U.S. patent application number 14/404067 was filed with the patent office on 2015-05-28 for bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto.
The applicant listed for this patent is EMORY UNIVERSITY. Invention is credited to Scott D Boden, Sreedhara Sangadala.
Application Number | 20150148292 14/404067 |
Document ID | / |
Family ID | 49916491 |
Filed Date | 2015-05-28 |
United States Patent
Application |
20150148292 |
Kind Code |
A1 |
Boden; Scott D ; et
al. |
May 28, 2015 |
BONE MORPHOGENETIC PROTEIN PATHWAY ACTIVATION, COMPOSITIONS FOR
OSSIFICATION, AND METHODS RELATED THERETO
Abstract
The disclosure relates to compounds and compositions for bone
formation, fracture treatment, bone grafting, bone fusion,
cartilage maintenance and repair, and methods related thereto. In
certain embodiments, the disclosure relates to compositions
comprising one or more compound(s) disclosed herein, such as
2-(2-Methoxybenzylidene)-1-indan-one; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl)ester;
(4'-hydroxybiphenyl-4-yl) (phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethyl-thiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl)2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl)2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-di-hydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyr-
an-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl-
]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salt thereof, for use
in bone growth processes. In a typical embodiment, a bone graft
composition is implanted in a subject at a site of desired bone
growth or enhancement. In certain embodiments, compounds disclosed
herein are useful for managing obesity and diabetes or other
metabolic syndromes by modulation of brown fat.
Inventors: |
Boden; Scott D; (Atlanta,
GA) ; Sangadala; Sreedhara; (Dallas, GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EMORY UNIVERSITY |
Atlanta |
GA |
US |
|
|
Family ID: |
49916491 |
Appl. No.: |
14/404067 |
Filed: |
July 8, 2013 |
PCT Filed: |
July 8, 2013 |
PCT NO: |
PCT/US2013/049565 |
371 Date: |
December 8, 2014 |
Related U.S. Patent Documents
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|
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Application
Number |
Filing Date |
Patent Number |
|
|
61669213 |
Jul 9, 2012 |
|
|
|
Current U.S.
Class: |
514/8.8 ;
514/280; 514/291; 514/326; 514/422; 514/492; 514/679 |
Current CPC
Class: |
A61L 27/52 20130101;
A61L 2400/06 20130101; A61L 27/46 20130101; C08L 89/06 20130101;
A61L 2430/02 20130101; A61L 27/24 20130101; A61L 27/12 20130101;
A61L 27/46 20130101; A61L 2300/414 20130101; C07D 249/14 20130101;
A61K 38/1875 20130101; A61L 27/54 20130101; A61L 2300/412 20130101;
A61K 45/06 20130101 |
Class at
Publication: |
514/8.8 ;
514/492; 514/280; 514/422; 514/291; 514/326; 514/679 |
International
Class: |
A61K 38/18 20060101
A61K038/18; A61K 45/06 20060101 A61K045/06 |
Claims
1. A bone graft composition 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N-[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carbo-
nimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin; Tirandamycin;
Noscapine; Aristolochic acid; Himbacine; Fumagillin; Fumitremorgin
C; Physalin B; derivatives, or salts thereof.
2. The bone graft composition of claim 1, further comprising a
growth factor.
3. The bone graft composition of claim 2, wherein the growth factor
is a bone morphogenetic protein.
4. The bone graft composition of claim 3, wherein the bone
morphogenetic protein is BMP-2, BMP-5, BMP-6, BMP-7, or BMP-9.
5. The bone graft composition of claim 1, further comprising
calcium phosphates.
6. The bone graft composition of claim 5, wherein said calcium
phosphates are hydroxyapatite and tricalcium phosphate.
7. The bone graft composition of claim 1, further comprising a
collagen or hydrogel matrix.
8. A kit comprising a 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N-[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carbo-
nimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin; Tirandamycin;
Noscapine; Aristolochic acid; Himbacine; Fumagillin; Fumitremorgin
C; Physalin B; derivatives, or salt thereof and a graft
composition.
9. The kit of claim 8, further comprising a bone morphogenetic
protein.
10. A method of forming bone or cartilage, comprising implanting a
graft composition comprising 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N-[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carbo-
nimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin; Tirandamycin;
Noscapine; Aristolochic acid; Himbacine; Fumagillin; Fumitremorgin
C; Physalin B; derivatives, or salt thereof in a subject under
conditions such that bone or cartilage forms in the graft
composition.
11. The method of claim 10, wherein the graft composition further
comprises a bone morphogenetic protein.
12. The method of claim 10, wherein the subject has a void in the
bony structure wherein the graft composition is implanted in the
void.
13. The method of claim 12, wherein the void is in a bone selected
from an extremity, maxilla, mandible, pelvis, spine and/or
cranium.
14. The method of claim 12, wherein said void is a result of
surgical removal of bone.
15. The method of claim 10, further comprising the step of securing
movement of bone structure with a fixation system, and removing the
system after bone forms in the implanted graft.
16-26. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisonal
Application No. 61/669,213 filed Jul. 9, 2012, hereby incorporated
by reference in its entirety.
FIELD
[0002] This disclosure relates to compounds and compositions for
bone formation, fracture treatment, bone grafting, bone fusion,
cartilage maintenance and repair, and methods related thereto. In
certain embodiments, the disclosure relates to bone graft
compositions comprising one or more compound(s) disclosed herein
such as 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihydroxy-4H-1-Benzopyr-
an-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof. In a
typical embodiment, a bone graft composition is implanted in a
subject at a site of desired bone growth or enhancement. In certain
embodiments, compounds disclosed herein are useful for managing
obesity and diabetes or other metabolic syndromes by modulation of
brown fat.
BACKGROUND
[0003] Bone grafting is typically performed for spinal fusions,
after cancerous bone removal, and in certain operations, e.g.,
plastic surgery. The iliac crest is often used as a donor site for
autologous grafts. Complications collecting bone from the iliac
crest include pain, nerve damage, hematoma and wound complications,
avulsion of the anterior superior iliac spine (ASIS), hematoma,
herniation of the abdominal cavity contents, and cosmetic
deformity. Thus, it is desirable to develop materials and methods
of forming bone that do not require harvesting bone from remote
sites of the patient.
[0004] Synthetic bone grafts typically include a matrix that holds
minerals and other salts. Natural bone has an intracellular matrix
mainly composed of type I collagen, and some synthetic bone grafts
include a collagen matrix. Synthetic bone grafts typically contain
bone growth factors such as bone morphogenetic proteins (BMPs)
because of their ability to induce ossification in the matrix
material. Recombinant human BMP-2 has been approved by the FDA in
synthetic bone grafts such as INFUSE.TM.. INFUSE.TM. is approved
for open tibial shaft fractures, lumbar interbody fusion, and sinus
and alveolar ridge augmentations. However, the high cost and need
for high concentrations of BMP-2 for treatment creates a barrier
for routine clinical use. Thus, there is a need to identify
additional compositions that can substitute or complement the use
of BMPs in treating bone-related conditions.
[0005] References cited herein are not an admission of prior
art.
SUMMARY
[0006] This disclosure relates to compounds and compositions for
ossification and methods related thereto. In certain embodiments,
it is an object of the disclosure to provide certain compounds,
compositions, and methods of using these compounds to improve bone
formation, fracture treatment, bone grafting, bone fusion,
cartilage maintenance and repair in a subject. In a typical
embodiment, the bone graft composition comprises a compound
disclosed herein or derivatives that potentiate BMP signaling. In
specific embodiments, the disclosure relates to compounds, such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; including derivatives and those
substituted with one or more substituents, which are the same or
different, or salts thereof.
[0007] In certain embodiments, bone graft compositions comprise
compounds disclosed herein and a bone morphogenetic protein and/or
another growth factor. Typically, the bone morphogenetic protein is
BMP-2, BMP-5, or BMP-7. In certain embodiments, the graft
composition comprises calcium phosphates and/or bone granules,
hydroxyapatite and/or beta-tricalcium phosphate, alpha-tricalcium
phosphate, polysaccharides or combinations thereof. Crushed bone
granules, typically obtained from the subject, are optionally added
to the graft composition.
[0008] In some embodiments, the disclosure relates to bone graft
compositions comprising a compound disclosed herein, such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof and a
graft matrix. Typically, the matrix comprises a collagen sponge
and/or a compression resistant type I collagen and calcium
phosphates. In other embodiments, the matrix is a hydrogel.
[0009] In certain embodiments, the disclosure contemplates a graft
composition or matrix comprising compounds disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof wherein
the graft matrix is a collagen or demineralized bone matrix or
ceramic of other scaffold disclosed herein without exogenous
cells.
[0010] In some embodiments, the disclosure relates to kits
comprising a graft composition, a compound disclosed herein, and a
graft matrix. In certain embodiments, the kits further comprise a
bone morphogenetic protein and/or another growth factor. In certain
embodiments, the kits further comprise a transfer device, such as a
syringe or pipette.
[0011] In some embodiments, the disclosure relates to methods of
generating BMP-mediated osteoblasts comprising administering an
effective amount of compound(s) disclosed herein to cells capable
of osteoblastic differentiation, such as mesenchymal stem cells and
pre-osteoblastic cells.
[0012] In some embodiments, the disclosure relates to methods of
forming bone or cartilage, comprising implanting a graft
composition comprising a compound disclosed herein, such
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof in a
subject under conditions such that bone or cartilage forms in the
graft. Typically, the subject has a void in the bony structure
wherein the graft composition is implanted in the void. In certain
embodiments, the void is in a bone selected from an extremity,
maxilla, mandible, pelvis, spine and/or cranium. In certain
embodiments, the void is a result of surgical removal of bone. In
certain embodiments, the void is between bone and an implanted
medical device. In another embodiment, the method further comprises
the step of securing movement of bone structure with a fixation
system, and removing the system after bone forms in the implanted
graft.
[0013] In certain embodiments, the disclosure contemplates local
bone formation for fracture repair, segmental bone defects, spine
fusion, bone grafting, and regional bone enhancement for osteopenic
bones before they fracture (e.g. hip, vertebral body, etc) by
deliver locally to induce local bone formation.
[0014] In certain embodiments, the disclosure relates to methods of
growing bone in subject by locally administering, such as by
injection, a composition comprising a compound disclosed herein,
optionally in combination with a growth factor, about the area of
desired bone growth. In certain embodiments, the disclosure relates
to methods of growing bone comprising administering a
pharmaceutical composition comprising
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or pharmaceutically
acceptable salts thereof to a subject in an area of desired growth,
wherein the administration is localized directly about the area of
desired growth. In certain embodiments, the administration is not
oral administration. In certain embodiments, the administration is
through a catheter or hypodermic needle with a tip that is not in a
vein. In certain embodiments, the administration is by injection
into the subcutaneous tissue or in or about an area typically
occupied by bone or between vertebra, e.g., in the area usually
occupied by in the intervertebral disc, to form a spinal
fusion.
[0015] In certain embodiments, the method contemplates implanting a
graft composition in a desired area of the subject and locally
administering a composition comprising a compound disclosed herein,
optionally in combination with a growth factor, in the graft or
about the area of the graft implant such as by injection.
[0016] In certain embodiments, the disclosure relates to uses of
compounds disclosed herein for cartilage regeneration e.g., between
intervertebral disc and articular, jaw, elbow, knee, ankle, wrist,
and hip joints. Methods contemplate oral administration,
intravenous administration, or direct injection at the desired
site(s) of the subject.
