US2008214541A1PendingUtilityA1
Compositions and methods for inducing osteogenesis
Est. expiryOct 15, 2022(expired)· nominal 20-yr term from priority
A61P 7/00A61P 19/10C07D 473/18C07D 473/40A61P 19/00C07D 473/34C07D 473/16
55
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Claims
Abstract
The present invention provides compositions and methods for differentiating and transdifferentiating mammalian cells into cells of an osteoblast lineage.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
wherein:
R 1 is a member selected from the group consisting of hydrogen, halogen and -L-R 2 ;
L is a member selected from the group consisting of —O— and —NR 3 —, wherein R 3 is H, or R 3 is optionally taken together with R 2 and the nitrogen to which both are attached to form a heterocycle, optionally substituted with C 1-4 alkyl;
R 2 is a member selected from the group consisting of C 1-4 alkyl, C 3-8 cycloalkyl and C 0-2 alkylaryl, substituted with 0-2 R 2a groups that are independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, —N(R 2b , R 2b ), —SO 2 N(R 2b , R 2b ), —C(O)N(R 2b , R 2b ) and —O-aryl, or when said R 2a groups are on adjacent ring atoms they are optionally taken together to form a member selected from the group consisting of —O—(CH 2 ) 1-2 —O—, —O—C(CH 3 ) 2 CH 2 — and —(CH 2 ) 3-4 —;
each R 2b group is a member that is independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 4 is a member selected from the group consisting of C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 alkylhydroxy, C 0-2 alkylaryl, substituted with 0-2 R 4a groups, and C 0-2 alkylheterocycle, optionally substituted with C 1-4 alkyl;
each R 4a group is a member independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, and aryl, or when said R 4a groups are on adjacent ring atoms they are optionally taken together to form —O—(CH 2 ) 1-2 —O—;
R 5 is hydrogen and R 6 is a member independently selected from the group consisting of halogen, C 1-4 alkyl, —C(O)—C 1-4 alkyl, —SO 2 —N(R 2b , R 2b ), C 1-4 alkylhalo, —O-aryl and —N(R 7 , R 8 ), or when R 5 and R 6 are on adjacent ring atoms they are optionally taken together to form —O—(CH 2 ) 1-2 —O—;
R 7 is a member selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkylhydroxy, aryl and —C(O)R 7a ;
R 7a is a member selected from the group consisting of C 1-4 alkyl, C 1-4 alkylhalo, C 3-8 cycloalkyl and aryl;
R 8 is a member selected from the group consisting of H and C 1-4 alkyl, or R 7 and R 8 are optionally taken together with the nitrogen to which they are attached to form a heterocycle, optionally substituted with C 1-4 alkyl; and
all pharmaceutically acceptable salts and hydrates thereof.
2 . A compound of claim 1 , wherein:
R 1 is a member selected from the group consisting of:
3 . A compound of claim 1 , wherein:
R 1 is
4 . A compound of claim 1 , wherein:
R 4 is a member selected from the group consisting of:
5 . A compound of claim 1 , wherein:
R 4 is cyclohexyl.
6 . A compound of claim 1 , wherein:
R 5 is H and R 6 is morpholine.
7 . A compound of claim 1 , wherein:
R 1 is
R 5 is H; and
R 6 is morpholine.
8 . A compound of claim 1 , wherein:
R 1 is
R 5 is H;
R 6 is morpholine; and
R 4 is a member selected from the group consisting of:
9 . A compound of claim 1 , wherein the compound is a member selected from the group consisting of:
10 . A compound of claim 1 , wherein the compound is:
11 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
12 . A method of inducing osteogenesis, the method comprising:
contacting a mammalian cell with a compound of claim 1 , whereby the mammalian cell differentiates into a cell of an osteoblast lineage.
13 . The method of claim 12 , wherein said compound of claim 1 is in a pharmaceutically acceptable carrier.
14 . The method of claim 12 , wherein the mammalian cell is in a mammal.
15 . The method of claim 14 , wherein the step of contacting is by oral administration of the compound to the mammal.
16 . The method of claim 14 , wherein the step of contacting is by intravenous administration of the compound to the mammal.
17 . The method of claim 14 , wherein the step of contacting is by subcutaneous administration of the compound to the mammal.
18 . The method of claim 14 , wherein the step of contacting is by intraperitoneal administration of the compound to the mammal.
19 . The method of claim 12 , further comprising detecting differentiation of the mammalian cell into a cell of an osteoblast lineage.
20 . The method of claim 19 , whereby differentiation of the mammalian cell into a cell of an osteoblast lineage is detected by detecting expression of an osteogenesis marker gene.
21 . The method of claim 20 , wherein the osteogenesis marker gene is a gene selected from the group consisting of alkaline phosphatase, collagen type I, osteocalcin, and osteoponin.
22 . The method of claim 19 , whereby differentiation of the mammalian cell into a cell of an osteoblast lineage is detected by detecting expression of a bone specific transcription factor.
23 . The method of claim 22 , wherein the bone specific transcription factor is Cbfa1/Runx2.
24 . The method of claim 12 , wherein the mammalian cell is a stem cell.
25 . The method of claim 24 , wherein the stem cell is a mesenchymal stem cell.
26 . The method of claim 25 , wherein the mesenchymal stem cell is isolated from a mouse.
27 . The method of claim 26 , wherein the mesenchymal stem cell is murine embryonic mesoderm fibroblast cell.
28 . The method of claim 25 , wherein the mesenchymal stem cell is isolated from a primate.
29 . The method of claim 28 , wherein the primate is a human.
30 . The method of claim 12 , wherein the mammalian cell is further contacted with bone morphogenetic protein 4 (BMP-4).
31 . The method of claim 30 , wherein the mammalian cell is a pre-adipocyte cell.
32 . The method of claim 30 , wherein the mammalian cell is a myoblast cell.
33 . The method of claim 12 , wherein the mammalian cell is attached to a solid support.
34 . The method of claim 33 , wherein the solid support is a three dimensional matrix.
35 . The method of claim 33 , wherein the solid support is a planar surface.
36 . A method of inducing osteogenesis, the method comprising:
contacting a mammalian cell with a compound of claim 10 , whereby the mammalian cell differentiates into a cell of an osteoblast lineage.
37 . The method of claim 36 , wherein the mammalian cell is in a mammal.
38 . The method of claim 36 , wherein the step of contacting is by oral administration of the compound to the mammal.
39 . The method of claim 36 , wherein the step of contacting is by intravenous administration of the compound to the mammal.
40 . The method of claim 36 , wherein the step of contacting is by subcutaneous administration of the compound to the mammal.
41 . The method of claim 36 , wherein the step of contacting is by intraperitoneal administration of the compound to the mammal.
42 . A method of treating a bone disorder, the method comprising:
contacting a mammalian cell with a compound of claim 1 , whereby the mammalian cell differentiates into a cell of an osteoblast lineage.
43 . The method of claim 42 , wherein the bone disorder is associated with defective osteoblasts.
44 . The method of claim 43 , wherein the bone disorder is osteoporosis.
45 . The method of claim 42 , further comprising administering the cell of an osteoblast lineage to an individual with the disorder, thereby treating the disorder.
46 . The method of claim 45 , wherein the administration is by surgical implantation.Cited by (0)
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