Vitamin d analogues of pharmaceutical interest

Patent metadata

Field	Value
Publication number	US-2016297731-A1
Application number	US-201415038303-A
Country	US
Kind code	A1
Filing date	Nov 19, 2014
Priority date	Nov 20, 2013
Publication date	Oct 13, 2016
Grant date	—

Abstract

The present invention relates to compounds of pharmaceutical interest. More particularly, it relates to compounds of formula (I), to processes for obtaining thereof, to the intermediates of their synthesis and processes for obtaining the latter. The compounds of formula (I) have a certain affinity with the vitamin D receptor, they are active in a similar order to 1,25α-dihydroxyvitamin D 3 (1,25D), with the advantage of producing less or no hypercalcemia.

First claim

1 . A compound of formula (I), or one stereoisomer or pharmaceutically acceptable salts thereof,

wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 , is independently selected from hydrogen, (C 1 -C 12 )alkyl, (C 1 -C 12 )hydroxyalkyl, (C 2 -C 12 )alkenyl, (C 2 C 12 )hydroxyalkenyl, (C 2 -C 12 )alkynyl, (C 2 -C 12 ) hydroxyalkynyl, (C 1 C 12 )heteroalkyl, (C 2 -C 12 )heteroalkenyl, (C 1 -C 12 )heteroalkynyl, (C 6 C 10 )aryl, (C 3 -C 15 )hetero aryl, (C 6 -C 10 )aryl(C 1 -C 12 )alkyl, (C 1 -C 12 )alkylacyl, (C 6 -C 10 )arylacyl, (C 1 C 12 )alkoxyl, (C 6 -C 0 )aryloxyl, (C 1 -C 12 )alkylcarboxy, (C 6 C 10 ) arylcarboxy, (C 1 -C 12 )carbocycle and (C 3 C 15 )heterocycle, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are optionally substituted by hydrogen, (C 1 -C 12 )alkyl or (C 1 C 12 )hydroxyalkyl, X 1 and X 2 are hydrogen or, together with the carbon atom to which they are bonded, form a methylene (═CH 2 ) group, and
each of P 1 and P 2 is independently selected from hydrogen, (C 1 C 12 )alkyl, (C 6 -C 10 )aryl, (C 1 C 12 )alkoxyl, (C 6 -C 10 )aryloxyl, (C 1 -C 12 )alkylcarboxy, (C 6 C 10 )arylcarboxy and —OSiR a R b R c , wherein each of R a , R b and R c are selected from (C 1 -C 12 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl, (C 1 -C 12 )alkyl, (C 1 C 12 )alkoxyl, (C 6 -C 10 )aryloxyl and (C 3 -C 15 )heterocycle,
wherein between 1 and 9 hydrogen atoms in the compound of formula (I) are optionally substituted by hydrogen, deuterium ( 2 H) or tritium ( 3 H) isotopes, and/or from 1 and 9 carbon atoms in the compound of formula (I) are optionally substituted by 11 C, 13 C, 14 C isotopes.

2 . The compound of formula (I) according to claim 1 , wherein each of R 1 and R 5 is independently selected from hydrogen, (C 1 -C 12 )alkyl and (C 1 C 12 )hydroxyalkyl and R 3 is selected from (C 1 -C 12 )alkyl and (C 1 C 12 )hydroxyalkyl.

3 . The compound of formula (I) according to claim 2 , wherein R 1 is (C 1 -C 12 )alkyl and R 3 is (C 1 -C 12 )hydroxyalkyl.

4 . The compound of formula (I) according to claim 1 , wherein R 7 is hydrogen, and wherein R 2 , R 4 and R 6 are hydrogen.

5 . (canceled)

6 . The compound of formula (Ia) according to claim 1 ,

wherein R 1 is hydrogen, (C1-C12)alkyl or (C1-C12)hydroxyalkyl,
R3 is hydrogen or (C 1 -C 12 )hydroxyalkyl, R5 is hydrogen or (C1C12)hydroxyalkyl,
R7 is hydrogen, (C 1 -C 12 )alkyl or (C 1 -C 12 )hydroxyalkyl, and
X1 and X2, P1 and P 2 are as defined in claim 1 .

7 . The compound of formula (Ia), according to claim 6 , wherein R 1 is (C 1 C 12 )alkyl, R 3 is (C 1 -C 12 )hydroxyalkyl and R 5 is hydrogen.

8 . The compound of formula (Ia), according to claim 6 , wherein R 1 is (C 1 C 12 )alkyl, R 3 is (C 1 -C 12 )hydroxyalkyl and R 5 is (C 1 -C 12 )hydroxyalkyl.