[0017] In some embodiments, the disclosure relates to methods of
performing spinal fusion comprising implanting a bone graft
composition comprising a compound disclosed herein, such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof
configured to grow bone between two vertebrae of a subject. In
certain embodiments, the composition further comprises a bone
morphogenetic protein and/or another growth factor. In a typical
embodiment, the subject is diagnosed with degenerative disc disease
or has symptoms of back pain.
[0018] In some embodiments, the disclosure relates to methods of
inserting a prosthetic device or anchor, comprising exposing a bone
and implanting a graft composition comprising a compound disclosed
herein in contact with the bone. In certain embodiments, one
implants the prosthetic device or anchor in the graft composition.
In certain embodiments, the composition further comprises a bone
morphogenetic protein and/or another growth factor.
[0019] In some embodiments, the disclosure relates to
pharmaceutical compositions comprising compounds disclosed herein
or pharmaceutically acceptable salts thereof. In certain
embodiments, the composition further comprises a bone morphogenetic
protein and/or another growth factor. In certain embodiments, the
pharmaceutical composition is formulated to release over a 12 hour,
1 day, 3 day, 5 day, 7 day, two week, or one month period.
[0020] In certain embodiments, the disclosure relates to methods of
preventing or treating a bone fracture, comprising administering a
pharmaceutical composition comprising a compound disclosed herein,
such as 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof or a
pharmaceutically acceptable salt thereof, to a subject at risk for,
exhibiting symptoms of, or diagnosed with a bone fracture. In
certain embodiments, the composition further comprises a bone
morphogenetic protein and/or another growth factor.
[0021] In certain embodiments, the administration is localized. In
certain embodiments, administration is achieved through oral
delivery, intravenous delivery, parenteral delivery, intradermal
delivery, percutaneous delivery, or subcutaneous delivery. In some
embodiments, the method further comprises the step of exposing the
bone fracture to pulsed electromagnetic fields. In further
embodiments, the subject is diagnosed with a long bone shaft
fracture such as a tibia or femur fracture corrected with
intramedullary nail fixation.
[0022] In some embodiments, the disclosure relates to methods of
preventing or treating a bone degenerative disease, comprising
administering a pharmaceutical composition comprising a compound
disclosed herein, such as 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof or a
pharmaceutically acceptable salts thereof, to a subject at risk
for, exhibiting symptoms of, or diagnosed with a bone degenerative
disease. In certain embodiments, the composition further comprises
a bone morphogenetic protein and/or another growth factor. In
certain embodiments, the administration is systemic, or
administration is achieved through oral delivery, intravenous
delivery, parenteral delivery, intradermal delivery, percutaneous
delivery, or subcutaneous delivery. In some embodiments, the
disease is osteoporosis, osteitis deformans, bone metastasis,
multiple myeloma, primary hyperparathyroidism, or osteogenesis
imperfecta.
[0023] In some embodiments, the disclosure relates to methods for
decreasing the time required to form new bone in the presence of a
bone morphogenetic protein, comprising co-administering at least
one compound disclosed herein, such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof and
optionally a bone morphogenetic protein, with a cell selected from
the group consisting of osteogenic cells, pluripotent stem cells,
mesenchymal cells, and embryonic stem cells.
[0024] In certain embodiments, the disclosure relates to using
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof in the
production of a medicament for the treatment or prevention of a
bone disease or other applications disclosed herein.
[0025] In certain embodiments, the bone morphogenetic protein is
selected from the group consisting BMP-2, BMP-5, BMP-6, BMP-7,
BMP-9, and combinations thereof.
[0026] Compounds described herein may be used locally such as
injection percutaneously at any bone formation site (fracture,
spine fusion delayed a day or several days after surgery). The
compounds may also be bound to a matrix or scaffold and delivered
with growth factors, cells (MSCs or others), or on a dry carrier
matrix to direct local bone formation in the shape of the
carrier/scaffold. Within certain embodiments, it is also
contemplated that one or more of these compounds disclosed herein
may be used alone or in combination with multiple compounds, with
or without exogenous growth factors, and/or in combination with
other promoting agents of the BMP pathway such as a noggin
inhibitor, a Smurf inhibitor and/or a JAB 1 inhibitor.
[0027] In certain embodiments, compounds such as
benzo[f]quinoline-4(3H)-carbaldehyde derivatives,
1-(5-thioxo-1,2,4-dithiazolidin-3-ylidene)thiourea derivatives,
1,2,4-triazol-5-amine derivatives,
4-(oxiran-2-yl)-1-oxaspiro[2.5]octane derivatives, and physalin
derivatives may be used in any compositions or methods disclosed
herein.
[0028] In certain embodiments, the disclosure relates to
compositions comprising compounds disclosed herein and uses as
nutritional supplement to promote bone health.
[0029] In certain embodiments, the disclosure relates to methods of
treating or preventing obesity, diabetes, or type II diabetes
comprising administering an effective amount of a pharmaceutical
composition comprising 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives or salts thereof to a
subject in need thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0030] FIG. 1 illustrates the BMP signaling pathway. Although it is
not intended that embodiments of the disclosure be limited by any
particular mechanism, it is believed that the embodiments may act
through the BMP pathway. In the BMP pathway, BMP binds to the BMP
receptor type II that in turn activates BMPR-1. Activated BMPR-1
phosphorylates receptor regulated Smads (Smad1/5/8) which form
complexes with Smad4. Activated Smad complexes regulate gene
expression of BMP-responsive genes. Noggin antagonizes signaling by
binding to BMP.
DETAILED DISCUSSION
Terms
[0031] "Ossification" refers to the process of laying down new bone
by cells called osteoblasts. The term includes the growth in
healing bone fractures treated by cast or by open reduction and
stabilization by metal plate and screws. Ossification can also
result in the formation of bone tissue in an extraskeletal
location.
[0032] The term "bone morphogenetic protein" or "BMP" refers to any
one of the family of growth factors or fragments thereof with the
ability to induce the formation of bone and/or cartilage. The BMP
receptors are typically serine-threonine kinases. It is not
intended that BMP refer to any particular protein sequence and may
or may not have certain glycosylation patterns attached thereto
provided that the molecule has sufficient structural homology to
any one of the known BMPs described below and retains some
functional ability to promote bone growth, cartilage growth, or
osteoblast differentiation. BMPs may be isolated from natural or
non-natural sources, such as, but not limited to, recombinant or
synthetic methods. References to BMPs generally or a specific BMP,
e.g, BMP-2, includes recombinant or synthetically isolated versions
unless otherwise provide for herein. Combinations of BMPs are
contemplated. BMP-2 is known to induce bone and cartilage formation
and play a role in osteoblast differentiation. BMP-3 is known to
induce bone formation. BMP-4 is known to regulate the formation of
teeth, limbs and bone from mesoderm and play a role in fracture
repair. BMP-5 is known to function in cartilage development. BMP-6
is known to play a role in joint integrity and bone
formation/repair. BMP-7 and BMP-9 are known to play a role in
osteoblast differentiation. BMP-1 is a known metalloprotease that
acts on procollagen I, II, and III and is involved in cartilage
development.
[0033] As used herein, the term "derivative" refers to a
structurally similar compound that retains sufficient functional
attributes of the identified analogue. The derivative may be
structurally similar because it is lacking one or more atoms,
substituted, a salt, in different hydration/oxidation states, or
because one or more atoms within the molecule are switched, such
as, but not limited to, replacing an oxygen atom with a sulfur atom
or replacing an amino group with a hydroxy group. The derivative
may be a prodrug. Derivatives can be prepare by any variety of
synthetic methods or appropriate adaptations presented in synthetic
or organic chemistry text books, such as those provide in March's
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,
Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in
Organic Synthesis, Wiley (2006) Lutz F. Tietze.
[0034] The term "substituted" refers to a molecule wherein at least
one hydrogen atom is replaced with a substituent. When substituted,
one or more of the groups are "substituents." The molecule may be
multiply substituted. In the case of an oxo substituent (".dbd.O"),
two hydrogen atoms are replaced. Example substituents within this
context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano,
oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl,
heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, --NRaRb, --NRaC(.dbd.O)Rb, --NRaC(.dbd.O)NRaNRb,
--NRaC(.dbd.O)ORb, --NRaSO2Rb, --C(.dbd.O)Ra, --C(.dbd.O)ORa,
--C(.dbd.O)NRaRb, --OC(.dbd.O)NRaRb, --ORa, --SRa, --SORa,
--S(.dbd.O)2Ra, --OS(.dbd.O)2Ra and --S(.dbd.O)2ORa. Ra and Rb in
this context may be the same or different and independently
hydrogen, halogen hydroxy, alkyl, alkoxy, alkyl, amino, alkylamino,
dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl,
heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl.
[0035] The term "optionally substituted," as used herein, means
that substitution is optional and therefore it is possible for the
designated atom to be unsubstituted.
[0036] As used herein, "subject" refers to any animal, preferably a
human patient, livestock, or domestic pet.
[0037] As used herein, the terms "prevent" and "preventing" include
the prevention of the recurrence, spread or onset. It is not
intended that the present disclosure be limited to complete
prevention. In some embodiments, the onset is delayed, or the
severity is reduced.
[0038] As used herein, the terms "treat" and "treating" are not
limited to the case where the subject (e.g. patient) is cured and
the disease is eradicated. Rather, embodiments of the present
disclosure also contemplate treatment that merely reduces symptoms,
and/or delays disease progression.
[0039] As used herein, the term "calcium phosphate(s)" refers to
minerals containing calcium ions together with orthophosphates,
metaphosphates or pyrophosphates and optionally hydroxide ions.
Tricalcium phosphate is a calcium phosphate with formula
Ca.sub.3(PO.sub.4).sub.2. The common mineral apatite has the basic
formula Ca.sub.5(PO.sub.4).sub.3X, where X is a ion, typically a
halogen or hydroxide ion, or a mixture. Hydroxyapatite refers to
apatite where X is mainly hydroxide ion.
[0040] When used in reference to compound(s) disclosed herein,
"salts" refer to derivatives of the disclosed compound(s) where the
parent compound is modified making acid or base salts thereof.
Examples of salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines, alkylamines,
or dialkylamines; alkali or organic salts of acidic residues such
as carboxylic acids; and the like.
[0041] As used herein, "alkyl" means a noncyclic straight chain or
branched, unsaturated or saturated hydrocarbon such as those
containing from 1 to 10 carbon atoms. Representative saturated
straight chain alkyls include methyl, ethyl, n-propyl, n-butyl,
n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while
saturated branched alkyls include isopropyl, sec-butyl, isobutyl,
tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at
least one double or triple bond between adjacent carbon atoms
(referred to as an "alkenyl" or "alkynyl", respectively).
Representative straight chain and branched alkenyls include
ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl,
1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl,
2,3-dimethyl-2-butenyl, and the like; while representative straight
chain and branched alkynyls include acetylenyl, propynyl,
1-butyryl, 2-butyryl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butyryl,
and the like.
[0042] Non-aromatic mono or polycyclic alkyls are referred to
herein as "carbocycles" or "carbocyclyl" groups. Representative
saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and the like; while unsaturated carbocycles include
cyclopentenyl and cyclohexenyl, and the like.
[0043] "Heterocarbocycles" or heterocarbocyclyl" groups are
carbocycles which contain from 1 to 4 heteroatoms independently
selected from nitrogen, oxygen and sulfur which may be saturated or
unsaturated (but not aromatic), monocyclic or polycyclic, and
wherein the nitrogen and sulfur heteroatoms may be optionally
oxidized, and the nitrogen heteroatom may be optionally
quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl,
pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, and the like.
[0044] "Aryl" means an aromatic carbocyclic monocyclic or
polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems
may, but are not required to, contain one or more non-aromatic
rings, as long as one of the rings is aromatic.
