Triazine derivatives as differentiation catalysts

Patent metadata

Field	Value
Publication number	US-9611457-B2
Application number	US-201214346328-A
Country	US
Kind code	B2
Filing date	Sep 21, 2012
Priority date	Sep 21, 2011
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

A method of inducing differentiation of mammalian cells into cardiomyocyte-like cells by contacting the mammalian cell with a triazine compound of formula (I), wherein X is independently —NR 4 —or —O—, R 4 is hydrogen or C 1-6 -alkyl; R 1 is hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, carboxy, C 1-6 -alkoxycarbonyl, halo, cyano, nitro, formyl, amino, C 1-6 -alkylamino, or di-C 1-6 -alkylamino, the C 1-6 -alkyl or -alkoxy residue being optionally substituted with one or more R 5 substituents selected from hydroxy, halo, cyano, and nitro; n is 0 to 5; R 2 is hydrogen, aryl, heteroaryl, or C 1-6 -alkyl, the aryl or heteroaryl residue being optionally substituted with one or more R 1 substituents, and where the C 1-6 -alkyl is optionally further substituted with one or more R 5 substituents; and R 3 is selected from hydrogen, halo, NR 4 R 7 , OR 7 , SR 7 , and R 7 , where the same options apply for R 7 as for R 2 ; with the proviso that the compound of formula (I) is not 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoic acid.

First claim

The invention claimed is:

1. A method of inducing differentiation of a mammalian pluripotent stem cell or myoblast cell into a cardiomyocyte-like cell, the method comprising:
incubating the mammalian cell with at least one compound of formula (I)

in an amount effective to induce the differentiation,
wherein:
X is independently —NR 4 —or —O—, the R 4 being hydrogen or C 1-6 -alkyl;
R 1 is hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, carboxy, C 1-6 -alkoxycarbonyl, halo, cyano, nitro, formyl, amino, C 1-6 -alkylamino, or di-C 1-6 -alkylamino, the C 1-6 -alkyl or -alkoxy being optionally substituted with one or more R 5 , the R 5 being hydroxy, halo, cyano, or nitro;
n is 0 to 5;
R 2 is hydrogen, aryl, heteroaryl, or C 1-6 -alkyl, the aryl or heteroaryl optionally substituted with one or more R 6 , identical options applying for R 6 as for R 1 and the C 1-6 -alkyl optionally further substituted by one or more R 5 ; and
R 3 is hydrogen, halo, NR 4 R 7 , OR 7 , SR S , and R 7 , identical options applying for R 7 as for R 2 ,
with the proviso that the compound of formula (I) is not 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoic acid.

2. The method of claim 1 , wherein R 1 is t-butyl, meth-oxy, hydroxymethyl, carboxy, methoxycarbonyl, t-butoxycarbonyl, cyano, formyl, nitro, or chloro.

3. The method of claim 1 , wherein R 2 is selected from phenyl, ethyl, and propyl.

4. The method of claim 1 , wherein R 3 is hydrogen, chloro, —NR 4 R 7 , or R 7 .

5. The method of claim 1 , wherein R 4 is hydrogen.

6. The method of claim 1 , wherein R 5 is hydroxy.

7. The method of claim 1 , wherein R 6 is t-butyl, methoxy, hydroxymethyl, carboxy, methoxycarbonyl, t-butoxycarbonyl, cyano, formyl, nitro, or chloro.

8. The method of claim 1 , wherein R 7 is phenyl optionally substituted with one or two R 6 .

9. The method of claim 1 , wherein both X are either —O—or —NH—.

10. The method of claim 9 , wherein both X are —O—, and
wherein R 3 is NHR 7 .

11. The method of claim 10 , wherein the compound of formula (I) is an anilinodiphenoxytriazine of formula (II),

wherein n, m, and o are independently 0 to 5.

12. The method of claim 9 , wherein both X are —NH—, and
wherein R 3 is hydrogen or chloro.

13. The method of claim 1 , wherein n is 0, 1, or 2.

14. The method of claim 1 , wherein the compound of formula (I) comprises:
2-[4-chloro-6-(4-methoxyphenylamino)-1,3,5-triazin-2-ylamino]ethanol (1),
3-[4-chloro-6-(4-methoxyphenylamino)-1,3,5-triazin-2-ylamino]propan-1-ol (2),
3-{[4-(3-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid methyl ester (8),
3-{[4-(4-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (29),
3-{[4-(3-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (30),
3-{[4-(2-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (31),
3-{[4-(4-t-butylphenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (32),
3-{[4-(4-methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (33),
3-{[4-(4-cyanophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (34),
3-{[4-(3-nitrophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (35),
3-{[4-(4-formyl-2-methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (36),
3-{[4-(4-cyanophenoxy)-6-(4-methoxyphenoxy)-1,3,5-triazin-2-yl]amino}benzoic acid (38),
{4-[(4.6-diphenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (39),
{3-[(4.6-diphenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (40),
{3-[(4-(3-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (42),
{3-[(4-(4-t-butylphenoxy)-6-phenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (44),
{3-[(4-(4-methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (45),
or a mixture of two or more thereof.

15. The method of claim 1 , wherein the compound of formula (I) comprises:
3-[4-chloro-6-(4-methoxyphenylamino)-1,3,5-triazin-2-ylamino]propan-1-ol (2),
3-{[4-(3-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid methyl ester (8),
3-{[4-(4-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (29),
3-{[4-(3-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (30),
3-{[4-(2-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (31),
3-{[4-(3-nitrophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (35),
3-{[4-(4-formyl-2-methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (36),
3-{[4-(4-cyanophenoxy)-6-(4-methoxyphenoxy)-1,3,5-triazin-2-yl]amino}benzoic acid (38),
{4-[(4.6-diphenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (39),
{3-[(4-(4-t-butylphenoxy)-6-phenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (44),
or a mixture of two or more thereof.

16. The method of claim 1 , wherein the compound of formula (I) comprises:
3-{[4-(4-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (29),
3-{[4-(4-formyl-2-methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino}benzoic acid (36),
{4-[(4.6-diphenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (39),
{3-[(4-(4-t-butylphenoxy)-6-phenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (44),
or a mixture of two or more thereof.

17. The method of claim 11 , wherein n, m, and o are independently 0, 1, or 2.

18. The method of claim 1 , wherein the cardiomyocyte-like cell comprises a cell exhibiting an increased expression of atrial natriuretic factor (ANF).

19. The method of claim 1 , wherein the compound of formula (I) comprises 3-{[4-(4-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]amino }benzoic acid (29).

20. The method of claim 1 , wherein the compound of formula (I) comprises {3-[(4-(4-t-butylphenoxy)-6-phenoxy-1,3,5-triazin-2-yl)amino]phenyl}methanol (44).

Assignees

• Mihovilovic Marko
• Schnuerch Michael
• Hilber Karlheinz
• Koenig Xaver
• Linder Thomas
• Mike Agnes
• Univ Wien Tech

Inventors

• Mihovilovic Marko
• Schnuerch Michael
• Hilber Karlheinz
• Koenig Xaver
• Linder Thomas
• Mike Agnes

Classifications

• C12N2501/999

  Small molecules not provided for elsewhere · CPC title

• C07D251/48

  Two nitrogen atoms · CPC title

• C07D251/46

  with oxygen or sulfur atoms attached to the two other ring carbon atoms · CPC title

• C12N5/0657 Primary

  Cardiomyocytes; Heart cells · CPC title

• C07D251/50

  with a halogen atom attached to the third ring carbon atom · CPC title