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US 2024/0360067 A1Published application
Derivatives of itaconic acid and their use as anti-inflammatory agents
AssigneeSitryx Therapeutics Limited
InventorsMichael Liam COOKE, Matthew Colin Thor FYFE, Alessandro MAZZACANI
Life of this patent
Estimating the term…
Abstract
The invention relates to compounds of formula (I) and to their use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response: wherein RA and RB are as defined herein.
Claims32
1:
- A compound of formula (I):
- wherein the moiety:
- represents
- RA is:
- wherein:
- RA1 is selected from the group consisting of H, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, —SC1-4 alkyl, —SC1-4 haloalkyl and SF5;
- RA2 is selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy;
- RA3 is C1-2 alkyl;
- m is 0, 1 or 2;
- n is 1 or 2;
- and
- p is 0, 1, 2, 3 or 4;
- or RA is:
- wherein:
- RA4 is H, C1-4 alkyl, C1-4haloalkyl or C≡CH;
- and
- RA5 is H, C1-4 alkyl or C1-4 haloalkyl;
- or RA4 and RA5 join to form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclic ring wherein the C3-6 cycloalkyl ring is optionally substituted by one or more RA6, wherein RA6 is independently selected from the group consisting of fluoro, methyl and cyano, or two RA6 groups which are attached to the same carbon atom join to form a C3-4 cycloalkyl ring;
- A is phenyl or 5-6-membered heteroaryl wherein when A is phenyl or 6-membered heteroaryl A is optionally substituted by one or more RA7, and when A is 5-membered heteroaryl A is substituted by one or more RA7, wherein when A is phenyl substituted by one or more RA7, one RA7 is in the 4-position with respect to C(RA4)(RA5);
- RA7 is independently selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, SF5, SC1-4 alkyl and SC1-4 haloalkyl;
- and
- RB is NRB1RB2 or ORB3;
- wherein:
- RB1 and RB2 are independently selected from the group consisting of H, C1-4 alkyl and C1-4 haloalkyl and 4-7-membered heterocyclyl wherein RB1 and/or RB2 are optionally substituted by one or more RB4 wherein RB4 is selected from the group consisting of C1-2 alkyl, NH2, N(C1-2 alkyl)2, hydroxy, oxo, 5-7-membered heterocyclyl and 5-6-membered heteroaryl optionally substituted by C1-2 alkyl;
- and
- RB3 is selected from the group consisting of H, C1-4 alkyl, C1-4 haloalkyl, CH2COOH, CH2CH2COOH, CH2tetrazolyl and CH2CH2tetrazolyl, wherein RB3 is optionally substituted on an available carbon atom by one or more RB3′ wherein RB3′ is selected from the group consisting of difluoromethyl, trifluoromethyl and methyl;
- and/or wherein RB3 is optionally substituted by two RB3′ groups which are attached to the same carbon atom and join to form a C3-6 cycloalkyl or a 4-6-membered heterocyclyl ring;
- or a pharmaceutically acceptable salt and/or solvate thereof.
25 more elements
2:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein the moiety:
- represents
(canceled)
The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein RA is:
- wherein RA1, RA2, RA3, m, n and p are defined in claim 1.
5:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 4 wherein RA1 is C1-4 haloalkyl.
6:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 4 wherein m is 0.
7:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according claim 4 wherein n is 1.
8:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 4 wherein p is 0.
9:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein RA is:
- wherein A, RA4 and RA5 are defined in claim 1.
10:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein RA4 is C1-4 alkyl such as methyl.
11:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein RA5 is H.
12:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein when RA4 and RA5 are different, the carbon atom to which RA4 and RA5 are attached has the following stereochemistry:
13:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein RA4 and RA5 join to form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclic.
14:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 13 wherein the C3-6 cycloalkyl ring is not substituted;
- or
- wherein the C3-6 cycloalkyl ring is substituted by one or more RA6, wherein RA6 is independently selected from the group consisting of fluoro, methyl and cyano, or two RA6 groups which are attached to the same carbon atom join to form a C3-4 cycloalkyl ring.
15-16. (canceled)
17:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein A is phenyl, thienyl or pyridinyl.
(canceled)
19:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein A is unsubstituted phenyl or unsubstituted 6-membered heteroaryl.
20:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein A is substituted by one or more, wherein RA7 is defined in claim 1, and wherein when A is phenyl substituted by one or more RA7, one RA7 is in the 4-position with respect to C(RA4)(RA5).
21:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 20 wherein RA7 is halo or C1-4 haloalkyl.
(canceled)
23:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein RB is NRB1RB2.
24-36. (canceled)
37:
- The compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein RB is ORB3.
38-45. (canceled)
46:
- The compound according to claim 1, which is selected from the list consisting of:
- (S)-3-((1-(4-(trifluoromethyl)phenyl)ethoxy)carbonyl)but-3-enoic acid;
- 3-((1-(4-(trifluoromethyl)phenyl)cyclobutoxy)carbonyl)but-3-enoic acid;
- 3-((1-(3-fluoro-4-(trifluoromethyl)phenyl)cyclobutoxy)carbonyl)but-3-enoic acid;
- 3-(((3-(4-(trifluoromethyl)phenyl)oxetane-3-yl)oxy)carbonyl)but-3-enoic acid;
- 3-((1-(5-(trifluoromethyl)pyridin-2-yl)cyclobutoxy)carbonyl)but-3-enoic acid;
- 3-((1-(5-(trifluoromethyl)thiophen-2-yl)cyclobutoxy)carbonyl)but-3-enoic acid;
- 3-(((6-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)carbonyl)but-3-enoic acid;
- 4-methyl 1-(1-(4-(trifluoromethyl)phenyl)cyclobutyl) 2-methylenesuccinate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-(methylamino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-(dimethylamino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-amino-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-((2-(dimethylamino)ethyl)amino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 2-methylene-4-((2-morpholinoethyl)amino)-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 2-methylene-4-((1-methylpiperidin-4-yl)amino)-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-(((1H-imidazol-2-yl)methyl)amino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-(((1-methyl-1H-imidazol-2-yl)methyl)amino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-((1-amino-3-hydroxy-1-oxopropan-2-yl)amino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-((1,1-dioxidothietan-3-yl)amino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-((2-hydroxyethyl)amino)-2-methylene-4-oxobutanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 2-methylene-4-oxo-4-((tetrahydro-2H-pyran-4-yl)amino)butanoate;
- 1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-((2-amino-2-oxoethyl)amino)-2-methylene-4-oxobutanoate;
- 2-((3-((1-(4-(trifluoromethyl)phenyl)cyclobutoxy)carbonyl)but-3-enoyl)oxy)acetic acid;
- and
- 3-methyl-4-oxo-4-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)but-2-enoic acid;
- or a pharmaceutically acceptable salt and/or solvate of any one thereof.
23 more elements
47:
- A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1.
48-50. (canceled)
51:
- A method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound, pharmaceutically acceptable salt and/or solvate thereof according to claim 1.
52-56. (canceled)
57:
- The method according to claim 51, wherein the inflammatory disease or disease associated with an undesirable immune response is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndromes, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease and asthma.
58-68. (canceled)
Dependencies are inferred from the claim text.