Patent EA-004703-B1 (EA)
Title: Vitamin d derivatives with cyclic substructures in the side chains, method and intermediates for their production and their use in the preparation of medicaments
Inventor: STEINMEYER ANDREAS
IPC: B21C25/02
Filed: 2000-07-24
Abstract: 1. Vitamin D derivatives of general formula I, in which Y1 and Y2, independently of one another, each mean a hydrogen atom or a group -C(O)R5, and Y3 means a hydrogen atom or a hydroxy group, a halogen atom, a group -OC(O)R5 or an -OR5 group, whereby R5 stands for a saturated C1-C12 alkyl radical, and group Y3 can be present both in the 2.alpha.-situation and the epimeric 2.beta.-situation, R1 and R2 each mean a hydrogen atom or together an exocyclic methylene group, R3 and R4, independently of one another, each mean a hydrogen atom, or an alkyl group with 1 to 4 carbon atoms, Q means a straight-chain alkylene group with 1 to 5 carbon atoms, X1 and X2 together mean a double-bonded keto-oxygen atom or, independently of one another, a hydrogen atom, a hydroxy group, an -O(CO)R5 group, a fluorine, chlorine or bromine atom, whereby X1 and X2, not at the same time, each should be a hydroxy group or each an -O(CO)R5 group, Z means a carbocyclic or heterocyclic, optionally aromatic or heteroaromatic ring with 5 or 6 ring members or a condensed ring system that consists of a 5- and a 6-membered ring or two 6-membered rings, which can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, one or more hydroxy groups, one or more COOR6 groups, one or more C1-C5 alkyl groups, which in turn can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, C1-C6 alkoxy groups and/or COOR6 groups, whereby R6 stands for a C1-C6 alkyl group, a benzyl group or a phenyl group, and all possible epimers or diastereomers and mixtures thereof. 2. Compounds of general formula I according to claim 1, in which R3 or R4 means hydrogen, X1 and X2 together mean a carbonyl group, or X1 means a hydroxyl group or a fluorine atom and X2 means a hydrogen atom or X1 means a hydrogen atom and X2 means a hydroxyl group or a fluorine atom or X1 means an -OC(O)R5 group and R2 means a hydrogen atom or X1 means a hydrogen atom and X2 means an -OC(O)R5 group, and Z represents an aromatic ring cyclic system. 3. Compounds of general formula I according to claim 1, in which R3 or R4 means hydrogen, X1 and X2 together mean a carbonyl group, or X1 means a hydroxyl group or a fluorine atom and X2 means a hydrogen atom or X1 means a hydrogen atom and X2 means a hydroxyl group or a fluorine atom or X1 means an -OC(O)R5 group and X2 means a hydrogen atom or X1 means a hydrogen atom and X2 means an -OC(O)R5 group, and Z represents a heteroaromatic cyclic ring system. 4. Compounds according to claim 1, in which the stereochemistry in 20-position in the unnatural 20-epi-configuration is present. 5. Vitamin D derivatives of general formula I according to claim 1: (7E)-(1R,3R,24aR)-24a-(Oxazole-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(oxazole-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (5Z,7E)-(1S,3R,24aR)-24a-(oxazole-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,24aS)-24a-(oxazole-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (7E)-(1R,3R,24aR)-24a-(thiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(thiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(thiazole-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (5Z,7E)-(1S,3R,24aR)-24a-(thiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,24aS)-24a-(thiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(thiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one; (7E)-(1R,3R,24aR)-24a-(4-methylthiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(4-methylthiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (5Z,7E)-(1S,3R,24aR)-24a-(4-methylthiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,24aS)-24a-(4-methylthiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one; (7E)-(1R,3R,24aR)-24a-(thiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(thiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dime-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(thiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (5Z,7E)-(1S,3R,24aR)-24a-(thiene-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,24aS)-24a-(thiene-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (7E)-(1R,25,3R,24aR)-24a-thiene-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol; (7E)-(1R,2S,3R,24aS)-24a-thiene-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol; (7E)-(1R,2S,3R)-24a-thiene-2-yl-1,2,3-trihydroxy-24a-homo-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(4-methylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(4-methylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (5Z,7E)-(1S,3R,24aR)-24a-(4-methylthiene-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,24aS)-24a-(4-methylthiene-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthiene-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one; (7E)-(1R,2S,3R,24aR)-24a-(4-methylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dime-1,2,3,24-tetrol; (7E)-(1R,2S,3R,24aS)-24a-(4-methylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol; (7E)-(1R,2S,3R)-24a-(4-methylthiene-2-yl)-1,2,3-trihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(5-ethylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-{5-ethylthiene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aR)-24a-[5-(2-hydroxyethyl)-4-methylthiazole-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dime-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-[5-(2-hydroxyethyl)-4-methylthiazole-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-[5-(2-hydroxyethyl)-4-methylthiazole-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(benzothiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dime-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(benzothiazohe-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-24a-(benzothiazole-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-24a-(benzofuran-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(benzothiophene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(benzothiophene-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-24a-(benzothiophene-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(1-methylbenzimidazole-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(1-methylbenzimidazole-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(1-methylbenzimidazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-diene-24a-yl)-3-[(4-methoxyphenyl)-methoxy]-1H-pyrazole-4-carboxylic acid ethyl ester; (7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-diene-24a-yl)-3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester; (7E)-(1R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,2R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol; (7E)-(1R,RS,3R,24aS)-24a-(4-methylphenyl)-24a-horno-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol; (7E)-(1R,3R,24aR)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,24aR)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,24aS)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (7E)-(1R,3R,20S,24aR)-24a-(thiazole-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,20S,24aS)-24a-(thiazole-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol; (7E)-(1R,3R,205)-1,3-dihydroxy-24a-(thiazole-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one; (5Z,7E)-(1S,3R,20S,24aR)-24a-(thiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,20S,24aS)-24a-(thiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol; (5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thiazole-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one; (5Z,7E)-(1S,3R,24S)-24-(thiazole-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol; (5Z,7E)-(1S,3R,24R)-24-(thiazole-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol; (5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thiazole-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one; (7E)-(1R,3R,20S,24aR)-24a-(oxazole-4-yl)-24a-homo-19-n