RU2000116270A

RU2000116270A - NEW ANTIESTROGENIC STEROIDS AND RELATED PHARMACEUTICAL COMPOSITIONS AND METHODS OF OBTAINING

Info

Publication number: RU2000116270A
Application number: RU2000116270/04A
Authority: RU
Inventors: Масато ТАНАБЕ; Ричард Х. ПИТЕРС; Ван-Ру ЧАО; Линг ДЗОНГ
Original assignee: Сри Интернэшнл
Priority date: 1997-12-24
Filing date: 1998-12-23
Publication date: 2002-11-10

Claims

1. A compound with anti-estrogenic activity and reduced estrogenic activity, determined by the degree of inhibition and the degree of stimulation, respectively, of alkaline phosphatase activity in human Ishikawa cells.

2. The compound according to claim 1, essentially not having estrogenic activity.

3. A compound according to claim 1, having anti-estrogenic activity effective for inhibiting alkaline phosphatase-stimulated 10 ^-9 M estradiol activity by at least 30% and estrogenic activity less than about 5% relative to stimulating alkaline phosphatase activity.

4. The compound according to claim 1, having a core of 1,3,5-estratriene.

5. The compound according to claim 2, having a core of 1,3,5-estratriene.

6. The compound according to claim 4, wherein the 1,3,5-estratriene is 17-deoxy.

7. The compound according to claim 5, wherein the 1,3,5-estratriene is 17-deoxy.

8. 17-deoxy-1,3,5-estratriene containing a molecular fragment

in each of the C11 or C-17 positions of the estratriene nucleus,
where m denotes an integer in the range from 0 to 6;
R ²¹ denotes hydrocarbyl, including at least one oxygen atom, sulfur atom and / or nitrogen atom in the form of -O-, -S-, -NH-, or -N (alkyl) -bonds and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, alkyl-substituted amino, halogen, aryl, heteroaryl and heterocycloalkyl; and
R ²² denotes hydrogen or alkyl, or,
when m is O, R ²¹ and R ²² may be associated with the formation of a five- or six-membered cyclic structure, which may or may not be aromatic, containing 0-3 heteroatoms selected from the group consisting of N, O and S, and substituted 0-4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, and alkoxy.

9. 17-deoxy-1,3,5-estratriene containing a molecular fragment

in each of the C11 or C-17 positions of the estratriene nucleus,
where m denotes an integer in the range from 0 to 6;
p is an integer ranging from 0 to 6;
R ²⁹ and R ³⁰ are independently hydrogen, lower alkyl, or halo-geno lower alkyl or are linked together to form a heterocycloalkyl ring; and
L denotes a five- or six-membered cyclic moiety, which may or may not be aromatic, optionally containing 1-4 heteroatoms selected from the group consisting of N, O and S, and combinations thereof, and optionally substituted with one or more substituents selected from a group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy, carboxyl, hydroxy, amino, nitro, cyano and halogen.

10. 17-deoxy-1,3,5-estratriene containing a molecular fragment

in each of the C11 or C-17 positions of the estratriene nucleus,
where m denotes an integer in the range from 0 to 6;
p is an integer ranging from 0 to 6;
R ²⁹ and R ³⁰ denote lower alkyl or are linked together to form a heterocycloalkyl ring; and
Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl substituted amino.

11. 17-deoxy-1,3,5-estratriene containing a molecular fragment

in the C-17 position of the estratriene nucleus,
where m denotes an integer in the range from 0 to 6;
R ²¹ denotes hydrocarbyl, including at least one oxygen atom, sulfur atom and / or nitrogen atom in the form of -O-, -S-, -NH-, or -N (alkyl) -bonds and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, alkyl-substituted amino, halogen, aryl, heteroaryl, and heterocycloalkyl; and
R ²² denotes hydrogen or alkyl, or,
when m is O, R ²¹ and R ²² may be associated with the formation of a five- or six-membered cyclic structure, which may or may not be aromatic, containing 0-3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0-4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, and alkoxy.

12. 17-deoxy-1,3,5-estratriene containing a molecular fragment

in the C-17 position of the estratriene nucleus,
where m denotes an integer in the range from 0 to 6;
p is an integer ranging from 0 to 6;
R ²⁹ and R ³⁰ are independently hydrogen, lower alkyl or halogenated lower alkyl or are linked together to form a heterocycloalkyl ring; and
L denotes a five- or six-membered cyclic moiety, which may or may not be aromatic, optionally containing 1-4 heteroatoms selected from the group consisting of N, O and S, and combinations thereof, and optionally substituted with one or more substituents selected from a group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy, carboxyl, hydroxy, amino, nitro, cyano and halogen.

