P2X3 andor P2X2/3 receptor antagonist, pharmaceutical composition comprising same, and use thereof
A P2X3 and/or P2X2/3 receptor antagonist of formula (I), a pharmaceutical composition comprising the same, and a use thereof in preparing a drug for preventing or treating a disease mediated by the P2X3 and/or P2X2/3 receptor antagonist.
1. A method for the treatment of a disease mediated by the P2X3 and/or P2X2/3 receptor antagonist, wherein the method comprises administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound or prodrug thereof:
wherein:
L is O;
V 1 is selected from the group consisting of N,
and NR;
V 2 is selected from the group consisting of CR 6 and C(═O);
represents either a single bond or a double bond, provided that when is a single bond, V 1 is NR and V 2 is C(═O);
R is selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl, and at most 2 ring members in the cyclic hydrocarbyl and heterocyclyl are C(═O);
R 1 , R 2 , R 3 and R 6 are each independently selected from the group consisting of H, halogen, —CN, —NH 2 , —OH, —SH, —Se—R, —Si(R) 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, C 1-6 haloalkyl, —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R b , —S(═O)(═NR)R a , —NR a R b , —C(═O)NR a R b , —C(═S)NR a R b , —C(═NR)NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —NR a —S(═O) 2 —R b , —NR a —C(═O)—NR a R b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkylene- C(═O)R, —C 1-6 alkenylene-OR a , —O—C 1-6 alkylene-NRaR b and —P(═O)RaR b ;
R 4 and R 5 are each independently selected from the group consisting of H, —C(═O)OR a , —NRaR b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —C 1-6 alkylene-NRaR b , —C 1-6 alkylene-OR a , —C 1-6 alkylene-O—C 1-6 alkylene-OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;
alternatively, R 1 and R 4 together form —NH—(C 1-6 alkylene)-L-(C 1-6 alkylene)-;
the above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, —Si(R) 3 , C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R b , —NR a R b , —C(═O)NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —NR a —S(═O) 2 —R b , —NR a —C(═O)—NR a R b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkenylene-OR a and —O—C 1-6 alkylene-NR a R b , the alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, —NR a R b , C 1-6 alkyl, —O—C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; and
R 1 and R b , at each occurrence, are each independently selected from the group consisting of H, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; alternatively, R 1 and R b together with the atom to which they are attached form a 3- to 12-membered heterocycle or heteroaromatic ring, the above groups are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, —O—C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl.
2. A method for the treatment of a disease mediated by the P2X3 and/or P2X2/3 receptor antagonist, wherein the method comprises administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound or prodrug thereof:
wherein:
L is O;
V 1 is selected from the group consisting of N,
and NR;
represents either a single bond or a double bond, provided that when is a single bond, V 1 is NR and V 2 is C(═O);
R is selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl, and at most 2 ring members in the cyclic hydrocarbyl and heterocyclyl are C(═O);
R 1 , R 2 , R 3 and R 6 are each independently selected from the group consisting of H, halogen, —CN, —NH 2 , —OH, —SH, —Se—R, —Si(R) 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, C 1-6 haloalkyl, —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R b , —S(═O)(═NR)R a , —NR a R b , —C(═O)NR a R b , —C(═S)NR a R b , —C(═NR)NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —NR a —S(═O) 2 —R b , —NR a —C(═O)—NR a R b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkylene- C(═O)R, —C 1-6 alkenylene-OR a , —O—C 1-6 alkylene-NRaR b and —P(═O)RaR b ;
R 4 and R 5 are each independently selected from the group consisting of H, —C(═O)OR a , —NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkylene-O—C 1-6 alkylene-OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;
alternatively, R 1 and R 4 together form —NH—(C 1-6 alkylene)-L-(C 1-6 alkylene)-;
the above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, —Si(R) 3 , C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R b , —NR a R b , —C(═O)NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —NR a —S(═O) 2 —R b , —NR a —C(═O)—NR a R b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkenylene-OR a and —O—C 1-6 alkylene-NR a R b , the alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, —NR a R b , C 1-6 alkyl, —O—C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; and
R a and R b , at each occurrence, are each independently selected from the group consisting of H, —OH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, benzyl, methoxy and ethoxy; or, R 1 and R b together with the atom to which they are attached form a 5- to 8-membered heterocycle or heteroaromatic ring.
