Compounds and compositions for ossification and methods related thereto

Patent metadata

Field	Value
Publication number	US-9511071-B2
Application number	US-201113816312-A
Country	US
Kind code	B2
Filing date	Aug 18, 2011
Priority date	Aug 18, 2010
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

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.

First claim

The invention claimed is:

1. A bone graft composition comprising a 2,4-diamino-1,3,5-triazine derivative or salt thereof and further comprising collagen, wherein the 2,4-diamino-1,3,5-triazine derivative is a compound of 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-diethyl sulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The bone graft composition 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.

3. The bone graft composition of claim 1 , further comprising a growth factor.

4. The bone graft composition of claim 3 , 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. A bone graft composition comprising a 2,4-diamino-1,3,5-triazine derivative or salt thereof and further comprising calcium phosphates, wherein the 2,4-diamino-1,3,5-triazine derivative is a compound of 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, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

7. The bone graft composition of claim 6 , 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.

8. The bone graft composition of claim 6 , wherein said calcium phosphates are hydroxyapatite and tricalcium phosphate.

9. The bone graft composition of claim 6 , wherein said calcium phosphates are in physiologically compatible bone granules.

10. The bone graft composition of claim 6 , further comprising a growth factor.

11. The bone graft composition of claim 10 , wherein the growth factor is a bone morphogenetic protein.

12. The bone graft composition of claim 11 , wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9.

13. The bone graft composition of claim 6 , further comprising hydrogel polymer.

14. A bone graft composition comprising a 2,4-diamino-1,3,5-triazine derivative or salt thereof and further comprising bioglass, wherein the 2,4-diamino-1,3,5-triazine derivative is a compound of 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

Assignees

• Boden Scott D
• Sangadala Sreedhara
• Univ Emory
• Us Veterans Affairs

Inventors

• Boden Scott D
• Sangadala Sreedhara

Classifications

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• C07D251/18

  with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines · CPC title

• A61L2430/02

  for reconstruction of bones; weight-bearing implants · CPC title

• A61K38/1875

  Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor · CPC title

• A61L2300/412

  Tissue-regenerating or healing or proliferative agents · CPC title