Compounds that expand hematopoietic stem cells

Patent metadata

Field	Value
Publication number	US-2021187033-A1
Application number	US-202017092107-A
Country	US
Kind code	A1
Filing date	Nov 6, 2020
Priority date	Oct 30, 2008
Publication date	Jun 24, 2021
Grant date	—

Abstract

The present invention relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. The invention further relates to a cell population comprising expanded hematopoietic stem cells (HSCs) and its use in autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficient and autoimmune diseases and diverse hematopoietic disorders to reconstitute the hematopoietic cell lineages and immune system defense.

First claim

1 . A composition comprising a cell population of expanded hematopoietic stem cells derived from one or two cord blood units; and an organic compound that inhibits the activity of aryl hydrocarbon receptor (AHR antagonist);
wherein the composition contains a total number of at least 10 8 cells, wherein 20-100% of the total cells are CD34+ cells; and wherein the AHR antagonist is of Formula I:

wherein:

G 1 is selected from N and CR 3 ;
G 2 , G 3 and G 4 are independently selected from CH and N; with the proviso that at least 1 of G 3 and G 4 is N; with the proviso that G 1 and G 2 are not both N;
L is selected from —NR 5a (CH 2 ) 0-3 , —NR 5a CH(C(O)OCH 3 )CH 2 —, —NR 5a (CH 2 ) 2 NR 5b —, —NR 5a (CH 2 ) 2 S—, —NR 5a CH 2 CH(CH 3 )CH 2 —, —NR 5a CH 2 CH(OH)— and —NR 5a CH(CH 3 )CH 2 —; wherein R 5a and R 5b are independently selected from hydrogen and C 1-4 alkyl;
R 1 is selected from hydrogen, phenyl, thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl, 1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, 1H-pyrazolyl, pyridinyl, 1H-imidazolyl, pyrrolidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl and thiazolyl; wherein said phenyl, thiophenyl, furanyl, 1H-benzoimidazolyl, isoquinolinyl, 1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, 1H-pyrazolyl, pyridinyl, 1H-imidazolyl, pyrrolidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolyl or thiazolyl of R 1 can be optionally substituted by 1 to 3 radicals independently selected from cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo, halo-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkoxy, hydroxy, amino, —C(O)R 6a , —S(O) 0-2 R 8a , —C(O)OR 8a and —C(O)NR 8a R 8b ; wherein R 8a and R 8b are independently selected from hydrogen and C 1-4 alkyl; with the proviso that R 1 and R 3 are not both hydrogen;
R 2 is selected from —S(O) 2 NR 6a R 6b , —NR 9a C(O)R 9b , —NR 6a C(O)NR 6b R 6c , phenyl, 1H-pyrrolopyridin-3-yl, 1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl and 1H-indazolyl; wherein R 6a , R 6b and R 6c are independently selected from hydrogen and C 1-4 alkyl; wherein said phenyl, 1H-pyrrolopyridin-3-yl, 1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl or 1H-indazolyl of R 2 is optionally substituted with 1 to 3 radicals independently selected from hydroxy, halo, methyl, methoxy, amino, —O(CH 2 ) n NR 7a R 7b , —S(O) 2 NR 7a R 7b , —OS(O) 2 NR 7a R 7b and —NR 7a S(O) 2 R 7b ; wherein R 7a and R 7b are independently selected from hydrogen and C 1-4 alkyl;
R 3 is selected from hydrogen, C 1-4 alkyl and biphenyl; and
R 4 is selected from C 1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, phenyl, tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl and 1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl; wherein said alkyl, cyclopropyl, cyclohexyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, oxetan-2-yl, benzhydryl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, phenyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, benzyl, (4-pentylphenyl)(phenyl)methyl or 1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl can be optionally substituted with 1 to 3 radicals independently selected from hydroxy, C 1-4 alkyl and halo-substituted-C 1-4 alkyl;
or a salt thereof.

2 . The composition of claim 1 , wherein 0.1-40% of the total cells in the composition are CD34+ Thy1+ cells.

