Patent EA-002766-B1 (EA)
Title: S-SUBSTITUTED 11beta-BENZALDOXIME-ESTRA-4,9-DIENE-CARBONIC ACID THIOLESTERS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS
Inventor: SCHULBERT GERD
IPC: C07J43/00
Filed: 1999-02-10
Abstract: 1. A S-substituted 11β-benzaldoxime-estra-4,9-dien-carbonic acid thioester compound of the formula I:   in which R<1> is an alkyl radical having 1 to 10 carbon atoms, an aryl radical having 6 to 10 carbon atoms or an alkylaryl or arylalkyl radical each having 7 to 10 carbon atoms; R<2> is a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms; R<3> is a hydroxyl group, an O-alkyl group having 1 to 10 carbon atoms, an O-aryl group having 6 to 10 carbon atoms, an O-aralkyl group or an O-alkylaryl group, each having 7 to 10 carbon atoms, -OCOR<5>, -OCONHR<5> or -OCOOR<5>; wherein R<5> is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl or alkylaryl group each having 7 to 10 carbon atoms, R<4> is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl or alkylaryl group each having 7 to 10 carbon atoms, , -(CH2)nCH2Y, N is 0, 1 or 2, Y is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, an amino group, an azido group, a thiocyano group, -OR<6>, -SR<6>, -(CO)OR<6> or -(CO)SR<6> wherein R<6> is a hydrogen atom, an alkyl radical having 1 to 10 carbon atoms, an aryl radical having 6 to 10 carbon atoms, an alkylaryl or arylalkyl radical each having 7 to 10 carbon atoms or -COR<5>, where R<5> is as defined above, -OR<5>, -OCOR<5>, where R<5> is as defined above, -(CH<2>)m-CH=CH(CH2)P-R<6,> wherein m is 0,1,2 or 3, p is 0,1 or 2 and R<6> is as defined above or -OR<5> or -OCOR<5>, where R<5> is as defined above, -(CH2)OC [triple bond] CR<7>, wherein o is 0,1 or 2 and R<7> is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl radical having 1 to 10 carbon atoms, an aryl radical having 6 to 10 carbon atoms, an alkylaryl or arylalkyl radical each having 7 to 10 carbon atoms, -OR<5>, where R<5> is as defined above, or -OCOR<5>, where R<5> is as defined above, or -CH2OR<5>, R<5> is as defined above, or -C [triple bond] CCH2OH, or R<3> and R<4> taken together form an optionally substituted five-member or six-member ring having at least one carbon atom and from 0 to 4 hetero atoms, and each of said hetero atoms is selected from the group consisting of oxygen, sulfur, selenium, tellurium, nitrogen, phosphorus, silicon and germanium and pharmaceutical salts thereof. 2. The compounds as defined in claim 1, wherein said R<1> is an alkyl group having 1 to 6 carbon atoms. 3. The compounds as defined in claims 1 to 2, wherein said R<2> is a methyl or ethyl group. 4. The compounds as defined in claims 1 to 3, wherein said R<3> is said hydroxyl group. 5. The compounds as defined in claims 1 to 3, wherein said R<3> is an O-alkyl radical having 1 to 6 carbon atoms. 6. The compounds as defined in claims 1 to 5, wherein said R<4> is said -OR<5> or said -OCOR<5> and said R<5> is an alkyl radical having 1 to 6 carbon atoms. 7. The compounds as defined in claims 1 to 5, wherein said R<4> is said -(CH2)m=CH(CH2)p-R<6>, wherein said m is 1 and said p is 1 and wherein said R<6> is an alkyl group having 1 to 6 carbon atoms, said -OR<5> or said -OCOR<5> ; said R<5> is said hydrogen atom or an alkyl radical having 1 to 6 carbon atoms. 8. The compounds as defined in claims 1 to 5, wherein said R<4> is said -(CH2)m=CH(CH2)p-R<6>, wherein said m is 0 and said p is 1 and wherein said R<6>' is said -OR<5> or said -OCOR<5> ; said R<5> is said hydrogen atom or an alkyl radical having 1 to 6 carbon atoms. 9. The compounds as defined in claims 1 to 5, wherein said R<4> is said -(CH2)oC [triple bond] CR<7> ; said o is 1; said R<7> is an alkyl group having 1 to 6 carbon atoms, said -CH2 OR<5> or said -OCOR<5>, said R<5> being said hydrogen atom or an alkyl radical having 1 to 6 carbon atoms. 10. The compounds as defined in claims 1 to 5, wherein said R<4> is said -(CH2)nCH2Y, said n is 0 or 1, said Y is said fluorine atom, said chlorine atom, said bromine atom, said iodine atom, said cyano group, said amino group, said azido group, said thiocyano group, said -OR<6>, said -SR<6>, said -(CO)OR<6> or said -(CO)SR<6> with said R<6> being said hydrogen atom or said alkyl radical having 1 to 10 carbon atoms. 11. The compounds as defined in claims 1 to 3, wherein said R<3> and R<4> taken together optionally substituted five-member or six-member ring with at least one carbon atom and said 0 to 4 hetero atoms, said hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen. 12. The compounds as defined in claim 11, said five-member ring is formed having 1 or 2 of said hetero atoms. 