CA2622798A1 - 17.beta.-nitro-11.beta.-arylsteroids and their derivatives having agonist or antagonist hormonal properties - Google Patents
17.beta.-nitro-11.beta.-arylsteroids and their derivatives having agonist or antagonist hormonal properties Download PDFInfo
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- CA2622798A1 CA2622798A1 CA002622798A CA2622798A CA2622798A1 CA 2622798 A1 CA2622798 A1 CA 2622798A1 CA 002622798 A CA002622798 A CA 002622798A CA 2622798 A CA2622798 A CA 2622798A CA 2622798 A1 CA2622798 A1 CA 2622798A1
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Abstract
The invention is directed to a novel class of steroids which exhibit potent antiprogestational activity.
Claims (14)
1. A hormonal or antihormonal steroid compound of structure I, wherein R1 is (R2R3 N(O)r)-, where r is 0 or 1 and R2 and R3 are each independently H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl, any of which may be optionally substituted; or R1 is where q is 0 or 1, Y is -(CH2)m- where m is an integer of 0 to 5, or Y is -(CH2)n-Z-(CH2)p-, where n is an integer of 0 to 2, p is an integer of 0 to 2, and Z is a heteroatom (optionally substituted); and where the CH2 groups may be optionally substituted; or R1 is N-imidazolyl-, N-pyrrolyl-, halo-, HO-, CF3SO2O-, C1-6 alkyl O-, C1-6 alkyl S-, C1-6 alkyl S(O)-, C1-6 alkyl S(O2)-, C1-6 alkyl CO-, C1-6 alkyl CH(OH)-, NC-, HCC-, C6H5CC-, 2'-furyl, 3'-furyl-, 2'-thiophenyl, 3'-thiophenyl-, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl-, 2'-thiazolyl-,
2'-N-methylimidazolyl-, 5'-pyrimidinyl-, C6H5-, H2C=CH-, C1-6alkyl or MeC(=CH2)-; and R12 is H or halo; or R1 and R12 combine to form a ring where W is CH2, CH, NH, N, O, or S, and R4 is H or C1-6 alkyl; and X is O or NOR5, where R5 is H or C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkynyl, C6-12 aryl, or heteroaryl, any of which may be optionally substituted; or X is (H, H), (H, OH),(H, OSi(C1-6 alkyl)3), or (H, OCOR5), where R5 is C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl , any of which may be optionally substituted; or X is where Y is -(CH2)m- where m is an integer of 0 to 3, or Y is -(CH2)n-Z-(CH2)p- where n is an integer of 0 to 2, p is an integer of 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two C1-6 alkyl groups;
R6 is H, C1-6 alkyl, or halogen;
R7 is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, C3-8 cycloalkyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, and pharmaceutically acceptable salts thereof.
2. A hormonal or antihormonal steroid compound of structure II, wherein R1 is (R2 R3 N(O)r)-, where r is 0 or 1 and R2 and R3 are each independently H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl, any of which may be optionally substituted; or R1 is where q is 0 or 1, Y is -(CH2)m- where m is an integer of 0 to 5, or Y is -(CH2)n-Z-(CH2)p- where n is an integer of 0 to 2, p is an integer of 0 to 2, and Z is a heteroatom (optionally substituted) and where the CH2 groups may be optionally substituted; or R1 is N-imidazolyl-, N-pyrrolyl-, halo-, HO-, CF3SO2O-, C1-6 alkyl O-, C1-6 alkyl S-, C1-6 alkyl S(O)-, C1-6 alkyl S(O2)-, C1-6 alkyl CO-, C1-6 alkyl CH(OH)-, NC-, HCC-, C6H5CC-, 2'-furyl, 3'-furyl-, (2'-thiophenyl, 3'-thiophenyl-, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl-, 2'-thiazolyl-, 2'-N-methylimidazolyl-, 5'-pyrimidinyl-, C6H5-, H2C=CH-, C1-6 alkyl or MeC(=CH2)-; and R12 is H or halo; or R1 and R1z combine to form a ring where W is CH2, CH, NH, N, O, or S, and R 4 is H or C1-6 alkyl; and X is O or NOR5, where R5 is H or C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, or heteroaryl, any of which may be optionally substituted; or X is (H, H), (H, OH) , (H, OSi(C1-6 alkyl)3), or (H, OCOR5), where R5 is C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl , any of which may be optionally substituted; or X is where Y is -(CH2)m- where m is an integer of 0 to 3, or Y is -(CH2)n-Z-(CH2)p- where n is an integer of 0 to 2, p is an integer of 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two C1-6 alkyl groups;
R6 is H, C1-6 alkyl, or halogen; and R8 is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, C3-8 cycloalkyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, and pharmaceutically acceptable salts thereof.