13. 17-deoxy-1,3,5-estratriene containing a molecular fragment

in the C-17 position of the estratriene nucleus,
where m denotes an integer in the range from 0 to 6;
p is an integer ranging from 0 to 6;
R ²⁹ and R ³⁰ denote lower alkyl or are linked together to form a five- or six-membered heterocycloalkyl ring; and
Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl substituted amino.

14. The compound having the structure of formula (I)

where R is selected from the group consisting of C and N, and when R is C, is in the E or Z configuration;
r1 and r2 stand for optional double bonds;
X denotes a hydrocarbyl comprising at least one oxygen atom, a sulfur atom and / or a nitrogen atom in the form of -O-, -S-, -NH- or -N (alkyl) -link and optionally containing one or more additional substituents selected from the group comprising hydroxyl, oxo, alkoxy, amino, alkyl substituted amino, halogen, aryl, heteroaryl, and heterocycloalkyl;
X ′ is hydrogen or hydrocarbyl comprising at least one oxygen atom, a sulfur atom and / or a nitrogen atom in the form of —O—, —S ~, —NH - or —N (alkyl) -linked, optionally substituted as described for X, or
X and X 'are associated with the formation of a heterocycle containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur;
when r2 is present, R ¹ is CR ¹¹ R ¹² , where R ¹¹ and R ¹² are hydrogen or lower alkyl, and when r2 is absent, R ¹ is hydrogen, alkyl or halogen;
R ^{2 is} selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, aryl, alkaryl, -ONO ₂ , -OR ¹³ and -SR ¹³ , where R ¹³ is alkyl, acyl or aryl;
R ^{3 is} selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, aryl, alkaryl, cyano, -OR ¹³ and -SR ¹³ , where R ¹³ is as defined above;
R ⁴ is hydrogen or lower alkyl;
R ^{5 is} selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, —CH ₂ CH = CH ₂ , —CHO, —NR ¹⁴ R ¹⁵ and - (CH ₂ ) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ may be the same or different and represent hydrogen or alkyl, or together form a five- or six-membered cycloalkyl group, optionally containing an additional nitrogen heteroatom;
R ^{6 is} selected from the group consisting of hydrogen, alkyl, acyl, —C (O) -aryl, —C (O) -alkyl, and —SO ₂ NH ₂ ;
R ^{7 is} selected from the group consisting of hydrogen, halogen, —NO ₂ , —CHO, —CH ₂ CH = CH ₂ , —NR ¹⁶ R ¹⁷ and - (CH ₂ ) NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ can be the same or different and represent hydrogen, alkyl or acetyl;
R ^{8 is} selected from the group consisting of hydrogen, hydroxy, —OR ^18, and —SR ¹⁸ , where R ¹⁸ is lower alkyl, lower acyl, or aryl;
R ⁹ is hydrogen or alkyl, provided that when R is N, R ^{9 is} not present; and
R ¹⁰ is methyl or ethyl,
or a pharmaceutically acceptable salt or ester thereof.

15. The compound according to claim 14, having the formula (Ia)

where m denotes an integer in the range from 0 to 6, inclusive;
p is an integer in the range from 0 to 6, inclusive; and
R ²⁹ and R ³⁰ are independently hydrogen, lower alkyl or halogenated lower alkyl or are linked together to form a five or six membered heterocycloalkyl ring; and
L denotes a five- or six-membered cyclic moiety, which may or may not be aromatic, optionally containing 1-4 heteroatoms selected from the group consisting of N, O and S, and combinations thereof, and optionally substituted with one or more substituents selected from a group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy, carboxyl, hydroxy, amino, nitro, cyano and halogen.

16. The compound according to claim 15, having the structural formula (Ib)

where R ²⁹ and R ³⁰ denote lower alkyl or are linked together to form a five- or six-membered heterocycloalkyl ring and Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen , amino and alkyl substituted amino.