[0045] As used herein, "heteroaryl" or "heteroaromatic" refers an
aromatic heterocarbocycle having 1 to 4 heteroatoms selected from
nitrogen, oxygen and sulfur, and containing at least 1 carbon atom,
including both mono- and polycyclic ring systems. Polycyclic ring
systems may, but are not required to, contain one or more
non-aromatic rings, as long as one of the rings is aromatic.
Representative heteroaryls are furyl, benzofuranyl, thiophenyl,
benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl,
pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl,
benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl,
benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is
contemplated that the use of the term "heteroaryl" includes
N-alkylated derivatives such as a 1-methylimidazol-5-yl
substituent.
[0046] As used herein, "heterocycle" or "heterocyclyl" refers to
mono- and polycyclic ring systems having 1 to 4 heteroatoms
selected from nitrogen, oxygen and sulfur, and containing at least
1 carbon atom. The mono- and polycyclic ring systems may be
aromatic, non-aromatic or mixtures of aromatic and non-aromatic
rings. Heterocycle includes heterocarbocycles, heteroaryls, and the
like.
[0047] "Alkylthio" refers to an alkyl group as defined above
attached through a sulfur bridge. An example of an alkylthio is
methylthio, (i.e., --S--CH.sub.3).
[0048] "Alkoxy" refers to an alkyl group as defined above attached
through an oxygen bridge. Examples of alkoxy include, but are not
limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,
s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy
groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,
s-butoxy, t-butoxy.
[0049] "Alkylamino" refers an alkyl group as defined above attached
through an amino bridge. An example of an alkylamino is
methylamino, (i.e., --NH--CH.sub.3).
[0050] "Alkanoyl" refers to an alkyl as defined above attached
through a carbonyl bridge (i.e., --(C.dbd.O)alkyl).
[0051] "Alkylsulfonyl" refers to an alkyl as defined above attached
through a sulfonyl bridge (i.e., --S(.dbd.O).sub.2alkyl) such as
mesyl and the like, and "Arylsulfonyl" refers to an aryl attached
through a sulfonyl bridge (i.e., --S(.dbd.O).sub.2aryl).
[0052] "Alkylsulfamoyl" refers to an alkyl as defined above
attached through a sulfamoyl bridge (i.e.,
--S(.dbd.O).sub.2NHalkyl), and an "Arylsulfamoyl" refers to an
alkyl attached through a sulfamoyl bridge (i.e.,
--S(.dbd.O).sub.2NHaryl).
[0053] "Alkylsulfinyl" refers to an alkyl as defined above with the
indicated number of carbon atoms attached through a sulfinyl bridge
(i.e. --S(.dbd.O)alkyl).
[0054] The terms "halogen" and "halo" refer to fluorine, chlorine,
bromine, and iodine.
[0055] The term "bone graft composition" refers to materials that
are substantially physiologically compatible when residing in bone
area, void, or exterior site. In certain embodiments, the bone
graft composition may be a bone graft matrix such as a collagen
sponge or a mixture of polymers and salts.
Compounds
[0056] Compounds derivatives disclosed herein may be used for bone
and cartilage growth and related applications. Derivatives of
certain compounds are further exemplified below.
[0057] In certain embodiments, the disclosure relates to
benzo[f]quinoline-4(3H)-carbaldehyde derivatives of formula I:
##STR00001##
[0058] or a salt thereof, wherein
[0059] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, and R.sup.10 are each the same or
different hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, and R.sup.10 are optionally substituted with one
or more, the same or different, R.sup.11;
[0060] R.sup.11 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.11
is optionally substituted with one or more, the same or different,
R.sup.12; and
[0061] R.sup.12 is halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0062] In certain embodiments, the disclosure relates to
1-(5-thioxo-1,2,4-dithiazolidin-3-ylidene)thiourea derivatives of
formula II:
##STR00002##
[0063] or a salt thereof, wherein
[0064] R.sup.1, R.sup.2, and R.sup.3 are each the same or different
hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto,
formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each
R.sup.1, R.sup.2, and R.sup.3 are optionally substituted with one
or more, the same or different, R.sup.4;
[0065] R.sup.4 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.4
is optionally substituted with one or more, the same or different,
R.sup.5; and
[0066] R.sup.5 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0067] In certain embodiments, R.sup.1 is alkyl substituted with a
heterocyclyl.
[0068] In certain embodiments, the disclosure relates to
1,2,4-triazol-5-amine derivatives of formula III:
##STR00003##
[0069] or a salt thereof, wherein
[0070] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each the same or
different hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are optionally substituted
with one or more, the same or different, R.sup.5;
[0071] R.sup.5 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.5
is optionally substituted with one or more, the same or different,
R.sup.6; and
[0072] R.sup.6 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0073] In certain embodiments, the disclosure relates to
4-(oxiran-2-yl)-1-oxaspiro[2.5]octane derivatives of formula
IV:
##STR00004##
[0074] or a salt thereof, wherein
[0075] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, and R.sup.10 are each the same or
different hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, and R.sup.19 are optionally substituted with one
or more, the same or different, R.sup.11;
[0076] R.sup.11 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.11
is optionally substituted with one or more, the same or different,
R.sup.12; and
[0077] R.sup.12 is halogen, nitro, cyano, hydroxy,
trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy,
carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,
acetyl, acetoxy, methylamino, ethylamino, dimethylamino,
diethylamino, N-methyl-N-ethylamino, acetylamino,
N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio,
ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl,
methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl,
N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
[0078] In certain embodiments, R.sup.1 is alkenyl.
[0079] In certain embodiments, the disclosure relates to physalin
derivatives of formula V:
##STR00005##
[0080] or a salt thereof, wherein
[0081] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and
R.sup.7 are each the same or different hydrogen, alkyl, halogen,
nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl,
carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl).sub.2amino,
alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or
heterocyclyl, wherein each R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are optionally substituted with one
or more, the same or different, R.sup.8; or R.sup.5 and R.sup.7
form a six membered oxygen containing ring;
[0082] R.sup.8 is alkyl, halogen, nitro, cyano, hydroxy, amino,
mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio,
alkylamino, (alkyl).sub.2amino, alkylsulfinyl, alkylsulfonyl,
arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R.sup.8
is optionally substituted with one or more, the same or different,
R.sup.9; and
[0083] R.sup.9 is halogen, nitro, cyano, hydroxy, trifluoromethoxy,
trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto,
sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy,
methylamino, ethylamino, dimethylamino, diethylamino,
N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl,
N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl,
ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl,
ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl,
N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl,
N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
Evaluations of Compound Activity
[0084] BMP-2 and BMP-4 have been established to be important
factors in embryonic skeletal development. BMP receptors are
transmembrane receptors classified as type I or type II based on
sequence homology and contain a Ser/Thr protein kinase domain. BMP
ligand binding to type I receptor (BMPR-I) induces the association
of BMPR-I and BMPR-II receptors, allowing the constitutively
phosphorylated BMPR-II to phosphorylate and activate the latent
BMPR-I. After activation of BMPR-I, the receptor regulated
(R)-Smad1/5/8 is phosphorylated. Phosphorylation of R-Smad releases
it from the receptor complex and forms hetero-complex associating
with common Smad (Co-Smad, Smad4). Subsequently, R-Smad/Co-Smad
complex translocates into the nucleus and regulates the
transcription of target genes by functioning in concert with other
proteins as transcription factors. See FIG. 1. BMP activity is
regulated prior to receptor recognition by the presence of several
structurally distinct extracellular BMP antagonists such as Noggin,
follistatin, sclerostatin, chordin, DCR, BMPMER, cerberus, gremlin,
DAN, and others.
[0085] Activity was evaluated by determining the potentiation of
alkaline phosphatase activity in sub-optimal doses of BMP in the
presence or absence of exogenously added noggin.
[0086] Data summary for selected compounds is provided in the table
below:
TABLE-US-00001 Fold-increase of BMP-induced ALP Compound (over BMP
alone control) 2-(2-Methoxybenzylidene)-1-indanone 2.5
N-(4-Arsonophenyl)glycine 2.5 1,2-Benzenedicarboxylic acid, 1-(1-
2.0 methylheptyl) ester (4'-Hydroxybiphenyl-4- 2.0
yl)(phenyl)methanone 2,2-Dimethylchroman-6-carboxylic acid 2.0
(4,7-dihydroxy-8-methyl-2-oxo-2H- chromen-3-yl)amide Ethyl
2-((4-chlorophenyl)thio)-1,3- 2.0 benzothiazol-6-yl carbamate Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6- 2.5 yl)carbamate Porfiromycin
2.0 l,3-Benzodioxol-5-yl-[4-(3,4,5- 4.0
trimethoxybenzoyl)-3-furyl]methanone Tricinolone acetophenonide 2.0
2,4-Bis(3,4-dimethoxyphenyl)-4H- 3.0 pyrano[3,2-c]chromen-5-one
Methyl 5-fluoro-4-methoxy-2,6- 2.5
dioxohexahydro-5-pyrimidinecarboxylate
5-(Naphthalen-1-yl)-1-phenyl-1h-tetrazole 2.5
5-(2-Phenylquinolin-4-yl)-1,3,4-oxadiazol-2- 3.0 ol
N-[2,4,5-Trimethyl-4- 2.0 (trichloromethyl)cyclohexa-2,5-
dien-1-ylidene]hydroxylamine
4-Benzoyl-3,4-dihydro-benzo[f]quinoline-3- 11.0 carbonitrile
2-Nitro-3-phenylspiro[cyclopropane-1,9'- 4.0 fluorene]
3-[4-(Furan-2-ylmethyl)-5-sulfanylidene- 9.0
1,2,4-dithiazolidin-3-ylidene]-1,1- dimethylthiourea
(6-Acetamido-7-methyl-5,8-dioxo-2,3- 2.5 dihydro-1H-pyrrolo[1,2-
a]benzimidazol-3-yl) 2-methoxyacetate 5-Iodo-1H-indole-2,3-dione
4.0 4,5-Dihydro- 1,2,9,10-tetramethoxy-, 2.0
dibenzo[d,e,g]quinoline-6-carboxylic acid, ethyl ester
[2,6-Bis(2,4-dimethylphenyl)-4-(2- 2.5 methoxyacetyl)oxy-phenyl] 2-
methoxyacetate 5,11-Dimethyl-2-(2-piperidin-1-ylethyl)-6H- 4.0
pyrido[4,3-b]carbazol-2-ium-9-ol 2-[3-[[4-[(3-Nitroacridin-9- 2.0
yl)amino]phenyl]sulfamoyl]propyl]guanidine hydrochloride
1-[[2-(Dimethylamino) ethyl]amino]-7- 3.0
hydroxy-4-methyl-9H-thioxanthen-9-one monohydriodide
5-Amino-1H-1,2,4-triazole-3-carboxylic 13.0 acid, methyl ester
Methyl N-cyano-N'-prop-2-en-1- 2.0 ylcarbamimidothioate
5,7-Dinitro-8-quinolinol 3.0 5-Nitrosoquinolin-8-ol 3.0 Cantharidin
4.0 1,7-Diaminoacridine hydrochloride, 2.0
3-Methyl-3-(1-naphthyl)-2-benzofuran- 2.0 1(3H)-one
Dichlorolapachol 2.5 Lycobetaine 2.0 6-(1-Aziridinyl)-
2,3-dihydro-3-(propionyl)- 2.5 7-methyl-1H-pyrrolo[1,8]-dione,
4-Nitroestrone 3-methyl ether 2.0
5,11-Dimethyl-6H-pyrido[4,3-b]carbazole-1- 2.0 carboxamide
hydrochloride 5-Methoxysterigmatocysin 4.0
(6-Acetamido-7-methyl-5,8-dioxo-2,3- 2.0
dihydro-1H-pyrrolo[1,2-a]benzimidazol-3- yl) 2-methoxyacetate
Horminon 3.0 7',8'-Dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro- 2.0
2'H-spiro[oxirane-2,1'-pentaleno[1,6a- c]pyran]-5'-carboxylate
benzylamine salt Nybomycin acetate 2.0
5H-[1,6]Indeno[1,2-c]isoquinoline-5,12- 3.5 dione,
2,3-dimethoxy-6-methyl- Nitidine, chloride 2.0 Iproplatin 2.0
3-[(Deoxyhexosyl)oxy]-2-(3,4- 2.0 dihydroxyphenyl)-6,8-dihdroxy-
4H-1- benzopyran-4-one 2-O-Benzyl 8-O-methyl 3-(4- 3.0
methylphenyl)sulfonyl-4,5-dioxo-6H-
pyrrolo[3,2-e]indole-2,8-dicarboxylate
6-Bromo-5,8-dihydroxy-7-[4-[2-(2- 4.0
hydroxyethoxy)ethyl]piperazin-1- yl]naphthalene-1,4-dione
hydrochloride 5-Methylbenzo[c]phenanthridin-5-ium- 2.0
2,3,8,9-tetrol (6-Acetyl-4-oxo-1,3-diphenyl-2- 2.5
sulfanylidenethieno[2,3-d]pyrimidin-5-yl) 2,4-dichlorobenzoate
N-[(E)-C-[4-[Bis(2-cyanoethyl)amino]-2- 2.0
methylphenyl]-N-(4-methylanilino)
carbonimidoyl]imino-4-methylbenzamide Gelcohol 5.0 Curcumin 3.0
Tirandamycin 4.0 Noscapine 4.0 Aristolochic acid 3.0 Himbacine 4.0
Fumagillin 5.0 Fumitremorgin C 3.0 Physalin B 5.0
[0087] In certain embodiments, the disclosure contemplates
compositions comprising any of the the compounds herein, or
derivatives or substituted forms, such as those in the table, and
uses for any of the applications disclosed herein.
