Pteridine dione monocarboxylate transporter inhibitors

Patent metadata

Field	Value
Publication number	US-10874675-B2
Application number	US-201916423362-A
Country	US
Kind code	B2
Filing date	May 28, 2019
Priority date	Jan 22, 2015
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

The invention provides compounds effective as inhibitors of monocarboxylate transporters such as MCT1 and MCT4, which can be used for treatment of medical conditions wherein treatment of the condition with a compound having an inhibitor effect on MCT1, MCT4, or both is medically indicated. Compounds of the invention can have antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effects, and can be effective for treatment of cancer and of type II diabetes.

First claim

What is claimed is:

1. A method of inhibiting monocarboxylate transporter MCT1, comprising contacting the monocarboxylate transporter with an effective amount or concentration of an MCT1-inhibitory compound of formula A or of formula B

wherein
R 1 and R 2 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, a (C 6 -C 10 )aryl ring system, a 5- to 9-membered heteroaryl ring system, a (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl ring system, and a (C 1 -C 6 )alkyl-(5- to 9-membered)heteroaryl ring system;
provided that when R 2 comprises an aryl or heteroaryl ring system, the ring system bears 0-2 independently selected substituents from the group consisting of fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )fluoroalkoxy;

E is CH 2 , CH(C 1 -C 6 )alkyl, or CH(C 3 -C 7 )cycloalkyl;
J is O, S, S(O), S(O) 2 , NH, N(C 1 -C 6 )alkyl, or NC(═O)(C 1 -C 6 )alkyl;
R 3 is a monocyclic or bicyclic (C 6 -C 10 )aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl can be substituted or unsubstituted;
R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 1 -C 6 )fluoroalkyl, (C 3 -C 7 )cycloalkyl, a (4- to 7-membered)heteroaryl, or a monocyclic or bicyclic (C 6 -C 10 )aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl can be substituted or unsubstituted;
Z is a bond, or is —O—, —CH 2 —, —CH(Me)-, —S—, —NH—, or —N(C 1 -C 6 )alkyl;
n=1, 2, 3, or 4;
the cyclic group indicated as “ring” is an aryl or heteroaryl group of any one of the following formulas:

wherein wavy lines indicate points of bonding, and wherein each M is an independently selected CH or N, provided that M group is a nitrogen atom in one or two instances;

G is S, O, NH, NMe, or NCF 3 ;
T is independently at each occurrence CH or N;
wherein R 5 is optionally present, R 5 being one to four instances of independently selected F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, OCF 3 , O(C 1 -C 6 )alkyl, or CO—(C 1 -C 6 )alkyl;
or,
the cyclic group indicated as “ring” is a (C 3 -C 7 )cycloalkyl or a saturated (3- to 7-membered)heterocyclyl comprising 1-2 heteroatoms selected from the group consisting of O, NH, N(C 1 -C 6 )alkyl, and N(C 1 -C 6 )fluoroalkyl; wherein the points of bonding may be cis or trans;

or a pharmaceutically acceptable salt thereof.

2. A method of treatment of a condition in a mammal wherein treatment of the condition with a compound having an inhibitor effect on MCT1 is medically indicated, wherein the condition comprises cancer, diabetes, inflammation, or a condition requiring immunosuppression, comprising administering an effective amount of an MCT1-inhibitory compound of formula A or of formula B

wherein
R 1 and R 2 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, a (C 6 -C 10 )aryl ring system, a 5- to 9-membered heteroaryl ring system, a (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl ring system, and a (C 1 -C 6 )alkyl-(5- to 9-membered)heteroaryl ring system;
provided that when R 2 comprises an aryl or heteroaryl ring system, the ring system bears 0-2 independently selected substituents from the group consisting of fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )fluoroalkoxy;

E is CH 2 , CH(C 1 -C 6 )alkyl, or CH(C 3 -C 7 )cycloalkyl;
J is O, S, S(O), S(O) 2 , NH, N(C 1 -C 6 )alkyl, or NC(═O)(C 1 -C 6 )alkyl;
R 3 is a monocyclic or bicyclic (C 6 -C 10 )aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl can be substituted or unsubstituted;
R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 1 -C 6 )fluoroalkyl, (C 3 -C 7 )cycloalkyl, a (4- to 7-membered)heteroaryl, or a monocyclic or bicyclic (C 6 -C 10 )aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group wherein the aryl or heteroaryl can be substituted or unsubstituted;
Z is a bond, or is —O—, —CH 2 —, —CH(Me)-, —S—, —NH—, or —N(C 1 -C 6 )alkyl;
n=1, 2, 3, or 4;
the cyclic group indicated as “ring” is an aryl or heteroaryl group of any one of the following formulas:

wherein wavy lines indicate points of bonding, and wherein each M is an independently selected CH or N, provided that M group is a nitrogen atom in one or two instances;

G is S, O, NH, NMe, or NCF 3 ;
T is independently at each occurrence CH or N;
wherein R 5 is optionally present, R 5 being one to four instances of independently selected F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, OCF 3 , O(C 1 -C 6 )alkyl, or CO—(C 1 -C 6 )alkyl;
or,
the cyclic group indicated as “ring” is a (C 3 -C 7 )cycloalkyl or a saturated (3- to 7-membered)heterocyclyl comprising 1-2 heteroatoms selected from the group consisting of O, NH, N(C 1 -C 6 )alkyl, and N(C 1 -C 6 )fluoroalkyl; wherein the points of bonding may be cis or trans;

or a pharmaceutically acceptable salt thereof;
wherein the compound shows an antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effect.

3. The method of claim 2 wherein the mammal is a human.

4. The method of claim 2 further comprising administering an effective amount of a biguanide to the mammal.

5. The method of claim 4 wherein the biguanide is metformin.

6. The method of claim 2 further comprising administering an effective amount of a standard-of-care therapeutic agent to the mammal.

7. The method of claim/wherein administration is carried out by an oral, intravenous, intranasal or transdermal method.

8. The method of claim 2 wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1.

9. The method of claim 8 wherein the condition is cancer or type II diabetes.

10. The method of claim 9 wherein the condition is cancer and the treatment follows a determination of elevated MCT1 expression levels in the tumor or tumors.

11. The method of claim 1 or 2 wherein the compound is any one of the following, including all stereoisomeric forms, all isotopic forms, and all pharmaceutically acceptable salt forms thereof:

Assignees

• Scripps Research Inst

Inventors

• Bannister Thomas D
• Wang Hui
• Wang Chao
• Cleveland John L

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K45/06

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

• A61K31/155

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title

• C07D475/02

  with an oxygen atom directly attached in position 4 · CPC title

• C07D475/00

  Heterocyclic compounds containing pteridine ring systems · CPC title