patent specification
No. 3,931,403, 3CÜ, 7o;, 12o;, 24, 25-pentahydroxy-coprostane; 3Q, 7o;, 12o;, 25-tetrahydroxy-coprostane; 3a; 7a; 25-trihydroxy-coprostane; 3a;, 7a; -24,25-tetrahydroxy-coprostane; 5/3-cholestan-3o;, 7o;, 12o;, 24o;, 25-pentol; 5/3-cholestan-3a;, 7o;, 12o;, 24/3, 25-penthol; 5/3-cholestan-3o;, 7o;, 12a;, 25, 26-pentol and 5 / d-cholestan-3o;, 7o;, 12o;, 25-tetrol in Example I and II. It is mentioned that the compounds described in that document can be used to prepare a composition having antimicrobial, antibiotic and bacteriostatic properties. In the United States patent specification
No. 4,011,250, 2o;, 3/3-trihydroxicolesta-5, 7-diene and 1; 2-dihydroxy-3/3-acetoxycholesta-5-ene are described as intermediates in Example 1 and 3, respectively. In U.S. Patent Specification No. 4,254,045, colest-5-en-2/3-fuoro-l, 3/3-diol is mentioned as compound 3. It is mentioned that the compounds described in that document have activity similar to vitamin D. In the United States patent specification No. 4,329,295, the preparation of 24-cyclopropylchol-5-en-3 / S, 22 (S) -diol-3-acatate, 24-cyclopropylcol is described. -5-en-3/3, 22 (S) -diol, 24-cyclopropylcol-5-en-3/3, 22 (S) -diol 3 hydrogen butanedioate and 24-cyclopropyl-5o; -colan-3/3 , 22 (S) -diol in Examples 3-6, respectively. It is mentioned that the compounds described in that document inhibit the activity of HMG Co A reductase. In the United States Patent Specification No. 4,670,190, cholesta-1,4,6-trien-3 -one is described; Ice, 3/3-dihydroxycholest-5-ene; lo;, 3/3-dihydroxy-5-cholestan; Ice, 3/3-dihydroxycholesta-5, 7-diene; lo;, 3 / 3-25-trihydroxycholest-5-ene; lo;, 25-dihydroxycholesterol; and Ice, 25-dihydroxy-cholesterol-3-benzoate in Examples la, 1c, 2b ', 3c, 4c, 9b and 9c, respectively. It is mentioned that the compounds described in that document have therapeutic applications. Other known compounds are colest-5-en-3/3, 20 (S) -diol (Sigma, St. Louis, Mo. USA, Cat. No. H 6378), colest-5-en-3 / 3.22 (S) -diol, (Sigma, St. Louis, Mo, USA, Cat. No. H 5884), colest-5-en-3 / 3,4 / 3-diol (Steraloid Inc., ilton, NH, USA , Cat. No. C 6410, Batch L 1066), colest-5-en-3β, 22 (R) -diol (Sigma, St. Louis, Mo. USA, Cat. No. H 9384) and 2/3, 3/3, 14ce, 22 (R), 25-pentahydroxicolest-7-en-6-one. In none of the previous publications is there a mention of "that the compounds are capable of regulating meiosis. The content of the previous publications is incorporated as a reference. Meiosis is the unique and final event of the germ cells on which reproduction is based. Meiosis comprises two meiotic divisions. During the first division, the exchange between maternal and paternal genes takes place before the pairs of chromosomes in the two daughter cells are separated. These contain only half the amount (ln) of chromosomes and DNA 2c. The second major meiotic division proceeds without DNA synthesis. Therefore, this division results in the formation of aploid germ cells only with DNA.
The meiotic phenomena are similar in male and female germ cells, but the protocol in time and the processes of differentiation which lead to the ovum and sperm differ profoundly. All female germ cells enter the prophase of the first meiotic division at the beginning of life, often before birth, but all are suppressed as oocytes later in the prophase (dictiato state) to ovulation after puberty. Therefore, from early life, females have an accumulation of oocytes which is extracted until the accumulated is finished. Meiosis in women is not complete until after fertilization, and results in only one egg and two abortive polar bodies per germ cell. In contrast, only part of the male germ cells enter meiosis from puberty and leave in the pluripotent population of the germ cells during life. Once started, meiosis in male cells is carried out without significant delay and produces 4 sperm. Little is known about the mechanisms which control the onset of meiosis in men and women. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, may be responsible for meiotic suppression (Downs, S.M. et al., Dev Biol 82 (1985) 454-458).; Eppig, J. J. et al. Dev Biol 119 (1986) 313-321; and Downs, S.M. Mol. Reprod Dev 35 (1993) 82-94). The presence of a diffusible meiosis regulatory substance was first described by Byskov et al. in a fetal mouse adrenal gland culture system (Byskov, A.G. et al., Dev Biol 52 (1976) 193-200). A meiosis activating substance (MAS) is secreted by the fetal mouse ovary in which meiosis is occurring, and a substantial meiosis avoidance (MPS) of the morphologically differentiated testes is released with resting non-meiotic germ cells. It has been suggested that the relative concentrations of MAS and MPS regulated at the beginning suppress and reassume meiosis in the male and female germ cells (Byskov, AG et al in The Physiology of Reproduction (eds. Nobil, E. and Neill , JD, Raven Press, New York (1994).) Clearly, if meiosis can be regulated, reproduction can be controlled.A recent article (Byskov, AG et al., Nature 374 (1995), 559-562) describes the isolation from bull testes and human follicular fluid from certain sterols that activate oocyte meiosis Unfortunately, these sterols are rather labile and their use to find interest would therefore be greatly facilitated if compounds were available more stable meiosis activators.
Compounds that are known to stimulate meiosis and are different from the compounds claimed in the present application are described in WO 96/27658. The compounds described herein have advantages compared to the known compounds.
BRIEF DESCRIPTION OF THE INVENTION
One purpose of the present invention is to provide compounds and methods useful for alleviating infertility in females and males, particularly in mammals, and more particularly in humans. A further purpose of the present invention is to provide compounds and methods useful as contraceptives in females and males, particularly in mammals, more particularly in humans. In accordance with the present invention, novel compounds with interesting pharmacological properties are provided. In particular, the compounds of the formula la, Ib and le are useful for regulating meiosis in oocytes and in male germ cells. In one aspect, the present invention relates to compounds of the general formula which is set forth in claim 1 below.
In another embodiment, the invention relates to esters of the compound of the general formula la. Such esters are formally derived by esterification of one or more hydroxyl groups of a compound of formula la, with an acid, which, for example, can be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulfamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids. In still another preferred embodiment, the present invention relates to compounds of the general formula Ib and esters thereof, as a medicament. In a further preferred embodiment, this invention relates to compounds of the general formula I or esters thereof in the manufacture of a medicament for use in the regulation of meiosis. In a further preferred aspect, the present invention relates to the use of a compound of formula le, or an ester thereof as a medicament, in particular as a medicament for use in the regulation of meiosis. The compound can be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.
In the present context, the expression "regulation of meiosis" is used to indicate that some of the compounds of the invention can be used to stimulate meiosis in vi tro, in vivo or ex vivo. Therefore, the compounds which can be agonists of a meiosis activating substance that occurs naturally, and can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in female and male subjects. male sex Other compounds of the invention, which may be antagonists of a meiosis activating substance that occurs naturally, can be used to regulate meiosis, preferably in vivo in a manner which renders them suitable as contraceptives. In this case, "regulation" means partial or total inhibition. In a further preferred aspect, the present invention relates to the use of a compound of the formula Ic above or an ester thereof in the regulation of the meiosis of an oocyte, in particular a mammalian oocyte, and more particularly a human oocyte. In a further preferred aspect, the present invention relates to the use of a compound of formula le or an ester thereof in the stimulation of the meiosis of an oocyte, in particular a mammalian oocyte, and more particularly an oocyte. human.
In a further preferred aspect, the present invention relates to the use of a compound of formula le or an ester thereof in the inhibition of the meiosis of an oocyte., in particular a mammalian oocyte, and more particularly a human oocyte. In a further preferred aspect, the present invention relates to the use of a compound of formula le or an ester thereof in the regulation of the meiosis of a male germ cell, in particular, a male germ cell of a mammal, and of more particularly a male germ cell of human. In a further preferred aspect, the present invention relates to the use of a compound of a compound of formula le or an ester thereof in the stimulation of the meiosis of a male germ cell, in particular, a male germ cell of a mammal, and more particularly a male germ cell of a human. In a further preferred aspect, the present invention relates to the use of a compound of formula I above or an ester thereof in the inhibition of meiosis of a male germ cell, in a further preferred aspect, the present invention relates to a method for regulating meiosis in a mammalian germ cell, which method comprises administering an effective amount of a compound of the above formula or an ester thereof to a germ cell in need of such treatment. In a further aspect, the present invention relates to a method for regulating meiosis in a mammalian germ cell, wherein a compound of formula I above or an ester thereof is administered to the germ cell by administering the compound to a mammal. that hosts a host cell. In a further aspect, the present invention relates to a method wherein the germ cell, the meiosis of which it is to be regulated, by means of a compound of the above formula or an ester thereof, is an oocyte. In a further aspect, the present invention relates to a method for regulating meiosis of an oocyte wherein a compound of formula I above or an ester thereof is administered to the oocyte ex vivo. In a further aspect, the present invention relates to a method for regulating meiosis of male germ cells by administering a compound of formula Ic above or an ester thereof to the cell. In a further aspect, the present invention relates to a method by which mature male germ cells are produced by administering in vivo or in vi tro a compound of formula le or an ester thereof to testicular tissue containing immature cells.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of formula la, Ib and le are those in which R1 and R2 are both hydrogen. Other preferred compounds of formula la, Ib, and le are those in which one of R1 and R2 is hydrogen while the other is methyl. Other preferred compounds of the formula la, Ib and le are those in which R1 and R2 are both methyl. Other preferred compounds of formula la, Ib, and le are those wherein R 1 is branched or unbranched Ci-Cg alkyl, optionally substituted by halogen, hydroxy or cyano. Other preferred compounds of formula la, Ib and le are acyloses wherein R2 is branched or unbranched C-L-Cg alkyl optionally substituted by halogen, hydroxy or cyano. Other preferred compounds of formula la, Ib and le are acyloses in which R1 is hydroxy and R2 is selected from the group consisting of hydrogen and branched or unbranched Ci-Cg alkyl which may be substituted by halogen, hydroxy or cyano. Other preferred compounds of formula la, Ib and le are those in which R2 is hydroxy and R1 is selected from the group comprising hydrogen and branched or unbranched alkyl which may be substituted by halogen, hydroxy or cyano. Other preferred compounds of formula la, Ib and le are those in which R1 and R2 together denote methylene. Other preferred compounds of formula la, Ib and le, are those in which R1 and R2, together with the carbon atom to which they are attached, form a cyclopropane ring. Other preferred compounds of formula la, Ib and le are those in which R1 and R2, together with the carbon atom to which they are attached, form a cyclopentane ring. Other preferred compounds of formula la, Ib and le are those in which R1 and R2, together with the carbon atom to which they are attached, form a cyclohexane ring. Other preferred compounds of formula la, Ib and le are those in which R3 is hydrogen. Other preferred compounds of formula la, Ib and le, are acyloses in which R3 is methylene. Other preferred compounds of formula la, Ib and le, are those in which R3 is hydroxy. Other preferred compounds of formula la, Ib and le, are those in which R3 is methoxy or acetoxy. Other preferred compounds of formula la, Ib and le, are those in which R3 is halogen. Other preferred compounds of formula la, Ib and le, are those in which R3 is oxo.
Other preferred compounds of formula la, Ib and le, are those in which R3 is = N0H. Other preferred compounds of formula la, Ib and le, are those in which R3 is = NOR26, wherein R26 is alkyl
Other preferred compounds of formula la, Ib and le, are those in which R3 is hydroxy and C ^ d alkyl attached to the same carbon atom of the sterol backbone. Other preferred compounds of formula la, Ib and le, are those in which R3 together with R9 designate an additional bond between the carbon atoms in which R3 and R9 are placed. Other preferred compounds of formula la, Ib and le, are those in which R3 together with R14 designate an additional bond between the carbon atoms in which R3 and R14 are placed. Other preferred compounds of formula la, Ib and le, are those in which R 4 is hydrogen. Other preferred compounds of formula la, Ib and le, are those in which R 4 is methylene. Other preferred compounds of formula la, Ib and le, are those in which R 4 is hydroxy. Other preferred compounds of formula la, Ib and le, are those in which R 4 is halogen.
Other preferred compounds of formula la, Ib and le, are those in which R 4 is methoxy or acetoxy. Other preferred compounds of formula la, Ib and le, are those in which R 4 is oxo. Other preferred compounds of formula la, Ib and le, are those in which R4 is = NOH. Other preferred compounds of formula la, Ib and le, are those in which R4 is = NOR27, wherein R27 is alkyl
Other preferred compounds of formula la, Ib and leare those in which R4 is hydroxy and alkyl of x-Ct linked to the same carbon atom of the main structure sterol. Other preferred compounds of formula la, Ib and le, are those in which R4 together with R13 designate an additional bond between the carbon atoms in which R4 and R13 are placed. Other preferred compounds of formula la, Ib and le, are those in which R4 together with R1S designate an additional bond between the carbon atoms in which R4 and R1S are placed. Other preferred compounds of formula la, Ib and le, are those in which Rs is hydrogen. Other preferred compounds of formula la, Ib and le, are those in which Rs is halogen.
Other preferred compounds of formula la, Ib and le, are those in which R5 is d- j alkyl. Other preferred compounds of formula la, Ib and le, are those in which Re is methylene. Other preferred compounds of formula la, Ib and le, are those in which R5 is hydroxy. Other preferred compounds of formula la, Ib and le, are those in which R5 is methoxy. Other preferred compounds of formula la, Ib and le, are those in which Rs is oxo. Other preferred compounds of formula la, Ib and le, are those in which R5 is = N0H. Other preferred compounds of formula la, Ib and le, are acyloses in which RB is = N0R22, wherein R22 is alkyl of 1-C3. Other preferred compounds of formula la, Ib and le, are those in which Rs together with Rs define an additional bond between the carbon atoms in which RB and R6 are placed. Other preferred compounds of formula la, Ib, and le, are those in which R6 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which Rs is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R6 together with R14 designate an additional bond between the carbon atoms in which R6 and R14 are placed. Other preferred compounds of formula la, Ib, and le, are those in which R9 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R9 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R9 is oxo. Other preferred compounds of formula la, Ib, and le, are those in which R9 together with R10 designate an additional bond between the carbon atoms in which R9 and R10 are placed. Other preferred compounds of formula la, Ib, and le, are those in which R10 is hydrogen. - "Other preferred compounds of formula la, Ib, and le, are those in which R10 is halogen." Other preferred compounds of formula la, Ib, and le, are those in which R10 is hydroxy. , Ib, and le, are those in which R11 is hydroxy Other preferred compounds of formula la, Ib, and le, are those in which R11 is alkoxy, aralkyloxy, alkoxyalkoxy or alkanoxyalkyl, each group comprises a total of up to 10. carbon atoms, preferably up to 8 carbon atoms.