R6 is H, C1-6 alkyl, or halogen;
R7 is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, C3-8 cycloalkyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, and pharmaceutically acceptable salts thereof.
2. A hormonal or antihormonal steroid compound of structure II, wherein R1 is (R2 R3 N(O)r)-, where r is 0 or 1 and R2 and R3 are each independently H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl, any of which may be optionally substituted; or R1 is where q is 0 or 1, Y is -(CH2)m- where m is an integer of 0 to 5, or Y is -(CH2)n-Z-(CH2)p- where n is an integer of 0 to 2, p is an integer of 0 to 2, and Z is a heteroatom (optionally substituted) and where the CH2 groups may be optionally substituted; or R1 is N-imidazolyl-, N-pyrrolyl-, halo-, HO-, CF3SO2O-, C1-6 alkyl O-, C1-6 alkyl S-, C1-6 alkyl S(O)-, C1-6 alkyl S(O2)-, C1-6 alkyl CO-, C1-6 alkyl CH(OH)-, NC-, HCC-, C6H5CC-, 2'-furyl, 3'-furyl-, (2'-thiophenyl, 3'-thiophenyl-, 2'-pyridyl, 3'-pyridyl, 4'-pyridyl-, 2'-thiazolyl-, 2'-N-methylimidazolyl-, 5'-pyrimidinyl-, C6H5-, H2C=CH-, C1-6 alkyl or MeC(=CH2)-; and R12 is H or halo; or R1 and R1z combine to form a ring where W is CH2, CH, NH, N, O, or S, and R 4 is H or C1-6 alkyl; and X is O or NOR5, where R5 is H or C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, or heteroaryl, any of which may be optionally substituted; or X is (H, H), (H, OH) , (H, OSi(C1-6 alkyl)3), or (H, OCOR5), where R5 is C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl , any of which may be optionally substituted; or X is where Y is -(CH2)m- where m is an integer of 0 to 3, or Y is -(CH2)n-Z-(CH2)p- where n is an integer of 0 to 2, p is an integer of 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two C1-6 alkyl groups;
R6 is H, C1-6 alkyl, or halogen; and R8 is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, C3-8 cycloalkyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl, any of which may be optionally substituted, and pharmaceutically acceptable salts thereof.
3. The steroid having structure I of claim 1 wherein R1-Ph is 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl,
4-(N-piperidino)phenyl, 4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl, 1-methylindol-5-yl or 1-methyl-2,3-dihydroindol-5-yl);
X is O, NOH, or NOCH3;
R6 is H, CH3, F or Cl;
R7 is H, methyl, ethynyl, 1-propynyl, 3-propynyl, 3-hydroxypropyl, 3-hydroxy-1-propenyl (E- or Z-), 3,3,3-trifluropropyn-1-yl, 3-hydroxypropyn-1-yl, (CH2)2COOCH3, (CH2)2COOC2H5, (CH2)2COCH3, CC-C6H5, or CH2C6H5.
4. The steroid of Claim 2, wherein R1-Ph is 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, (N-piperidino)phenyl, 4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl, 1-methylindol-5-yl or 1-methyl-2,3-dihydroindol-5-yl;
X is O, NOH, or NOCH3;
R6 is H, CH3, F or Cl; and R8 is H, CH3 or CH2C6H5.
X is O, NOH, or NOCH3;
R6 is H, CH3, F or Cl;
R7 is H, methyl, ethynyl, 1-propynyl, 3-propynyl, 3-hydroxypropyl, 3-hydroxy-1-propenyl (E- or Z-), 3,3,3-trifluropropyn-1-yl, 3-hydroxypropyn-1-yl, (CH2)2COOCH3, (CH2)2COOC2H5, (CH2)2COCH3, CC-C6H5, or CH2C6H5.