17. The compound having the structure of formula (II)

where R is selected from the group consisting of C and N, and when R is C, is in the E or Z configuration;
r1 and r2 stand for optional double bonds;
X denotes a hydrocarbyl comprising at least one oxygen atom, a sulfur atom and / or a nitrogen atom in the form of -O-, -S-, -NH-, or -N (alkyl) -bonds and optionally substituted by one or more substituents selected from the group comprising hydroxyl, oxo, alkoxy, amino, alkyl-substituted amino, halogen, aryl, heteroaryl, and hetero-cycloalkyl;
X 'denotes hydrogen or hydrocarbyl, comprising at least one oxygen atom, sulfur atom and / or nitrogen atom in the form of -O-, -S-, -NH- or -N (alkyl) -linked, optionally substituted as described for X, or
X and X 'are associated with the formation of a heterocycle containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur;
when r2 is present, R ¹ is CR ¹¹ R ¹² , where R ¹¹ and R ¹² are hydrogen or lower alkyl, and when r2 is absent, R ¹ is hydrogen, alkyl or halogen;
R ^{3 is} selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, aryl, alkaryl, cyano, -OR ¹³ and -SR ¹³ , where R ¹³ is as defined above;
R ⁴ is hydrogen or lower alkyl;
R ^{5 is} selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, —CH ₂ CH = CH ₂ , —CHO, —NR ¹⁴ R ¹⁵ and - (CH ₂ ) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ may be the same or different and represent hydrogen or alkyl, or together form a five- or six-membered cycloalkyl group, optionally containing an additional nitrogen heteroatom;
R ^{6 is} selected from the group consisting of hydrogen, alkyl, acyl, —C (O) -aryl, —C (O) -alkyl, and —SO ₂ NH ₂ ;
R ^{7 is} selected from the group consisting of hydrogen, halogen, —NO ₂ , —CHO, —CH ₂ CH = CH ₂ , —NR ¹⁶ R ¹⁷ and - (CH ₂ ) NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ can be the same or different and represent hydrogen, alkyl or acetyl;
R ^{8 is} selected from the group consisting of hydrogen, hydroxyl, —OR ¹⁸ and —SR ¹⁸ , where R ¹⁸ is lower alkyl, lower acyl or aryl;
R ⁹ is hydrogen or alkyl, provided that when R is N, R ^{9 is} not present; and
R ¹⁰ is methyl or ethyl; and
R ¹⁹ and R ^{20 are} independently selected from the group consisting of hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, and halogen, or R ¹⁹ and R ²⁰ together form = O,
or a pharmaceutically acceptable salt or ester thereof.

18. Connection on p. 17, having the structure of formula (IIA)

where m denotes an integer in the range from 0 to 6, inclusive;
p is an integer in the range from 0 to 6, inclusive; and
R ²⁹ and R ³⁰ are independently hydrogen, lower alkyl or halogenated lower alkyl or are linked together to form a heterocycloalkyl ring; and
L denotes a five- or six-membered cyclic moiety, which may or may not be aromatic, optionally containing 1-4 heteroatoms selected from the group consisting of N, O and S, and combinations thereof, and optionally substituted with one or more substituents selected from a group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy, carboxyl, hydroxy, amino, nitro, cyano and halogen.

19. The compound according to claim 18, having the structure of formula (IIb)

20. The compound having the structure of formula (III)

where m denotes an integer in the range from 0 to 6, inclusive;
n is 0 or 1;
r2 represents an optional double bond and, when r2 is present, R ¹ represents CR ¹¹ R ¹² , where R ¹¹ and R ¹² denote hydrogen or lower alkyl, and when r2 is absent, R ¹ denotes hydrogen, alkyl or halogen;
R ^{2 is} selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, aryl, alkaryl, -ONO ₂ , -OR ¹³ and -SR ¹³ , where R ¹³ is alkyl acyl or aryl;
R ^{3 is} selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, aryl, alkaryl, cyano, -OR ¹³ and -SR ¹³ , where R ¹³ is as defined above;
R ⁴ is hydrogen or lower alkyl;
R ^{5 is} selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, —CH ₂ CH = CH ₂ , —CHO, —NR ¹⁴ R ¹⁵ and - (CH ₂ ) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ may be the same or different and represent hydrogen or alkyl, or together form a five- or six-membered cycloalkyl group, optionally containing an additional nitrogen heteroatom;
R ^{6 is} selected from the group consisting of hydrogen, alkyl, acyl, —C (O) -aryl, —C (O) -alkyl, and —SO ₂ NH ₂ ;
R ^{7 is} selected from the group consisting of hydrogen, halogen,
—NO ₂ , —CHO, —CH ₂ CH = CH ₂ , —NR ¹⁶ R ¹⁷ and - (CH ₂ ) NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ may be the same or different and are hydrogen, alkyl or acetyl;
R ^{8 is} selected from the group consisting of hydrogen, hydroxy, —OR ^18, and —SR ¹⁸ , where R ¹⁸ is lower alkyl, lower acyl, or aryl;
R ¹⁰ is methyl or ethyl;
R ²¹ denotes a hydrocarbyl comprising at least one oxygen atom, a sulfur atom and / or a nitrogen atom in the form of -O-, -S-, -NH- or -N (alkyl) -bonds and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogen, aryl, heteroaryl, and heterocyclic alkyl;
R ²² denotes hydrogen or alkyl, or, when m is O, R ²¹ and R ²² may be associated with the formation of a five or six membered cyclic structure, which may or may not be aromatic, containing 0-3 heteroatoms selected from the group consisting from N, O and S, and substituted with 0-4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, -C (O) -alkyl, -C (O) -O-alkyl, -O- ( CO) -alkyl, -C (O) -aryl, hydroxyl, carboxyl, halogen, nitrile, nitrate and fluorinated alkyl;
R ²³ is hydrogen or lower alkyl; and R ²⁴ and R ²⁵ both represent hydrogen or are both methylene and are linked to each other through one covalent bond,
or a pharmaceutically acceptable salt or ester thereof.