9 . The compound of formula (Ia), according to claim 6 , wherein R 1 is hydrogen, R 3 is (C 1 -C 12 )hydroxyalkyl and R 5 is (C 1 -C 12 )hydroxyalkyl.

10 . The compound of formula (I), according to claim 1 wherein at least one of R 1 , R 3 and R 5 is a branched (C 1 C 12 )hydroxyalkyl.

11 . The compound of formula (I) according to claim 1 , wherein X 1 and X 2 are methylene.

12 . The compound of formula (I) according to claim 1 , characterised in that it comprises isotopic labelling.

13 . The compound of formula (I) according to claim 12 , wherein the isotopic labelling is selected from 11 C, 13 C, 14 C, 2 H and 3 H.

14 . (canceled)

15 . The compound of formula (I) according to claim 1 , selected from the group consisting of:
(1R,3S,Z)-5-((E)-3-(3-(6-hydroxy-6-methylheptyl)phenyl)pent-2-enyliden)-4-met hylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteromethylheptyl)phen yl)pent-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(6-hydroxy-6-methylheptyl)phenyl)hex-2-enyliden)4-meth ylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteromethylheptyl)phen yl)hex-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(6-hydroxy-6-methylheptyl)phenyl)hept-2-enyliden)4-meth ylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteroheptyl)phenyl)hept-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(6-hydroxy-6-methylheptyl)phenyl)non-2-enyliden)4-meth ylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteroheptyl)phenyl)non-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(6-hydroxy-6-methylheptyl)phenyl)dec-2-enyliden)4-meth ylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteroheptyl)phenyl)dec-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-9-hydroxy-3-(3-(6-hydroxy-6-methylheptyl)phenyl)-9-methyldec-2-enyliden)4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-9-hydroxy-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteroheptyl) phenyl)-9-methyldec-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-9-hydroxy-3-(3-(6-hydroxy-6-methylheptyl)phenyl)-9-methyldec-2-enyliden)4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-9-hydroxy-3-(3-(7,7,7-trideutero-6-hydroxy-6-trideuteroheptyl) phenyl)-9-methyldec-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3,5-bis(6-hydroxy-6-methylheptyl)phenyl)allyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3,5-bis(7,7,7-trideutero-6-hydroxy-6-trideuteroheptyl)phenyl) allyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(5-hydroxy-5-methylhexyl)phenyl)pent-2-enyliden)-4-meth ylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(6,6,6-trideutero-5-hydroxy-5-trideuterohexyl)phenyl)pent-2-enyliden)-4-methylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(5-hydroxy-5-methylhexyl)phenyl)hept-2-enyliden)4-meth ylenecyclohexane-1,3-diol, (1R,3S,Z)-5-((E)-3-(3-(6,6,6-trideutero-5-hydroxy-5-trideuterohexyl)phenyl)hept-2-enyliden)-4-methylenecyclohexane-1,3-diol.

16 .- 26 . (canceled)

27 . A combination of at least a compound of formula (I), as defined in claim 1 , and at least an anti-neoplastic compound.

28 . The combination according to claim 27 , wherein the anti-neoplastic compound is selected from the group consisting of alkylating agents, anti-metabolites, anti-neoplastic antibiotics, topoisomerase inhibitors, mitotic inhibitors, hormonal agents, regulators of the immune system and targeted therapies.

29 . The combination according to claim 28 , wherein the alkylating agent is selected from nitrogen mustards, nitrosoureas, alkylsulfonates, triazines, ethylamines and drugs with platinum; the anti-metabolite is selected from 5-fluorouracil, 6-mercaptopurine, capecitabine, cladribine, clofarabine, cytarabine, floxiuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, pentostatin and thioguanine; the anti-neoplastic antibiotic is selected from anthracyclines and non-anthracins; the topoisomerase inhibitor is selected from inhibitors of topoisomerase I and inhibitors of topoisomerase II; the mitotic inhibitor is selected from taxanes, epothilones, vinca alkaloids and estramustine; the hormonal agent is selected from anti-estrogens, aromatase inhibitors, progestins, anti-androgens, gonadotropin-releasing hormone agonists (GnRH) and analogues of the luteinizing hormone releasing hormone (LHRH)

Assignees

• Univ Santiago Compostela
• Univ Da Coruña
• Servizo Galego De Saude (Sergas)

Inventors

• Perez Fernandez Roman
• Seoane Ruzo Samuel
• Mourino Mosquera Antonio
• Maestro Saavedra Miguel
• Castelao Fernandez Jose Esteban
• Gogoi Pranjal

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07C35/21 Primary

  polycyclic, at least one hydroxy group bound to a non-condensed ring · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• A61K31/59

  Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems · CPC title

• A61K31/593

  9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3 · CPC title