Methods of managing graft versus host disease (GvHD) using indole carboxyaldehydes or derivatives thereof

Patent metadata

Field	Value
Publication number	US-10154989-B2
Application number	US-201615268577-A
Country	US
Kind code	B2
Filing date	Sep 17, 2016
Priority date	Sep 17, 2015
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

In certain embodiments, this disclosure relates to methods of treating or preventing HvGD comprising administering an effective amount of indole-2-carboxyaldehyde, indole-3-carboxyaldehyde, or derivative to a subject in need thereof. In certain embodiments, this disclosure relates to methods of treating a subject with a hematological malignancy or other cancer comprising transplanting allogenic bone marrow or stem cells in combination with administering an effective amount of an indole-2-carboxyaldehyde, indole-3-carboxyaldehyde, or derivative thereof to a subject in need thereof.

First claim

The invention claimed is:

1. A method of treating a subject with a hematological malignancy comprising transplanting allogenic bone marrow in combination with administering an effective amount of an indole-2-carboxyaldehyde, indole-3-carboxyaldehyde, or derivative thereof to a subject in need thereof, wherein the derivative is a compound having formula I,

esters, or salts thereof, wherein;
A is N or CR 4 ; B is N or CR 5 , D is N or CR 6 ; E is N or CR 7 ;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each, individually and independently, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylene glycol, alkanoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are optionally substituted with one or more, the same or different, R 10 ,
R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylene glycol, alkanoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 11 ;
R 11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylene glycol, alkanoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 12 ; and
R 12 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy,2-methoxyethoxy, 2-ethoxyethoxy, 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 administration is enteral.

3. The method of claim 1 , wherein the subject is administered a daily dose for more than a week or month.

4. The method of claim 1 , wherein the subject is diagnosed with leukemia.

5. The method of claim 1 , wherein the subject is diagnosed with lymphoma, multiple myeloma, or myelodysplastic syndromes.

6. The method of claim 1 , wherein the subject is a human.

7. A method of treating a subject with a hematological malignancy comprising providing a conditioning regimen and administering an effective amount of an indole-2-carboxyaldehyde, indole-3-carboxyaldehyde, or derivative thereof to a subject in need thereof, wherein the derivative is a compound having formula I,

esters, or salts thereof, wherein;
A is N or CR 4 ; B is N or CR 5 , D is N or CR 6 ; E is N or CR 7 ;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each, individually and independently, hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylene glycol, alkanoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are optionally substituted with one or more, the same or different, R 10 ;
R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylene glycol, alkanoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 11 ;
R 11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylene glycol, alkanoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 12 , and
R 12 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetyamino, 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.

8. The method of claim 7 , wherein the conditioning regimen is a myelosuppressive or myeloablative doses of chemotherapy.

9. The method of claim 7 , wherein the conditioning regimen comprises administering busulfan, melphalan, fludarabine, cyclophosphamide, etoposide, thioTEPA, or combinations thereof.

10. The method of claim 7 , wherein the conditioning regimen is doses of ionizing radiation.

Assignees

• Univ Emory

Inventors

• Kalman Daniel
• Waller Edmund K
• Giver Cynthia R
• Swimm Alyson
• Rangaraju Sravanti

Classifications

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title