Other preferred compounds of formula la, Ib, and le, are those in which R11 is d-C * alkoxy. Other preferred compounds of formula la, Ib, and le, are those in which R11 is methoxy. Other preferred compounds of formula la, Ib, and le, are those in which R 11 is ethoxy. Other preferred compounds of formula la, Ib, and le, are those in which R11 is CH30CH20-. Other preferred compounds of formula la, Ib, and le, are those in which R11 is pivaloyloxymethoxy. Other preferred compounds of formula la, Ib, and le, are those in which R 11 is an acyloxy group derived from an acid having from 1 to 20 carbon atoms. Other preferred compounds of formula la, Ib, and le, are those in which R 11 is an acyloxy group selected from the group consisting of acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemisuccinoyloxy, hemiglutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxycarbonyloxy , tert-butoxycarbonyloxy and ethoxycarbonyloxy. Other preferred compounds of formula la, Ib, and le, are those in which R 11 is sulfonyloxy. Other preferred compounds of formula la, Ib, and le, are those in which R 11 is phosphonyloxy.
Other preferred compounds of formula la, Ib, and le, are those in which R11 is oxo. Other preferred compounds of the formula la, Ib, and le, are acyelids in the Cg R11 is NOH. Other preferred compounds of formula la, Ib, and le, are those in which R11 is = N0R28, wherein R28 is alkyl
Other preferred compounds of formula la, Ib, and le, are those in which R11 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R11 is hydroxy and C1-C4 alkyl: attached to the same carbon atom of the sterol backbone. Other preferred compounds of formula, Ib, and le, are those in which R11 together with R12 designate an additional bond between the carbon atoms in which R11 and R12 are placed. Other preferred compounds of formula la, Ib, and le, are those in which R12 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R12 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R12 is C1-C3 alkyl. Other preferred compounds of formula la, Ib, and le, are those in which R12 is C-Gj alkoxy.
Other preferred compounds of formula la, Ib, and le, are those in which R12 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R13 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R13 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R13 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R13, together with R14, designate an additional bond between the carbon atoms in which R13 and R14 are placed. Other preferred compounds of formula la, Ib, and le, are those in which R14 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R14 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R14 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R1S is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R1S is halogen.
Other preferred compounds of formula la, Ib, and le, are those in which R1B is d-d alkyl. Other preferred compounds of formula la, Ib, and le, are those in which R1S is methylene. Other preferred compounds of formula la, Ib, and le, are those in which R1S is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R15 is methoxy. Other preferred compounds of formula la, Ib, and le, are acyloses in which R1S is oxo. Other preferred compounds of formula la, Ib, and le, are those in which R1S is = N0H. Other preferred compounds of formula la, Ib, and le, are those in which R1S is = N0R23, wherein R23 is d-C alkyl ,. Other preferred compounds of formula la, Ib, and le, are those in which R is hydrogen, Other preferred compounds of formula la, Ib, and le, are those in which R: 16 is halogen, Other preferred compounds of formula , Ib, and le, are acyloses in which R: is alkyl of - - Other preferred compounds of formula la, Ib, and le, are those in which R 16 is methylene. Other preferred compounds of formula la, Ib, and le, are those in which R1 (is hydroxy.
Other preferred compounds of formula la, Ib, and le, are those in which R16 is methoxy. Other preferred compounds of formula la, Ib, and le, are those in which R16 is oxo. Other preferred compounds of formula la, Ib, and le, are those in which R16 is = NOH. Other preferred compounds of formula la, Ib, and le, are those in which R16 is = NOR24, wherein R24 is alkyl
C-i - «-3. Other preferred compounds of formula la, Ib, and le, are those in which R16 together with R17, designate an additional bond in the carbon atoms which are placed between
R16 and R17_ Other preferred compounds of formula la, Ib, and le, are those in which R17 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R17 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R18 and R19 are both hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which one of R18 and R19 is hydrogen while the other is halogen. Other preferred compounds of formula la, Ib, and le, are those in which one of R18 and R19 is hydrogen while the other is hydroxy.
Other preferred compounds of formula la, Ib, and le, are acyloses in which one of R18 and R19 is hydrogen while the other is methoxy. Other preferred compounds of formula la, Ib, and le, are those in which one of R18 and R19 is fluoro and the other is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which one of R18 and R19 together designate oxo. Other preferred compounds of formula la, Ib, and le, are acyloses in which R25 is hydroxymethyl. Other preferred compounds of formula la, Ib, and le, are those in R25 is d-d alkyl. Other preferred compounds of formula, Ib, and le, are those in which R25 together with R31 designate mephileno. Other preferred compounds of formula la, Ib, and le, are those in which R25 together with R31 designate oxo. Other preferred compounds of formula la, Ib, and le, are those in which R29 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R29 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R29 is methyl. Other preferred compounds of formula la, Ib, and le, are those in which R29 is hydroxy.
Other preferred compounds of formula la, Ib, and le, are acyclovir in which R29 is oxo. Other preferred compounds of formula la, Ib, and le, are those in which R30 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R30 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which R30 is methyl. Other preferred compounds of formula la, Ib, and le, are those in which R30 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which R31 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which R31 is halogen. Other preferred compounds of formula la, Ib, and le, are those wherein R31 is methyl. Other preferred compounds of formula la, Ib, and le, are those in which R31 is hydroxy. Other preferred compounds of formula la, Ib, and le, are acyloses in which A is a carbon atom. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R7 is hydrogen.
Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R7 is hydroxy. Other preferred compounds of formula la, Ib, and le, are acyloses in which A is a carbon atom and R7 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R7 together with R8 designate an additional bond between carbon atoms in which R7 and R8 are placed. Other preferred compounds of formula la, Ib, and le, are acyelids in the Cg A is a carbon atom and R8 is hydrogen. Other preferred compounds of formula la, Ib, and le, are acyloses in which A is a carbon atom and R8 is d-C4 alkyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R8 is methylene. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R8 is oxo. Other preferred compounds of formula la, Ib, and le, are acyloses in which A is a carbon atom and R8 is cyano.
Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R8 is halogen. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R8 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R20 is d-C4 alkyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R20 is trifluoromethyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R20 is C3-C6 cycloalkyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R21 is d-C4 alkyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R21 is hydroxyalkyl of d-C4. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R21 is haloalkyl of d-C4 (Iie contains up to 3 halogen atoms.
Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R21 is methoxymethyl or acetoxymethyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R21 is C3-Ce cycloalkyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a carbon atom and R20 and R21 together with the carbon atom to which they are attached form a C3-C3 cycloalkyl ring / preferably a cyclopropyl ring , a cyclopentyl ring or a cyclohexyl ring. Other preferred compounds of formula la, Ib, and le, are those in which A is a nitrogen atom. Other preferred compounds of formula la, Ib, and le, are those in which A is a nitrogen atom and R8 is hydrogen. Other preferred compounds of formula la, Ib, and le, are those in which A is a nitrogen atom, and R8 is hydroxy. Other preferred compounds of formula la, Ib, and le, are those in which A is a nitrogen atom, and R8 is d-C4 alkyl. Other preferred compounds of formula la, Ib, and le, are those in which A is a nitrogen atom, and R8 is oxo.
Other preferred compounds of formula la, Ib, and le, are those in which A is a nitrogen atom, and R20 and R21, independently, are selected from the group cgue include d-C4 alkyl, cyclopropyl, cyclopentyl and cyclohexyl. Other preferred compounds of formula la, Ib, and le, are those in which the long side chain at position 17 is in the β position. It should be understood that the above preferred substituents can be combined in any way with each other. Additional preferred embodiments are mentioned in the appended claims. As used in the present description and claims, the term "d-C3 alkyl" designates an alkyl group having from 1 to 3 carbon atoms; preferred examples are methyl, ethyl and propyl, more preferably methyl and ethyl. Similarly, the term "d-C4 alkyl" designates an alkyl group having from 1 to 4 carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl and butyl, most preferably methyl and ethyl. The term "d-C3 alkyl" designates an alkyl group having from one to six carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl, butyl, te -butyl, pentyl and hexyl, more preferably methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, most preferably methyl and ethyl.
As used in the present description and claims, the term "d-C3 alkoxy" designates an alkoxy group having from 1 to 3 carbon atoms; preferred examples are methoxy, ethoxy and propoxy, most preferably methoxy and ethoxy. As used in the present description and claims, the halogen expression preferably designates fluoro and chloro, more preferably fluoro. As used in the present description and claims, the term "d-C4 alkanediyl" designates branched or unbranched alkane from which two hydrogen atoms have been removed. By observing formula I it can be seen in these portions alkandiyl have joined the two free bonds to the same carbon atom of the structure-main sterol. The general terms for alkandiyl are considered to be alkylidene and alkylene. Examples of preferred alkylene groups are methylene, ethylene, propylene, propylidene, isopropylidene, sec-butylidene and 1,4-butylene. As used in the present description and claims, the term "C3-C3 cycloalkyl" designates a cycloalkyl group containing 3-6 carbon atoms in the ring. Preferred examples are cyclopropyl and cyclopentyl. As used in the present description and claims, the term "acyloxy" refers to a monovalent substituent comprising an optionally substituted d-C6 alkyl or pyridyl group attached through a carbonyloxy group; such as, for example, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, benzoyl and the like. The compounds of claim 1 have a number of chiral centers in the molecule and therefore exist in various isomeric forms. All of these isomeric forms and mixtures thereof are within the scope of the invention. The compounds of the general formula I can be prepared analogously with the preparation of known compounds. Therefore, syntheses of the compounds of formula I can be followed by well-established synthetic routes described in the comprehensive literature of sterol and steroids. The following books can be used as the key source in the synthesis. L. F. Fieser & M. Fieser: Steroids. Reinhold Publishing Corporation, NY 1959; Rood's Chemistry of Carbon Compounds (ed. S. Coffrey): Elsevier Publishing Company, 1971; and especially Dictionary of Steriods (eds .: R.A. Hill; D.N. Kirk; H.L.J. Making and G.M. Murphy): Chapmann & Hall. The latter contains an extensive list of citations to the original documents covering the period up to 1990. All of these books include the last mentioned citations and are incorporated by reference.
The compounds of the present invention will influence meiosis in oocytes as well as in male germ cells. The existence of a meiosis-inducing substance in nature has been known for some time. However, until recently the identity of the substance or substances inducing meiosis was unknown. The prospects of being able to influence meiosis were several. According to a preferred embodiment of the present invention, a compound of claim 1 or an ester thereof can be used to stimulate meiosis. According to another preferred embodiment of the present invention, a compound of the claim may be used.
1 or an ester thereof to stimulate meiosis in humans. Therefore, the compounds of claim 1 and the esters thereof are promising as new fertility regulating agents without the usual collateral effects on somatic cells which are known from the hormonal contraceptives used up to now which are based on estrogen and / or gestagens. For use as a contraceptive agent in women, a meiosis-inducing substance can be administered in a manner that prematurely induces meiosis resumption in oocytes while still in the growing follicle, before the gonadotropin ovulatory peak occurs. In women, the resumption of meiosis can be induced, for example, a week after the preceding menstruation has ceased. When ovulating, the resulting oocyte oocytes later are more likely to not be fertilized. It is not likely to affect the normal menstrual cycle. In this regard it is important to note that the progesterone biosynthesis in cultured human granulosa cells (somatic cells of the follicle) are not affected by the presence of a meiosis-inducing substance while the estrogens and progestins used in the hormonal contraceptives used so far do not have an adverse effect on progesterone biosynthesis. According to another aspect of this invention, a meiosis-inducing substance of claim 1 or an ester thereof can be used in the treatment of certain cases of infertility in females, including females, by administration to the same females who, because to insufficient own production of meiosis activating substance, are unable to produce mature oocytes. In addition, when performing in vitro fertilization, better results can be obtained when a compound of claim 1 or an ester thereof is added to the medium in which the oocytes are maintained. When infertility in males, including man, is caused by insufficient self-production of the meiosis activating substance and therefore a lack of mature sperm cells, the administration of a compound of claim 1 or an ester thereof can alleviate the problem. As an alternative to the method described above, contraception can also be obtained in females by administering a compound of claim 1 or an ester thereof which inhibits meiosis, so that mature oocytes are not produced. Similarly, male contraception can be obtained by administering a compound of claim 1 or an ester thereof which inhibits meiosis, so that mature sperm cells are not produced. The route of administration of compositions containing a compound of claim 1 or an ester thereof can be any route which effectively transports the active compound to its site of action. Therefore, when the compounds of this invention are to be administered to a mammal, it is conveniently provided in the form of a pharmaceutical composition which comprises at least one compound of claim 1 or an ester thereof in connection with a pharmaceutically carrier. acceptable. For oral use, such compositions are preferably in the form of capsules or tablets.