Growth Factors
[0088] In some embodiments, the disclosure relates to the combined
use of growth factor(s) and compounds disclosed herein such as a
compound selected from 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salt thereof and one
or more growth factors in bone growth applications. Typically, the
growth factor is a bone morphogenetic proteins (BMPs), including
but not limited to, BMP-1, BMP-2, BMP-2A, BMP-2B, BMP-3, BMP-3b,
BMP-4, BMP-5, BMP-6, BMP-7 (OP-1), BMP-8, BMP-8b, BMP-9, BMP-10,
BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. BMPs act through specific
transmembrane receptors located on cell surface of the target
cells.
[0089] Non-limiting examples of additional suitable growth factors
include osteogenin, insulin-like growth factor (IGF)-1, IGF-II,
TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta4, TGF-beta5,
osteoinductive factor (OIF), basic fibroblast growth factor (bFGF),
acidic fibroblast growth factor (aFGF), platelet-derived growth
factor (PDGF), vascular endothelial growth factor (VEGF), growth
hormone (GH), growth and differentiation factors (GDF)-5 through 9,
and osteogenic protein-1 (OP-1). The growth factors may be isolated
from synthetic methods, recombinant sources or may be purified from
a biological sample. Preferably the growth factors are obtained
from a recombinant technology and for clarity certain embodiments
include rhBMP-2, rhBMP-4, rhBMP-6, rhBMP-7, and rhGDF-5, as
disclosed, for example, in the U.S. Pat. Nos. 4,877,864; 5,013,649;
5,661,007; 5,688,678; 6,177,406; 6,432,919; 6,534,268, and
6,858,431, and in Wozney, J. M., et al. (1988) Science,
242(4885):1528-1534 hereby incorporated by reference.
[0090] In a typical embodiment, a graft composition comprises a
matrix, BMP-2, and one or more compound(s) disclosed herein such a
compound selected from 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salt thereof in
combinations with other growth factors such as GDF-5. In one
embodiment, the matrix contains an effective amount of a BMP-2
protein, an rhBMP-2 protein, functional fragments thereof, or
combinations thereof. For certain embodiments, the range of
concentrations of BMP-2 may be about 1.0 to 4.0 mg/ml and GDF-5
concentrations may be 0.25 to 4.0 mg/ml. Although a graft matrix
may be loaded during manufacturing, it is typically loaded just
prior to implantation.
[0091] The polypeptide of human BMP-2 is 396 amino acids in length,
and its gene is localized to chromosome 20p12. BMP-2 belongs to the
transforming growth factor-beta (TGF-beta) superfamily. The human
amino acid sequence BMP-2 is SEQ ID NO:1 shown below. Amino acids
38-268 are the TGF-beta propeptide domain, and 291-396 are the
TGF-beta family N-terminal domain. Amino acids 283-396 are the
mature peptide. The mature form of BMP-2 contains four potential
N-linked glycosylation sites per polypeptide chain, and four
potential disulfide bridges. (SEQ ID NO: 1) 1 MVAGTRCLLA LLLPQVLLGG
AAGLVPELGR RKFAAASSGR PSSQPSDEVL SEFELRLLSM 61 FGLKQRPTPS
RDAVVPPYML DLYRRHSGQP GSPAPDHRLE RAASRANTVR SFHHEESLEE 121
LPETSGKTTR RFFFNLSSIP TEEFITSAEL QVFREQMQDA LGNNSSFHHR INIYEIIKPA
181 TANSKFPVTR LLDTRLVNQN ASRWESFDVT PAVMRWTAQG HANHGFVVEV
AHLEEKQGVS 241 KRHVRISRSL HQDEHSWSQI RPLLVTFGHD GKGHPLHKRE
KRQAKHKQRK RLKSSCKRHP 301 LYVDFSDVGW NDWIVAPPGY HAFYCHGECP
FPLADHLNST NHAIVQTLVN SVNSKIPKAC 361 CVPTELSAIS MLYLDENEKV
VLKNYQDMVV EGCGCR.
[0092] In one embodiment, bone morphogenetic protein includes one
of the following synthetic peptide fragments of BMP-2: SEQ ID NO: 2
(KIPKASSVPTELSAISTLYLDDD), SEQ ID NO: 3
(CCCCDDDSKIPKASSVPTELSAISTLYL) SEQ ID NO: 4
(C.sub.16H.sub.31O--NH--CCCCGGGSKIPKASSVPTELSAISTLYL) which may be
synthesized by FMOC/tBu solid-phase peptide synthesis.
[0093] BMP-7 also belongs to the TGF-beta superfamily. It induces
cartilage and bone formation. The amino acid sequence of BMP-7 is
SEQ ID NO: 5. (SEQ ID NO: 5) 1 MHVRSLRAAA PHSFVALWAP LFLLRSALAD
FSLDNEVHSS FIHRRLRSQE RREMQREILS 61 ILGLPHRPRP HLQGKHNSAP
MFMLDLYNAM AVEEGGGPGG QGFSYPYKAV FSTQGPPLAS 121 LQDSHFLTDA
DMVMSFVNLV EHDKEFFHPR YHHREFRFDL SKIPEGEAVT AAEFRIYKDY 181
IRERFDNETF RISVYQVLQE HLGRESDLFL LDSRTLWASE EGWLVFDITA TSNHWVVNPR
241 HNLGLQLSVE TLDGQSINPK LAGLIGRHGP QNKQPFMVAF FKATEVHFRS
IRSTGSKQRS 301 QNRSKTPKNQ EALRMANVAE NSSSDQRQAC KKHELYVSFR
DLGWQDWIIA PEGYAAYYCE 361 GECAFPLNSY MNATNHAIVQ TLVHFINPET
VPKPCCAPTQ LNAISVLYFD DSSNVILKKY 421 RNNVVRACGC H. Amino acids 1-29
are a potential signal sequence; 30-431 are the prepropeptide, and
293-431 are the mature protein. The mature form of BMP-7 contains
four potential N-linked glycosylation sites per polypeptide chain,
and four potential disulfide bridges.
Graft Compositions
[0094] In some embodiments, the disclosure relates to a graft
composition comprising growth factor(s) and
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof. In some
embodiments, these compositions can be created from polymers, bone
granules, and ceramics such as calcium phosphates (e.g.
hydroxyapatite and tricalcium phosphate), bioglass, and calcium
sulphate.
[0095] Bioglass refers to materials of SiO.sub.2, Na.sub.2O, CaO,
and P.sub.2O.sub.5 in specific proportions. The proportions differ
from the traditional soda-lime glasses in lower amounts of silica
(typically less than 60 mol %), higher amounts of sodium and
calcium, and higher calcium/phosphorus ratio. A high ratio of
calcium to phosphorus promotes formation of apatite crystals;
calcium and silica ions can act as crystallization nuclei. Some
formulations bind to soft tissues and bone, some only to bone, some
do not form a bond at all and after implantation get encapsulated
with non-adhering fibrous tissue, and others are completely
absorbed overtime. Mixtures of 35-60 mol % SiO.sub.2, 10-50 mol %
CaO, and 5-40 mol % Na.sub.2O bond to bone and some formulations
bond to soft tissues. Mixtures of >50 mol % SiO.sub.2, <10
mol % CaO, <35 mol % Na.sub.2O typically integrate within a
month. Some CaO may be replaced with MgO and some Na.sub.2O may be
replaced with K.sub.2O. Some CaO can be replaced with
CaF.sub.2.
[0096] In some embodiments, the disclosure relates to a graft
composition comprising growth factor(s) and compounds disclosed
herein such as 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof and/or
polysaccharides such as hyaluronate, cellulose or cellulose
derivatives such as, but not limited to, hydroxypropyl cellulose,
methyl cellulose, ethyl cellulose, and carboxymethyl cellulose.
Typically, cellulose derivates are used in graft compositions that
produce a paste or putty.
[0097] In some embodiments, the disclosure relates to a bone graft
composition comprising a bone morphogenetic protein and
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salt thereof and a
graft matrix. The matrix is typically a polymer designed to hold
bone compatible salts, such as calcium phosphates, for replacement
during bone growth. An example is a bovine Type I collagen embedded
with biphasic calcium phosphate granules. Optionally, matrix
compositions may also include one or more agents that support the
formation, development and growth of new bone, and/or the
remodeling thereof. Typical examples of compounds that function in,
such a supportive manner include extracellular matrix-associated
bone proteins such as alkaline phosphatase, osteocalcin, bone
sialoprotein (BSP) and osteocalcin, phosphoprotein (SPP)-1, type I
collagen, fibronectin, osteonectin, thrombospondin,
matrix-gla-protein, SPARC, and osteopontin.
[0098] In certain embodiments, the graft matrix can be made up of a
hydrogel polymer. Typically, a hydrogel is made-up of acrylate
polymers and copolymers substituted with an abundance of
hydrophilic groups, such as terminal hydroxy or carboxyl groups. In
certain embodiments, the graft composition is biodegradable. In
certain embodiments, the matrix comprises homopolymers and
copolymers consisting of gylcolide and lactide. For certain
embodiments, the graft composition comprises a matrix of
hydroxyethylmethacrylate or hydroxymethylmethyacrylate polymers
containing hydroxyapatite in a mineral content approximately that
of human bone. Such a composition may also be made with
crosslinkers comprising an ester, anhydride, orthoester, amide, or
peptide bond. In some embodiments, crosslinkers contain the
following polymers: polyethylene glycol (PEG), polylactic acid,
polyglycolide or combinations thereof.
