US2023029266A1PendingUtilityA1
MrgprX2 Antagonists for the Treatment of Inflammatory Disorders
Est. expiryNov 5, 2039(~13.3 yrs left)· nominal 20-yr term from priority
A61K 31/5377A61K 31/454A61K 31/4439A61K 31/427A61K 31/426A61K 31/428A61K 31/42A61K 31/4184A61P 17/06A61P 17/04A61P 17/02A61P 17/00A61K 31/4523A61K 31/433A61K 31/422A61K 31/40A61K 31/397A61K 31/382A61K 31/381A61K 31/351A61K 31/34A61K 31/337A61K 9/0014
53
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Claims
Abstract
The present disclosure is directed to use of MrgprX2 antagonists in the treatment of inflammatory disorders, e.g., inflammatory disorders of the skin. This invention is also directed to pharmaceutical compositions comprising a MrgprX2 antagonist and a pharmaceutically or orally acceptable carrier for administration.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A composition comprising a dermatologically acceptable excipient and a compound having the following Formula I:
wherein:
W is H or -(L 1 ) p -A 2 ;
A 1 is a ring system selected from the eight systems as follows:
R A is absent or is selected from H, C 1-3 alkyl, halogen, and CN;
k, q, m and p are each independently 0 or 1;
provided that q is not 0 when m and k are each 1;
R 3 is H;
R 1 is selected from H; C 1-6 alkyl or C 3-6 cycloalkyl, which is optionally substituted with 1, 2 or 3 independently selected R 50 groups; or a 3-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1, 2 or 3 independently selected R 51 groups, and which optionally comprises a —(C═O)— group or —S(═O) 2 - group in the ring;
each R 50 is independently selected from hydroxy, —NR 20 N 21 ; C 1-3 haloalkyl; halogen; CN; C 3-6 cycloalkyl which is optionally substituted with 1-3 R 25 groups; C 1-3 alkoxy; C 1-3 hydroxyalkyl; and a 5-10 membered heterocycloalkyl having 1-3 ring heteroatoms independently selected from N, O and S, which is optionally substituted with 1 or 2 independently selected R 51 groups;
each R 20 and R 21 is independently selected from H, C 1-6 alkyl and —SO 2 NR 30 R 31 ;
each R 22 is independently C 1-6 alkyl;
each R 25 is hydroxy;
each R 51 is independently selected from C 1-6 alkyl; —SO 2 NR 30 R 31 ; —C(═O)—O—R 32 ; halogen; hydroxy; cyano; C 1-3 hydroxyalkyl; —C(═O)—NR 33 R 34 ; —C(═O)—R 35 ; CN; —SO 2 R 22 ; C 1-3 haloalkyl; NR 33 R 34 ; and C 1-3 alkoxy;
each R 30 and R 31 is independently selected from H and C 1-6 alkyl;
each R 32 is independently selected from H and C 1-6 alkyl;
each R 33 and R 34 is independently selected from H and C 1-6 alkyl;
each R 35 is independently C 1-6 alkyl;
R 2 is H, C 1-6 alkyl or Cm cycloalkyl, each optionally substituted with 1, 2 or 3 groups selected from hydroxy, C 1-3 haloalkyl, halogen, C 1-3 alkoxy and CN;
L 1 is O, CH 2 , —CH(C 1-3 alkyl)-, —C(═O)—NH—CH 2 —, —N(C 1-6 alkyl)-, or —NH—;
A 2 is C 6-10 aryl, C 3-7 cycloalkyl, or a 5-10 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein each of C 6-10 aryl, C 3-7 cycloalkyl and 5-10 membered heteroaryl is optionally substituted with 1, 2 or 3 independently selected R 60 groups; and
each R 60 is independently selected from halogen, CN, hydroxy, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 haloalkyl, —C(═O)—O—R 35 and C 1-3 alkyl optionally substituted with 1-3 substituents independently selected from hydroxy, CN and C 1-3 alkoxy;
or a stereoisomer, solvates, tautomers, or pharmaceutically acceptable salts thereof.
2 . The composition of claim 1 , wherein A 1 is ring system 1.
3 . The composition of claim 1 , wherein A 1 is ring system 3.
4 . The composition of claim 1 , wherein A 2 is optionally substituted phenyl.
5 . The composition of claim 1 , wherein A 2 is optionally substituted pyridyl.
6 . The composition of claim 1 , wherein A 2 is optionally substituted pyrid-2-yl.
7 . The composition of claim 1 , wherein A 2 is optionally substituted pyrid-3-yl.
8 . The composition of claim 1 , wherein A 2 is optionally substituted pyrid-4-yl.
9 . The composition of claim 1 , wherein A 2 is optionally substituted pyrid-2-yl.
10 . The composition of claim 1 , wherein A 2 is optionally substituted cyclopentyl.
11 . The composition of claim 1 , wherein A 2 is optionally substituted cyclohexyl.
12 . The composition of claim 1 , wherein A 2 is substituted with one R 60 group.
13 . The composition of claim 1 , wherein A 2 is substituted with two R 60 groups.
14 . The composition of claim 1 , wherein A 2 is phenyl or pyridyl substituted with one R 60 group in the 2-position relative to the point of attachment to L 1 or A 1 .
15 . The composition of claim 1 , wherein A 2 is phenyl or pyridyl substituted with one R 60 group in the 3-position relative to the point of attachment to L 1 or A 1 .
16 . The composition of claim 1 , wherein A 2 is phenyl or pyridyl substituted with one R 60 group in the 4-position relative to the point of attachment to L 1 or A 1 .
