US2003083319A1PendingUtilityA1
1,3-Dihydroxy-20,20-dialkyl-vitamin D3 analogs
Est. expirySep 8, 2017(expired)· nominal 20-yr term from priority
A61P 43/00A61P 35/00C07C 401/00A61P 19/10A61K 31/593
51
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Claims
Abstract
This invention relates to 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs of Formula (I): compositions comprising the analogs, methods of preparing the analogs and methods of treatment of osteoporosis, secondary hyperparathyroidism, cancer and autoimmune diseases using such analogs.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound selected from the group of compounds represented by Formula (I)
wherein
X is hydrogen or ═CH 2 ;
R 1 and R 2 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cyclofluoroalkyl, or R 1 and R 2 together form ═CH 2 ;
R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R 3 and R 4 together with C25 form a (C 3 -C 9 )cycloalkyl or (C 3 -C 9 )cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, provided that:
(i) when R 1 and R 2 are (C 1 -C 4 )alkyl or R 1 and R 2 together with C20 form a cyclopropyl group or ═CH 2 , R 3 and R 4 are (C 1 -C 4 )alkyl, trifluoromethyl or R 3 and R 4 together with C25 form (C 3 -C 6 )cycloalkyl and A is a single bond, then B is not a trans double bond;
(ii) when B is a single bond, then R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cyclofluoroalkyl group; and
(iii) when R 1 and R 2 are (C 1 -C 4 )alkyl, R 3 and R 4 are (C 1 -C 4 )alkyl, X═CH 2 and A is a single bond, then B is not a double bond.
2 . The compound of claim 1 , wherein:
B is a triple bond.
3 . The compound of claim 2 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; X is ═CH 2 ; and A is a single bond.
4 . The compound of claim 3 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
5 . The compound of claim 4 , wherein R 3 and R 4 are methyl namely, 1,25-dihydroxy-23-yne-20,21,28-cyclopropyl-cholecalciferol.
6 . The compound of claim 4 , wherein R 3 and R 4 are trifluoromethyl, namely 1,25-dihydroxy-23-yne-26,27-hexafluoro-20,21,28-cyclopropyl-cholecalciferol.
7 . The compound of claim 2 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; X is hydrogen; and A is a single bond.
8 . The compound of claim 7 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
9 . The compound of claim 8 , wherein R 3 and R 4 are methyl, namely 1,25-dihydroxy-23-yne-20,21,28-cyclopropyl-19-nor-cholecalciferol.
10 . The compound of claim 8 , wherein R 3 and R 4 are trifluoromethyl, namely 1,25-dihydroxy-23-yne-26,27-hexafluoro-20,21,28-cyclopropyl-19-nor-cholecalciferol.
11 . The compound of claim 2 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; X is ═CH 2 ; and A is a double bond.
12 . The compound of claim 11 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 44 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
13 . The compound of claim 2 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; X is H 2 ; and A is a double bond.
14 . The compound of claim 13 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
15 . The compound of claim 1 , wherein:
A is a double bond; and B is a double bond.
16 . The compound of claim 15 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; and X is ═CH 2 .
17 . The compound of claim 16 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
18 . The compound of claim 15 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; and X is H 2 .
19 . The compound of claim 18 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
20 . The compound of claim 1 , wherein:
A is a single bond; and B is a cis double bond.
21 . The compound of claim 20 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; and X is ═CH 2 .
22 . The compound of claim 21 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
23 . The compound of claim 22 , wherein R 3 and R 4 are trifluoromethyl namely, 1,25-dihydroxy-23-(Z)-ene-26,27-hexafluoro-20,21,28-cyclopropyl-cholecalciferol.
24 . The compound of claim 20 , wherein:
R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl; R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or a (C 1 -C 4 )fluoroalkyl; and X is H 2 .
25 . The compound of claim 24 , wherein:
R 1 and R 2 together with C20 form a cyclopropyl group; and R 3 and R 4 are, independently of each other, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl.
26 . The compound of claim 25 , wherein R 3 and R 4 are trifluoromethyl namely, 1,25-dihydroxy-23-(Z)-ene-26,27-hexafluoro-20,21,28-cyclopropyl-19-nor-cholecalciferol.
27 . A method of treating osteoporosis via administration of a therapeutically effective amount of a compound of Formula (I)
wherein:
X is hydrogen or ═CH 2 ;
R 1 and R 2 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cyclofluoroalkyl, or R 1 and R 2 together form ═CH 2 ;
R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R 3 and R 4 together with C25 form a (C 3 -C 9 )cycloalkyl or (C 3 -C 9 )cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof.
28 . A method of treating cancer via administration of a therapeutically effective amount of a compound of Formula (I)
wherein:
X is hydrogen or ═CH 2 ;
R 1 and R 2 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cyclofluoroalkyl, or R 1 and R 2 together form ═CH 2 ;
R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R 3 and R 4 together with C25 form a (C 3 -C 9 )cycloalkyl or (C 3 -C 9 )cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, provided that:
(i) when R 1 and R 2 are (C 1 -C 4 )alkyl or R 1 and R 2 together with C20 form a cyclopropyl group or ═CH 2 , R 3 and R 4 are (C 1 -C 4 )alkyl, trifluoromethyl or R 3 and R 4 together with C25 form (C 3 -C 6 )cycloalkyl and A is a single bond, then B is not a trans double bond;
(ii) when B is a single bond, then R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cyclofluoroalkyl group; and
(iii) when R 1 and R 2 are (C 1 -C 4 )alkyl, R 3 and R 4 are (C 1 -C 4 )alkyl, X═CH 2 and A is a single bond, then B is not a double bond.
29 . A method of treating secondary hyperparathyroidism via administration of a therapeutically effective amount of a compound of Formula (I)
wherein:
X is hydrogen or ═CH 2 ;
R 1 and R 2 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R 1 and R 2 together with C20 form a (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cyclofluoroalkyl, or R 1 and R 2 together form ═CH 2 ;
R 3 and R 4 are, independently of each other, a (C 1 -C 4 )alkyl or (C 1 -C 4 )fluoroalkyl, or R 3 and R 4 together with C25, form a (C 3 -C 9 )cycloalkyl or (C 3 -C 9 )cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof.
30 . A pharmaceutical composition comprising an effective amount of a compound of claim 1.Join the waitlist — get patent alerts
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