[0099] In certain embodiments, the graft composition may contain
one or more antibiotics and/or anti-inflammatory agents. Suitable
antibiotics include, without limitation, nitroimidazole
antibiotics, tetracyclines, penicillins, cephalosporins,
carbopenems, aminoglycosides, macrolide antibiotics, lincosamide
antibiotics, 4-quinolones, rifamycins and nitrofurantoin. Suitable
specific compounds include, without limitation, ampicillin,
amoxicillin, benzylpenicillin, phenoxymethylpenicillin,
bacampicillin, pivampicillin, carbenicillin, cloxacillin,
cyclacillin, dicloxacillin, methicillin, oxacillin, piperacillin,
ticarcillin, flucloxacillin, cefuroxime, cefetamet, cefetrame,
cefixine, cefoxitin, ceftazidime, ceftizoxime, latamoxef,
cefoperazone, ceftriaxone, cefsulodin, cefotaxime, cephalexin,
cefaclor, cefadroxil, cefalothin, cefazolin, cefpodoxime,
ceftibuten, aztreonam, tigemonam, erythromycin, dirithromycin,
roxithromycin, azithromycin, clarithromycin, clindamycin,
paldimycin, lincomycirl, vancomycin, spectinomycin, tobramycin,
paromomycin, metronidazole, tinidazole, ornidazole, amifloxacin,
cinoxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin,
norfloxacin, ofloxacin, temafloxacin, doxycycline, minocycline,
tetracycline, chlortetracycline, oxytetracycline, methacycline,
rolitetracyclin, nitrofurantoin, nalidixic acid, gentamicin,
rifampicin, amikacin, netilmicin, imipenem, cilastatin,
chloramphenicol, furazolidone, nifuroxazide, sulfadiazin,
sulfametoxazol, bismuth subsalicylate, colloidal bismuth
subcitrate, gramicidin, mecillinam, cloxiquine, chlorhexidine,
dichlorobenzylalcohol, methyl-2-pentylphenol or any combination
thereof.
[0100] Suitable anti-inflammatory compounds include both steroidal
and non-steroidal structures. Suitable non-limiting examples of
steroidal anti-inflammatory compounds are corticosteroids such as
hydrocortisone, cortisol, hydroxyltriamcinolone, alpha-methyl
dexamethasone, dexamethasone-phosphate, beclomethasone
dipropionates, clobetasol valerate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclorolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylesters,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone, fludrocortisone,
diflurosone diacetate, fluocinolone, fluradrenolone acetonide,
medrysone, amcinafel, amcinafide, betamethasone and the balance of
its esters, chloroprednisone, chlorprednisone acetate,
clocortelone, clescinolone, dichlorisone, diflurprednate,
flucloronide, flunisolide, fluoromethalone, fluperolone,
fluprednisolone, hydrocortisone valerate, hydrocortisone
cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone,
prednisolone, prednisone, beclomethasone dipropionate,
triamcinolone. Mixtures of the above steroidal anti-inflammatory
compounds may also be used.
[0101] Non-limiting examples of non-steroidal anti-inflammatory
compounds include nabumetone, celecoxib, etodolac, nimesulide,
apasone, gold, oxicams, such as piroxicam, isoxicam, meloxicam,
tenoxicam, sudoxicam, the salicylates, such as aspirin, disalcid,
benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;
the acetic acid derivatives, such as diclofenac, fenclofenac,
indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,
zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,
felbinac, and ketorolac; the fenamates, such as mefenamic,
meclofenamic, flufenamic, niflumic, and tolfenamic acids; the
propionic acid derivatives, such as ibuprofen, naproxen,
benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,
indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen,
miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic;
and the pyrazoles, such as phenylbutazone, oxyphenbutazone,
feprazone, azapropazone, and trimethazone.
Methods
[0102] Bone grafting is possible because bone tissue, unlike most
other tissues, has the ability to regenerate if provided the space
into which to grow with appropriate chemical signals. With regard
to synthetic grafts, as native bone grows, it typically replaces
most or all of the artificial graft material, resulting in an
integrated region of new bone. However, with regard to certain
embodiments of the disclosure, it is not intended that new bone
must remove all artificial material. In addition, with regard to
certain embodiments of the disclosure, it is not intended that
graft location need contact any other bone of the skeletal
system.
[0103] In certain embodiments, the disclosure relates to a method
of forming bone comprising implanting a graft composition
comprising a compound disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof, in a
subject. In certain embodiments, the disclosure relates to methods
of forming bone comprising implanting a graft composition
comprising a bone morphogenetic protein and compound(s) disclosed
herein, such as 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof, in a
subject. The graft may be the result of a void created by surgical
removal or created as a result of an attempt to correct a physical
abnormality of a bone, such as but not limited to, cranial bones;
frontal, parietal, temporal, occipital, sphenoid, ethmoid; facial
bones; mandible, maxilla, palatine, zygomatic, nasal, lacrimal,
vomer, inferior nasal conchae; shoulder girdle; scapula or shoulder
blade, clavicle or collarbone; in the thorax; sternum, manubrium,
gladiolus, and xiphoid process, ribs; in the vertebral column;
cervical vertebrae, thoracic vertebrae; lumbar vertebrae; in the
arms, humerus, radius, ulna; in the pelvis; coccyx; sacrum, hip
bone (innominate bone or coxal bone); in the legs; femur, patella,
tibia, and fibula. It is contemplated that the graft may be added
for cosmetic purposes, e.g., cheek augmentation. In the case of a
broken bone or removal of a bone during surgery, it may be
desirable to secure movement of bone structure with a fixation
system and remove the system after bone forms in the implanted
graft.
[0104] With regard to prostheses, it may be desirable to grow bone
between existing bone and an implanted device, or in preparation of
an implanted device, such as in the case of a hip replacement, knee
replacement, and dental implant, i.e., artificial tooth root used
to support restorations that resemble a tooth or group of
teeth.
[0105] In some embodiments, the disclosure relates to
three-dimensional structures made of biocompatible and
biodegradable bone graft materials in the shape of the bone infused
with compositions disclosed herein to promote bone growth. Implants
can be used to support a number of prostheses. A typical implant
consists of a titanium device. In certain embodiments, the graft
compositions disclosed herein contain implants.
[0106] With regard to a sinus augmentation or alveolar ridge
augmentation, surgery may be performed as an outpatient under
general anesthesia, oral conscious sedation, nitrous oxide
sedation, intravenous sedation or under local anesthesia. Bone
grafting is used in cases where there is a lack of adequate
maxillary or mandibular bone in terms of depth or thickness.
Sufficient bone is needed in three dimensions to securely integrate
with the root-like implant. Improved bone height is important to
assure ample anchorage of the root-like shape of the implant.
[0107] In a typical procedure, the clinician creates a large flap
of the gingiva or gum to fully expose the bone at the graft site,
performs one or several types of block and onlay grafts in and on
existing bone, then installs a membrane designed to repel unwanted
infection-causing bacteria. Then the mucosa is carefully sutured
over the site. Together with a course of systemic antibiotics and
topical antibacterial mouth rinses, the graft site is allowed to
heal. The bone graft produces live vascular bone and is therefore
suitable as a foundation for the dental implants.
[0108] In certain embodiments, the disclosure relates to methods of
performing spinal fusion using compositions disclosed herein.
Typically this procedure is used to eliminate the pain caused by
abnormal motion of the vertebrae by immobilizing the vertebrae
themselves. Spinal fusion is often done in the lumbar region of the
spine, but the term is not intended to be limited to method of
fusing lumbar vertebrae. Patients desiring spinal fusion may have
neurological deficits or severe pain which has not responded to
conservative treatment. Conditions where spinal fusion may be
considered include, but are not limited to, degenerative disc
disease, spinal disc herniation, discogenic pain, spinal tumor,
vertebral fracture, scoliosis, kyphosis (i.e, Scheuermann's
disease), spondylolisthesis, or spondylosis.
[0109] In certain embodiments, different methods of lumbar spinal
fusion may be used in conjunction with each other. In one method,
one places the bone graft between the transverse processes in the
back of the spine. These vertebrae are fixed in place with screws
and/or wire through the pedicles of each vertebra attaching to a
metal rod on each side of the vertebrae. In another method, one
places the bone graft between the vertebra in the area usually
occupied by the intervertebral disc. In preparation for the spinal
fusion, the disc is removed entirely. A device may be placed
between the vertebrae to maintain spine alignment and disc height.
The intervertebral device may be made from either plastic or
titanium or other suitable material. The fusion then occurs between
the endplates of the vertebrae. Using both types of fusion are
contemplated.
[0110] In certain embodiments, the disclosure relates to methods of
growing bone at a desired area by locally administering a
pharmaceutical formulation containing a compound disclosed herein
such as 2-(2-Methoxybenzylidene)-1-indanone;
N-(4-arsonophenyl)glycine; 1,2-Benzenedicarboxylic acid,
1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof, to the
area of desired bone growth with or without the presence of a graft
composition or bone growth matrix optionally in combination with a
growth factor such as a bone morphogenetic protein. In certain
embodiments, the disclosure contemplates administering the
pharmaceutical compositions between vertebra, e.g., in the area
usually occupied by in the intervertebral disc, to form a spinal
fusion.
Cartilage Repair
[0111] Cartilage is typically composed of chondroblasts, Type I and
Type II collagen fibers, elastin fibers, and proteoglycans. Typical
locations within the human body to find cartilage are the joints
between bones, the ear, the nose, the elbow, the knee, the ankle,
and the intervertebral discs. Cartilage can become damaged because
of trauma or disease. In some embodiments, the disclosure relates
to using compounds disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof for the
repair or regeneration of cartilage such as articular cartilage
repair or regeneration or intervertebral disc cartilage repair or
regeneration.
[0112] Articular cartilage repair is typically done to restore the
cartilage on the surface of a bone, i.e., hyaline cartilage.
Osteochondrial autografts or allografts may be performed. In
certain embodiments, the disclosure contemplates methods of
cartilage repair comprising transplanting sections of cartilage
and/or bone to a location where cartilage and/or bone was removed
and placing a compound disclosed herein such as herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof about
the surrounding area, e.g., by injections at the site of
transplantation. Bone with its cartilage covering may be removed
from the same or a different joint and replanted into the hole left
from removing degraded bone and cartilage. The transplanted bone
and cartilage are typically taken from areas of low stress.
[0113] In autologous chondrocyte implantation, cartilage cells are
typically extracted arthroscopically from normal articular
cartilage of the subject that is located in a nonload-bearing area,
e.g., the intercondylar notch or the superior ridge of the femoral
condyles, and the cells are replicated, in vitro, in the presence
of growth factors. In certain embodiments, the disclosure relates
to replicating cartilage cells comprising mixing hyaline cartilage
and a compound disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof, under
conditions such that the cartilage cells replicate. Typically this
is done by adding other growth factors to the cartilage replicating
medium, e.g., cartilage-derived morphogenetic proteins and/or BMP
proteins. The replicated chondrocytes are implanted to the desired
area, e.g., injected about the site of the area for repair
optionally in combination with either a membrane or a matrix
comprising growth factors such as a CDMP, BMP protein or a compound
disclosed herein.