17 . The composition of claim 1 , wherein A 2 is phenyl or pyridyl substituted with two R 60 group in the 2- and 3-positions relative to the point of attachment to L 1 or A 1 .
18 . The composition of claim 1 , wherein A 2 is phenyl substituted with two R 60 groups in the 2- and 4-positions relative to the point of attachment to L 1 or A 1 .
19 . The composition of claim 1 , wherein A 2 is phenyl substituted with two R 60 groups in the 2- and 5-positions relative to the point of attachment to L 1 or A 1 .
20 . The composition of claim 1 , A 2 is phenyl substituted with two R 60 groups in the 3- and 4-positions relative to the point of attachment to L 1 or A 1 .
21 . The composition of claim 1 , wherein A 2 is phenyl substituted with two R 60 groups in the 3- and 5-positions relative to the point of attachment to L 1 or A 1 .
22 . The composition of claim 1 , wherein A 2 is phenyl substituted with two R 60 groups in the 2- and 5-positions relative to the point of attachment to L 1 or A 1 .
23 . The composition of claim 1 , wherein the R 60 groups are selected from F, Cl, CN, CF 3 , methoxy and methyl.
24 . The composition of claim 1 , wherein A 2 is phenyl substituted with fluorine in the 3-position relative to the point of attachment to L 1 or A 1 .
25 . The composition of claim 1 , wherein p is 1 and L 1 is O.
26 . The composition of claim 1 , wherein p is 1 and L 1 is CH 2 .
27 . The composition of claim 1 , wherein R 2 is H, methyl, ethyl, or cyclopropyl.
28 . The composition of claim 1 , wherein R 1 is C 1-4 alkyl optionally substituted with 1 or 2 R 50 groups independently selected from OH; cyclopropyl optionally substituted with —OH; methoxy; trifluoromethyl; dimethylamino; methylsulfonyl; fluorine and CN.
29 . The composition of claim 1 , wherein R 1 is 2-hydroxypropyl and R 2 is methyl or ethyl.
30 . The composition of claim 1 , wherein R 1 is an optionally substituted heterocycloalkyl ring selected from pyrrolidine-3-yl; pyrrolidine-2-yl; pyrrolidine-1-yl; oxetane-3-yl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl; azetidine-1-yl; azetidine-3-yl; morpholin-4-yl; 2-pyrrolidinone-4-yl; 2-pyrrolidinone-5-yl; piperidine-4-yl; piperidin-2-one-4-yl; tetrahydro-2H-thiopyran-1,1,-dione-4-yl; piperazine-1-yl; thiomorpholine-1,1-dioxide-4-yl; and morpholin-2-one-1-yl.
31 . The composition of claim 1 , wherein each R 51 is selected from —SO 2 NH 2 , methyl, t-butoxycarbonyl, fluorine, hydroxymethyl, —C(═O)NH 2 , —SO 2 CH 3 , —C(═O)CH 3 , hydroxy, and CN.
32 . The composition of claim 1 , wherein R 1 is C 1-4 alkyl optionally substituted with an optionally substituted heterocycloalkyl ring selected from pyrrolidine, piperidine, 2-pyrrolidinone, morpholine and tetrahydropyran.
33 . The composition of claim 1 , wherein the compound is selected from the Compounds in Table 1 herein, or a stereoisomer, solvates, tautomers, or pharmaceutically acceptable salts thereof.
34 . A method for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of compound of claim 1 , and a dermatologically or orally acceptable excipient.
35 . The method of claim 34 , wherein the composition is in the form of a cream, a gel, a spray, an ointment, or is a unit dosage form for oral administration.
36 . The method of claim 34 , wherein the MrgprX2 antagonist is present at a concentration of about 0.001 wt. % to about 10 wt. %, based on the total weight of the composition.
37 . The method of claim 34 , wherein the MrgprX2 antagonist is present at a concentration of about 0.1 wt. % to about 5 wt. %, based on the total weight of the composition.
38 . The method of claim 34 , wherein the composition further comprises a skin absorption enhancer.
39 . The method of claim 34 , wherein the composition further comprises a skin absorption enhancer comprising one or more of mannitol, sulphoxides (e.g., dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (e.g., ethanol, or decanol), glycols (e.g., propylene glycol, hexylene glycol, polyoxyethylene glycol, diethylene glycol), surfactants (also common in dosage forms) and terpenes.
40 . The method of any of claims 34 - 39 , wherein the composition is applied to a patient's skin once daily.
41 . The method of any of claims 34 - 40 , wherein the composition is applied to a patient's skin twice daily.
42 . The method of any of claims 34 - 41 , wherein the composition is applied to a patient's skin three times daily.
43 . The method of any of claims 34 - 42 , wherein the composition is administered to a patient suffering from an inflammatory disorder.
44 . The method of any of claims 34 - 43 , wherein the inflammatory disorder is a disorder of the skin.
45 . The method of any of claims 34 - 44 , wherein the skin is human skin.
46 . The method of any of claims 43 - 45 , wherein the inflammatory disorder activates or is consequent to activation, of MrgprX2.
47 . The method of any of claims 43 - 46 , wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis), chronic urticaria, pseudo-allergic reactions triggered by small molecules for example anaphylactoid drug reactions, anaphylactic shock, rosacea, asthma, systemic itch such as cholestatic or uremic itch, chronic itch triggered by systemic diseases, or drug-adverse reactions.
48 . The method of any of claims 43 - 47 , wherein the inflammatory disorder is atopic dermatitis (e.g., Asian atopic dermatitis, European atopic dermatitis).
50 . The method of any of claims 34 - 48 , wherein the subject is a human.
51 . The method of any of claims 34 - 50 wherein the mammalian skin is human skin.Join the waitlist — get patent alerts
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