MRGPRX2 antagonist for the treatment of pseudo allergic reactions
Compounds that have antiallergic and/or anti-inflammatory properties and methods of making thereof are disclosed. These compounds can block MMRGPRX2 and prevent or reduce mast cells activation. Pharmaceutical formulations in a unit dosage form suitable for the delivery of the compounds to a subject in need thereof are disclosed. The pharmaceutical formulations may include one or more active agents in addition to the compounds, such as one or more additional antiallergic and/or anti-inflammatory agents. The pharmaceutical formulation can be administered by oral administration, parenteral administration, inhalation, mucosal administration, or a combination thereof. Methods for preventing or treating pseudo allergic reactions, pseudo allergic diseases, and/or pseudo inflammatory diseases, or treating or ameliorating one or more symptoms associated with a pseudo allergic reaction, a pseudo allergic disease, and/or a pseudo inflammatory disease in a subject are also disclosed.
1 . A compound having the structure of
(a) wherein n is 0 or 1;
(b) wherein R′ and R″ are independently a hydrogen or an unsubstituted alkyl;
(c) wherein
has the structure of
(d) wherein
has the structure of
(e) wherein each occurrence of Y′ is independently CR 1 , O, S, or NR 2 , R 1 and R 2 are independently a hydrogen, an unsubstituted alkyl, a carbonyl, an alkoxy, an amido, an amino, an oxo, a thiol, or a hydroxyl,
with the proviso that when G′ and E′ are substituted aryl, the substituent is not an alkoxy.
2 . The compound of claim 1 , wherein n is 0.
3 . The compound of claim 1 , wherein
has the structure of
(a) wherein X′ is C, N, O, or S;
(b) wherein each occurrence of R 3 is independently a hydrogen, an unsubstituted alkyl, a carbonyl, an alkoxy, an amido, an amino, an oxo, a thiol, or a hydroxyl.
4 . The compound of claim 3 ,
(a) wherein X′ is C or N; and
(b) wherein each occurrence of R 3 is independently a hydrogen, an unsubstituted alkyl, a carbonyl, an amido, an oxo, or a hydroxyl.
5 . The compound of claim 3 ,
(a) wherein X′ is C or N;
(b) wherein each occurrence of R 3 is independently a hydrogen, an unsubstituted C 1 -C 6 alkyl, a formyl group, an oxo, or a hydroxyl.
6 . The compounds of claim 1 , wherein
has the structure of
wherein each occurrence of R 4 can be independently a hydrogen, an unsubstituted alkyl, a carbonyl, an alkoxy, an amido, an amino, an oxo, a thiol, or a hydroxyl.
7 . The compound of claim 6 ,
wherein each occurrence of R 4 is independently a hydrogen,
and R 5 -R 10 are independently a hydrogen or an unsubstituted alkyl.
8 . The compound of claim 6 , wherein each occurrence of R 4 is independently a hydrogen,
and R 5 -R 8 are independently hydrogen or an unsubstituted C 1 -C 4 alkyl.
9 . A compound selected from the group consisting of
10 . A pharmaceutical formulation comprising
one or more compounds of claim 1 ; and
a pharmaceutically acceptable excipient,
wherein the one or more compounds are in an effective amount to prevent or treat a pseudo allergic reaction, a pseudo allergic disease, or a pseudo inflammatory disease, or treat or ameliorate one or more symptoms associated with a pseudo allergic reaction, a pseudo allergic disease, or a pseudo inflammatory disease in a subject.
11 . The pharmaceutical formulation of claim 10 further comprising a second active agent, optionally more than one second active agent.
12 . The pharmaceutical formulation of claim 10 , wherein the second active agent is an antiallergic agent or an anti-inflammatory agent, or a combination thereof.
13 . A method for making the compound of claim 1 comprising
(i) mixing a reactant mixture and a catalyst to form a reaction mixture, wherein the reactant mixture comprises a first reactant, a second reactant, and a solvent; and
(ii) heating the reaction mixture at a suitable temperature for a period of time sufficient to form a product containing the compound of claim 1 ,
wherein step (i) is performed prior to or simultaneously with step (ii).