[0114] Repair of articular cartilage may be performed by marrow
stimulating procedures sometimes referred to as microfracture
surgery. Damaged cartilage is typically ablated by, e.g., drilling
or pounding, exposing the underlying bone--sometimes referred to as
a microfracture. The subchondal bone typically generates a blood
clot followed by cartilage regeneration. In some embodiments the
disclosure relates to methods of generating cartilage by disrupting
bone underlying articular cartilage and placing a compound
disclosed herein about the area of disruption, e.g., by injecting
compounds disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof about
the site of disrupted bone for the improved repair or regeneration
of cartilage optionally in combination with a growth factor such as
a CDMP and/or BMP protein. Alternatively it is contemplated that
the compounds are administered to the subject in a pharmaceutical
composition before, during or after the procedure. In another
alternative, it is contemplated that a collagen matrix is implanted
at the site of the exposed underlying bone to improve chondrogenic
differentiation of mesenchymal stem cells. It is also contemplated
that the subject may optionally be postoperative injected with
compounds disclosed herein, hyaluronic acid, and/or mesenchymal
stem cells, e.g., obtained from autologous peripheral blood
progenitor cells.
[0115] Inflammation of the synovial membrane in a joint causes
swelling and joint surface destruction. Removing excess fluid and
material by a lavage or debridement frequently resolves arthritic
knee inflammation and pain. In certain embodiments, the disclosure
relates to the use of compounds disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof before,
during, or after a lavage or debridement inside a joint, e.g.,
arthroscopic lavage, arthroscopic debridement. In arthroscopic
debridement, joint material or degenerative cartilage it typically
removed by injecting a fluid and removing it with a vacuum.
[0116] An intervertebral disc (IVD) is found in between two
vertebrae. The IVD contains different tissue types such as the
annulus fibrosus (AF), the nucleus pulposus (NP), and end-plates.
The AF is made up of mainly collagen type I. The amount of collagen
type I decreases and collagen type II increase gradually nearer the
NP which is mostly collagen type II dispersed within a
proteoglycan-rich gelatinous matrix surrounding the NP.
[0117] Porous silk scaffolds may be used for a variety of
tissue-engineering applications, such as the regeneration of bone
and cartilage. Removal of sericin from silk reduces immunogenic
responses. Silk may form a desired sponge-like structure by
freeze-drying a silk solution. Bone marrow mesenchymal stem cells
(BMSC) may be incorporated into porous silk scaffolds wrapped
around a silicone NP substitute to form an artificial
intervertebral disc. In certain embodiments, it is contemplated
that compounds disclosed herein may be used to generate a matrix of
annulus fibrosus by mixing with mesenchymal stem cells and growth
factors. In certain embodiments, the disclosure contemplates
implanting a fabricated intervertebral disc into a subject wherein
the disc comprises annulus fibrosus tissue and placing a compound
disclosed herein about the site of the implant location, e.g., by
injection, optionally in combination with a growth factor such as a
cartilage-derived morphogenetic protein (CDMP), e.g., CDMP-1 or
CDMP-2, and/or bone morphogenetic proteins, e.g., BMP-7 or BMP-14.
The fabricated disc may comprise a NP area with a hydrogel
polymer/copolymer matrix or a collagen and/or hyaluronan and/or
chondroitin-6-sulfate copolymer. A variety of stem cells, such as
mesenchymal stem cells, synovium-derived stem cells (SDSCs), or
notochord cells, may be used for rejuvenation of NP cells.
Therapeutic Applications
[0118] In some embodiments, the disclosure relates to
pharmaceutical compositions comprising compounds disclosed herein
for therapeutic applications. In some embodiments, the disclosure
relates to methods of treating bone degenerative disorders, such as
osteoporosis, osteitis deformans ("Paget's disease of bone"), bone
metastasis (with or without hypercalcaemia), multiple myeloma,
primary hyperparathyroidism, or osteogenesis imperfecta.
Osteoporosis is a disease of bones that leads to an increased risk
of fracture. In osteoporosis, the bone mineral density (BMD) is
reduced, bone microarchitecture is disrupted, and the amount and
variety of proteins in bone is altered. Osteoporosis is most common
in women after menopause, when it is called postmenopausal
osteoporosis, but may also develop in men, and may occur in anyone
in the presence of particular hormonal disorders and other chronic
diseases or as a result of medications, specifically
glucocorticoids, when the disease is called steroid- or
glucocorticoid-induced osteoporosis (SIOP or GIOP).
[0119] Osteoporotic fractures are those that occur in situations
where healthy people would not normally break a bone; they are
therefore regarded as fragility fractures. Typical fragility
fractures occur in the vertebral column, rib, hip and wrist. The
diagnosis of osteoporosis can be made using conventional
radiography by measuring the bone mineral density (BMD).
[0120] In some embodiments, the disclosure relates to treating bone
degenerative disorders by administering pharmaceutical composition
described herein in combination with other agents, such as calcium
carbonate and calcium citrate, vitamine D, cholecalciferol,
1,25-dihydroxycholecalciferol, calcitriol, estrogen, testosterone,
raloxifene, pamidronate, neridronate, olpadronate, alendronate
(Fosamax), ibandronate (Boniva), risedronate (Actonel), zoledronate
(Zometa, Aclasta), etidronate (Didronel), clodronate (Bonefos,
Loron), or tiludronate (Skelid).
[0121] In some embodiments, the disclosure relates to using
compounds disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof in the
treatment of chondrodystrophies. Typically an effective amount of a
pharmaceutical composition comprising the compound is administered
to a subject diagnosed with, at risk of, or exhibiting symptoms of
osteoarthritis, achondroplasia, costochondrits, relapsing
polychondritis, or articular cartilage damage. The pharmaceutical
compositions may provide pain relief or slow down the progression
of damage delaying joint replacement (knee replacement)
surgery.
[0122] In certain embodiments, compounds disclosed herein are
useful for managing obesity and diabetes or other metabolic
syndromes by modulation of brown fat. In some embodiments, the
disclosure relates to using compounds disclosed herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof in the
treatment of a degenerative intervertebrial disc. Typically an
effective amount of a pharmaceutical composition comprising the
compound is administered to a subject diagnosed with, at risk of,
or exhibiting symptoms of a degenerative disc. The compositions may
be administered orally or injected directly into an intervertebral
disc (IVD), e.g., into the annulus fibrosus (AF) and/or the nucleus
pulposus (NP) optionally in combination with a growth factor such
as a cartilage-derived morphogenetic protein (CDMP), e.g., CDMP-1
or CDMP-2, or a bone morphogenetic protein, e.g., BMP-7 or
BMP-14.
[0123] In certain embodiments, the disclosure relates to methods of
treating or preventing obesity, diabetes, or type II diabetes
comprising administering a pharmaceutical composition comprising an
effective amount of a compound disclosed herein herein such as
2-(2-Methoxybenzylidene)-1-indanone; N-(4-arsonophenyl)glycine;
1,2-Benzenedicarboxylic acid, 1-(1-methylheptyl) ester;
(4'-hydroxybiphenyl-4-yl)(phenyl)methanone;
2,2-dimethylchroman-6-carboxylic acid,
(4,7-dihydroxy-8-methyl-2-oxo-2H-chromen-3-yl)amide; Ethyl
2-((4-chlorophenyl)thio)-1,3-benzothiazol-6-yl carbamate; Ethyl
(2-(azepan-1-yl)benzo[d]thiazol-6-yl) carbamate; Porfiromycin;
1,3-benzodioxol-5-yl-[4-(3,4,5-trimethoxybenzoyl)-3-furyl]methanone;
Tricinolone acetophenonide;
2,4-bis(3,4-dimethoxyphenyl)-4H-pyrano[3,2-c]chromen-5-one; Methyl
5-fluoro-4-methoxy-2,6-dioxohexahydro-5-pyrimidine carboxylate;
5-(naphthalen-1-yl)-1-phenyl-1h-tetrazole;
5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazol-2-ol;
N-[2,4,5-trimethyl-4-(trichloromethyl)cyclohexa-2,5-dien-1-ylidene]hydrox-
ylamine; 4-benzoyl-3,4-dihydro-Benzo[f]quinoline-3-carbonitrile;
2-nitro-3-phenylspiro[cyclopropane-1,9'-fluorene];
3-[4-(furan-2-ylmethyl)-5-sulfanylidene-1,2,4-dithiazolidin-3-ylidene]-1,-
1-dimethylthiourea;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; 5-Iodo-1H-indole-2,3-dione;
4,5-dihydro-1,2,9,10-tetramethoxy
dibenzo[de,g]quinoline-6-carboxylic acid, ethyl ester;
[2,6-bis(2,4-dimethylphenyl)-4-(2-methoxyacetyl)oxy-phenyl]2-methoxyaceta-
te;
5,11-dimethyl-2-(2-piperidin-1-ylethyl)-6H-pyrido[4,3-b]carbazol-2-ium-
-9-ol;
2-[3-[[4-[(3-nitroacridin-9-yl)amino]phenyl]sulfamoyl]propyl]guanid-
ine;
1-[[2-(dimethylamino)ethyl]amino]-7-hydroxy-4-methyl-9H-thioxanthen-9-
-one; 5-amino-1H-1,2,4-triazole-3-carboxylic acid, methyl ester;
methyl N-cyano-N'-prop-2-en-1-ylcarbamimidothioate;
5,7-dinitro-8-quinolinol; 5-nitrosoquinolin-8-ol; Cantharidin;
1,7-Diaminoacridine;
3-Methyl-3-(1-naphthyl)-2-benzofuran-1(3H)-one; Dichlorolapachol;
Lycobetaine;
6-(1-aziridinyl)-2,3-dihydro-3-(propionyl)-7-methyl-1H-Pyrrolo[1,8]-dione-
; 4-Nitroestrone 3-methyl ether;
5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide
hydrochloride; 5-Methoxysterigmatocysin;
(6-acetamido-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-
-3-yl) 2-methoxyacetate; Horminon;
7',8'-dimethyl-2'-oxo-4',4a',6a',7'-tetrahydro-2'H-spiro[oxirane-2,1'-pen-
taleno[1,6a-c]pyran]-5'-carboxylate; Nybomycin acetate;
5H-[1,6]indeno[1,2-c]isoquinoline-5,12-dione;
2,3-dimethoxy-6-methyl-Nitidine; Iproplatin;
3-[(deoxyhexosyl)oxy]-2-(3,4-dihydroxyphenyl)-6,8-dihdroxy-4H-1-Benzopyra-
n-4-one; 2-O-benzyl 8-O-methyl
3-(4-methylphenyl)sulfonyl-4,5-dioxo-6H-pyrrolo[3,2-e]indole-2,8-dicarbox-
ylate;
6-bromo-5,8-dihydroxy-7-[4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-y-
l]naphthalene-1,4-dione;
5-methylbenzo[c]phenanthridin-5-ium-2,3,8,9-tetrol;
(6-acetyl-4-oxo-1,3-diphenyl-2-sulfanylidenethieno[2,3-d]pyrimidin-5-yl)--
2,4-dichlorobenzoate;
N--[C-[4-[bis(2-cyanoethyl)amino]-2-methylphenyl]-N-(4-methylanilino)carb-
onimidoyl]imino-4-methylbenzamide; Gelcohol; Curcumin;
Tirandamycin; Noscapine; Aristolochic acid; Himbacine; Fumagillin;
Fumitremorgin C; Physalin B; derivatives, or salts thereof to a
subject in need thereof. In certain embodiments, the subject is at
risk or diagnosed with obesity, diabetes, or type II diabetes. In
certain embodiments, the subject has is calculated to have or
reports a body mass index of greater than 25, 30, 35, or 40
kg/m.sup.2. Diabetes mellitus type II (Diabetes type II or
noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset
diabetes) is a metabolic disorder that is characterized by high
blood glucose in the context of insulin resistance and/or insulin
deficiency. This is in contrast to diabetes mellitus type 1, in
which there is an absolute insulin deficiency typically due to
destruction of islet cells in the pancreas.