From the above, it will be understood that the administrative regime that is required will depend on the condition in question. Thus, when used in the treatment of infertility, the administration can be carried out once only, or for a limited period, for example until pregnancy occurs. When used as a contraceptive, the compound of claim 1 or an ester thereof should be administered continuously or cyclically. When used as a contraceptive for females and not taken continuously, it will be important to synchronize the administration in relation to ovulation. Examples of preferred compounds according to the invention are given below: cholesta-5-en-3ce, 1/3-diol; cholesta-5-en-3ce, lce-diol; cholesta-5-en-3ce, 2 3-diol; cholesta-5-en-3ce, 2ce-diol; cholesta-5-en-3ce, 4/3-diol; cholesta-5-en-3ce, 4ce-diol; cholesta-5-en-3ce, 7/3-diol; cholesta-5-en-3ce, 7ce-diol; cholesta-5-en-3ce, 11/3-diol; cholesta-5-en-3ce, llce-diol; cholesta-5-en-3ce, 12/3 -diol; cholesta-5-en-3ce, 12ce-diol; cabbage ta-5-en-3ce, 15/3 -diol; cholesta-5-en-3ce, 15a; -diol; cholesta-5-en-3ce, 16/3-diol; cholesta-5-en-3ce, 16ce-diol; cholesta-5-en-3ce, llß-d ± ol; cholesta-5-en-3ce, 17ce-diol; cholesta-5-en-3ce, (20R) -diol; cholesta-5-en-3ce, (20S) -diol; cholesta-5-en-3ce, 21-diol; cholesta-5-en-3ce, (22R) -diol; cholesta-5-en-3ce, (22S) -diol; cholesta-5-en-3ce (23R) -diol; cholesta-5-en-3ce, (23S) -diol; cholesta-5-en-3ce, (24R) -diol; cholesta-5-en-3ce, (24S) -diol; cholesta-5-en-3ce, 25-diol; (25R) -cholesterol-5-en-3ce, 26-diol; (25S) -cholesterol-5-en-3ce, 26-diol; cholesta-5-en-3/3, 1/3-diol; cholesta-5-en-33, lce-diol; cholesta-5-en-3/3, 2 / d-diol; cholesta-5-en-3/3, 2ce-diol; cholesta-5-en-3 / 3,4 / 3-diol; cholesta-5-en-3 / 3,4ce-diol; cholesta-5-en3 / 3, 7/3-diol; cholesta-5-en-3/3, 7ce-diol; cholesta-5-en-3/3, 11/3-diol; cholesta-5-en-3/3, llce-diol; cholesta-5-en-3jd, 12/3-diol; cholesta-5-en-3/3, 12ce-diol; cholesta-5-en-3jß, 15/3-diol; cholesta-5en-3/3, 15a-diol; cholesta-5-en-3/3, 16/3 -diol; cholesta-5-en-3/3, 16ce-diol; cabbage ta-5-en-3 / S, 17/3-diol; cholesta-5-en-3/3, 17ce-diol; cholesta-5-en-3/3, (20R) -diol; cholesta-5-en-3 / S, (20S) -diol; cholesta-5-en-3/3, 21-diol; cholesta-5-en-3/3, (22S) -diol; cholesta-5-en-3/3, (23R) -diol; cholesta5-en-3jS, (23S) -diol; cholesta-5-en-3/3, (24R) -diol; cholesta-5-en-3/3, (24S) -diol; cholesta-5-en-3/3, 25-diol; (25S) -cholesterol-5-en-3/3, 26-diol; cholesta-5, 24-dien-3ce, ljd-diol; cholesta-5"-, 24-dien-3ce, lce-diol cholesta-5, 24-dien-3ce, 2/3-diol, cholesta-5, 24-dien-3ce, 2ce-diol cholesta-5, 24- dien-3ce, 4/3-diol, cholesta-5, 24-dien-3ce, 4ce-diol cholesta-5, 24-dien-3ce, 7/3-diol, cholesta-5, 24-dien-3ce, 7a -diol cholesta-5, 24-dien-3ce, 11 / ß-diol, cholesta-5, 24-dien-3ce, llce-diol, cholesta-5, 24-dien-3cel2 / d-diol, cholesta-5, 24-dien-3ce, 12ce-diol, cholesta-5, 24-dien-3cel5jS-diol, cholesta-5, 24-dien-3ce, 15/3-diol, cholesta-5, 24-dien-3ce, 16 / d-diol, cholesta-5, 24-dien-3ce, 16ce-diol, cholesta-5, 24-dien-3ce, 17 / S-diol, cholesta-5, 24-dien-3ce, 17ce-diol; cholesta- 5, 24-dien-3ce, (20R) -diol, cholesta-5, 24-dien-3ce, (2 OS) -diol, cholesta-5, 24-dien-3/3, 21-diol, cholesta5,24 -dien-3o; (22R) -diol, cholesta-5, 24-dien-3ce, (22S) -diol, cholesta- 5,24-dien-3ce, (23R) -diol, cholesta-5, 24-dien -3ce, (23S) -diol cholesta-5,24-dien-3ce, 26-diol cholesta-5,24-dien-3/3, 1/3-diol cholesta-5, 24-dien-3/3, lce-diol cholesta-5, 24-dien-3/3, 2/3-diol cholesta-5,24-dien-3 / d, 2ce-dio l cholesta-5, 24-dien-3/3, 4/3-diol cholesta-5, 24-dien-3/3, 4ce-diol cholesta-5, 24-dien-3/3, 7/3-diol cholesta-5, 24-dien-3/3, 7ce-diol cholesta-5, 24-dien-3/3, 113-diol cholesta-5, 24 -dien3 / 3, llce-diol cholesta-5, 24-dien -3/3, 12/3-diol cholesta-5, 24-dien-3/3, 12-diol; cholesta-5, 24-dien-3/3, 15/3-diol cholesta-5, 24-dien-3/3, 15ce-diol; cholesta-5, 24-dien-3/3, 16/3-diol cholesta5,24-dien-3 / 3,16 / 3-diol; cholesta-5, 24-dien-3/3, 17/3-diol cholesta-5,24-dien-3j-3, 17ce-diol; cholesta-5, 24-dien-3/3, (20R) -diol cabbage ta-5, 24 -yen-3/3, (2 OS) -diol, -cholesterol-5, 24-dien-3/3, 21-diol cholesta-5,24-dien-3/3, (22R) -diol; cholesta-5, 24-dien-3/3, (22S) diol; cholesta-5, 24dien-3jS, (23R) -diol; cholesta-5, 24-dien 3/3, (23S) -diol; cholesta-5, 24 -yen-3/3, 26 -diol; 4,4-dimethylcholesterol-5-en-3-ze, l-3-diol; 4,4-dimethylchocolate-5-en-3-ze, Ice diol; 4,4-dimethylcholat-5-en-3-ze, 2/3-diol; 4, 4-dimethylcholat-5-en-3-acetyl-diol; 4, 4-dimethylchocolate-5-en-3ce, 7/3-diol; 4,4 dimethylchocolate-5-en-3-ze, 7-diol; 4, 4-dimethylchocolate-5-en-3ce, 11/3 diol; 4, 4-dimethylchocolate-5-en-3-ze, 11-diol; 4, 4-dimethylchocolate 5-en-3-ze, 12/3-diol; 4, 4-dimethylcholat-5-en-3-ze, 12-diol; 4,4 dimethylcholeate-5-en-3ce, 15/3 -diol; 4, 4 -dimethyl cabbage ta-5 -en
3ce, 15ce-diol; 4, 4-dimethylcholeate-5-en-3ce, 16/3-diol; 4,4 dimethylcholeate-5-ene-3ce, 16/3-diol; 4, 4-dimethylcholat-5-en-3ce, 17/3 diol; 4, 4-dimethylcholat-5-en-3-ze, 17-diol; 4, 4-dimethylchocolate 5-en-3ce, (20R) -diol; 4, 4-dimethylchocolate-5-en-3ce, (20S) -diol; 4,4-dimethyl il choles ta-5-en-3ce, 21 -diol; 4, 4-dimethyl il choles ta-5- en-3ce, (22R) -diol; 4, 4-dimethylchocolate-5-en-3ce, (22S) -diol; 4,4-dimethylcholesterol-5-en-3ce, (23R) -diol; 4, 4-dimethylchocolate-5-en-3ce, (23S) -diol; 4, 4-dimethylchocolate-5-en-3ce, (24R) -diol; 4,4-dimethylcholat-5-en-3ce, (24S) -diol; 4, 4-dimethocholesterol-5-en-3-c, 25-diol; (25R) -4,4-dimethylcholeta-5-en3ce, 26-diol; (25S) -4,4-dimethylchocolate-5-en-3-ze 26-diol; 4, 4-dimethylchocolate-5-en-3 / S, 1/3-diol; 4, 4-dimethylcholat-5-en-3/3, lce-diol; 4, 4-dimethylchocolate-5-en-3/3, 2/3-diol; 4, 4-dimethylcholat-5-en-3/3, 2-diol; 4,4-dimethylchocolate-5-en-3 / d, 7/3-diol, -4,4-dimethylcholat-5-en-33,7-diol; 4, 4-dimethylchocolate-5-en-3/3, lljß-diol; 4, 4-dimethylcholat-5-en-3/3, llce-diol; 4, 4-dimethylchocolate-5-en-3/3, 12/3-diol; 4,4-dimethyl choles ta-5-in-3/3, 12-cedol; 4, 4-dimethylchocolate-5-en-3/3, 15/3-diol; 4, 4-dimethylchocolate-5-en-3jS, 15/3-diol; 4,4-dimethyl-cholesta-5-en-3/3, 16/3-diol; 4, 4-dimethylchocolate-5-en-3/3, 16-diol; 4, 4-dimethylcholat-5-en-3 | 8, 17 / d-diol; 4, 4-dimethylchocolate-5-en-3β, 17ce-diol; 4,4-dimethylchocolate-5-en-3 | S, (20R) diol; 4,4-dimethylcholat-5-en-3/3, (20S) -diol; 4, 4-dimethylcholat-5-en-3 ^, 21-diol; 4, 4, -dimethylcholesterol-5-en-33, (22R) -diol; 4,4-dimethylcholat-5-en-3 | d, (22S) -diol; 4, 4-dimethylcholat-5-en-33, (23R) -diol; 4, 4-dimethylcholat-S-en-3/3, (23S) -diol; 4,4-dimethylcholat-5-en-3/3, (24R) -diol; 4, 4-dimethylchocolate-5-en-3/3, (24S) -diol; 4, 4-dimethylchocolate-5-en-3/3, 25-diol; (25R) -4,4-dimethylchocolate-5-en-3 / d, 26-diol; (25S) -4,4-dimethylcholat-5-en-3 / 3,26-diol, 4,4-dimethylchocolate-5,24-diene-3ce, 1/3-diol; 4,4-dimethylchocolate-5, 24-diene-3ce, 1/3-diol; 4, 4-dimethylchocolate-5, 24-diene-3ce, 2 /? -diol; 4, 4-dimethylchocolate-5, 24-diene-3ce, 2a-diol; 4,4-dimethylchocolate-5, 24-dien-3-acetic acid, 7/3-diol; 4, 4-dimethylchocolate-5, 24-diene-3o;, 7S-diol; 4, 4-dimethylchocolate-5, 24-diene-3ce, 11/3-diol; 4,4-dimethylcholesterol-5, 24-diene-3-ze, 11-diol, 4,4-dimethylchocolate-5,24-diene-3-ze, 12/3-diol; 4, 4-dimethylchocolate-5, 24-diene-3-ze, 12-diol;
4, 4-dimethylchocolate-5, 24-diene-3ce, 15/3-diol; 4, 4-dimethylchocolate-5, 24-dien-3-one, 15-diol; 4, 4-dimethylchocolate-5, 24-diene-3ce, 16/3-diol; 4, 4-dimethylchocolate-5, 24-diene-3ce, 16-diol; 4,4-dimethylchocolate-5, 24-dien-3-ze, 17 -3-diol; 4,4-dimethylchocolate-5,24-diene-3-cysteine, 17a-diol; 4, 4-dimethylchocolate-5, 24-dien-3ce, (20R) -diol;
4, 4-dimethylchocolate-5, 24-dien-3ce (2OS) -diol; 4,4-dimethylchocolate-5, 24-diene-3ce, 21-diol; 4, 4-dimethylchocolate-5, 24-dien-3ce, (22R) -diol; 4, 4-dimethylchocolate-5, 24-dien-3ce, (22S) -diol; 4,4-dimethylchocolate-5, 24-dien-3ce, (23R) -diol; 4, 4-dimethylchocolate-5, 24-dien-3ce, (23S) -diol; 4, 4-dimethylchocolate-5, 24-diene-3ce, 26-diol; 4, 4-dimethylchocolate-5, 24-dien-3 / S, ljS-diol; 4,4-dimethylchocolate-5, 24-dien-3/3, lce-diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 2ß-diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 2-diol; 4,4-dimethylchocolate-5,24-diene-3jß, 7/3-diol; 4, 4-dimethylchocolate-5, 24-dien-3/3, 7-diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 11/8-diol;
4, 4-dimethylchocolate-5, 24-diene-3/3, 11/3-diol; 4, 4-dimethylchocolate-5, 24-dien-3 / β, 12β-diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 12a-diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 150-diol; 4,4-dimethylchocolate-5,24-dien-3 / 3,15 / 3-diol; 4,4-dimethylchocolate-5,24-diene-3/3, 16β-diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 16a-diol;
