Heteroaryl disulfide compounds as allosteric effectors for increasing the oxygen-binding affinity of hemoglobin

Patent metadata

Field	Value
Publication number	US-10758569-B2
Application number	US-201515111149-A
Country	US
Kind code	B2
Filing date	Jan 13, 2015
Priority date	Jan 13, 2014
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

This invention relates to compounds of Formula I: (Formula I), and pharmaceutically acceptable salt thereof, which are allosteric effectors that increase the oxygen-being affinity of hemoglobin, which are useful in the treatment of sickle cell disease, high altitude tissue hypoxia, and other conditions.

First claim

What is claimed is:

1. A method of improving tolerance to a low oxygen environment or treating a complication resulting from sickle cell disease in an individual in need thereof, comprising contacting red blood cells of said individual with a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
each W is independently selected from CR 1 and N;
each X is independently selected from CR 2 and N;
each Y is independently selected from CR 3 , NR 5 , N, S, and O;
each Z is independently selected from CR 4 , NR 6 , N, S, and O;
provided each

is, independently, a 5-membered heteroaryl ring, which does not contain any S—S, O—O, or S—O bonds; and provided that the selections for W, X, Y, and Z maintain proper valency;
each R 1 , R 2 , R 3 , and R 4 are independently selected from H, —(C 1-4 alkylene)-Cy, Cy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO 2 , OR a , SR a , C(═O)R a , C(═O)NR c R d , C(═O)OR a , OC(═O)R b , OC(═O)NR c R d , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c R d , NR c C(═O)R b , NR c C(═O)OR a , NR c C(═O)NR c R d , NR c S(═O)R b , NR c S(═O) 2 R b , NR c S(═O) 2 NR c R d , S(═O)R b , S(═O)NR c R d , S(═O) 2 R b , S(═O) 2 NR c R d , and C═NR f ; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl are each optionally substituted by 1, 2, or 3 independently selected R x groups;
each R 5 and R 6 are independently selected from H, —(C 1-4 alkylene)-Cy, Cy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C(═O)R a , C(═O)NR c R d , C(═O)OR a , C(═NR e )NR c R d , S(═O)R b , S(═O)NR c R d , S(═O) 2 R b , and S(═O) 2 NR c R d ; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl are each optionally substituted by 1, 2, or 3 independently selected R x groups;
each Cy is independently selected from C 3-10 monocyclic or bicyclic cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R x groups;
each R a , R c , and R d are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and Cy; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl are each optionally substituted with 1, 2, or 3 independently selected R x groups;
each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and Cy; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl are each optionally substituted with 1, 2, or 3 independently selected R x groups;
each R e is independently selected from H, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, NO 2 , C(O)(C 1-4 alkyl), and S(═O) 2 (C 1-4 alkyl);
each R f is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and Cy; wherein said C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, or 3 independently selected R x groups;
each R x is independently selected from halo, OH, NO 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

2. The method of claim 1 , where the method is a method of improving tolerance to a low oxygen environment in an individual in need thereof.

3. The method of claim 1 , where the method is a method of treating a or complication resulting from sickle cell disease in an individual in need thereof.

4. The method of claim 1 , wherein said contacting comprising administering the compound or salt to said individual.

5. The method of claim 3 , wherein the complication resulting from sickle cell disease is sickle cell crisis.

6. The method of claim 3 , wherein the complication resulting from sickle cell disease is selected from acute painful episodes, dactylitis, infection, overwhelming post-(auto)splenectomy infection (OPSI), anemia, acute chest syndrome, splenic sequestration, stroke, silent stroke, jaundice, infections, leg ulcers. bone damage, pulmonary hypertension, eye damage, organ failure, priapism, joint pain, cholelithiasis (gallstones), cholecystitis, avascular necrosis, osteomyelitis, acute papillary necrosis, background retinopathy, proliferative retinopathy, vitreous hemorrhages, retinal detachments, chronic renal failure, sickle cell nephropathy, neurocognitive decline, intracranial and intracerbebral hemorrhage, transient ischemic attacks, infarctive stroke, spinal cord infarction or compression, vestibular dysfunction, sensory hearing loss, growth retardation, delayed puberty, splenic infarction, osteoporosis, bone marrow infarction and necrosis, bone marrow infarction with resulting exacerbation of anemia or pancytopenia, fat embolism, orbital compression syndrome, myocardial infarction, acute heptatic dysfunction, and pregnancy complications of mother or fetus.

7. The method of claim 1 , wherein each

is a moiety of Formula (B):

wherein:
each W is independently selected from CR 1 and N;
each X is independently selected from CR 2 and N;
each Y is independently selected from NR 5 , S, and O; and
each Z is independently selected from CR 4 and N.

8. The method of claim 1 , wherein each R 1 is independently selected from H, C 1-6 alkyl, and C 1-6 alkoxycarbonyl.

9. The method of claim 1 , wherein each R 2 is independently selected from H, halo, and C 1-6 alkyl.

10. The method of claim 1 , wherein each R 3 is independently selected from H, Cy, OR a , SR a , C(═O)R a , C(═O)OR a , NR c R d , and C═NR f .

11. The method of claim 1 , wherein each R 5 is independently selected from H and Cy.

12. The method of claim 1 , wherein each R 4 is independently selected from H, C 1-6 alkyl, and C(═O)R a .

13. The method of claim 1 , wherein each R 6 is independently selected from H and Cy.

14. The method of claim 1 , wherein each R a , R c , and R d are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; each R b is independently selected from C 1-6 alkyl and C 1-6 haloalkyl; and each R f is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and Cy.

15. The method of claim 1 , wherein each

is a moiety of Formula (A) or (B):

wherein:
each R 1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a , SR a , C(═O)R a , C(═O)NR c R d , C(═O)OR a , NR c R d , NR c C(═O)R b , NR c C(═

Assignees

• Massachusetts Gen Hospital
• Bloch Donald B

Inventors

• Zapol Warren M
• Bloch Kenneth D
• Nakagawa Akito
• Lui Francine E
• Freedman Revital

Classifications

• A61K31/4196 Primary

  1,2,4-Triazoles · CPC title

• A61K31/42

  Oxazoles · CPC title

• A61K31/17

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61K31/198

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• A61K31/4015

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title