[0124] Bottcher et al. report that adipose tissue expression and
genetic variants of the bone morphogenetic protein receptor 1A gene
(BMPR1A) are associated with human obesity. See Diabetes, 2009,
58:2119-2128. Although it is not intended that certain embodiments
of the disclosure be limited by any particular mechanism, it is
believed that inducing BMP signaling improves the production of
brown fat or brown-like fat causing increase metabolic rates to
reduce white fat content. It has been reported that there is cross
talk between insulin and bone morphogenetic protein signaling
systems in brown adipogenesis. See Wee Zhang et al, MOLE CELL BIO,
2010, 30(17): 4224-4233. BMP4-mediated brown fat-like changes are
reported in white adipose tissue alter glucose and energy
homeostasis. See Qian et al., PNAS, 2013, 110(9) E798-E807.
Brown-fat paucity due to impaired BMP signaling is reported to
induce compensatory browning of white fat. See Schulz et al.,
Nature, 2013, 49:379-383.
Formulations
[0125] Pharmaceutical compositions disclosed herein may be in the
form of pharmaceutically acceptable salts, as generally described
below. Some preferred, but non-limiting examples of suitable
pharmaceutically acceptable organic and/or inorganic acids are
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
acetic acid and citric acid, as well as other pharmaceutically
acceptable acids known per se (for which reference is made to the
references referred to below).
[0126] When the compounds of the disclosure contain an acidic group
as well as a basic group, the compounds of the disclosure may also
form internal salts, and such compounds are within the scope of the
disclosure. When the compounds of the disclosure contain a
hydrogen-donating heteroatom (e.g. NH), the disclosure also covers
salts and/or isomers formed by transfer of said hydrogen atom to a
basic group or atom within the molecule.
[0127] Pharmaceutically acceptable salts of the compounds include
the acid addition and base salts thereof. Suitable acid addition
salts are formed from acids which form non-toxic salts. Examples
include the acetate, adipate, aspartate, benzoate, besylate,
bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, cyclamate, edisylate, esylate, formate, fumarate,
gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, saccharate,
stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate
and xinofoate salts. Suitable base salts are formed from bases
which form non-toxic salts. Examples include the aluminium,
arginine, benzathine, calcium, choline, diethylamine, diolamine,
glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc salts. Hemisalts of acids and bases may also
be formed, for example, hemisulphate and hemicalcium salts. For a
review on suitable salts, see Handbook of Pharmaceutical Salts:
Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,
2002), incorporated herein by reference.
[0128] The compounds described herein may be administered in the
form of prodrugs. A prodrug can include a covalently bonded carrier
which releases the active parent drug when administered to a
mammalian subject. Prodrugs can be prepared by modifying functional
groups present in the compounds in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compounds. Prodrugs include, for example,
compounds wherein a hydroxy group is bonded to any group that, when
administered to a mammalian subject, cleaves to form a free hydroxy
group. Examples of prodrugs include, but are not limited to,
acetate, formate, and benzoate derivatives of alcohol functional
groups in the compounds. Methods of structuring a compound as
prodrugs can be found in the book of Testa and Mayer, Hydrolysis in
Drug and Prodrug Metabolism, Wiley (2006). Typical prodrugs form
the active metabolite by transformation of the prodrug by
hydrolytic enzymes, the hydrolysis of amide, lactams, peptides,
carboxylic acid esters, epoxides or the cleavage of esters of
inorganic acids.
[0129] Pharmaceutical compositions for use in the present
disclosure typically comprise an effective amount of a compound and
a suitable pharmaceutical acceptable carrier. The preparations may
be prepared in a manner known per se, which usually involves mixing
the at least one compound according to the disclosure with the one
or more pharmaceutically acceptable carriers, and, if desired, in
combination with other pharmaceutical active compounds, when
necessary under aseptic conditions. Reference is made to U.S. Pat.
No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat. No. 6,369,087 and
U.S. Pat. No. 6,372,733 and the further references mentioned above,
as well as to the standard handbooks, such as the latest edition of
Remington's Pharmaceutical Sciences.
[0130] Generally, for pharmaceutical use, the compounds may be
formulated as a pharmaceutical preparation comprising at least one
compound and at least one pharmaceutically acceptable carrier,
diluent or excipient and/or adjuvant, and optionally one or more
further pharmaceutically active compounds.
[0131] The pharmaceutical preparations of the disclosure are
preferably in a unit dosage form, and may be suitably packaged, for
example in a box, blister, vial, bottle, sachet, ampoule or in any
other suitable single-dose or multi-dose holder or container (which
may be properly labeled); optionally with one or more leaflets
containing product information and/or instructions for use.
Generally, such unit dosages will contain between 1 and 1000 mg,
and usually between 5 and 500 mg, of the at least one compound of
the disclosure, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per
unit dosage.
[0132] The compounds can be administered by a variety of routes
including the oral, ocular, rectal, transdermal, subcutaneous,
intravenous, intramuscular or intranasal routes, depending mainly
on the specific preparation used. The compound will generally be
administered in an "effective amount", by which is meant any amount
of a compound that, upon suitable administration, is sufficient to
achieve the desired therapeutic or prophylactic effect in the
subject to which it is administered. Usually, depending on the
condition to be prevented or treated and the route of
administration, such an effective amount will usually be between
0.01 to 1000 mg per kilogram body weight of the patient per day,
more often between 0.1 and 500 mg, such as between 1 and 250 mg,
for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per
kilogram body weight of the patient per day, which may be
administered as a single daily dose, divided over one or more daily
doses. The amount(s) to be administered, the route of
administration and the further treatment regimen may be determined
by the treating clinician, depending on factors such as the age,
gender and general condition of the patient and the nature and
severity of the disease/symptoms to be treated. Reference is again
made to U.S. Pat. No. 6,372,778, U.S. Pat. No. 6,369,086, U.S. Pat.
No. 6,369,087, and U.S. Pat. No. 6,372,733 and the further
references mentioned above, as well as to the standard handbooks,
such as the latest edition of Remington's Pharmaceutical
Sciences.
[0133] For an oral administration form, the compound can be mixed
with suitable additives, such as excipients, stabilizers or inert
diluents, and brought by means of the customary methods into the
suitable administration forms, such as tablets, coated tablets,
hard capsules, aqueous, alcoholic, or oily solutions. Examples of
suitable inert carriers are gum arabic, magnesia, magnesium
carbonate, potassium phosphate, lactose, glucose, or starch, in
particular, corn starch. In this case, the preparation can be
carried out both as dry and as moist granules. Suitable oily
excipients or solvents are vegetable or animal oils, such as
sunflower oil or cod liver oil. Suitable solvents for aqueous or
alcoholic solutions are water, ethanol, sugar solutions, or
mixtures thereof. Polyethylene glycols and polypropylene glycols
are also useful as further auxiliaries for other administration
forms. As immediate release tablets, these compositions may contain
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and lactose and/or other excipients, binders, extenders,
disintegrants, diluents and lubricants known in the art.
[0134] When administered by nasal aerosol or inhalation, the
compositions may be prepared according to techniques well-known in
the art of pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other solubilizing or dispersing agents known
in the art. Suitable pharmaceutical formulations for administration
in the form of aerosols or sprays are, for example, solutions,
suspensions or emulsions of the compounds of the disclosure or
their physiologically tolerable salts in a pharmaceutically
acceptable solvent, such as ethanol or water, or a mixture of such
solvents. If required, the formulation can also additionally
contain other pharmaceutical auxiliaries such as surfactants,
emulsifiers and stabilizers as well as a propellant.
[0135] For subcutaneous or intravenous administration, the
compounds, if desired with the substances customary therefore such
as solubilizers, emulsifiers or further auxiliaries are brought
into solution, suspension, or emulsion. The compounds of formula I
can also be lyophilized and the lyophilizates obtained used, for
example, for the production of injection or infusion preparations.
Suitable solvents are, for example, water, physiological saline
solution or alcohols, e.g. ethanol, propanol, glycerol, sugar
solutions such as glucose or mannitol solutions, or mixtures of the
various solvents mentioned. The injectable solutions or suspensions
may be formulated according to known art, using suitable non-toxic,
parenterally-acceptable diluents or solvents, such as mannitol,
1,3-butanediol, water, Ringer's solution or isotonic sodium
chloride solution, or suitable dispersing or wetting and suspending
agents, such as sterile, bland, fixed oils, including synthetic
mono- or diglycerides, and fatty acids, including oleic acid.
[0136] When rectally administered in the form of suppositories, the
formulations may be prepared by mixing the compounds of formula I
with a suitable non-irritating excipient, such as cocoa butter,
synthetic glyceride esters or polyethylene glycols, which are solid
at ordinary temperatures, but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0137] In certain embodiments, it is contemplated that these
compositions can be extended release formulations. Typical extended
release formations utilize an enteric coating. Typically, a barrier
is applied to oral medication that controls the location in the
digestive system where it is absorbed. Enteric coatings prevent
release of medication before it reaches the small intestine.
Enteric coatings may contain polymers of polysaccharides, such as
maltodextrin, xanthan, scleroglucan dextran, starch, alginates,
pullulan, hyaloronic acid, chitin, chitosan and the like; other
natural polymers, such as proteins (albumin, gelatin etc.),
poly-L-lysine; sodium poly(acrylic acid);
poly(hydroxyalkylmethacrylates) (for example poly(hydroxyethyl
methacrylate)); carboxypolymethylene (for example Carbopol.TM.);
carbomer; polyvinyl pyrrolidone; gums, such as guar gum, gum
arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum,
gellan gum, gum tragacanth, agar, pectin, gluten and the like;
poly(vinyl alcohol); ethylene vinyl alcohol; polyethylene glycol
(PEG); and cellulose ethers, such as hydroxymethylcellulose (HMC),
hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),
methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose
(CEC), ethylhydroxyethyl cellulose (EHEC),
carboxymethylhydroxyethylcellulose (CMHEC),
hydroxypropylmethyl-cellulose (HPMC), hydroxypropylethylcellulose
(HPEC) and sodium carboxymethylcellulose (Na CMC); as well as
copolymers and/or (simple) mixtures of any of the above polymers.
Certain of the above-mentioned polymers may further be crosslinked
by way of standard techniques.
[0138] The choice of polymer will be determined by the nature of
the active ingredient/drug that is employed in the composition of
the disclosure as well as the desired rate of release. In
particular, it will be appreciated by the skilled person, for
example in the case of HPMC, that a higher molecular weight will,
in general, provide a slower rate of release of drug from the
composition. Furthermore, in the case of HPMC, different degrees of
substitution of methoxyl groups and hydroxypropoxyl groups will
give rise to changes in the rate of release of drug from the
composition. In this respect, and as stated above, it may be
desirable to provide compositions of the disclosure in the form of
coatings in which the polymer carrier is provided by way of a blend
of two or more polymers of, for example, different molecular
weights in order to produce a particular required or desired
release profile.
[0139] Microspheres of polylactide, polyglycolide, and their
copolymers poly(lactide-co-glycolide) may be used to form
sustained-release protein or compound delivery systems. Proteins
and/or compounds can be entrapped in the poly(lactide-co-glycolide)
microsphere depot by a number of methods, including formation of a
water-in-oil emulsion with water-borne protein and organic
solvent-borne polymer (emulsion method), formation of a
solid-in-oil suspension with solid protein dispersed in a
solvent-based polymer solution (suspension method), or by
dissolving the protein in a solvent-based polymer solution
(dissolution method). One can attach poly(ethylene glycol) to
proteins (PEGylation) to increase the in vivo half-life of
circulating therapeutic proteins and decrease the chance of an
immune response.
