Compounds and compositions for ossification and methods related thereto
The disclosure relates to compounds and compositions for forming bone and methods related thereto. In one embodiment, the disclosure relates to a composition comprising a compound disclosed herein, such as 2,4-diamino-1,3,5-triazine derivatives or salts 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.
1. A bone graft composition comprising collagen, calcium phosphates, bioglass, or hydrogel polymer; and a 1-(phenyl)-5-isopropyl-biguanide or salt thereof optionally substituted with one or more substituents.
2. A bone graft composition comprising collagen, calcium phosphates, bioglass, or hydrogel polymer; and a compound of formula II:
or a salt thereof wherein
R 1 is hydrogen or alkyl;
R 2 is hydrogen or alkyl;
R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more the same or different R 4 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
R 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, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
3. The bone graft composition of claim 1 , wherein the 1-(phenyl)-5-isopropyl-biguanide substituted with one or more substituents is 1-(4-chlorophenyl)-5-isopropyl-biguanide.
4. The bone graft composition of claim 1 , further comprising a growth factor, wherein the growth factor is a bone morphogenetic protein.
5. The bone graft composition of claim 4 , wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9.
6. The bone graft composition of claim 1 , wherein said calcium phosphates are hydroxyapatite and tricalcium phosphate.
7. A kit comprising a 1-(phenyl)-5-isopropyl-biguanide or salt thereof optionally substituted with one or more substituents; and a graft composition comprising collagen, calcium phosphates, bioglass, or hydrogel polymer.
8. A kit comprising a graft composition comprising collagen, calcium phosphates, bioglass, or hydrogel polymer; and a compound of formula II:
or a salt thereof wherein
R 1 is hydrogen or alkyl;
R 2 is hydrogen or alkyl;
R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more the same or different R 4 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
R 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, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
9. The kit of claim 7 , wherein the 1-(phenyl)-5-isopropyl-biguanide substituted with one or more substituents is 1-(4-chlorophenyl)-5-isopropyl-biguanide.
10. The kit of claim 7 , further comprising a growth factor, wherein the growth factor is a bone morphogenetic protein.
11. The kit of claim 10 , wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9.
12. A method of forming bone or cartilage, comprising implanting a graft composition comprising 1-(phenyl)-5-isopropyl-biguanide or salt thereof optionally substituted with one or more substituents in a subject under conditions such that bone or cartilage forms in the graft composition.
13. A method of forming bone or cartilage, comprising implanting a graft composition comprising a compound of formula II:
or a salt thereof wherein
R 1 is hydrogen or alkyl;
R 2 is hydrogen or alkyl;
R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more the same or different R 4 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
R 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, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
in a subject under conditions such that bone or cartilage forms in the graft composition.
14. The method of claim 12 , wherein the 1-(phenyl)-5-isopropyl-biguanide substituted with one or more substituents is 1-(4-chlorophenyl)-5-isopropyl-biguanide.
15. The method of claim 12 , wherein the graft composition further comprises a bone morphogenetic protein.
16. A bone graft composition comprising a growth factor and a 1-(phenyl)-5-isopropyl-biguanide or salt thereof optionally substituted with one or more substituents.
17. A bone graft composition comprising a growth factor and a compound of formula II:
or a salt thereof wherein
R 1 is hydrogen or alkyl;
R 2 is hydrogen or alkyl;
R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl optionally substituted with one or more the same or different R 4 ;
R 4 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
R 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, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethyl sulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
18. The bone graft composition of claim 16 , wherein the growth factor is a bone morphogenetic protein.
19. The bone graft composition of claim 18 , wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9.
20. The bone graft composition of claim 17 , wherein the 1-(phenyl)-5-isopropyl-biguanide substituted with one or more substituents is 1-(4-chlorophenyl)-5-isopropyl-biguanide.