N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides and their pharmaceutical and cosmetic use

Patent metadata

Field	Value
Publication number	US-9732044-B2
Application number	US-201615237236-A
Country	US
Kind code	B2
Filing date	Aug 15, 2016
Priority date	Nov 4, 2011
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The present invention relates generally to the field of pharmaceuticals and cosmetics. More specifically, the present invention pertains to certain N-(pyrid-4-yl)amides and N-(pyrimidin-4-yl)amides of the following formula which are potent modulators (e.g., inhibitors) of an androgen receptor, and which are useful, for example, in therapy, for example, in the treatment of a dermatological disease or disorder; a disease or disorder of the sebaceous gland(s); acne; hyperseborrhoea; oily skin; seborrhoeic dermatitis; hyperpilosity or hirsutism; atopic dermatitis; or androgenic alopecia; especially acne. The present invention also relates to compositions (e.g., pharmaceutical compositions, cosmetic compositions) comprising the compounds; methods of preparing the compositions; methods of modulating (e.g., inhibiting) an androgen receptor using the compounds and/or compositions; and medical and/or cosmetic use of the compounds and compositions.

First claim

The invention claimed is:

1. A compound of formula (1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein:
R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, —S(O) m —C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkyloxy, C 1-6 alkyl-OH, —(CH 2 ) i —C 1-6 alkyloxy, —(CH 2 ) j —O—C 1-6 fluoroalkyl, COR a , CN, NO 2 , NR 5 R 6 , or a halogen atom;
R 2 is a hydrogen atom, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, —S(O) n —C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkyloxy, C 1-6 alkyl—OH, —(CH 2 ) k —C 1-6 alkyloxy, —(CH 2 ) l —O—C 1-6 fluoroalkyl, COR b , CN, NO 2 , NR 5 ′R 6 ′, OH, or a halogen atom, and at least one of R 1 and R 2 is C 1-6 alkyloxy;
R 3 and R 4 are identical or different and are a hydrogen atom, C 1-12 alkyl, C 3-9 cycloalkyl, C 1-6 fluoroalkyl, —C 1-6 alkyl—OH, —(CH 2 ) p —C 1-6 alkyloxy, —(CH 2 ) q —C 3-9 cycloalkyl, —(CH 2 ) r —C 1-6 fluoroalkyl, —(CH 2 ) s —O—C 1-6 fluoroalkyl, phenyl, heteroaryl, heterocyclyl group, —(CH 2 ) t -phenyl, or —(CH 2 ) v -heteroaryl, wherein each phenyl and heteroaryl is optionally substituted with one to three identical or different R c groups;
or R 3 and R 4 , together with the carbon atom carrying them, may form a C 3-9 cycloalkyl group or a heterocyclyl group, wherein the heterocylyl group is selected from tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydro-1-oxo-thiopyranyl, or tetrahydro-1,1-dioxo-thiopyranyl;
R c is C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, —S(O) u —C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkyloxy, C 1-6 alkyl-OH, COR d , CN, NO 2 , NR 9 R 10 , OH, or a halogen atom;
R a , R b , and R d are identical or different and are C 1-6 alkyl, C 1-6 alkyloxy, or NR 7 R 8 ;
R 5 , R 5 ′, R 6 , R 6 ′, R 7 , R 8 , R 9 and R 10 are identical or different and are a hydrogen atom, C 1-6 alkyl, C 3-7 cycloalkyl, or —(CH 2 ) w —C 3-7 cycloalkyl;
wherein R 5 and R 6 , together with the nitrogen atom carrying them, may form a heterocyclyl group;
wherein R 5 ′ and R 6 ′, together with the nitrogen atom carrying them, may form a heterocyclyl group;
wherein R 7 and R 8 , together with the nitrogen atom carrying them, may form a heterocyclyl group;
wherein R 9 and R 10 , together with the nitrogen atom carrying them, may form a heterocyclyl group;
i, j, k, l, p, q, r, s, t, v, and w are different or identical and are 1, 2 or 3; and
m, n, and u are different or identical and are 0, 1 or 2.

2. The compound according to claim 1 , wherein at least one of R 1 and R 2 is methoxy.

3. The compound according to claim 1 , the compound being one of 2-Hydroxy-2-methyl-pentanoic acid (2,6-dimethoxy-pyrimidin-4-yl)-amide and N-(2-Bromo-6-methoxy-pyrimidin-4-yl)-2-ethyl-2-hydroxy-butyramide.

4. The compound according to claim 2 , the compound being 2-Hydroxy-2-methyl-pentanoic acid (2,6-dimethoxy-pyrimidin-4-yl)-amide.

5. The compound according to claim 2 , the compound being N-(2-Bromo-6-methoxy-pyrimidin-4-yl)-2-ethyl-2-hydroxy-butyramide.

6. A composition comprising a compound according to claim 1 , and a carrier, diluent, or excipient.

7. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.

8. A method of preparing a pharmaceutical composition, the method comprising a step of mixing a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

9. A method of treating a dermatological disease or disorder; the method comprising administering an effective amount of the compound according to claim 1 to an individual subject in need thereof, wherein the disease or disorder is selected from the group consisting of a disease or disorder of the sebaceous gland(s), acne, hyperseborrhoea, oily skin, seborrhoeic dermatitis, and atopic dermatitis.

10. A method of treating a dermatological disease or disorder; the method comprising administering a therapeutically-effective amount of a compound according to claim 1 to a patient in need of said treatment, wherein the disease or disorder is selected from the group consisting of a disease or disorder of the sebaceous gland(s), acne, hyperseborrhoea, oily skin, seborrhoeic dermatitis, and atopic dermatitis.

11. A method of treating acne, the method comprising administering a therapeutically-effective amount of a compound according to claim 1 to a patient in need of said treatment.

12. A cosmetic composition comprising a compound according to claim 1 , and a cosmetic carrier, diluent, or excipient.

13. The cosmetic composition according to claim 12 , wherein the composition is in the form of an ointment, a cream, a milk, a pomade, a gel, a suspension, lipidic or polymeric blisters or polymeric or gelled patches allowing controlled release, a powder, a lipidic or polymeric blister, an alcohol swab, a syndet, a solution, a spray, a mousse, a stick, a soap, a cleansing base, or a shampoo.

14. A non-therapeutic method of body care and/or hair care, the method comprising applying to the body and/or hair of a subject an effective amount of a compound according to claim 1 .

15. A non-therapeutic method of body care and/or hair care, the method comprising administering an effective amount of the compound according to claim 1 to an individual subject in need thereof.

16. A method of making a cosmetic composition for use in a non-therapeutic method of body care and/or hair care, the method comprising making the composition with an effective amount of the compound according to claim 1 .

17. A non-therapeutic method of body care and/or hair care, the method comprising applying to the body and/or hair of a subject an effective amount of a cosmetic composition comprising a compound according to claim 1 .

18. A non-therapeutic method of body care and/or hair care, the method comprising administering a cosmetic composition comprising an effective amount of the compound according to claim 1 to an individual subject in need thereof.

Assignees

• Galderma Res & Dev

Inventors

• Poinsard Cédric

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P5/26

  Androgens · CPC title

• A61P17/08

  Antiseborrheics · CPC title