21. The compound according to claim 20, having the structure of formula (IIIa)

where R ²⁹ and R ³⁰ denote independently hydrogen, lower alkyl or halogenated lower alkyl or are linked together to form a heterocycloalkyl ring; and
L denotes a five- or six-membered cyclic moiety, which may or may not be aromatic, optionally containing 1-4 heteroatoms selected from the group consisting of N, O and S, and combinations thereof, and optionally substituted with one or more substituents selected from a group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl and alkoxy, carboxyl, hydroxy, amino, nitro, cyano and halogen.

22. Connection on p. 21, having the structure of formula (IIIb)

where R ²⁹ and R ³⁰ denote lower alkyl or are linked together to form a five- or six-membered heterocycloalkyl ring and Q ¹ , Q ² , Q ³ and Q ^{4 are} independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl , halogen, amino and alkyl substituted amino.

23. A method of treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1.

24. The method of claim 23, wherein the estrogen-dependent disorder is breast cancer.

25. The method of claim 23, wherein the estrogen-dependent disorder is uterine cancer.

26. A method of treating an individual with a non-estrogen-dependent cancer, comprising administering to the individual a therapeutically effective amount of a compound according to claim 1.

27. The method of claim 26, wherein the cancer is resistant to a variety of drugs.

28. A method of increasing the bone mass in the body of an individual mammal, comprising administering to this individual an effective amount of a compound according to claim 1, increasing bone mass.

29. A method of inhibiting bone rarefaction (rarefaction) in the body of an individual mammal, comprising administering to this individual an effective amount of a compound according to claim 1, which inhibits bone loss.

30. A method of reducing serum cholesterol in the body of an individual mammal, comprising administering to this individual an effective amount of a compound according to claim 1, reducing serum cholesterol.

31. A method for suppressing a pulmonary hypertensive disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound according to claim 1.

32. A method of suppressing atrophy of the skin, comprising prophylactically administering to an individual female in a post menopausal period an effective amount of the compound of claim 1.

33. A method of suppressing vaginal atrophy, which provides for the prophylactic administration to an individual of a female in a postmenopausal period an effective amount of a compound according to claim 1.

34. A method of suppressing an estrogen-dependent disorder of the CNS, which provides for the prophylactic administration to a female individual of a menopause period with an effective amount of a compound according to claim 1.

35. A method of treating osteoporosis in the body of an individual mammal, comprising administering to this individual a therapeutically effective amount of a compound according to claim 1.

36. A method of suppressing a CNS disorder in a woman, in the post-menopausal period, involving the administration to this woman of a therapeutically effective amount of a compound according to claim 1.

37. A method of treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a compound, structural formula

38. A method of treating an individual with an estrogen-dependent disorder, comprising administering to the individual a therapeutically effective amount of a compound, a structural formula

39. An improved method for transdermal administration of a steroid drug having a 1,3,5-estratriene core, so that effective blood levels can be obtained, providing (a) providing this drug in the form of an 11-nitrate derivative and (b) delivering this drug means to the skin or tissue of the mucous membrane in the composition, which does not contain an amplifier penetration into the skin.

40. The method of synthesis of 7α-methylestron, involving the contacting of an acidic solution of 7α-methylandrost-4-ene-3,17-dione with CuCl ₂ .

41. A pharmaceutical composition for administering an anti-estrogen agent comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.