4, 4-dimethylchocolate-5, 24-diene-3/3, 170-diol; 4, 4-dimethylchocolate-5,2 / 3-diene-3 / 3,17a-diol; 4, 4-dimethylchocolate-5, 24-dien-3β, (20R) -diol; 4,4-dimethylchocolate-5, 24-diene-33, (20S) -diol; 4,4-dimethylchocolate-5, 24-diene-3/3, 21-diol; 4, 4-dimethylchocolate-5, 24-dien-3/3, (22R) -diol; 4,4-dimethylchocolate-5, 24-dien-3/3, (22S) -diol; 4,4-dimethylchocolate-5,24-dien-3/3, (23R) -diol; 4, 4-dimethylchocolate-5, 24-dien-3/3, (23S) -diol; 4, 4-dimethylchocolate-5, 24-diene-3/3, 26-diol; spiro [cholesta-5-en-3ce, 7/3 -diol -4, 1'-cyclopropane] spiro cabbage ta - 5 - en - 3ce, 7ce - diol - 4, 1 '- cyclopropane] spiro cholesta - 5 en - 3 cs, 11/3 -diol -4, 1'-cyclopropane] spiro cabines ta- 5 en- 3ce, llce-diol-4,1 '-cyclopropane] spiro-cholesta- 5 en-3ce, 12/3-diol -4,1 '-cyclopropane] spiro-choles t a-5 en-3ce, l2ce-diol-4,1' -cyclopropane] Spiro cholesta- 5 en-3ce, 15/3-diol-4,1 '-cyclopropane] spiro cholesta- 5 en-3ce, 15ce-diol-4, 1 'cyclopropane] spiro col is -5 in-3ce, 16 / S-diol-4,1' -cyclopropane] spiro cholesta- 5 in-3ce, 16ce -diol-4, 1'-cyclopropane] spiro-cholesta-5-en-3ce, 17 / d-diol-4,1'-cyclopropane] spiro-cholesta-5-en-3ce, l7ce-diol-4,1'-cyclopropane] spiro cholesta- 5 en-3ce, (20R) -diol-4, l 'cyclopropane] spiro cholesta-5 en-3ce (20S) -diol -4, 1'-cyclopropane] spiro cholesta- 5 • en-3ce, 21 -diol-4, 1'-cyclopropane] spiro [cholesta-5-en-3ce, (22R) -diol-4,1 '-cyclopropane]; esp-iro [cholesta-5-en-3ce, (22S) -diol-4,1 '-cyclopropane spiro [cholesta-5-en-3ce, (23R) -diol -4, 1' cyclopropane spiro [cholesta-5] - in -3ce, (23S) -diol-4,1 '-cyclopropane spiro [cholesta-5-en-3ce, (24R) -diol -4,1' -cyclopropane spiro [cholesta-5-en-3ce, ( 24S) -diol -4, 1'-cyclopropane spiro [cholesta-5-en-3ce, 25-diol-4,1 '-cyclopropane spiro [(25R) -cholesterol-5-en-3ce, 26-diol4, 1 '-cyclopropane spiro [(25S) - cholesta-5 -en-3-c, 26-diol-4,1' -cyclopropane spiro [cholesta5-en-3/3, 7/3-diol-4,1 '-cyclopropane] spiro [cholesta-5-en-3/3, 7ce-diol-4,1 '-cyclopropane spiro [cholesta-5-en-3/3, ll / 3-diol-4,1' -cyclopropane spiro [cholesta- 5-en-3/3, lljS-diol-4, 1 'cyclopropane spiro [cholesta-5-en-3/3, 12/3-diol-4, 1' -cyclopropane spiro [cholesta-5-en3 / 3 , 12ce-diol-4, 1'-cyclopropane spiro [cholesta-5-en-3/3, 15/3-diol-4,1'-cyclopropane spiro [cholesta-5-en-3/3, 15ce-diol] -4, 1'-cyclopropane spiro [cholesta-5-en-3/3, 16/3-diol-4, 1 'cyclopropane spiro [cholesta-5-e n-3/3, 16ce-diol-4, 1'-cyclopropane spiro [cholesta-5-en33, 17/3-diol-4,1 '-ciceopropane spiro [cholesta-5-en-3/3, 17a- diol-4,1 '-cyclopropane]; esp iro [cholesta-5-en-3/3, (20R) -diol-4,1 '-cyclopropane spiro [cholesta-5-en-3/3, (20S) -diol-4,1' cyclopropane spiro [ cholesta-5-en-3/3, 21-diol-4, 1'-cyclopropane spiro [cholesta-5-in -3/3, (22R) -diol-4, l '~ cyclopropane spiro [cholesta-5 - in-33, (22S) -diol -4, 1 '- cyclopropane spiro [choles ta-5 -in-3/3, (23R) -diol-4,1' -cyclopropane] spiro [cholesta-5 in 3/8, (23S) -diol-4,1 'cyclopropane] spiro [cholesta-5- in -3/3, (24R) -diol -4,1' -cyclopropane] spiro [cholesta-5- in -3] / 3, (24S) -diol-4,1'-cyclopropane] spiro [cholesta-5-en-3/3, 25-diol-4,1 '-cyclopropane]; esp iro [(25R) -cholesterol-5-en-3/3, 26-diol-4,1 '-cyclopropane] spiro [(25S) -cholesterol-5-en-3 / 6,26-diol 4.1 '-cyclopropane] spiro [cholesta-5, 24-dien-3ce, 7/3 -diol -4, 1'-cyclopropane) spiro [cholesta5, 24-dien-3ce, 7ce-diol-4,1' -cyclopropane] spiro [cholesta-5, 24-dien-3ce, 11 / 3- diol -4, 1 'cyclopropane] spiro [cholesta-5, 24-dien-3ce, llce-diol-4,1' -cyclopropane] spiro [cholesta -5, 24 dien-3ce, 12/3-diol -4,1'-cyclopropane] spiro [cholesta-5, 24-dien-3ce, 12ce-diol-4,1 'cyclopropane] spiro [choles ta-5, 24-dien-3ce, 15/3-diol-4, l '-cyclopropane] spiro [cholesta-5, 24 di in -3 ce, 15ce-diol-4,1' -cyclopropane] spiro [cholesta-5, 24 -di in -3 ce, 163-diol-4, 1 '-cyclopropane] spiro [cholesta-5, 24-dien-3ce, 16ce-diol-4,1' -cyclopropane] spiro [cholesta-5, 24-dien3ce , 17 / 3- diol -4, 1'-cyclopropane] spiro [cholesta-5, 24 -di in -3 ce, 17 c -diol -4,1 '-cyclopropane] spiro [cholesta-5, 24-dien- 3ce, (20R) -diol-4, 1'-cyclopropane] spiro [choles ta-5, 24-dien-3ce, (2 0S) - diol -4,1'-cyclopropane] spiro [cholesta-5, 24 -di in -3 ce, 2l-diol-4,1 '-cyclopropane] spiro [choles ta-5, 24-dien-3ce, (22R) -diol -4, 1'-cyclopropane] spiro [cholesta-5, 24-dien-3ce, (22S) -diol-4,1'-cyclopropane] spiro [cholesta-5], 24-dien-3ce, (23R) -diol-4, 1'-cyclopropane] spiro [cholesta-5, 24-dien-3ce, (23S) -diol-4,1'-cyclopropane spiro [cholesta-5, 24-dien-3ce, 26-diol-4, l'-cyclopropane spiro [cholesta-5, 24-dien-3Jβ, 7/8-diol-4,1 '-cyclopropane spiro [cholesta-5, 24-dien- 3/8, 7ce-diol -4, 1'-cyclopropane spiro [cholesta-5, 24-dien-3/3, 11/6-diol4, 1'-cyclopropane spiro [cholesta-5, 24-dien-3 / 3, 11-diol-4,1 '-cyclopropane spiro [cholesta-5, 24-dien-3 / 3,12 / 3-diol-4, l' -cyclopropane spiro [cholesta-5,24-dien-3 / 6,12ce-diol-4, l 'cyclopropane spiro [cholesta-5, 24-dien-3/8, 15/3-diol-4,1' -cyclopropane spiro [cholesta-5, 24-dien-3/3 , 15ce-diol-4, 1'-cyclopropane spiro [cholesta-5, 24-di-3/6, 16/3-diol-4,1 '-cyclopropane spiro [cholesta-5, 24-dien-3/8 , 16ce-diol-4, 1'-cyclopropane spiro [cholesta-5, 24-dien-3 / 3,17 / 3-diol-4, l '-cyclopropane spiro [cholesta-5, 24-dien-3/3 , 17ce-diol-4, 1'-cyclopropane spiro [cholesta-5, 24-dien-3/3, (20R) -diol-4,1 '-cyclopropane spiro [cholesta-5, 24-dien3 / 3, (20S) -diol -4,1 '-cyclopropane spiro [cholesta-5, 24-dien-3/3, 21-diol-4,1' -cyclopropane spiro [cholesta-5, 24- dien-3/3, (22R) -diol-4, 1'-cyclopropane spiro [cholesta-5, 24-dien3 / 3, (22S) -diol -4, 1'-cyclopropane spiro [cholesta-5, 24- dien-3/3, (23R) -diol-4, 1'-cyclopropane spiro [cholesta-5, 24-dien-3/3, (23S) -diol -4, 1'-cyclopropane spiro [cholesta-5, 24-dien-3/3, 26-diol-4, 1'-cyclopropane], - 3ce hydroxycholesta-5-en-1-one; 3ce-hydroxycholesta-5-en-2-one; 3ce hydroxycholesta-5-en-7-one; 3ce-hydroxycholesta-5-en-ll-one; 3ce hydroxycholesta-5-en-12-one; 3ce-hydroxycholesta-5-en-15-one; 3ce hydroxycholesta-5-en-16-one; 3ce-hydroxycholesta-5-en-22-one; 3ce-hydroxycholesta-5-en-23-one; 3ce-hydroxycholesta-5-en-24-one; 3/3-hydroxycholesta-5-en-l-one; 3/3-hydroxycholesta-5-en-2-one; 3/3-hydroxycholesta-5-en-7-one; 3/3-hydroxycholesta-5-en-ll-one; 3/6-hydroxycholesta-5-en-12-one; 3/6-hydroxycholesta-5-en-15-one; 3/3-hydroxycholesta-5-en-16-one; 3/3-hydroxycholesta-5-en-22-one; 3/3-hydroxycholesta-5-en-23-one; 3/3-hydroxycholesta-5-en-24-one; 3/3-hydroxycholesta-5,24-dien-1-one; 3ce-hydroxycholesta-5,24-dien-2-one; 3ce-hydroxycholesta-5,24-dien-7-one; 3ce-hydroxycholesta-5, 24-dien-ll-one; 3ce-hydroxycholesta-5,24-dien-12 -one; 3ce-hydroxycholesta-5,24-dien-15-one; 3ce-hydroxycholesta-5,24-dien-16-one; 3ce-hydroxycholesta-5,24-dien-22-one; 3ce-hydroxycholesta-5, 24-dien-23-one; 3/3-hydroxycholesta-5,24-dien-l-one; 3/3-hydroxycholesta-5, 24-dien-2-one, -3 / 6-hydroxycholesta-5, 24-dien-7-one; 3/8-hydroxycholesta-5,24-dien-ll-one; 3/3-hydroxycholesta-5, 24-dien-12-one; 38-hydroxycholesta-5,24-dien-15-one; 3/6-hydroxycholesta-5, 24-dien-16-one; 3/3-hydroxycholesta-5,24-dien-22-one; 3/3-hydroxycholesta-5,24-dien-23-one; 4, 4-dimethyl-3/3-hydroxycholesta-5-en-l-one; 4,4-dimethyl-3-hydroxycholesta-5-en-2-one; 4, 4-dimethyl-3-hydroxycholesta-5-en-7-one; 4,4-dimethyl-3,6-hydroxycholesta-5-en-ll -one; 4, 4-dimethyl-3/3-hydroxycholesta-5-en-12-one, 4,4-dimethyl-3ce-hydroxycholesta-5-en-15-one; 4,4-dimethyl-3ce-hydroxycholesta-5-en-16-one; 4, 4-dimethyl-3ce-hydroxycholesta-5-en-22-one; 4, 4-dimethyl-3-hydroxycholesta-5-en-23-one; 4, 4-dimethyl-3ce-hydroxycholesta-5-en-24one; 4,4-dimethyl-3/8-hydroxycoles ta-5-en-1-one; 4, 4-dimethyl-3/3-hydroxycoles ta-5-en-2-one; 4,4-dimethyl-3/3-hydroxycholesta-5-en-7-one; 4,4-dimethyl-3/3-hydroxycholesta-5-en-ll-one; 4,4-dimethyl-3/3-hydroxycholesta-5-en-12-one; 4, 4-dimethyl-3/3-hydroxycolesta-5-en-15-one, 4,4-dimethyl-3,6-hydroxycolesta-5-en-16-one; 4, 4-dimethyl-3/3-hydroxycholesta-5-ene-22-one, -4,4-dimethyl-3/3 -hydroxycoles ta-5-en-23-one; 4, 4-dimethyl-3/3-hydroxycholesta-5-en-24-one; 4, 4-dimethyl-3ce-hydroxycholesta-5,24-di-en-1 -one; 4, 4-dimethyl-3-ce-hydroxycholesta-5,24-dien-2-one; 4, 4-dimethyl-3-hydroxycholesta-5,24-dien-7-one; 4, 4-dimethyl-3ce-hydroxycholesta-5,24-dien-l-one; 4,4-dimethyl-3ce-hydroxycholesta-5,24-dien-12-one, 4,4-dimethyl-3ce-hydroxycholesta-5,24-dien-15-one; 4, 4-dimethyl-3ce-hydroxycholesta-5, 24-dien-16-one, -4,4-dimethyl-3-hydroxy-lectern-5, 24-dien-22-one; 4, 4-dimethyl -3ce-hydroxycoles ta-5, 24-dien-23-one; 4, 4-dimethyl-3/8-hydroxycholesta-5, 24-dien-l-one; 4,4-dimethyl-3,6-hydroxycholesta-5,24-dien-2-one; 4, 4-dimethyl-3/3-hydroxycholesta-5,24-dien-7-one, -4,4-dimethyl-3/3-hydroxycholesta-5,24-dien-l-one; 4, 4-dimethyl -3/3 -hydroxycholes t a- 5, 24-dien-12-one; 4, 4-dimethyl-3,6-hydroxycholesta-5,24-dien-15-one; 4,4-dimethyl-3,6-hydroxycholesta-5,24-dien-16-one; 4, 4-dimethyl-3/3-hydroxycholesta-5, 24-dien-22-one; 4, 4-dimethyl-3/3-hydroxycholesta-5, 24-dien-23-one; spiro [3ce-hydroxycholesta5-en-7-one-4,1 '-cyclopropane]; spiro [3ce-hydroxycholesta-5-en-ll-one-4,1 '-cyclopropane]; spiro [3ce-hydroxycholesta-5-en-l-2-one-4,1 '-cyclopropane]; spiro [3ce-hydroxycholesta-5-en-15-one-4,1 '-cyclopropane] spiro [3ce-hydroxycolesta-5-en-16-one-4,1' -cyclopropane] spiro [3/3-hydroxycholesta] -5-en-22-ona-4, 1'-cyclopropane] spiro [3ce-hydroxycolesta-5-en-23 -one -4, 1 '• cyclopropane] spiro [3ce-hydroxycolesta-5-en-24-one -4, 1'-cyclopropane] spiro [3/3-hydroxycholesta-5-en-7-one-4,1 '-cyclopropane] spiro [3,6-hydroxycolesta-5-en-l-lone-4,1 '-cyclopropane] spiro [3/3-hydroxycholesta-5-en-l-2-one-4,1' -cyclopropane] spiro [3/8-hydroxycolesta-5-en-15-one-4,1 '-cyclopropane] spiro [3/3-hydroxycholesta-5-en-16-one-4,1 '-cyclopropane] spiro [3,6-hydroxycholesta-5-en-22-one-4,1' -cyclopropane] spiro [3 / 6-hydroxycholesta-5-en-23-one-4, 1'-cyclopropane] spiro [3/3-hydroxycholesta-5-en-24-one-4,1 '-cyclopropane] spiro [3ce-hydroxycholesta-5,24-dien-7-one-4,1' - cyclopropane] spiro [3ce-hydroxycholesta-5,24-dien-ll-one-4,1 '-cyclopropane) spiro [3ce-hydroxycholesta-5,24-dien-2-one-4,1' -cyclopropane] spiro [3ce- hydroxycholesta-5, 24-dien-15-one-4, 1'-cyclic opropane] spiro [3ce-hydroxycholesta-5, 24-dien-16-one-4, 1 '• C / 6-propane] spiro [3ce-hydroxycholesta5 , 24-dien-22-one-4, 1 '• cycloopropane] spiro [3/3-hydroxycholesta-5, 24-dien-7-one-4, 1'-cyclopropane and spiro [3/0 -hydroxicoles ta -5, 24-dien-ll-one-4, 1'-cyclopropane] spiro [3/6-hydroxycholesta-5, 24-dien-l2-one-4, 1 '• cyclopropane] spiro [3/3-hydroxycholesta] -5, 24-dienl5-one-4, 1'-cyclopropane] spiro [3/3-hydroxycholesta-5, 24-dien-l6-one-4, 1 '• cyclopropane] spiro [3/8 -hydroxycholes ta 5, 24-dien-22-one-4, 1'-cyclopropane]; 4, 4-dimethylcholest-5-enl, 3-dione; 4,4-dimethylcholest-5-en-3,7-dione; 4, 4-dimethylcholest-5-en-3, 11-dione; 4, 4-dimethylcholest-5-en-3, 12-dione; 4, 4-dimethylcholest-5-en-3, 15-dione; 4,4-dimethylcholest-5-en-3, 16-dione; 4,4-dimethylcholest-5-en-3, 22-dione; 4, 4-dimethylcholest-5-en-3, 23-dione; 4, 4-dimethylcholest-5-en-3, 24-dione; 4, 4-dimethylcholest-5,24-dien-l, 3dione; 4, 4-dimethylcholest-5, 24-diene-3,7-dione; 4,4-dimethylcholest-5, 24-dien-3, 11-dione, -4,4-dimethylcholest-5, 24-dien-3, 12-dione; 4, 4-dimethylcholest-5, 24-diene-3,15-dione, 4,4-dimethylcholest-5,24-diene-3,16-dione; 4, 4-dimethylcholest-5, 24-dien-3, 22-dione; 4, 4-dimethylcholest-5, 24-dien-3, 23 -dione; spiro [cholest-5-en-3, 7-dione-4,1 '-cyclopropane]; spiro [cholest-5-en-3, ll-dione-4, 1'-cyclopropane]; spiro [cholest-5-en-3, 12-dione-4,1 'cyclopropane]; spiro [cholest-5-en-3, 15 -dione-4, 1'-cyclopropane]; spiro [cholest-5-en-3, 16-dione-4, 1'-cyclopropane] • e sp i r o [col e s t-5-en-3, 22-dione-4, 1'-ci cl opropane]; spiro [cholest-5en-3, 23-dione-4, 1'-cyclopropane]; spiro [cholest-5-in-3, 24 -dione-4, 1'-cyclopropane]; spiro [cholest-5, 24-dien-3, 7 -dione-4, 1'-cyclopropane]; spiro [cholest-5, 24-dien-3, 11-dione-4,1 '-cyclopropane]; spiro [cholest-5, 24-dien-3, 2-dione-4,1 '-cyclopropane]; spiro [cholest-5, 24-dien-3, 15-dione-4,1 '-cyclopropane]; spiro [cholest-5-, 24-dien-3, 16-dione-4,1 '-cyclopropane]; spiro [cholest-5, 24-dien-3, 22 -dione-4, 1'-cyclopropane]; spiro [cholest-5, 24-dien-3, 23-dione4, 1'-cyclopropane]; 4, 4-dimethyl-l / 3-hydroxycholesta-5-en-3-one; 4,4-dimethyl-lce-hydroxycholesta-5-en-3-one; 4, 4-dimethyl-2/3-hydroxycoles ta-5- en-3 -one; 4, 4 -dimet il-2ce-hydroxycoles ta-5-en-3-one; 4,4-dimethyl-7/3-hydroxycholesta-5-en-3-one; 4,4-dimethyl-7ce-hydroxicoslesta-5-en-3-one; 4,4-dimethyl-11/3-hydroxycolesta-5-en-3-one, 4,4-dimethyl-11-hydroxycholesta-5-en-3-one; 4,4-dimethyl-12/6-hydroxycholesta-5-en-3-one; 4, 4-dimethyl-12ce-hydroxycholesta-5-en-3-one; 4,4-dimethyl-15/3-hydroxycholesta-5-en-3-one; 4, 4-dimethyl-15ce-hydroxycholesta-5-en-3-one; 4, 4-dimethyl-16/3-hydroxycholesta-5-en-3-one; 4, 4-dimethyl-16ce-hydroxycolesta-5-en-3-one; 4,4-dimethyl-17/3-hydroxycholesta-5-en-3-one; 4,4-dimethyl-17ce-hydroxycholesta-5-en-3-one; 4, 4-dimethyl- (20R) -hydroxycholesta-5-en-3-one; 4,4-dimethyl- (20S) -hydroxycholesta-5-en-3-one; 4, 4-dimethyl-21-hydroxycholesta5-en-3-one; 4, 4-dimethyl- (22R) -hydroxycholesta-5-en-3-one, -4,4-dimethyl- (22S) -hydroxy-cholesta-5-en-3-one; 4, 4-dimethyl- (23R) -hydroxicolest &-5-en-3-one; 4, 4-dimethyl- (23S) -hydroxycholesta-5-en-3-one; 4, 4-dimethyl- (24R) -hydroxycoles ta-5-en-3 -one; 4,4-dimethyl (24S) -hydroxycholesta-5-en-3-one; 4, 4-dimethyl-25-hydroxycoles ta-5-en-3-one; 4, 4-dimethyl- (25R) -26-hydroxycholesta-5-en-3-one; 4,4-dimethyl- (25S) -26-hydroxycholesta-5-en-3-one; 4, 4-dimethyl-l / 3-hydroxycholesta-5, 24-dien-3-one; 4, 4-dimethyl-l-hydroxyxicolesta-5, 24-dien-3-one; 4, 4-dimethyl-28-hydroxycholesta-5, 24-dien-3-one;
4, 4-dimethyl-2ce-hydroxycholesta-5, 24-dien-3-one; 4, 4 -dimethyl-7/3 -hydroxycole ta-5, 24-dien-3-one; 4, 4-dimethyl-7ce-hydroxycholesta-5, 24-dien-3-one, -4,4-dimethyl -11/3 -hydroxycoles ta-5, 24-dien-3-one; 4, 4-dimethyl-la; -hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-123-hydroxycholesta-5,24-dien-3-one; 4, 4-dimethyl-12ce-hydroxycholesta-5,24-dien-3-one; 4,4-dimethyl-15 /? -hydroxycholesta-5,24-dien-3-one; 4, 4-dimethyl il-15ce-hydroxycoles ta-5, 24 -dien-3-one; 4, 4-dimethyl-16,6-hydroxycholesta-5,24-dien-3-one, 4,4-dimethyl-16ce-hydroxycholesta-5,24-dien-3-one; 4, 4-dimethyl-17/3-hydroxycholesta-5,24-dien-3-one; 4, 4-dimethyl -17ce-hydroxycholesta-5, 24-diene-3-one; 4, 4-dimethyl- (20R) -hydroxycholes ta-5, 24 -dien-3-one, -4,4-dimethyl- (20S) -hydroxycholesta-5, 24-dien-3-one; 4,4-dimethyl-21-hydroxycholesta-5,24-di-3-one; 4, 4-dimethyl- (22R) -hydroxycholesta-5,24-aden-3-one, -4,4-dimethyl- (22S) -hydroxycholesta-5,24-di-3-one; 4, 4-dimethyl- (23R) -hydroxycoles ta-5,24-dien-3-one; 4,4-dimethyl- (23S) -hydroxycoles ta-5, 24-dien-3-one, -4,4-dimethyl-26-hydroxycholesta-5,24-di-3-one; spiro [7/3-hydroxycholesta-5-en-3-one-4,1'-cyclopropane] spiro [7ce-hydroxycolesta-5-en-3-one-4,1 'cyclopropane] spiro [11 / 6hydroxicolesta-5] -in-3-one-4, 1 'cyclopropane] spiro [llce-hydroxycolesta-5-en-3-one-4,1' cyclopropane] spiro [12/3-hydroxycholesta-5-en-3-one-4] , 1 'cyclopropane] spiro [12oehydroxycholesta-5-en-3-one-4,1' cyclopropane] spiro [15/6-hydroxycholesta-5-en-3-one-4,1 'cyclopropane] spiro [15ce-hydroxycholesta] -5-en-3-ona-4, 1 'cyclopropane] spiro [16/3-hydroxycholesta-5-en-3-one-4,1' cyclopropane] spiro [16ce-hydroxycolesta-5-en-3-one-4 , 1 'cyclopropane] spiro [17/3-hydro-r-.icolesta-5-en-3-one-4,1' cyclopropane] spiro [l, 7-hydroxyxicolesta-5-en-3-one-4, 1 'cyclopropane]; spiro [(20R) -hydroxicolesta-5-en-3-one-4-cyclopropane]; spiro [(20S) -hydroxycholesta-5-en-3-one-4 'cyclopropane]; spiro [21-hydroxycholesta-5-en-3-one-4 1 'cyclopropane] spiro [(22R) -hydroxicolesta-5-en-3-one-4 1' cyclopropane] spiro [(22S) -hydroxycholesta-5-en- 3-ona-4 1 'cyclopropane] spiro [(23R) hydroxycolesta-5-en-3-one-4 1' cyclopropane] spiro [(23S) -hydroxycholesta-5-en-3-one-4 'cyclopropane] spiro [(24R) -hydroxicolesta-5-en-3-one-4 1 'cyclopropane] spiro [(24S) hydroxycolesta-5-en-3-one-4 1' cyclopropane] r spiro [25-hydroxycholesta-5-] en-3-ona-4 1 'cyclopropane] spiro [(25R) -26-hydroxycolesta-5-en-3-one-4 1' cyclopropane] spiro [(25S) -26-hydroxycolesta-5-en-3 ona-4 1 'cyclopropane] spiro [7/3-hydroxycholesta-5,24-dien-3-one-4 1' cyclopropane] spiro [7ce-hydroxycholesta-5,24-dien-3-one-4 1 'cyclopropane ] spiro [ll / 3-hydroxycholesta-5, 24-dien-3-one-4 1 'cyclopropane] spiro (llce-hydroxycholesta-5, 24-dien-3-one-4 1' cyclopropane] spiro [12/3] -hydroxycholesta-5, 24-dien-3-one-4 1 'cyclopropane] -, spiro [12ce-hydroxycholesta-5, 24-dien-3-one-4 1' cyclopropane] spiro [1 5/3-hydroxycholesta-5, 24-dien-3-ione-4 1'-cyclopropane] spiro [15ce-hydroxycholesta-5,24-dien-3-one-4'-cyclopropane] spiro [163-hydroxycholesta-5, 24-dien- 3-ona-4 1 'cyclopropane] spiro [16ce-hydroxycholesta-5, 24-dien-3-one-4 1' cyclopropane] spiro [17/6-hydroxycholesta-5,24-dien-3-one-4 1 cyclopropane] spiro [17-hydroxy-choles ta-5, 24-di-3-amino-4'-cyclopropane] spiro [(20R) -hydroxy-cholesta-5,24-dien-3-one-4,1'-cyclopropane ]; spiro [(20S) hydroxycholesta-5,24-dien-3-one-4,1 '-cyclopropane]; spiro [21-hydroxycholesta-5,24-dien-3ona-4,1 '-cyclopropane]; Spiro [(22R) -hydroxycholesta-5, 24-dien-3-one-4,1 '-cyclopropane]; spiro [(22S) -hydroxycholesta-5,24-dien-3-one-4,1' -cyclopropane] ]; spiro [(23R) -hydroxycholesta-5,24-dien-3-one-4,1 '-cyclopropane]; spiro [(23S) -hydroxycholesta-5, 24-dien-3-one4, 1'-cyclopropane]; and spiro [26-hydroxycholesta-5,24-dien-3-one-4,1 '-cyclopropane].
Pharmaceutical compositions
The pharmaceutical compositions comprise a compound of claim 1 or an ester thereof may further comprise carriers, diluents, absorption enhancers, preservatives, buffers, osmotic pressure adjusting agents, tablet disintegrating agents and other ingredients which are conventionally used in the art. Examples of solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methylcellulose, sodium carboxymethylcellulose, melting waxes at low temperature and cocoa butter. Liquid compositions include sterile solutions, suspensions and emulsions. Such liquid compositions may be suitable for injection or for use in connection with ex vivo and in vitro fertilization. The liquid compositions may contain other ingredients which are conventionally used in the art, some of which are mentioned in the above list. In addition, a composition for transdermal administration of a compound of this invention can be provided in the form of a patch and a composition for nasal administration can be provided in the form of a nasal spray in liquid or powder form. The dose of a compound of the invention to be used will be determined by a physician and will depend, for example, on the particular compound used, the route of administration and the purpose of use. The compounds of claim 1 and esters thereof can be synthesized by methods known per se. The present invention is further illustrated by the following examples which, however, should not be considered as limiting the scope of protection. The features described in the preceding description and in the following examples may be, in any combination thereof, material to release the investment in the various forms thereof.
EXAMPLES
EXAMPLE 1
Test of colest-5-en-3/3, 4/3-diol as a meiosis activating substance in the oocyte test.
Animals
Oocytes are obtained from immature female mice
(C57B1 / 6J x DBA / 2J hybrids Fl, Bomholtgaard, Denmark) weighing 13-16 grams, and kept under controlled illumination and temperature. The mice received intraperitoneal injection of 0.2 ml of gonadotropins (Gonal-F, Serono, Solna, Sweden, containing 20 IU of FSH, alternatively, Puregon, Organon, S ords, Ireland containing 20 IU of FSH) and 48 hours later. animals were sacrificed by cervical dislocation.
Collection and culture of oocytes
The ovaries were removed and oocytes were isolated in Hx medium (see below) under a stereomicroscope by manual rupture of the follicles using a pair of 27-gauge needles. The spherical oocytes showing intact germinal vesicle (GV) are divided into oocytes enclosed in clusters (CEO) and naked oocytes (NO) and were placed in minimal essential medium ce (ce-MEM without ribonucleosides, Gibco BRL, Cat. No. 22561) supplemented with 3 mM hypoxanthine (Sigma Cat. No. H-9377), human serum albumin 8 mg / ml (HSA, State Serum Institute, Denmark), 0.23 mM pyruvate (Sigma, Cat. No. s-8636), 2 mM glutamine (Flow Cat. No. 16-801), 100 IU / ml of penicillin and 100 μg / ml streptomycin (Flow, Cat No. 16-700). This means is designated Hx medium. The oocytes were rinsed three times with medium with half Hx and the oocytes of uniform size were divided into groups of CEO and NO. CEO and NO were grown in multiple 4-well plates (Nunclon, Denmark) in which each well contained 0.4 ml of Hx medium and 35-45 oocytes. A control was always run (ie, 35-45 oocytes cultured in Hx medium without the addition of test compounds (together with the test cultures, which were made with different concentrations of the compounds to be tested, as indicated in the following tables, the cultures were carried out at 37 ° C and 100% humidity with 5% CE02 in air.The culture time was 22-24 hours.
Oocyte examination
At the end of the culture period, the number of oocytes with germinal vesicle (GV) or germinal vesicle rupture (GVB) and polar body acylos (PB) is counted using a stereoscopic microscope or an inverted microscope with differential interference contrast equipment . The percentage of oocytes with GVB per total number of oocytes and the percentage of oocytes with PB per total number of oocytes is calculated in the test cultures and compared with the control culture.
