Compounds and compositions for ossification and methods related thereto

1. A method of forming bone or cartilage, comprising implanting a graft composition comprising a 2,4-diamino-1,3,5-triazine derivative or salt thereof in a subject under conditions such that bone or cartilage forms in the graft composition, wherein the 2,4-diamino-1,3,5-triazine derivative has the following formula:

or salts thereof, wherein

if is a single bond then

R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl wherein R 3 is optionally substituted with one or more the same or different R 4 ;

R 2 is hydrogen or alkyl; and

R 1 is hydrogen or alkyl; or

if is a double bond then

R 2 and R 3 are absent;

R 1 is alkyl, alkenyl, carbocyclyl, aryl, or heterocyclyl wherein R 3 is 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, alkylsulfonyl, arylsulfonyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The method of claim 1 , wherein the graft composition further comprises a bone morphogenetic protein.

3. The method of claim 1 , wherein the subject has a void in the bony structure wherein the graft composition is implanted in the void.

4. The method of claim 3 , wherein the void is in a bone selected from an extremity, maxilla, mandible, pelvis, spine and/or cranium.

5. The method of claim 3 , wherein said void is a result of surgical removal of bone.

6. The method of claim 1 , 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.

7. The method of claim 1 , wherein the 2,4-diamino-1,3,5-triazine derivative is a compound selected from the group consisting of:

1-benzyl-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-methoxyb enzyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-methoxyb enzyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-4-methoxyphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-bromo-2-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(2-bromo-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

6,6-dimethyl-1-(4-methyl-3-nitrophenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine;

1-(3-chloro-4-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-5-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

2-chloro-4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1((2H))-yl)phenol;

1-(2-chloro-5-methoxyphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine; and

1-(2-chloro-4-methyl phenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine or salts thereof.

8. A method of performing spinal fusion, comprising implanting a bone graft composition comprising a 2,4-diamino-1,3,5-triazine derivative or salt thereof configured to grow bone between two vertebrae of a subject, wherein the 2,4-diamino-1,3,5-triazine derivative has the following formula:

or salts thereof, wherein

if is a single bond then

R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl wherein R 3 is optionally substituted with one or more the same or different R 4 ;

R 2 is hydrogen or alkyl; and

R 1 is hydrogen or alkyl; or

if is a double bond then

R 2 and R 3 are absent;

R 1 is alkyl, alkenyl, carbocyclyl, aryl, or heterocyclyl wherein R 3 is 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, alkylsulfonyl, arylsulfonyl, 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 method of claim 8 , wherein the graft composition further comprises a bone morphogenetic protein.

10. The method of claim 8 , wherein the 2,4-diamino-1,3,5-triazine derivative is a compound selected from the group consisting of:

1-benzyl-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-methoxybenzyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3- methoxybenzyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-4-methoxyphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-bromo-2-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(2-bromo-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

6,6-dimethyl-1-(4-methyl-3-nitrophenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine;

1-(3-chloro-4-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-5-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

2-chloro-4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1((2H))-yl)phenol;

1-(2-chloro-5-methoxyphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine; and

1-(2-chloro-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine or salts thereof.

11. A method of preventing or treating a bone fracture comprising administering a pharmaceutical composition comprising a 2,4-diamino-1,3,5-triazine derivative or pharmaceutically acceptable prodrug or salt thereof to a subject at risk for, exhibiting symptoms of, or diagnosed with a bone fracture, wherein the 2,4-diamino-1,3,5-triazine derivative has the following formula:

or salts thereof, wherein

if is a single bond then

R 3 is alkyl, phenyl, benzyl, carbocyclyl, aryl, or heterocyclyl wherein R 3 is optionally substituted with one or more the same or different R 4 ;

R 2 is hydrogen or alkyl; and

R 1 is hydrogen or alkyl; or

if is a double bond then

R 2 and R 3 are absent;

R 1 is alkyl, alkenyl, carbocyclyl, aryl, or heterocyclyl wherein R 3 is 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, alkylsulfonyl, arylsulfonyl, 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-methyl carbamoyl, N-ethyl carbamoyl, N,N-dimethyl carbamoyl, N,N-diethyl carbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N, N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

12. The method of claim 1 , wherein the administration is localized by percutaneous injection.

13. The method of claim 1 , wherein the 2,4-diamino-1,3,5-triazine derivative is a compound selected from the group consisting of:

1-benzyl-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-methoxybenzyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-methoxybenzyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chlorophenyl)-4,6- diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-4-methoxyphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(4-bromo-2-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(2-bromo-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

6,6-dimethyl-1-(4-methyl-3-nitrophenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine;

1-(3-chloro-4-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

1-(3-chloro-5-fluorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine;

2-chloro-4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1(2H)-yl)phenol;

1-(2-chloro-5-methoxyphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine; and

1-(2-chloro-4-methylphenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine or salts thereof.