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US 2019/0055272 A1Published application
Prodrugs of phenolic trpv1 agonists
AssigneeConcentric Analgesics, Inc.
InventorsCraig HUSFELD, Andrei W. KONRADI
Life of this patent
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Abstract
Described herein are compounds, pharmaceutical compositions and medicaments that include such compounds, and methods of using such compounds to modulate transient receptor potential vanilloid 1 receptor (TRPV1) activity.
Claims107
A compound having the structure of Formula (I):
- X-Y Formula (I);
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —X;
- X is an agent capable of being cleaved upon exposure to physiological conditions;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof;
- wherein the structure of Formula (I) is not a compound of Formula (J):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to —C(O)—X—(C(R)(R2))n—Z;
- X is —C(R1)(R2)—, —O—, —N(R5)—, or —S—;
- n is an integer from 1 to 10;
- Z is —NR3R4 or —CO2H;
- R5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1 and R2 is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl, or two R1 or R2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, form a substituted or unsubstituted cycloalkyl group, or R1 and R5 groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted heterocycloalkyl group;
- and
- R3 and R4 is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
11 more elements
A compound having the structure of Formula (II):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —O— or —N(R3)—;
- R1 and R2 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, —C(═O)OR4, and —C(═O)NR3R4;
- R3 and R4 are each independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, and unsubstituted or substituted C3-8cycloalkyl;
- m is 0 or 1;
- n is 0 or 1;
- wherein when m is 0, then n is 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
6 more elements
A compound having the structure of Formula (III):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —O— or —N(R3)—;
- R1 and R2 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, —C(═O)OR4, and —C(═O)NR3R4;
- R3 and R4 are each independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, and unsubstituted or substituted C3-8cycloalkyl;
- m is 0 or 1;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
5 more elements
A compound having the structure of Formula (IV):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- each R1 is independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and —C(═O)R3;
- R2 is selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and —C(O)R4;
- R3 is hydrogen, or unsubstituted or substituted C1-6alkyl;
- R4 is hydrogen, or unsubstituted or substituted C1-6alkyl;
- each R5 is independently selected from unsubstituted C1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-SH, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)NH2, —C1-6alkyl-NH2, —C1-6alkyl-N(H)C(═NH)NH2, —C1-6alkyl-(phenyl), —C1-6alkyl-(4-hydroxyphenyl), and —C1-6alkyl-(heteroaryl);
- n is 1 or 2;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
6 more elements
A compound having the structure of Formula (V):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- A is O or S;
- each R1 is independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, and unsubstituted or substituted C3-8cycloalkyl;
- R2 is selected from hydrogen, unsubstituted or substituted C1-6alkyl, and unsubstituted or substituted C3-8cycloalkyl;
- each R5 is independently selected from unsubstituted C1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-SH, —C1-6alkyl-SCH3, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)NH2, —C1-6alkyl-NH2, —C1-6alkyl-N(H)C(═NH)NH2, —C1-6alkyl-(phenyl), —C1-6alkyl-(4-hydroxyphenyl), and —C1-6alkyl-(heteroaryl);
- and
- n is 1 or 2;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
6 more elements
A compound having the structure of Formula (VI):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —P(O)(OH)2, —S(O)2OH, or —C(═O)R1;
- R1 is selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, aryl, heteroaryl, PEG, and —CH(NH2)R5;
- and
- R5 is hydrogen, unsubstituted C1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-SH, —C1-6alkyl-SCH3, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)NH2, —C1-6alkyl-NH2, —C1-6alkyl-N(H)C(═NH)NH2, —C1-6alkyl-(phenyl), —C1-6alkyl-(4-hydroxyphenyl), or —C1-6alkyl-(heteroaryl);
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
4 more elements
A compound having the structure of Formula (VII):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- each A is independently O or S;
- each Z is independently —O— or —N(R3)—;
- each R1 and R2 are independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-8cycloalkyl, —C(═O)OR4, and —C(═O)NR4R5;
- each R3 is independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, and unsubstituted or substituted C3-8cycloalkyl;
- each R4 and R5 are independently unsubstituted or substituted C1-6alkyl;
