5-{2-hydroxy-3-[1-(3-trifluoromethylphenyl)cyclopropyl]-propionylamino}-phthalide and related compounds possessing modulating activity with respect to progesterone receptor for using in control of reproductive function and hormone-substitution therapy

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the general formula (I) wherein R1 and R2 mean independently of on another hydrogen atom (H) or fluorine atom (F); R3 means -CH3 or -CF3 ; Ar means structural formulae (a) or (b) Invention relates also to a pharmaceutical composition possessing the modulating activity with respect to progesterone receptor and containing compound of the formula (I), adjuvants, carriers and excipents. Compounds of the formula (I) are used in preparing a medicinal agent designated for selective modulation of processes in organ-targets mediated by progesterone receptor, such as uterus/breast and for selective activation of transcription of progesterone receptor isoform A as compared with transcription of progesterone receptor isoform B, selective enhancing processes mediated by progesterone receptor isoform A as compared with processes mediated by progesterone receptor isoform B and as a contraceptive. Invention provides a compound using as a medicinal agent in hormone-substitution therapy and for control of reproductive function.

EFFECT: valuable medicinal and biological properties of compound and pharmaceutical composition.

45 cl, 4 dwg, 5 tbl, 6 ex

 

The text descriptions are given in facsimile form.

(57) 1. The compound of General formula

where R1and R2independently of one another denote H or F,

R3means-CH3or-CF3and

Ar means

or

provided that the compound does not mean 5-[3-{1-(3-triptoreline)cyclopropyl}-2-hydroxy-2-triftormetilfullerenov]phtalic.

2. The compound according to claim 1, representing a compound selected from the group including

5-{2-Hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(-)-5-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-t is IFormatProvider}ftale,

6-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

6-{2-hydroxy-3-[1-(3-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(3-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(3-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

5-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(+)-5-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(-)-5-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-is diftormetilirovaniya}-4-methyl-2,3-benzoxazin-1-he,

6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-it,preferably

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}phtalic.

3. Pharmaceutical composition having modulating activity against progesterone receptor-containing compound according to claims 1 and 2, and adjuvants, carriers, diluents.

4. The pharmaceutical composition according to claim 3 where the compound according to claim 1 is present in a quantity sufficient for the introduction of a daily dose of from 0.01 to 2 mg

5. The pharmaceutical composition according to claim 3, further comprising 17α-levonorgestrel or other estrogenic component.

6. The pharmaceutical composition according to claim 5, where 17α-etinilestradiol or other estrogenic component is present in a quantity sufficient for the introduction of a daily dose of from 0.01 to 0.05 mg

7. The compound according to claim 1 for use as a drug in hormonesensitive therapy for the control of reproductive function.

8. The compound according to claim 1, which represents a connection, using the data from the group including

5-{2-Hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(-)-5-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

6-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov)-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

6-{2-hydroxy-3-[1-(3-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(3-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(3-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

5-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(+)-5-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triftormetilfullerenov}ftale,

(-)-5-{2-hydroxy-3-[1-(2-fluoro-3-triptoreline)cyclopropyl]-2-triptoreline is but}ftale,

6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}-4-methyl-2,3-benzoxazin-1-he,

6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(+)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

(-)-6-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-methylpropionamide}-4-methyl-2,3-benzoxazin-1-he,

preferably

(+)-5-{2-hydroxy-3-[1-(2-fluoro-5-triptoreline)cyclopropyl]-2-triftormetilfullerenov}phtalic

for use as a drug in hormonesensitive therapy for the control of reproductive function.

9. The connection according to claim 7 as a drug for use in the control of reproductive function, hormonesensitive therapy or the treatment of gynecological disorders, for example, for the treatment of endometriosis.

10. The pharmaceutical composition according to claim 3, for use as a drug in hormonesensitive tera is AI, for the control of reproductive function.

11. The pharmaceutical composition of claim 10, comprising the compound according to claim 2 for use as a drug in hormonesensitive therapy for the control of reproductive function.

12. The pharmaceutical composition of claim 10, for use in the control of reproductive function, hormonesensitive therapy or the treatment of gynecological disorders, for example, for the treatment of endometriosis.

13. The use of compounds according to claim 1, comprising 5-[3-{1-(3-triptoreline)cyclopropyl}-2-hydroxy-2-cryptomaterial-amino]phtalic excluded from claim 1, for obtaining a medicinal product intended for the selective modulation processes in target tissues such as the uterus/breast-mediated progesterone receptor.

14. Use item 13, where the first selected tissue is tissue of the uterus, and the second selected tissue is breast tissue.