Activation of meiosis in oocytes using colest-5-en-3ff, 4/3-diol. Compound source: Steraloids Inc., Wilton, NH, USA, Cat. No. C 6410, Batch No. L1066. The results are provided in the following table:
DO NOT:
CEO:
As evident from the table, 5-en-3 / 3,4 / 3-diol induces meiosis in oocytes both nude and enclosed in clusters when cultured in vitro.
EXAMPLE 2
Test of meiosis inhibitory substances in the oocyte test.
Germ cell vesicle (GV) oocytes are obtained from female mice treated with immature FSH using the same methods described in Example 1 (see above). The oocytes are moistened three times in Hx medium and oocytes of uniform size are divided into the CO and NO groups. It was previously shown that 4,4-dimethylcholest-8, 14, 24-trien-3/3-ol (FF-MAS) induces meiosis in CEO and NO in vitro (Byskov, AG et al., Nature 374 (1995) 559 -562). CEO and NO were grown in Hx medium supplemented with 0.7-7.0 μM FF-MAS in co-culture with the test compounds in different concentrations in multiple four-well containers (Nunclon, Denmark) where each well contained 0.4 ml of Hx medium and 35-45 oocytes. One control (ie, 34-45 oocytes cultured in Hx cgue medium containing FF-MAS without addition of test compounds) always runs simultaneously with the test cultures, which are supplemented with different concentrations of the compounds that are to be try. The test results for the inhibition of meiosis in oocytes using colest-5-in-3/3, (22R) -diol (in the following referred to as "22R") is given in the Table below:
DO NOT
CEO:
As is evident, from the tables, 22R antagonizes the resumption of meiosis induced by FF-MAS in a dose-related manner. This modality can be covered in other ways or it can be carried out in other ways without departing from the spirit or essential characteristics of it. The present description should therefore be considered in all its illustrative and non-restrictive aspects, the scope of the invention is indicated by the appended claims, and all changes which are within the meaning and scope of equivalence are encompassed by the same. .
EXAMPLE 3
4, 4-dimethylchocolate-5,8-dione-3-one.
A D-8 double bond is introduced as described in the literature [J. Lip. Res. 37, 1529 (1996)]. According to the procedure in the literature, cholesta-5, 8-dien-3/6-ol is prepared in a three-step sequence. This alcohol is oxidized in a classical oxidation of Oppenauer [Helv. Chim. Acta 22, 1178, (1939)] to provide cholesta-4, 8-dien-3-one. This ketone is used as starting material for some of the following compounds. Potassium tert-butylate (550 mg) is dissolved in the presence of tert-butanol at 45 ° C. A solution of cholesta-4,8-dien-3-one (470 mg) in 1.5 ml of tetrahydrofuran is added dropwise. After 10 minutes, methyl iodide (0.63 ml) is added. The reaction mixture is stirred for 1 hour. After aqueous treatment and column chromatography, it is isolated (310 mg). ? -NRM (CDC13): d = 0.64 ppm (S, 3 H, H-18); 0.86 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 1.04 (S, 3 H, H-19); 1.24 (s, 3 H, 4-CH3); 1.29 (s, 3H, 4-CH3); 2 . 63 (m, 2 H, H-7); 5 . 69 (t, J = 3 Hz, ÍH, H-6). C29H4e =, MW (molecular weight): 410.684.
EXAMPLE 4
4,4-dimethylchocolate-5, 8-dien-3/3-ol
4,4-Dimethylchocolate-5,8-dien-3-one (100 mg) is reduced with lithium aluminum hydride (5 mg) in 2 ml of tetrahydrofuran at room temperature. The solution is stirred for 1 hour. After aqueous treatment and column chromatography, 4,4-dimethylchocolate-5,8-dien-3- / 3-ol (60 g) is isolated. • * •• XH-NMR (CDC13): d = 0.63 ppm (s, 3H, H-18); 0.86 (s x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 1.12
(S, 3 H, H-19); 1.15 (s, 3 H, 4-CH3) 1.21 (s, 3 H, 4-CH3); 2.56
(m, 2 H, H-7); 3.82 (dd, J = 10 Hz, J = 5 Hz, ÍH H-3); 5.75 (t,
J = 3 Hz, ÍH, H-6). C29H480, MW: 412,700.
EXAMPLE 5
Acetate of Cholesta-5, 8-dien-3/3-yl ^ H-NMR (CDC13): d = 0.64 PPM (s, 3 H, H-18); 0.87 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 1.20
(s, 3H, H-19); 2.03 (s, 3H, 3-OAc) 2.28 (m, 2H, H-4); 2.53 (m,
2H, H-7); 4.61 (m, ÍH, H-3); 5.45 (m, 1 H, H-6). C29H4602, MW:
426. 683 J. Lipid Res. 37, 1529, 1996).
EXAMPLE 6
/6-cholest-8-en-3/6, 5/3-diol
Cholesta-5, 8-diene-3-one is epoxidized in analogy to the literature procedure [J. Med. Chem. 39, 5092, (1996)] to provide 4ce, 5-epoxy-5ce-cholest-8-en-3-one. This is reduced as described in the following. 4ce, 5-epoxy-5 < -e-cholest-8-en-3-one (75 mg) in 3 ml of tetrahydrofuran. Lithium aluminum hydride (30 mg) is added at room temperature. The reaction mixture is stirred for 15 hours. After aqueous treatment and column chromatography, 5/3-cholest-8-in-3/3, 5/3-diol (19 mg) and 5/3-cholest-8-in-3ce, 5/3 are isolated. -diol (24 mg). -NRM (CDC13): d = 0.63 ppm (s, 3H, H-18); 0.86 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 1.06 (s, 3H, H-19); 2.53 (broad, ÍH, OH) 4.09 (m, ÍH, H-3). C27 -? 4602, MW: 402,661.
EXAMPLE 7
/6-Colest-8-en-3ce, 5/3-diol
XH-NMR (CDC13): d = 0.63 ppm (s, 3H, H-18); 0.87 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 0.99 (S, 3H, H-19); 3.97 (m, 1H, H-3). C27H4602, MW: 402,661.
EXAMPLE 8
4, 4-dimethylchocolate-5, 7, 14-trien-3-one
XH-NMR (CDC13): d = 0.87 (2 x d, J = 7 Hz, 6H, H- 26/27); 0.94 (s, H3); 0.95 (d, J = 7 Hz, 3H, H-21); 1.09 (s, 3H); 1.17 (s, 3H, 4-CH3); 1.36 (s, 3H, 4-CH3); 5.69 (s, ÍH, H-14); 6.05 (d, J = 10 Hz, ÍH, H-7); 6.57 (d, J = 10 Hz, ÍH,
H-6); C29H440, MW: 408,668. J. Chem. Soc. P.T. 1, 812, (1977).
EXAMPLE 9
3 / 8- (Acetyloxy) -5ce-colest-8-en-6ce-ol
Cholesta acetate-5,8-dien-3/3-yl is dissolved
(1.0 g) in 250 ml of diethyl ether. The reaction mixture is cooled to 0 ° C and 2.35 ml of borane-dimethylsulfide complex (2 M solution in tetrahydrofuran) are added. The reaction mixture is heated to room temperature in the next 2 hours. Then 26 ml of water, 26 ml of sodium hydroxide solution (aqueous, 10%) and 3.65 ml of hydrogen peroxide (30%) are added at 0 ° C. After aqueous treatment and column chromatography, 3 / 3- (acetyloxy) -5ce-cholest-8-en-6-o-ol (140 mg) is isolated. XH-NMR (CDC13): d = 0.59 ppm (s, 3H, H-18); 0.87 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 0.99 (S, H3, H-19); 2.03 (s, 3H, 3-OAc); 2.26 (m, ÍH); 2.48 (m, ÍH); 3.72 (m, ÍH, H-6); 4.69 (m, ÍH, H-3); C29H4903, MW: 444,698.
EXAMPLE 10
5ce-cholest-7-in-3/3, 5ce, 63-triol
XH-NMR (CDC13): d = 0.59 ppm (s, 3H, H-18); 0.87 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 1.08
(s, H3, H-19); 3.63 (m, ÍH, H-6); 4.08 (m, ÍH, H-3); 5.35 (m,
ÍH, H-7). C27H4603, MW: 418,660. J. Org. Chem. 50, 1835, (1985).
EXAMPLE 11
Cholesta-5, 8, 14-tiren-3/3-ol Cholesta-5, 8-dien-3/3-ol (1.54 g) is dissolved in 50 ml of dichloromethane. A solution of m-chloroperoxybenzoic acid (1.04 g) in 50 ml of dichloromethane is added at room temperature. The reaction mixture is stirred for 5 hours. After aqueous treatment and subsequent column chromatography, 8ce, 9ce-epoxylestol-5-en-3/3-ol (740 mg) is isolated. 8ce, 9ce-epoxylestol-5-en-3/3-ol (200 mg) is dissolved in dichloromethane and the solution is cooled to 0 ° C. A solution of diethylaluminum cyanide (1 M in toluene) is added dropwise. After the addition, the reaction mixture is warmed to room temperature and stirred at an additional 18 hours. After basic treatment and column chromatography, cholesta-5, 8, 14-trien-3/6-ol (51 mg) is isolated. XH-NMR (CDC13): d = 0.84 ppm, (s, 3H, H-18); 0.86 (2 x d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 1.22
(s, H3, H-19); 2.59 (m, ÍH, H-7); 2.88 (m, ÍH, H-7); 3.57 (m,
ÍH, H-3); 5.38 (m, ÍH, H-15); 5.52 (m, ÍH, H-6). C27H420, MW:
382. 630
EXAMPLE 12
lce-hydroxy-3/3-cholestan-3-one XH-NMR (CDCl 3): d = 0.68 ppm (s, 3H, H-18); 0.86 (2 x d, J = 7 Hz, 6H, H-26/27); 0.90 (d, J = 7 Hz, 3H, H-21); 1.21 (S, H3, H-19); 3.62 (m, 1 H, H-1). C27H4602, MW: 402,661. J. Chem. Soc. P.T. 1, 2488, (1977).
EXAMPLE 13
Colest-5-en-3 / 3-9ce-diol
Dissolve 8ce, 9ce-epoxylest-5-en-3/3-ol (200 mg) in
13 ml of diethylamine at -20 ° C. Small lithium (100 mg) is added in small portions. The reaction mixture is stirred for 3 hours.
After aqueous treatment, the untreated product is isolated
(207 mg). Crystallization from diisopropyl ether provides colest-5-en-3/3, 9a; -diol (62 mg).
EXAMPLE 14
5ce-cholest-7-en-3 / 6-5ce-diol
"? -NRM (CDCI3): d = 0.56 ppm (s, 3H, H-18), 0.86 (2 xd, J = 7 Hz, 6H, H-26/27), 0.92 (s, 3H, H-19) ), 0.94 (d, J = 7 Hz, 3H, H-21), 2.24 (m, HH), 4.05 (m, HH, H-3), 5.08 (m, HH, H-7), C27H4602, MW : 402,661, Biochem. J. 105, 1194, (1967).
EXAMPLE 15
5cecols tan- Ice-3ce-diol
Lce-hydroxy-5/6-cholestan-3-one [J. Chem. Soc. Perkin. Trans. 1, 1977, 2488] (110 mg) in 6 ml of ethanol. Sodium borohydride (52 mg) is added at room temperature, in one portion. The reaction mixture is stirred for 4 hours. After aqueous treatment and column chromatography, 5/3-cholestan-lce, 3ce-diol (75 mg) is isolated.
XH-NMR (CDC13): d = 0.64 ppm (s, 3H, H-18); 0.86 (2 X d, J = 7 Hz, 6H, H-26/27); 0.88 (d, J = 7 Hz, 3H, H-21); 1.12 (s, 3H, H-19); 3.29 (dd, J = 12 Hz, J = 3 Hz, ÍH,; 3.77 (m, ÍH, H-3), C27H4802, MW: 404,677.
EXAMPLE 16
5cecoles tan- 3 / 3- 5/6 -diol
XH-NMR (CDC13): d = 0.65 ppm (s, 3H, H-18); 0.86 (2 x d, J = 7 Hz, 6H, H-26/27); 0.92 (d, J = 7 Hz, 3H, H-21); 0.95
(s, 3H, H-19); 2.01 (m, ÍH, H-4); 2.20 (dd, J = 15 Hz, J = 4
Hz, ÍH, H-4); 3.00 (broad, ÍH, OH); 4.13 (m, ÍH, H-3). C27H4802,
MW: 404,677. J. Org. Chem. 27, 1433, (1962).
EXAMPLE 17
/3 - tan-3ce-5/6-diol
XH-NMR (CDC13): d = 0.64 ppm (s, 3H, H-18); 0.86 (2 X d, J = 7 Hz, 6H, H-26/27); 0.89 (s, 3H, H-19); 0.91 (d, J = 7 Hz, 3H, H-21); 4.02 (m, ÍH, H-3). C27H4802, MW: 404,677. J. Org. Chem. 27, 1433, (1962).
EXAMPLE 18
5ce-cholestan-3ce-5-diol
^ -R (CDC13): d = 0.65 ppm (s, 3H, H-18); 0.86 (2 x d, J = 7 Hz, 6H, H-26/27); 0.92 (d, J = 7 Hz, 3H, H-21); 0.95
(s, 3H, H-19); 3.25 (broad, ÍH, OH); 4.10 (m, 1H, H-3). C27H4802, MW: 404,677. J. Chem. Soc, 4482, (1961).
EXAMPLE 19
3 / 3- (benzoyloxy) -22-hydroxy-4,4-dimethyl-5c-cholest-8 (14) -en-15,24-dione XH-NMR (CDC13): d = 0.85 ppm (s, 3H, H-18); 0.96 -1.16 (m, 18H, H-19, H-21, 2x4-CH3, H-26/27); 2.6 (m, 1 H, H-25); 3.3 (d, J = 2 Hz, 1H, 22-OH); 4.06 (m, ÍH, H-22); 4.22 (m, ÍH, H-7); 4.8 (dd, J = 11 Hz, J = 5 Hz, ÍH, H-3). C36H50Os, MW: 562,790. J. Am. Chem. Soc. 11 (1989), 278.
EXAMPLE 20
3 / 6- (benzoyloxy) -4,4-dimethyl-5-acetyl-8 (14) -en-15,24-dione
"? -NRM (CDC13): d = 0.85 pp (s, 3H, H-18); 0.970-1-14 (m, 18H, 2x4-CH3, H-19, H-21, H-26/27) 2.6 (m, H, H-25), 4.21 (m, H, H-7), 4.8 (dd, J = 11 Hz, J = 5 Hz, H, H-3) C3SH50O4, MW: 546.791. J. A. Chem. Soc. 11 (1989), 278.