- each n is independently 1, 2, 3, 4, or 5;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
6 more elements
A compound having the structure of Formula (VIII):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —O— or —N(R5)—;
- R1, R2, R3, R4, and R5 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
3 more elements
A compound having the structure of Formula (IX):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —O— or —N(R5)—;
- R1, R2, R3, R4, and R5 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
3 more elements
A compound having the structure of Formula (X):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- is a counterion;
- A is selected from —N(R8)—, —C(O)N(R8)—, —N(R8)C(O)—, —C(O)O—, —OC(O)—, and —O—;
- Z is —O— or —N(R8)—;
- each R1, R2, R3, R4, and R8 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- R5, R6, and R7 are independently selected from unsubstituted C1-6alkyl;
- m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- n is 0 or 1;
- p is 0 or 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
8 more elements
A compound having the structure of Formula (XI):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —O— or —N(R7)—;
- each R1 and R2 are independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8 heterocycloalkyl;
- R3, R4, R5, R6, and R7 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8 heterocycloalkyl;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
4 more elements
A compound having the structure of Formula (XII):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —O— or —N(R4)—;
- Z is O or S;
- R1, R2, R3, and R4 are independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
3 more elements
A compound having the structure of Formula (XIII):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- A is —P(O)(OH)2, —S(O)2OH, or —C(═O)CH(NH2)R8;
- X is —O— or —N(R3)—;
- Z is —O— or —N(R4)—;
- R1, R2, R3, and R4 are independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- each R5 is independently selected from halogen, —CN, —NO2, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-8cycloalkyl, C2-8heterocycloalkyl, aryl, heteroaryl, —C(O)R6, —CO2R6, —C(O)NR6R7, —SO2R6, and —SO2NR6R7;
- R6 and R7 are independently selected from hydrogen and C1-6alkyl;
- R8 is hydrogen, unsubstituted C1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-SH, —C1-6alkyl-SCH3, —C1-6 alkyl-C(═O)OH, —C1-6alkyl-C(═O)NH2, —C1-6alkyl-NH2, —C1-6alkyl-N(H)C(═NH)NH2, —C1-6alkyl-(phenyl), —C1-6alkyl-(4-hydroxyphenyl), or —C1-6alkyl-(heteroaryl);
- m is 0, 1, 2, 3, or 4;
- and
- n is 0 or 1;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
10 more elements
A compound having the structure of Formula (XIV):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- A is —P(O)(OH)2, —S(O)2OH, or —C(═O)CH(NH2)R8;
- X is —O— or —N(R5)—;
- Z is —O— or —N(R6)—;
- R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- or R2, R3, R4, and R6 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl, and R1 and R5 groups on adjacent atoms, together with the atoms to which they are attached, form a substituted or unsubstituted C2-8heterocycloalkyl group;
- and
- R8 is hydrogen, unsubstituted C1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-SH, —C1-6alkyl-SCH3, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)NH2, —C1-6alkyl-NH2, —C1-6alkyl-N(H)C(═NH)NH2, —C1-6alkyl-(phenyl), —C1-6alkyl-(4-hydroxyphenyl), or —C1-6alkyl-(heteroaryl);
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
7 more elements
A compound having the structure of Formula (XV):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —OS(O)2OH, —OS(O)2NHR1, —N(R1)S(O)2NHR2, —OC(O)NHR1, —N(R1)C(O)NHR2, C(R1)(R2)OH, —OP(O)(OR1)OH, —N(R1)P(O)(OR2)OH, —OP(O)(OR1)NHR2, or —N(R1)P(O)(OR1)NHR1;
- R1 and R2 are independently selected from hydrogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- each R3 is independently selected from halogen, —OH, —CN, —NO2, —NR6R7, C1-6alkyl, C1-6 haloalkyl, C1-6heteroalkyl, C1-6alkoxy, C3-8cycloalkyl, C2-8heterocycloalkyl, aryl, heteroaryl, —C(O)R6, —CO2R6, —C(O)NR6R7, —SO2R6, and —SO2NR6R7;
- R6 and R7 are independently selected from hydrogen and C1-6alkyl;
- m is 0, 1, 2, 3, or 4;
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
5 more elements
A compound having the structure of Formula (XVI):
- wherein:
- Y is a phenolic TRPV1 agonist, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to
- X is —P(O)(OH)2, —S(O)2OH, or —C(═O)CH(NH2)R8;
- R1, R2, and R3 are independently selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-8cycloalkyl, and unsubstituted or substituted C2-8heterocycloalkyl;
- and
- R8 is hydrogen, unsubstituted C1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-SH, —C1-6alkyl-SCH3, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)NH2, —C1- 6alkyl-NH2, —C1-6alkyl-N(H)C(═NH)NH2, —C1-6alkyl-(phenyl), —C1-6alkyl-(4-hydroxyphenyl), or —C1-6alkyl-(heteroaryl);
- or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate thereof.
4 more elements
Dependencies are inferred from the claim text.