15. Use item 13, where the drug is intended for use in the control of reproductive function, hormonesensitive therapy or the treatment of gynecological disorders, for example, for the treatment of endometriosis.

16. Use 13 for selective amplification effects, mediated by the progesterone receptor in the uterus compared with the effects mediated by receptor prog is Theron, in the breast.

17. The application of article 16 for selective amplification of antiproliferative action in the uterus compared with proliferation and differentiation in the mammary gland.

18. The application indicated in paragraph 13 where the compound is a compound according to claim 2.

19. Use item 13, where the drug is administered by oral method.

20. The application indicated in paragraph 13 where the compound according to claim 1 is present in a quantity sufficient for the introduction of a daily dose of from 0.01 to 2 mg

21. Use item 13, where the medicinal product further includes 17α-levonorgestrel or other estrogenic component.

22. Use item 21, where 17α-levonorgestrel or other estrogenic component is present in a quantity sufficient for the introduction of a daily dose of from 0.01 to 0.05 mg

23. The application of article 22, where the daily dose of the compound according to claim 1 and 17α-ethinyl estradiol or other estrogenic component for introducing change independently from each other during the menstrual cycle.

24. The use of compounds according to claim 1 as a contraceptive.

25. The application of paragraph 24, where the compound is a compound according to claim 2.

26. The application of paragraph 24, where contraceptive drug is administered by oral method.

27. The application of paragraph 24, where the contraceptive pill is an oral contraceptive, not sod is Rashi estrogen.

28. The application of paragraph 24, where the connection according to claim 1 is administered in a quantity sufficient to provide a daily dose of from 0.01 to 2 mg

29. The application of paragraph 24, where the connection according to claim 1 is administered together with the 17α-ethinyl estradiol or other estrogenic component.

30. The application of clause 29, in which the 17α-levonorgestrel or other estrogenic component is administered in a quantity sufficient to create a daily dose of from 0.01 to 0.05 mg

31. The application of paragraph 24, where the daily dose of the compound according to claim 1 and 17α-ethinyl estradiol or other estrogenic component for introducing change independently from each other during the menstrual cycle.

32. The use of compounds according to claim 1, comprising 5-[3-{1-(3-triptoreline)cyclopropyl}-2-hydroxy-2-cryptomaterial-amino]phtalic excluded from claim 1, for obtaining a medicinal product intended for the selective activation of transcription isoforms And receptor progesterone compared with transcription isoforms of the progesterone receptor.

33. Use p, where the compound is a compound according to claim 2.

34. The use of compounds according to claim 1, comprising 5-[3-{1-(3-triptoreline)cyclopropyl}-2-hydroxy-2-cryptomaterial-amino]phtalic excluded from claim 1, for obtaining a medicinal product intended for selective amplification process is s, mediated isoform And receptor progesterone, compared with processes mediated isoform In receptor progesterones.

35. The application 34, where the compound is a compound according to claim 2.



 

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13 cl, 1 tbl, 5 ex

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107 cl, 2 dwg, 2 tbl, 10 ex

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EFFECT: valuable medicinal properties of compounds.

33 cl, 1 dwg, 2 tbl, 5 ex

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EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

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35 cl, 10 ex, 3 dwg

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of discodermolid and its analogs of the formula (V): At the first step method involves the coupling reaction of ketone compound of the formula (I): with aldehyde compound of the formula (II): in the presence of dialkylboron halide or triphlate, amine base and polar organic solvent to yield β-hydroxyketone of the formula (III): at the second step method involves reduction of ketone compound synthesized at the first step by its treatment with boron hydride reagent in polar organic solvent medium and proton solvent to yield 1,3-diol of the formula (IV): at the third step method involves lactonization and removal of free acid-labile hydroxyl protective group of 1,3-diol synthesized at the second step by its treatment with hydrogen halide dissolved in polar solvent or mixture of solvents to yield the end compound of the formula (V) wherein R1 means (C1-C6)-alkyl; R2 means (C1-C6)-alkyl; R3 means hydrogen atom or acid-labile hydroxyl protective group; R3'' means acid-labile hydroxyl protective group; R4 means hydrogen atom or methyl group; X means oxygen atom (O) under condition that when X means O and R3 means acid-labile hydroxyl protective group of compound of the formula (I) then residue -X-R3 in compound of the formula (V) represents hydroxyl group (-OH). Also, invention relates to novel intermediate compounds of formulae (I), (III) and (IV) and to a method for synthesis of compound of the formula (I). Invention provides a new method for synthesis of the valuable compound discodermolid and its analogs with the satisfied yields.

EFFECT: improved method of synthesis.

16 cl, 4 ex

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