EXAMPLE 21
3 / 6- (Benzoyloxy) -24-hydroxy-4,4-dimethyl-5-acetyl-8 (14) -en-15-one
-NRM (CDC13): d = 0.85 ppm (s, 3H, H-18); 0.88-1-04 (m, 18H, H-19, H-21, 2x4-CH3, H-26/27); 2.38 (m, ÍH, H-16); 3.31 (m, ÍH, H-24); 4.21 (m, ÍH, H-7); 4.8 (dd, J = 11 Hz, J = 5 Hz, ÍH, H-3). C36HS204, MW: 548.807. J. Am. Chem. Soc. 11 (1989), 278.
EXAMPLE 22
/3-cholest-7-en-3/3, 5/6-diol
, 6/3-epoxy-5/3-cholest-7-en-3/6-ol is dissolved [J. Org. Chem. 50. (1985), 1835] (150 mg) in 2.5 ml of a solution of potassium hydroxide (5% in methanol). The reaction mixture is refluxed for 1 hour. Aqueous workup, extraction with ethyl acetate and column chromatography provide 5/3-cholest-7-en-3/3, 5/3-diol (54 mg).
'• H-NMR (CDC13): d = 0.55 ppm (s, 3H, H-18); 0.86 (2 x d, J = 7 Hz, 9H, H-26/27); 0.92 (s, 3H, H-19); 0.94 (d, J =
7 Hz, 3H, H-21); 4.16 (, ÍH, H-3); 5.05 (m, ÍH, H-7). 27Hy602, MW: 402,661.
EXAMPLE 23
/6-cholest-6-in-3/6, 5/6, 8/3-triol
-NRM (CDC13): d = 0.66 ppm (s, 3H, H-18); 0.87 (3 x d, J = 7 Hz, 9H, H-21/26/27); 1.28 (s, 3H, H-19); 2.24 (m,
ÍH); 2.77 (m, ÍH); 3.48 (m, ÍH, H-3); 5.64 (d, J = 11 Hz, ÍH);
. 88 (d, J = 11 Hz, ÍH). C27H4603, MW: 418,660. J. Org. Chem. 50
(1961), 1835.
EXAMPLE 24
5ce-cholest-8-en-3/6, 6o; -diol
-NMR (CDCl 3): d = 0.60 ppm (s, 3H, H-18); 0.87 (2
X d, J = 7 Hz, 6H, H-26/27); 0.94 (d, J = 7 Hz, 3H, H-21); 0.98
(S, 3H, H-19); 2.48 (m, ÍH); 3.62 (m, ÍH, H-3); 3.75 (m, ÍH,
H-6). C27H4602, MW: 402,661. Proc. Chem. Soc. London, 450 (1961).
EXAMPLE 25
/6-cholest-8-en-3/3, 6/3-diol
Dissolve 3 / 3- (acetyloxy) -5ce-cholest-8-en-6-ol (124 mg) in 20 ml of ethanol. Solid potassium hydroxide (710 mg) is added and the reaction mixture is stirred for
2 hours. After aqueous treatment, 5/3-cholest-8-in-3/6, 6/8-diol (96 mg) is isolated.
-NRM (CDC13): d = 0.65 ppm (s, 3H, H-18); 0.87 (2 x d, J = 7 Hz, 6H, H-26/27); 0.93 (d, J = 7 Hz, 3H, H-21); 1.14 (S, 3H, H-19); 2.33 (m, 2H); 3.83 (m, 2H, H-3/6). C27H4602, MW: 402,661.
EXAMPLE 26 (24R, S) -4,4-dimethyl-5ce-cholesta-8, 14-dien-3/3, 24-diol
XH-NMR (CDCl 3): d = 5.36 ppm (s, ÍH); 3.33 (m, ÍH); 3.23 (dd, ÍH); 1.05 (s, 3H); 1.02 (s, 3H); 0.92 (m, 9H); 0.84 (s, 3H); 0.81 (S, 3H). This compound is separated into the isomers (24R) and (24S). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (10)
- CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the general formula la: characterized in that R1 and R2, which are different or identical, with the proviso that they are not both hydroxy, are selected from the group consisting of hydrogen, halogen, hydroxy and branched or unbranched alkyl which may be substituted by halogen , hydroxy or cyano, or in which R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are attached, form a cyclopropane ring, a cyclopentane ring or a cyclohexane ring; R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, d-C4 alkanediyl (linked to the same carbon atom of the main sterol structure) y = NOR26 wherein R26 is hydrogen or d-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms in which place R3 and R9 or R14; R 4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, d-C 4 -alkaryl ((attached to the same carbon atom of the main sterol structure) y = NOR27 wherein R27 is hydrogen or Cx- or R4 alkyl designates, together with R13 or R15, an additional bond between the carbon atoms in which place R4 and R13 or R15; R5 is selected from the group consisting of hydrogen, halogen, C ^ d alkyl, methylene, hydroxy, methoxy, oxo, and = NR22 wherein R22 is hydrogen or d-C3 alkyl, or R5 designates , together with R6, an additional bond between the carbon atoms in which R5 and R6 are placed, R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms in which Re is placed and Rd; R9 is hydrogen, hydroxy, halogen or oxo, or R9 designates, together with R3 or R10, an additional bond between the carbon atoms in which R9 and R3 or R10 is placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between carbon atoms in which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulfonyloxy, phosphonyloxy, oxo, halogen, d-C4 -alkaryl (attached to the same carbon atom of the sterol backbone) and = NOR28 wherein R28 is hydrogen or d-C3 alkyl , or R11 designates, together with R12, an additional bond between the carbon atoms in which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, d-C3 alkyl / vinyl, CX-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms in which R12 is placed and R11; R13 is hydrogen, hydroxy or halogen, or R13 designates, together with R4 or R14, an additional bond between the carbon atoms in which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen or R14 denotes, together with R3, R6 or R13, an additional bond between the carbon atoms in which R14 and R3 or R6 or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl / methylene, hydroxy, methoxy, ethoxy, oxo and = NOR23 wherein R23 is hydrogen or alkyl of d- - or R1S designates, together with R4, a bond additional between the carbon atoms in which R15 and R4 are placed; R16 is selected from the group consisting of hydrogen, halogen, d-C3 alkyl, methylene, hydroxy, methoxy, oxo and = N0R24 wherein R24 is hydrogen or d-3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms in which R16 and R17 are placed, R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms in which R17 and R16 are placed, R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or ethoxy, or R18 and R19 together designate oxo; R2S is selected from the group comprising d-C4 alkyl and hydroxymethyl, or R25 and R31 designate methylene together or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25 designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, dC4 alkyl, or R7 designates, together with R8, an additional bond between the carbon atoms in which R7 and R8 are placed; R20 is selected from the group comprising d-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group consig of d_d alkyl. hydroxyalkyl of d- # haloalkyl of d-C4 containing up to 3 atoms of halogen, methoxymethyl, acetoxymethyl and cycloalkyl of C3-C6 'or R20 and R21, together with the carbon atom to which they are attached, forms a cycloalkyl ring of C3 -C6; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, d-C4 alkyl, cyano and oxo; Y R-20 and R21 are, independently, d-C alkyl, C3-d cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl and with the additional general condition that R9, R10 and R11 are not all hydroxy and with the additional general condition that is not 5a-bromocholesterol-3β, 6β-diol; 7a-bromocholesterol-3β, 6a-diol; 7a-bromocholesterol-3β, 6β-diol; 7a-bromocholesterol-3β, 5a-diol-6-one; 7β-bromocholesterol-3β, 5a-diol-6-one; 3β-bromocholesterol-2a-ol; 5o-chlorocholesterol-3β, 6a-diol; 5a-chlorocholesterol-3β, 6β-diol; 6β-chlorocholesterol-3β, 5 a-diol; A7, s | nl -cerostadien-3β, -6a-diol; 7'9 (11) -cystetadiene-3β, 6β-diol: cholestan-2a, 3 a-diol; cholestan-2a, 3β-diol; cholestan-2β, 3a-diol; cholestan-2β, 3β-diol; cholestan-3a, 4ce-diol; cholestan-3a, 4β-diol; cholestan-3β, 4β-diol; cholestan-3a, 5a-diol; cholestan-3β, 5a ~ diol; cholestan-3β, 6a-diol; cholestan-3β, 6β-diol; cholestan-3β, 22a-diol; cholestan-3β, 22β-diol; cholestan-3β, la, 8a-triol; 5-cholesten-3β, β-diol; 5-cholesten-3β, 20a-diol; ? 5-cholesten-3?, 22a-diol; ? 5-colsten-3β, 22? -diol; ? 5-cholesten-3β, 24 -diol; 5-cholesten-3β, 24β-diol; 6-cholesten-3β, 5aaa-diol; ? 8 < 14) -cholesterol-3β, 9cc-diol; ? ^ - cholesten-Sa, 24-diol; 5-cholesten-3β, 6-diol-7-one; 5-cholesten-4a-ol-3 -one; 5-cholesten-3β, 4β, 7a-triol; coprostane-3a, 5β-diol; coprostane-3β, 5β-diol; coprostane-3β, 6β-diol; coprostane-4β, 5β-diol-3-one; 20β-hydroxy-20-isocholesterol; ^ 4a-hydroxy-5a-cholestan-3 -one; cholestan-3β, 5a, 6β-triol-3β-hemisuccinate; cholestan-3β, 5a, 6β-triol-3β-hemisuccinate-6β-acetate; cholestan-3β, 5cí, 6β-triol-3β-hemisuccinate-6β-formate; cholestan-3β, 5a, 6β-trisl-3β-sulfate; cholestan-3β, 5a, 6β-triol-3β-phosphate; 2ß, 3β, 14a22 (R), 25-pentahydroxicolest-7-en-6-one; cholest-7-en-2β, 3β, 5β, lla, 14a, 20 (R), 22 (R) -heptahydroxy-6 -one; 5,24-cholestadien-3ß-ol; 5-cholesten-3β-24, 25-triol-3β-acetate; 5-cholesten-3β, 24, 25-triol-3β, 24-diacetate; 5,25-cholestadien-3ß-ol acetate; 5-cholesten-3β, 25, 26-triol-3β-acetat ?; 5-cholesten-3β-25,26-triol; 24.25 (or 25, 26) -dihydroxy-cholecalciferol; cholest-5a-an-3β, 6a-diol; choles-5β-an-3β, 6β-diol; cholest-5a-an-3,6-dione; cholest-5oc, an-6β-ol-3-one; cholest-5a-an-2a-bromo-6β-ol-3-one; cholestan-3β, 25-diol-3β-acetate; cholestan-3β, 5a, 25 -triol -3β -acetate; cholestan-3β, 5a, 25-triol; cholestan-5a, 25-diol-3-one; cholest-4-en-25-ol-3-one; cholesta-4, 6-dien-25-ol-3-one; cholesta-4, 6-dien-25-ol-3-one; la, 3β-dihydroxicolest-5-en; la, 3β-dihydroxycholest-6-en; 3a, 6a-dihydroxy-5β-cholestan-24-one; 3a, 6a, 24-trihydroxy-5β-cholestan 3-chlorocholest-5,24-diene; 3ß-hydroxycholest-5-en-24-on-acetate 3-chlorocholest-5-en-24-on; cholestan-25-f luoro-3β, 22 (S) -diol cholestan-25-chloro-3β, 22 (S) -diol; cholestan-25-methyl-3β, 22-diol-tan-25-methyl-3β, 22-diol-3-hydroxybutenedioate; choles tan-25-methyl-3β, 22-diol-bis-hydrogenbutanedioate; la, 25-dihydroxy -26, 26, 26, 27, 27, 27-hexaf luorocholes-5-en; 2ß, 3β, 14a, 22,25-pentahydroxy-? 7-5-β-esten-6-one; 25-hydroxy-3β- [(tetrahydro-2 H -pyran-2-yl) oxy] cholest-5-en-24-on; 3β- [(tetrahydro-2 H -ran-2-yl) oxy] cholest-5-en-2-on; 25 -hydroxy- 24 -octools terol-3 β-acetate; 24 -oxocholesterol-3 β-acetate; 25-hydroxy-24-oxocholesterol; 24, 25-dihydroxycholesterol; 3a, 6a, 25-trihydroxy-24-oxo-5β-cholestane; la, 25-dihydroxy-24 -oxocholesterol; 24,25-trihydroxycholesterol; 3β-hydroxy-24-oxocholesterol-5, 7-diene; 3β, 25-dihydroxy-24-oxocholesterol-5, 7-diene; 3β-hydroxy-24-oxocholes ta-5, 7-diene; la, 3-β-dihydroxy -24-oxocholes ta-5, 7-diene, 3β, 25-trihydroxy-24-oxocholesterol-5, 7-diene; (24R) -3β, 24, 25-trihydrocolest-5-ene; (24RS) -3ß, 24, 25-trihydroxicolest-5-en and (24R) -lß, 3ß, 24, 25-tetrahydroxicolest-5-ene 4, 4-dimethyl-24-methylene-3β-sulfonoxy-12a-acetoxycholesta -8, 14-dien-2a, llß-diol; 4, 4-dimethyl-24-methylene-3β-sulfooxi-12a-acetoxycholest-8-en-2a, 11β-diol; 4, 4-dimethyl-24-methylene-12a-acetoxycholesta-8, 14-diene-2a, 3ß, llß-triol; 4, 48-dimethyl-24-methylene-12a-acetoxy-cholesta-8, 14-diene-3β, 11β-diol; 4, 4-dimethyl-24-methylene-12 a-acetoxycholest-8-en-2a, 3β, llß-triol; 4,4-dimethyl-24-methyl-12a-acetoxylest-8-en-3β, 11β, 12a-tetraol; 4, 4-dimethyl-24-methylene-3β-sulfooxicoles-8, 14-diene-2a, 11β, 12a-triol; 4, 4-dimethyl-24-methylene-8-beta, 14-dien-2a, 3β, 11β, 12a-tetraol; 4, 4-dimethyl-24-meth i len-3 ß-sulfoxy-12 a -ace oxicoles -8-en-2-ol-ll -one, mono (4, 4-dimethyl-24-methylene-12 a -acetoxicolesta-8, 14-di-2a, ll-diol) -3-β-succinate, 3-dihydroxycholest-5-ene; la, 3β, 24-trihydroxycholest-5-ene; cholesta-5, 7-dien-3β, 23 (R), 25-triol and cholesta-5, 7-dien-3β, 23 (S), 25-triol; la, 3 ß -dihydroxy-cholest-5-ene; la, 3β, 25-trihydroxycholest-5-ene; ? 7-cholesten-2β, 3? -diol-6 -one; 2β, 3β, 14a, 22 (R), 25-pentahydroxy-? 7-5β-cholesten-6-one; 2β, 3β, 14a, 22 (S), 25-pentahydroxy-? 7-5β-cholesten-6-one; cholest-5-en-3β, 22 (R, S), 25-triol; cholest-5-en-25-fluoro-3β, 22 (R, S) -diol; cholest-5-in-25-fluoro-22 (R, S) -ol-3β-semisuccinate; cholest-5-en-25-chloro-3β, 22-diol and cholest-5-en-25-chloro-22-ol-3β-hemisuccinate, -3a, 7a, 12a, 25-tetrahydroxy-coprostane; 3, 7a, 25-trihydroxy coprostane; 3a, 7a-24,25-tetrahydroxy-coprostane; 5β-cholestan-3a, 7a, 12a, 24a, 25-penthol; 5β-cholestan-3a, 7a, 12a, 24β, 25-penthol; 5β-cholestan-3a, 7a, 12a, 25, 26-penthol; 5β-cholestan-3a, 7a, 12a, 25 -tetrol; la, 2a, 3ß-trihydroxicolesta-5, 7-diene; la, 2a-dihydroxy-3-β-acetoxylesta-5-ene; cholest-5-en-2β-fuoro-la, 3β-diol; 24-cyclopropylcol-5-en-3β, 22 (S) -diol, 24-cyclopropylcol-5-en-3β, 22 (S) -diol 3 hydrogen butanedioate and 24-cyclopropylcol-5a-colan-3β, 22 (S ) -diol; cholesta-1, 4,6-trien-3 -one; la, 3β-dihydroxycholest-5-ene; la, 3β-dihydroxy-5a-cholestan; 3β-dihydroxycholesta-5, 7-diene; la, 3 ß-25-trihydroxycholest-5-ene; la, 25-dihydroxycholesterol; la, 25-dihydroxycholesterol-3-benzoate; cholest-5-en-3β, 20 (S) -diol; 2ß, 3ß, 14a, 22 (R), 25-pentahydroxicolest-7-en-6-one and cholest-5-en-3β, 22 (S) -diol; cholest-5-en-3β, 20 (S) -diol; cholest-5-en-3β, 22 (S) -diol; cholest-5-en-3β-4β-diol; cholest-5-en-3β, 22 (R) -diol and 2β, 3β, 14a, 22 (R), 25-pentahydroxicolest-7-en-6-one.