3 . The composition of claim 1 , wherein 20-80% of the total cells in the composition are CD34+ CD45RA+ cells.

4 . The composition of claim 1 , wherein 10-95% of the total cells in the composition are CD38+ cells.

5 . The composition of claim 1 , wherein 5-70% of the total cells in the composition are CD133+ cells.

6 . The composition of claim 1 , wherein the composition comprises a pharmaceutically acceptable medium.

7 . The composition of claim 1 , wherein the AHR antagonist is of any one of Formulae Ia, Ib, Ic, Id and Ie:

or a salt thereof.

8 . The composition of claim 1 , wherein L is selected from —NR 5a (CH 2 ) 0-3 —, —NR 5a CH(C(O)OCH 3 )CH 2 —, —NR 5a (CH 2 ) 2 NR 5b —, —NR 5a (CH 2 ) 2 S—, —NR 5a CH 2 CH(CH 3 )CH 2 —, —NR 5a CH(CH 3 )CH 2 — and —NR 5a CH 2 CH(OH)—;
wherein R 5a and R 5b are independently selected from hydrogen and methyl; and R 1 is selected from hydrogen, phenyl, thiophen-2-yl, thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl, 1H-pyrazol-4-yl, pyridin-2-yl, pyridin-4-yl, 1H-imidazol-1-yl, pyrrolidin-1-yl, pyrazin-2-yl, pyridin-3-yl, pyridazin-4-yl, 1H-pyrrol-2-yl and thiazol-5-yl; wherein said phenyl, thiophen-2-yl, thiophen-3-yl, furan-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl, pyridinyl-2-yl, pyridin-4-yl, 1H-imidazol-1-yl, pyrrolidin-1-yl, pyrazin-2-yl, pyridinyl-3-yl, pyridazin-4-yl, 1H-pyrrol-2-yl or thiazol-5-yl of R 1 can be optionally substituted by 1 to 3 radicals independently selected from cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo, halo-substituted-C 1-4 alkyl, —S(O) 0-2 R 8a and —C(O)OR 8a ; or
wherein R 5a and R 5b are independently selected from hydrogen and C 1-4 alkyl; and R 1 and R 3 are not both hydrogen.

9 . The composition of claim 1 , wherein L is —NR 5a (CH 2 ) 0-3 —.

10 . The composition of claim 9 , wherein L is —NR 5a (CH 2 ) 1-3 —.

11 . The composition of claim 1 , wherein R 2 is selected from urea, phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-5-yl and 1H-imidazol-4-yl; wherein said phenyl, 1H-indol-2-yl, 1H-indol-3-yl, thiophen-3-yl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl or 1H-benzo[d]imidazol-5-yl of R 2 is optionally substituted with hydroxy, methoxy, methyl, halo, amino and amino-sulfonyl.

12 . The composition of claim 1 , wherein R 3 is selected from hydrogen, methyl and biphenyl; and R 4 is selected from isopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, nonan-2-yl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, oxetan-2-yl, benzhydryl, tetrahydro-2H-pyran-2-yl, phenyl, tetrahydrofuran-3-yl and benzyl; wherein said cyclohexyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, oxetan-2-yl, benzhydryl, tetrahydro-2H-pyran-4-yl, phenyl, tetrahydrofuran-3-yl or benzyl can be optionally substituted with 1 to 3 radicals independently selected from methyl and trifluoromethyl.

13 . The composition of claim 1 , wherein the AHR antagonist is selected from:
4-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol; 4-(2-(2-(benzo[b]thiophen-3-yl)-9-sec-butyl-9H-purin-6-ylamino)ethyl)phenol; 4-(2-(9-benzhydryl-2

Assignees

• Novartis Ag

Inventors

• Boitano Anthony Edward
• Cooke Michael
• Pan Shifeng
• Schultz Peter G
• Tellew John Edward
• Wan Yongqin
• Wang Xing

Classifications

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61P35/02

  specific for leukemia · CPC title