4. The steroid of Claim 2, wherein R1-Ph is 4-aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, (N-piperidino)phenyl, 4-(N-pyrrolidino)phenyl, 4-(N-morpholino)phenyl, 1-methylindol-5-yl or 1-methyl-2,3-dihydroindol-5-yl;
X is O, NOH, or NOCH3;
R6 is H, CH3, F or Cl; and R8 is H, CH3 or CH2C6H5.
5. The steroid of Claim 1 selected from the group consisting of: 11.beta.-(4-acetylphenyl)-17.alpha.-(1-propynyl)-17.beta.-nitroestra-4,9-dien-3-one; 11.beta.-(4-(N,N-dimethylamino)phenyl)-17.alpha.-(1-propynyl)-17.beta.-nitroestra-4,9-dien-3-one; 11.beta.-(4-acetylphenyl)-17.alpha.-(E-3-hydroxy-1-propenyl)-17.beta.-nitroestra-4,9-dien-3-one; 11.beta.-(4-acetylphenyl)-17.alpha.-(3-hydroxypropyl)-17.beta.-nitroestra-4,9-dien-3-one; 11.beta.-(4-(N,N-dimethylamino)phenyl)-17.alpha.-(E-3-hydroxy-1-propenyl)-17.beta.-nitroestra-4,9-dien-3-one; 11.beta.-(4-(N,N-dimethylamino)phenyl)-17.alpha.-(3-hydroxypropyl)-17.beta.-nitroestra-4,9-dien-3-one and 17.beta.-nitro-11.beta.-(4-(N-piperidino)phenyl)-17.alpha.-propynyl-estra-4,9-dien-3-one.
6. The steroid of Claim 2, selected from the group consisting of 3',4'-dihydro-11.beta.-(4-(N,N-dimethylamino)phenyl)-5'-methyl-1'-oxo-spiro[estra-4,9-diene-17.beta.,2'(2'H)-pyrrole]-3-one; 3',4'-dihydro-11.beta.-(4-(N,N-dimethylamino)phenyl)-1'-oxo-spiro[estra-4,9-diene-17.beta.,2'(2'H)-pyrrole]-3-one and 3', 4'-dihydro-11.beta.-(4-(N-piperidino)phenyl)-5'-methyl-1'-oxo-spiro[estra-4,9-diene-17.beta.,2'(2'-H)-pyrrole]-3-one.
7. A method of therapeutically treating the activity of progesterone comprising administering a therapeutically effective amount of the compound of Claim 1, to a patient in need thereof for a therapeutic purpose.
8. The method of claim 7, wherein said therapeutic purpose is the treatment of endometriosis or uterine fibroids.
9. The method of claim 7, wherein said therapeutic purpose is cervical ripening preparatory to labor and delivery of offspring.
10. The method of claim 7, wherein said therapeutic purpose is the control or regulation of fertility.
11. The method of claim 7, wherein said therapeutic purpose is the treatment of tumors or cancers.
12. The method of claim 7, wherein said therapeutic purpose is hormone replacement therapy.
13. The method of Claim 10, further comprising co-administration of a compound selected from the group consisting of a prostaglandin, an oxytocic, an estrogen and a mixture thereof.
14. A method of therapeutically treating the activity of progesterone comprising administering a therapeutically effective amount of the compound of Claim 2, to a patient in need thereof for a therapeutic purpose.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/086,674 US5962444A (en) | 1998-05-29 | 1998-05-29 | 17β-nitro-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
| US09/086,674 | 1998-05-29 | ||
| CA002333668A CA2333668C (en) | 1998-05-29 | 1999-05-28 | 17.beta.-nitro-11.beta.-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002333668A Division CA2333668C (en) | 1998-05-29 | 1999-05-28 | 17.beta.-nitro-11.beta.-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2622798A1 true CA2622798A1 (en) | 1999-12-09 |
| CA2622798C CA2622798C (en) | 2011-03-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2622798A Expired - Fee Related CA2622798C (en) | 1998-05-29 | 1999-05-28 | 17.beta.-nitro-11.beta.-arylsteroids and their derivatives having agonist or antagonist hormonal properties |
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| Country | Link |
|---|---|
| CA (1) | CA2622798C (en) |
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1999
- 1999-05-28 CA CA2622798A patent/CA2622798C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CA2622798C (en) | 2011-03-29 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20190528 |