- 2. The use as drugs of compounds characterized because they are of the general formula Ib: wherein R1 and R2, which are different or identical, with the proviso that they are not both hydroxy, are selected from the group consisting of hydrogen, halogen, hydroxy and branched or unbranched alkyl, the sual may be substituted by halogen, hydroxy or cyano, or in which R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are attached, form a cyclopropane ring, a cyclopentane ring or a cyclohexane ring; R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, d-C4 alkanediyl (attached to the same carbon atom of the sterol backbone) and = NOR26 wherein R26 is hydrogen or d-C3, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms in which R3 and R9 or R14 are placed; R4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, d-C4 -alkaryl ((attached to the same carbon atom of the sterol backbone) and = NOR27 wherein R27 is hydrogen or alkyl of Cx-C3, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms in which R4 and R13 or R15 are placed; Rs is selected from the group comprising hydrogen, halogen, d-C4 alkyl , methylene, hydroxy, methoxy, oxo, y = NR22 wherein R22 is hydrogen or alkyl of d- »RS designates, together with R6, an additional bond between the carbon atoms in which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 denotes, together with R5, an additional bond between the carbon atoms in which R5 and R6 are placed, R9 is hydrogen, hydroxy, halogen or oxo, or R9 designates, together with R3 or R10, a bond additional between the carbon atoms in which R9 and R3 or R10 is placed, R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms in which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulfonyloxy, phosphonyloxy, oxo, halogen, d-C4 alkanediyl (attached to the same carbon atom of the sterol backbone) and = NOR28 wherein R28 is hydrogen or alkyl of d '' Rl1 designates, together with R12, an additional bond between the carbon atoms in which R11 and R12 are placed; R 12 is selected from the group comprising hydrogen, hydroxy, d-3 alkyl, vinyl, d-C 3 alkoxy and halogen, or R 12 designates, together with R 11, an additional bond between the carbon atoms in which R 12 and R 11 are placed; R13 is hydrogen, hydroxy or halogen, or R13 designates, together with R4 or R14, an additional bond between the carbon atoms in which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen or R14 denotes, together with R3, R6 or R13, an additional bond between the carbon atoms in which R14 and R3 or R6 or R13 are placed; R15 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and = NOR23 wherein R23 is hydrogen or alkyl of d "C3 ° Rl5 designates, together with R4, a bond additional between the carbon atoms in which R15 and R4 are placed, R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and = NOR24 wherein R24 is hydrogen or d-C3, or R16 designates, together with R17, an additional bond between the carbon atoms in which R16 and R17 are placed, R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms. carbon in which R17 and R16 are placed, R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or ethoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising alkyl of d-C4 and hydroxymethyl, or R25 and R31 designate together methylene or oxo; R29 is hydrogen, hal Oxygen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25 designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, d-C4 alkyl or R7 designates, together with R8, an additional bond between the carbon atoms in which R7 and R8 are placed; R20 is selected from the group comprising d-C4 alkyl trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising d-C4 alkyl, C4-hydroxyalkyl, d-C4 haloalkyl containing up to 3 halogen atoms, methoxymethyl, acetoxymethyl and C3-C6 cycloalkyl, or R20 and R21, together with the atom of carbon to which they join, forms a cycloalkyl ring of C3 ~ d / * and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, d-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C3-C6 d- cycloalkyl alkyl; with the general proviso that at least one of R \ R2, R6, R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl and with the additional general condition that R9, R10 and R11 are not all hydroxy and with the additional general condition that it is not cholestan-3β, 5a-6β-triol-3β-hemisuccinate; cholestan-3β, 5a, 6β-triol-3β-hemisuccinate-6β-acetate; cholestan-3β, 5a, 6β-triol-3β-hemisuccinate-6β-formate; cholestan-3ß, 5a, 6ß-triol-3ß-sulfat ?; cholestan-3β, 5a, 6β-triol-3β-phosphate, cholestan-3β, 25-diol-3β-acetate; cholestan-3β, 5a, 25-triol-3β-acetate; cholestan-3β, 5a, 25-triol; cholestan-5a, 25-diol-3-one; cholest-4-en-25-ol-3-one; cholesta-4,6-di-25-ol-3 -one; la, 3β-dihydroxycholest-5-ene; la, 3β-dihydrocolest-6-ene; 3a, 6a-dihydroxy-5β-cholestan-24-one; 3a, 6a, 24-trihydroxy-5β-cholestan; 3-chlorocholest-5, 24-diene; 3β-hydroxycholest-5-en-24-one acetate; 3-chlorocholest-5-en-24-one; cholestan-25-fluoro-3β, 22 (S) -diol; cholestan-25-chloro-3β, 22 (S) -diol; cholestan-25-methyl-3β, 22-diol; cholestan-25-methyl-3β, 22-diol-3-hydrogenbutanediolate; cholestan-25-methyl-3β, 22-diol-jbis-hydrogenbutanedioate; 2ß, 3β, 14a, 22, 25-pentahydroxy-? 7-5β-cholesten-6-one; (24R) -3ß, 24, 25-trihydrocolest-5-yen "; (24RS) -3β, 24, 25-trihydroxicolest-5-ene; (24R) -1β, 3β, 24, 25 -tetrahydroxicolest- 5-ene; 4, 4-dimethyl-24-methylene-3β-sulfoxy-12a-acetoxylesta-8, 14-diene-2a, 11β-diol; 4,4-dimethyl-24-methylene-3β-sulfooxi- 12a-acetoxycholest-8-en-2a, 11β-diol, 4,4-dimethyl-24-methylene-12a-acetoxycholesta-8, 14-di-2 a, 3β, 11β-triol; 4, 48 -dime il -24-methylene-12 a-acetoxy-choles a-8, 14-dien-3β, 11β-diol; 4, 4-dimethyl-24-methylene-12a-acetoxycholest-8-en-2a, 3β, llß- triol; 4,4-dimethyl-24-methylene-12a-acetoxycholest-8-en-3β, 11β, 12a-tetraol; 4,4-dimethyl-24-methylene-3β-sulphonoxylesta-8, 14-diene; 2a, 11β, 12a-triol, 4, 4-dimethyl-24-methylenecholesterol-8, 14-dien-2a, 3β, 11β, 12a-tetraol, 4, 4-dimethyl-24-methylene-3β-sulfoxy- 12a-acetoxycholest-8-en-2-ol-ll-one; mono (4, 4-dimethyl-24-methylene-12a-acetoxycholesta-8,14-dien-2a, 11β-diol) -3β-succinate; cholesta-5,7-dien-3ß, 23 (R), 25-triol, cholesta-5, 7-dien 3β, 23 (S), 25-triol; cholesta-5, 7-diene-3β, 23 (S), 25-triol; 2ß, 3β, 14a, 22 (R), 25 -pent there drox i -? 7 - 5 ß - col is t en-6 -one; 2β, 3β, 14a, 22 (S), 25-pentahydroxy-? 7-5β-cholesten-6-one; cholest-5-en-3β, 22 (R, S), 25-triol; cholest-5-en-25-fluoro-3β, 22 (R, S) -diol; cholest-5-en-25-f luoro-22 (R, S) -ol-3β-semisuccinate; cholest-5-en-25-chloro-3β, 22-diol; cholest-5-en-25-chloro-22-ol-3ß-hemisuccinate; 3a, 7a, 12a, 25-pentahydroxy-coprostane; 3a, 7a, 12a, 25-tetrahydroxy-coprostane; 3a, 7a, 25-trihydroxy coprostane; 3a, 7a-24, 25-tetrahydroxy-coprostane; 5β-cholestan-3a, 7a, 12a, 24a, 25-penthol; 5β-cholestan-3a, 7a, 12a, 24β, 25 -pent ol; 5β-cholestan-3a, 7a, 12 a, 25, 26-penthol; 5β-cholestan-3a, 7a, 12 a, 25-tetrol; cholest-5-en-2β-f luoro-la, 3β-diol; 24-cyclopropylcol-5-en-3β, 22 (S) -diol-3-acatate, 24-cyclopropyl-5-en-3β, 22 (S) -diol, 24-cyclopropyl-5-en-3β, 22 ( S) -diol 3 hydrogen butanedioate; 24-cyclopropyl-5a-colan-3β, 22 (S) -diol; cholesta-1, 4,6-trien-3-one; la, 3β-dihydroxycholest-5-ene; the, 3ß-dihydroxy-5a -coles tan; 3β-dihydroxycholesta-5, 7-diene; la, 3ß-25-trihydroxycholest-5-ene; la, 25-dihydroxycholesterol; and the, 25-dihydroxy-cholesterol-3-benzoate. Compounds of the general formula le: characterized in that R1 and R2, which are different or identical, with the proviso that they are not both hydroxy, are selected from the group comprising hydrogen, halogen, hydroxy and branched or unbranched d-C6 alkyl which may be substituted by halogen, hydroxy or cyano, or in which R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are attached, form a cyclopropane ring, a cyclopentane ring or a cyclohexane ring; R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, CX-C4 alkanyl (attached to the same carbon atom of the sterol backbone) and = NOR26 wherein R26 is hydrogen or d-C3, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms in which R3 and R9 or R14 are placed; R 4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, d-C 4 -alkaryl (attached to the same carbon atom of the sterol backbone) and = NOR 27 wherein R 27 is hydrogen or d-C3, or R4 designates, together with R13 or R1S, an additional bond between the carbon atoms in which R4 and R13 or R15 are placed; R5 is selected from the group consisting of hydrogen, halogen, d-C4 alkyl, methylene, hydroxy, methoxy, oxo, y = NR22 wherein R22 is hydrogen or Cx-C3 alkyl, or R5 designates, together with R6, a bond additional between the carbon atoms in which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms in which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo, or R9 designates, together with R3 or R10, an additional bond between the carbon atoms in which R9 and R3 or R10 is placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms in which R10 and R9 are placed; R11 is selected from the group consisting of hydroxy, optionally substituted alkoxy, acyloxy, sulfonyloxy, phosphonyloxy, oxo, halogen, d-C4 alkanediyl (attached to the same carbon atom of the sterol backbone) and = NOR28 wherein R28 is hydrogen or Cx-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms in which R11 and R12 are placed; R12 is selected from the group consisting of hydrogen, hydroxy, Cx-C3 alkyl, vinyl, d-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms in which R12 is placed and R11; R13 is hydrogen, hydroxy or halogen, or R13 designates, together with R4 or R14, an additional bond between the carbon atoms in which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen or R14 designates, together with R
- 3, R6 or R13, an additional bond between the carbon atoms in which R14 and R3 or R6 or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, d-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and = NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, a additional bond between the carbon atoms in which R15 and R4 are placed; R16 is selected from the group consisting of hydrogen, halogen, d-C3 alkyl, methylene, hydroxy, methoxy, oxo and = N0R24 wherein R24 is hydrogen or Cx-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms in which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms in which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together denote oxo; R25 is selected from the group comprising CX-C4 alkyl and hydroxymethyl, or R25 and R31 designate methylene or oxo together; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25 designate methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, d-C4 alkyl, methylene and oxo; or R7 designates, together with R8, an additional bond between the carbon atoms in which R7 and R8 are placed; R20 is selected from the group comprising d-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group consisting of CX-C4 alkyl, Cx-C4 hydroxyalkyl, d-C4 haloalkyl containing up to 3 halogen atoms, methoxymethyl, acetoxymethyl and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom to which they join, forms a cycloalkyl ring of C3-C6; and when A is a nitrogen atom, R7 designates a single pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R 20 and R 21 are, independently, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl and with the additional general condition that R9, R10 and R11 are not all hydroxy and with the additional general condition that if not, for use in the regulation of meiosis.
- 4. The use of a compound of the general formula lc, described above, characterized in that it is used for the preparation of a medicament for use in the regulation of meiosis.
- 5. A method for regulating meiosis in a mammalian germ cell, which method comprises administering an effective amount of a compound of the general formula described above to a germ cell in need of such treatment.
- 6. A method, characterized in that a compound of the general formula is administered as described above to a germ cell by administering it to a cell harbored in the mammal.
- 7. The method according to any of the preceding two claims, characterized in that in the germ cell the meiosis of which it is going to regulate, is an oocyte.
- The method according to any of the two previous method claims, characterized in that a compound according to any of the preceding product claims is administered to an ex vivo oocyte.
- 9. The method according to any of the two previous method claims, characterized in that the germ cell from which meiosis is going to be regulated is a male germ cell.
- 10. The method according to any of the two previous method claims, characterized in that mature male germ cells are produced by administering a compound according to any of the preceding product claims to testicular tissue in vivo or in vitro.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1478/96 | 1996-12-20 | ||
| US041488 | 1997-02-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99005771A true MXPA99005771A (en) | 2000-02-02 |
Family
ID=
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