Compounds and Compositions for Ossification and Methods Related Thereto

Patent metadata

Field	Value
Publication number	US-2018207166-A1
Application number	US-201715801964-A
Country	US
Kind code	A1
Filing date	Nov 2, 2017
Priority date	Aug 18, 2010
Publication date	Jul 26, 2018
Grant date	—

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

1 . A bone graft composition comprising a 1-(phenyl)-5-isopropyl-biguanide or salt thereof optionally substituted with one or more substituents.

2 . The bone graft composition of claim 1 , wherein 1-(phenyl)-5-isopropyl-biguanide optionally substituted with one or more substituents has 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 , further comprising calcium phosphates.

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

8 . The bone graft composition of claim 1 , further comprising collagen.

9 . The bone graft composition of claim 1 , further comprising a hydrogel matrix.

10 . A kit comprising a 1-(phenyl)-5-isopropyl-biguanide or salt thereof optionally substituted with one or more substituents and a graft composition.

11 . The kit of claim 10 , wherein 1-(phenyl)-5-isopropyl-biguanide optionally substituted with one or more substituents has 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.

12 . The kit of claim 10 , wherein the 1-(phenyl)-5-isopropyl-biguanide substituted with one or more sub stituents is 1-(4-chlorophenyl)-5-isopropyl-biguanide.

13 . The kit of claim 10 , further comprising a growth factor, wherein the growth factor is a bone morphogenetic protein.

14 . The kit of claim 13 , wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9.

15 . The kit of claim 10 , wherein the graph composition comprises collagen.

16 . The kit of claim 10 , wherein the graph composition comprises a hydrogel matrix.

17 . 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.

18 . The method of claim 17 , wherein 1-(phenyl)-5-isopropyl-biguanide optionally substituted with one or more substituents has formula

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.

19 . The method of claim 17 , wherein the 1-(phenyl)-5-isopropyl-biguanide substituted with one or more substituents is 1-(4-chlorophenyl)-5-isopropyl-biguanide.

20 . The method of claim 17 , wherein the graft composition further comprises a bone morphogenetic protein.

Assignees

• Univ Emory
• Us Gov Veterans Affairs

Inventors

• Boden Scott D
• Sangadala Sreedhara

Classifications

• A61P19/08

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

• A61K38/1875

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

• C07D251/18

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

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61L2430/02

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