13. The compound as defined in claim 12, wherein said ring is a heterocyclic ring is selected from the group consisting of oxazolidinone, oxazolinone, thiazolidinone, thiazolinone, imidazolidinone, imidazolinone, 1,3-dioxolanone, 1,3-dioxolenone, 1,3-oxathiolanone, 1,3-oxathiolenone, pyrrolidinone, pyrrolinone, oxazolidinethione, oxazolinethione, thiazolidinethione, thiazolinethione, imidazolidinethione, imidazolinethione, dioxolanethione, pyrrolidinethione and pyrrolinethione. 14. The compound as defined in claim 13, wherein said optionally substituted five-member ring is an optionally substituted heterocyclic ring and said optionally substituted heterocyclic ring is an oxazolidin-2-one or an oxazolidin-2-thione. 15. The compounds of claim 1 selected from the group consisting of 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(methylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde11-(E)[O-(methylthio)carbonyl]oxime, 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(Z)[O-(ethylthio)carbonyl]oxime, 4-[17β-methoxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl)oxime, 4-[17β-hydroxy-17α-(methoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(n-propylthio)-carbonyl]oxime, 4-[17β-methoxy-17α-(n-propoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(methylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(i-propoxymethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)(O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(methoxyethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(Z)-(3-hydroxypropenyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(methylthio)-carbonyl]oxime, 4-[17β-hydroxy-17α-(E)-(3-hydroxypropenyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(methylthio)carbonyl]oxime, 4-[17β-methoxy-17α-(3-hydroxy-1-propinyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(azidomethyl)-3-oxoestra-4,9-dien-11β-yl ]-benzaldehyde-1-(E)-[O-(methylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(chloromethyl)-3-oxoestra-4,9-dien-11β-y l]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-ethoxy-17α-(chloromethyl)-3-oxoestra-4,9-dien-11β-yl ]-benzaldehyde-1-(E)[O-(methylthio)carbonyl)oxime, 4-[17β-hydroxy-17α-(cyanomethyl)-3-oxoestra-4,9-dien-11β-yl -benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(ethylthiomethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(ethylthiomethyl)-3-oxoestra-4,9-dien-11β-yl]-benzaldehyde-1-(E)[O-(methylthio)carbonyl]oxime, 4-[17β-ethoxy-17α-(methylthiomethyl)-3-oxoestra-4,9-dien-11-yl]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-[(ethylthiocarbonyl)methyl-3-oxoestra-4,9-die n-11β-yl]benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime, 4-[17β-hydroxy-17α-(aminomethyl)-3-oxoestra-4,9-dien-11β-yl ]-benzaldehyde-1-(E)[O-(ethylthio)carbonyl]oxime and (17R)-4-(3-oxoestra-4,9-dien-17-spiro-5'-oxazolidin-2'-on-11β-yl)-benz aldehyde-1-(E)-[O-(ethylthio)-carbonyl]oxime. 16. A process for preparation of an S-substituted 11β-benzaldoxime-estra-4,9-dien-carbonic acid thioester compound of the formula I:   in which R<2>, R<3> and R<4> are as defined in claim 1, wherein the compound of general formula (II)   in which R<2>, R<3> and R<4> are as R<2>, R<3> and R<4> in formula (I), said process comprising the steps of reacting a formic acid derivative of formula (III) Nuc-(CO)-SR<1                         >(III), wherein R<1> is as defined in claim 1, and Nuc is a nucleophile, in a solvent with a compound of formula (II) and converting to said compound of said formula (I). 17. The process as defined in claim 16, wherein said solvent is a tertiary amine and said reacting takes place at a temperature of from 20 degree C to 80 degree C. 18. The process as defined in claim 17, wherein said reacting is carried out using chloroformic acid thioesters, said tertiary amine is pyridine or triethylamine and said temperature is from 20 degree C to 40 degree C. 19. Pharmaceutical compositions, wherin comprising at least one compound as defined in any of claims 1 to 15. 20. Use compounds as defined in any of claims 1 to 15 for treating endometriosis, uterus myomatosus, dysmenorrhea, premenstrual syndrome, for induction of reversible amenorrhea without estrogen deficit and for menopausal hormone replacement therapy, and when necessary in combination with estrogen 21. Use compounds as defined in any of claims 1 to 15 for preparing contraceptives.