[0140] In certain embodiments, the disclosure relates to
nutritional supplements comprising compounds disclosed herein to
promote bone health. The compositions may optionally contain or may
be administered in combination with other nutrients such as
vitamins, minerals, fiber such as psyllium seed husk, fatty acids,
amino acids, hormones such as DHEA, pregnenolone, antioxidants such
as resveratrol from red grape products, flavonoids (isoflavonoids),
soy, clover, anthocyanins, Vitamin C, broccoli (sulforaphane),
fiddleheads (Matteuccia Struthiopteus) alpha-linolenic acid, omega
3 fatty acids, and/or an herb extracts such as ginseng, garlic oil
or other botanical or combinations thereof.
EXPERIMENTAL
Compound Screenings
[0141] The BMP-potentiating activities of compounds are evaluated
by monitoring several markers of the osteoblastic phenotype
corresponding to various time points during phenotype
differentiation of C2C12 cells towards terminally differentiated
osteoblasts.
Cell Culture
[0142] Mouse C2C12 cells and Dulbecco's modified Eagle's medium
(DMEM) were purchased from ATCC (Manassas, Va.). The non-heat
inactivated fetal bovine serum (FBS) was purchased from HyClone
Laboratories, Inc. (Logan, Utah). The C2C12 cells at passages 5 to
10 were subcultured in T-75 cm.sup.2 flasks in DMEM supplemented
with 10% FBS at 37.degree. C. in 5% CO.sub.2 with humidification.
When the flasks reached 80% confluence, the cells were trypsinized
and seeded in triplicate.
Alkaline Phosphatase (ALP) Assay
[0143] The C2C12 cells were plated at 200,000 cells/well in 6-well
plates and grown overnight in DMEM containing 10% FBS. On day 2,
the culture medium was replaced with DMEM containing 2% FBS and the
cells were treated with various concentrations of compound for 24
hours. On day 3, the culture medium was replaced with DMEM
containing 2% FBS and the cells were treated with 50 ng/ml of BMP-2
and various concentrations of compound for 72 hours. The cells were
washed with phosphate-buffered saline (PBS) and lysed by addition
of lysis buffer (10 mM Tris-HCl pH 8.0, 1 mM MgCl.sub.2 and 1.0%
Triton X-100). The cell lysates were centrifuged for 5 minutes at
13,000.times.g. The supernatant was removed and the aliquots were
assayed for ALP activity and protein amount. The ALP activity was
measured in triplicate using an ALP assay kit (Sigma-Aldrich, St.
Louis, Mo.) in microtiter plates. The protein amount was determined
with Bio-Rad protein assay reagent (Bio-Rad, Hercules, Calif.)
using bovine serum albumin (BSA) as a standard. The ALP activity
(nmoles of p-nitrophenol per ml) was normalized to the protein
amount (nmoles of p-nitrophenol per .mu.g).
BMP-Noggin Competitive Alkaline Phosphatase (ALP) Assay
[0144] The C2C12 cells were plated at 200,000 cells/well in 6-well
plates and grown overnight in DMEM containing 10% FBS. On day 2,
the culture medium was replaced with DMEM containing 2% FBS and the
cells were treated with 90-100 ng/ml of BMP-2 (as noted in each
experiment), various concentrations of compound, and 100-120 ng/ml
of noggin (as noted in each experiment) for 72 hours. The cells
were washed with phosphate-buffered saline (PBS) and lysed by
addition of lysis buffer (10 mM Tris-HCl pH 8.0, 1 mM MgCl.sub.2
and 1.0% Triton X-100). The cell lysates were centrifuged for 5
minutes at 13,000.times.g. The supernatant was removed and the
aliquots were assayed for ALP activity and protein amount. The ALP
activity was measured in triplicate using an ALP assay kit
(Sigma-Aldrich, St. Louis, Mo.) in microtiter plates. The protein
amount was determined with Bio-Rad protein assay reagent (Bio-Rad,
Hercules, Calif.) using bovine serum albumin (BSA) as a standard.
The ALP activity (nmoles of p-nitrophenol per ml) was normalized to
the protein amount (nmoles of p-nitrophenol per .mu.g).
Sequence CWU 1
1
51396PRTHomo sapiens 1Met Val Ala Gly Thr Arg Cys Leu Leu Ala Leu
Leu Leu Pro Gln Val 1 5 10 15 Leu Leu Gly Gly Ala Ala Gly Leu Val
Pro Glu Leu Gly Arg Arg Lys 20 25 30 Phe Ala Ala Ala Ser Ser Gly
Arg Pro Ser Ser Gln Pro Ser Asp Glu 35 40 45 Val Leu Ser Glu Phe
Glu Leu Arg Leu Leu Ser Met Phe Gly Leu Lys 50 55 60 Gln Arg Pro
Thr Pro Ser Arg Asp Ala Val Val Pro Pro Tyr Met Leu 65 70 75 80 Asp
Leu Tyr Arg Arg His Ser Gly Gln Pro Gly Ser Pro Ala Pro Asp 85 90
95 His Arg Leu Glu Arg Ala Ala Ser Arg Ala Asn Thr Val Arg Ser Phe
100 105 110 His His Glu Glu Ser Leu Glu Glu Leu Pro Glu Thr Ser Gly
Lys Thr 115 120 125 Thr Arg Arg Phe Phe Phe Asn Leu Ser Ser Ile Pro
Thr Glu Glu Phe 130 135 140 Ile Thr Ser Ala Glu Leu Gln Val Phe Arg
Glu Gln Met Gln Asp Ala 145 150 155 160 Leu Gly Asn Asn Ser Ser Phe
His His Arg Ile Asn Ile Tyr Glu Ile 165 170 175 Ile Lys Pro Ala Thr
Ala Asn Ser Lys Phe Pro Val Thr Arg Leu Leu 180 185 190 Asp Thr Arg
Leu Val Asn Gln Asn Ala Ser Arg Trp Glu Ser Phe Asp 195 200 205 Val
Thr Pro Ala Val Met Arg Trp Thr Ala Gln Gly His Ala Asn His 210 215
220 Gly Phe Val Val Glu Val Ala His Leu Glu Glu Lys Gln Gly Val Ser
225 230 235 240 Lys Arg His Val Arg Ile Ser Arg Ser Leu His Gln Asp
Glu His Ser 245 250 255 Trp Ser Gln Ile Arg Pro Leu Leu Val Thr Phe
Gly His Asp Gly Lys 260 265 270 Gly His Pro Leu His Lys Arg Glu Lys
Arg Gln Ala Lys His Lys Gln 275 280 285 Arg Lys Arg Leu Lys Ser Ser
Cys Lys Arg His Pro Leu Tyr Val Asp 290 295 300 Phe Ser Asp Val Gly
Trp Asn Asp Trp Ile Val Ala Pro Pro Gly Tyr 305 310 315 320 His Ala
Phe Tyr Cys His Gly Glu Cys Pro Phe Pro Leu Ala Asp His 325 330 335
Leu Asn Ser Thr Asn His Ala Ile Val Gln Thr Leu Val Asn Ser Val 340
345 350 Asn Ser Lys Ile Pro Lys Ala Cys Cys Val Pro Thr Glu Leu Ser
Ala 355 360 365 Ile Ser Met Leu Tyr Leu Asp Glu Asn Glu Lys Val Val
Leu Lys Asn 370 375 380 Tyr Gln Asp Met Val Val Glu Gly Cys Gly Cys
Arg 385 390 395 223PRTHomo sapiens 2Lys Ile Pro Lys Ala Ser Ser Val
Pro Thr Glu Leu Ser Ala Ile Ser 1 5 10 15 Thr Leu Tyr Leu Asp Asp
Asp 20 328PRTHomo sapiens 3Cys Cys Cys Cys Asp Asp Asp Ser Lys Ile
Pro Lys Ala Ser Ser Val 1 5 10 15 Pro Thr Glu Leu Ser Ala Ile Ser
Thr Leu Tyr Leu 20 25 428PRTHomo sapiens 4Cys Cys Cys Cys Gly Gly
Gly Ser Lys Ile Pro Lys Ala Ser Ser Val 1 5 10 15 Pro Thr Glu Leu
Ser Ala Ile Ser Thr Leu Tyr Leu 20 25 5431PRTHomo sapiens 5Met His
Val Arg Ser Leu Arg Ala Ala Ala Pro His Ser Phe Val Ala 1 5 10 15
Leu Trp Ala Pro Leu Phe Leu Leu Arg Ser Ala Leu Ala Asp Phe Ser 20
25 30 Leu Asp Asn Glu Val His Ser Ser Phe Ile His Arg Arg Leu Arg
Ser 35 40 45 Gln Glu Arg Arg Glu Met Gln Arg Glu Ile Leu Ser Ile
Leu Gly Leu 50 55 60 Pro His Arg Pro Arg Pro His Leu Gln Gly Lys
His Asn Ser Ala Pro 65 70 75 80 Met Phe Met Leu Asp Leu Tyr Asn Ala
Met Ala Val Glu Glu Gly Gly 85 90 95 Gly Pro Gly Gly Gln Gly Phe
Ser Tyr Pro Tyr Lys Ala Val Phe Ser 100 105 110 Thr Gln Gly Pro Pro
Leu Ala Ser Leu Gln Asp Ser His Phe Leu Thr 115 120 125 Asp Ala Asp
Met Val Met Ser Phe Val Asn Leu Val Glu His Asp Lys 130 135 140 Glu
Phe Phe His Pro Arg Tyr His His Arg Glu Phe Arg Phe Asp Leu 145 150
155 160 Ser Lys Ile Pro Glu Gly Glu Ala Val Thr Ala Ala Glu Phe Arg
Ile 165 170 175 Tyr Lys Asp Tyr Ile Arg Glu Arg Phe Asp Asn Glu Thr
Phe Arg Ile 180 185 190 Ser Val Tyr Gln Val Leu Gln Glu His Leu Gly
Arg Glu Ser Asp Leu 195 200 205 Phe Leu Leu Asp Ser Arg Thr Leu Trp
Ala Ser Glu Glu Gly Trp Leu 210 215 220 Val Phe Asp Ile Thr Ala Thr
Ser Asn His Trp Val Val Asn Pro Arg 225 230 235 240 His Asn Leu Gly
Leu Gln Leu Ser Val Glu Thr Leu Asp Gly Gln Ser 245 250 255 Ile Asn
Pro Lys Leu Ala Gly Leu Ile Gly Arg His Gly Pro Gln Asn 260 265 270
Lys Gln Pro Phe Met Val Ala Phe Phe Lys Ala Thr Glu Val His Phe 275
280 285 Arg Ser Ile Arg Ser Thr Gly Ser Lys Gln Arg Ser Gln Asn Arg
Ser 290 295 300 Lys Thr Pro Lys Asn Gln Glu Ala Leu Arg Met Ala Asn
Val Ala Glu 305 310 315 320 Asn Ser Ser Ser Asp Gln Arg Gln Ala Cys
Lys Lys His Glu Leu Tyr 325 330 335 Val Ser Phe Arg Asp Leu Gly Trp
Gln Asp Trp Ile Ile Ala Pro Glu 340 345 350 Gly Tyr Ala Ala Tyr Tyr
Cys Glu Gly Glu Cys Ala Phe Pro Leu Asn 355 360 365 Ser Tyr Met Asn
Ala Thr Asn His Ala Ile Val Gln Thr Leu Val His 370 375 380 Phe Ile
Asn Pro Glu Thr Val Pro Lys Pro Cys Cys Ala Pro Thr Gln 385 390 395
400 Leu Asn Ala Ile Ser Val Leu Tyr Phe Asp Asp Ser Ser Asn Val Ile
405 410 415 Leu Lys Lys Tyr Arg Asn Asn Val Val Arg Ala Cys Gly Cys
His 420 425 430
* * * * *