14 . The method of claim 13 , wherein the first reactant has the structure of
(a) wherein a is an integer from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or 0 or 1;
(b) wherein R′ and R″ are independently a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, an amido, an amino, an oxo, a phosphonium, a phosphanyl, a phosphonyl, a silyl, a sulfinyl, a sulfonyl, a thiol, a hydroxyl, or a halogen;
(c) wherein A′ is a substituted or unsubstituted polyaryl or a substituted or unsubstituted polyheteroaryl;
(d) wherein R 11 is a halogen or has the structure of
wherein each occurrence of R 12 is independently a hydrogen or a substituted or unsubstituted alkyl; and
(e) wherein the substituents are independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, a halogen, a hydroxyl, a phenoxy, an aroxy, an alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, an carboxyl, an amino, an amido, an oxo, a silyl, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, or a thiol.
15 . The method of claim 13 , wherein the second reactant has the structure of
(a) wherein b is an integer from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or 0 or 1;
(b) wherein R′ and R″ are independently a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, an amido, an amino, an oxo, a phosphonium, a phosphanyl, a phosphonyl, a silyl, a sulfinyl, a sulfonyl, a thiol, a hydroxyl, or a halogen;
(c) wherein Z′ is a substituted or unsubstituted polyaryl or a substituted or unsubstituted polyheteroaryl;
(d) wherein R 13 is trifluoromethanesulfonate (“OTf”) or has the structure of Formula XIV; and
(e) wherein the substituents are independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, a halogen, a hydroxyl, a phenoxy, an aroxy, an alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, an carboxyl, an amino, an amido, an oxo, a silyl, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, or a thiol.
16 . The method of claim 13 , wherein the solvent is water, dioxane, dimethoxyethane, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, tetrahydrofuran, tert-butyl methyl ether, or dichloromethane, or a combination thereof.
17 . The method of claim 13 , wherein the catalyst is PdCl 2 (dppf), PdCl 2 (dppf)DCM Complex, Tetrakis, PdCl 2 (PPh 3 ) 2 , XPhos Pd G3, or Pd(OAc) 2 /PPh 3 , or a combination thereof.
18 . The method of claim 13 , wherein in step (ii), the reaction mixture is heated at a temperature in a range from 50° C. to 150° C., from 60° C. to 150° C., from 70° C. to 150° C., from 80° C. to 150° C., from 50° C. to 140° C., from 50° C. to 120° C., from 70° C. to 120° C., from 80° C. to 120° C., such as about 100° C., for a time period of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 8 hours, at least 10 hours, up to 20 hours, up to 18 hours, up to 16 hours, in a range from 1 hour to 18 hours, from 2 hours to 16 hours, or from 2 hours to 15 hours.
19 . The method of claim 13 further comprising mixing the first reactant, the second reactant, and the solvent to form the reactant mixture prior to step (i), purging the reactant mixture with an inert gas prior to step (ii), stirring the reaction mixture during step (ii), and/or purifying the product containing the compound.
20 . A method for treating mast cells (“MCs”) in a subject in need thereof comprising,
(i) administering to the subject an effective amount of a compound selected from the compounds in claim 9 ,
wherein step (i) occurs one or more times, and
wherein the effective amount of the compound is effective to inhibit MCs degranulation, inhibit MRGPRX2 activation, reduce calcium cation (“Ca 2+ ”) flux in the MCs, and/or reduce release of inflammatory chemokine and/or cytokine.
21 . The method of claim 20 , wherein step (i) occurs more than one time.
22 . A compound having the structure of
wherein:
(a) X′ is C, N, O, or S; and
(b) each occurrence of R 3 and R 4 are independently a hydrogen, an unsubstituted alkyl, a carbonyl, an alkoxy, an amido, an amino, an oxo, a thiol, or a hydroxyl.
23 . The compound of claim 22 , wherein:
(a) X′ is C or N; and
(b) each occurrence of R 3 is independently a hydrogen, an unsubstituted C 1 -C 6 alkyl, a formyl group, an oxo, or a hydroxyl.
24 . The compound of claim 22 , wherein each occurrence of R 4 is independently a hydrogen,
and R 5 -R 8 are independently hydrogen or an unsubstituted C 1 -C 4 alkyl.