3. The method according to claim 1 , wherein R 1 , R 2 , R 3 and R 6 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, —NH 2 , —OH, —SH, —Se—CH 3 , —Si(CH 3 ) 3 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, propenyl, allyl, ethynyl, propynyl, trifluoromethyl, acetyl, —C(═O)OH, —C(═O)NH 2 , —C(═S)NH 2 , —C(═NH)NH 2 , —NHCH 3 , —NHCH 2 CH 3 , —NHCH 2 CF 3 , —N(CH 3 ) 2 , —N(CH 3 )(C 2 H 5 ), —N(C 2 H 5 ) 2 , —NHCH 2 CH 2 OH, —NH—C(═O)CH 3 , —NH—C(═O)CH═CH 2 , methoxy, ethoxy, propoxy, phenyl, —NH—C(═O)—NH 2 , —NH—C(═O)OCH 3 , —SCH 3 , —SCH 2 CH 3 , —SC(CH 3 ) 3 , —SBn, —S(═O)CH 3 , —S(═O)Bn, —S(═O) 2 CH 3 , —S(═O) 2 Bn, —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —S(═O)(═NH)CH 3 , —P(═O)(CH 3 ) 2 , —P(═O)(C 2 H 5 ) 2 ,
4. The method according to claim 1 , wherein R 4 and R 5 are each independently selected from the group consisting of H, —C(═O)OC(CH 3 ) 3 , —NH 2 , —NHCH 3 , —NHPh, —NHC(═O)CH 3 , —NHBoc, methyl, ethyl, —CH 2 CF 3 , n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl,
5. The method according to claim 1 , wherein the method comprises administering to a subject in need thereof an effective amount of the compound has the structure of any of the following formulae, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, or prodrug thereof:
6. The method according to claim 1 , wherein the compound has the following structure:
7. A method for the treatment of a disease mediated by the P2X3 and/or P2X2/3 receptor antagonist, wherein the method comprises administering to a subject in need thereof a pharmaceutical composition, the pharmaceutical composition comprises a prophylactically or therapeutically effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier:
wherein:
L is O;
V 1 is selected from the group consisting of N,
and NR;
V 2 is selected from the group consisting of CR 6 and C(═O);
represents either a single bond or a double bond, provided that when is a single bond, V 1 is NR and V 2 is C(=O);
R is selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl, and at most 2 ring members in the cyclic hydrocarbyl and heterocyclyl are C(═O);
R 1 , R 2 , R 3 and R 6 are each independently selected from the group consisting of H, halogen, —CN, —NH 2 , —OH, —SH, —Se—R, —Si(R) 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, C 1-6 haloalkyl, —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R b , —S(═O)(═NR)R a , —NR a R b , —C(═O)NR a R b , —C(═S)NR a R b , —C(═NR)NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —NR a —S(═O) 2 —R b , —NR a —C(═O)—NR a R b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkylene- C(═O)R, —C 1-6 alkenylene-OR a , —O—C 1-6 alkylene-NRaR b and —P(═O)RaR b ;
R 4 and R 5 are each independently selected from the group consisting of H, —C(═O)OR a , —NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkylene-O—C 1-6 alkylene-OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;
alternatively, R 1 and R 4 together form —NH—(C 1-6 alkylene)-L-(C 1-6 alkylene)-;
the above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, —Si(R) 3 , C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —OR a , —SR—, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R b , —NR a R b , —C(═O)NR a R b , —NR a —C(═O)R b , —NR a —C(═O)OR b , —NR a —S(═O) 2 —R b , —NR a —C(═O)—NR a R b , —C 1-6 alkylene-NR a R b , —C 1-6 alkylene-OR a , —C 1-6 alkenylene-OR a and —O—C 1-6 alkylene-NR a R b , the alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, —NR a R b , C 1-6 alkyl, —O—C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; and
R a and R b , at each occurrence, are each independently selected from the group consisting of H, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl; alternatively, R 1 and R b together with the atom to which they are attached form a 3- to 12-membered heterocycle or heteroaromatic ring, the above groups are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, —O—C 1-6 alkyl, saturated or partially unsaturated C 3-6 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl.
8. The method according to claim 1 , wherein the disease is selected from the group consisting of a urinary tract disease selected from reduced bladder capacity, frequent micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity; pain disease selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine and cluster headaches, nerve injury, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury and pain associated with irritable bowel syndrome; cardiovascular system disease; respiratory disease selected from chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disease selected from irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic, and pain associated with gastrointestinal distension.
9. The method according to claim 7 , wherein the disease is selected from the group consisting of a urinary tract disease selected from reduced bladder capacity, frequent micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity; pain disease selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine and cluster headaches, nerve injury, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury and pain associated with irritable bowel syndrome; cardiovascular system disease; respiratory disease selected from chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disease selected from irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic, and pain associated with gastrointestinal distension.
10. A method for the treatment of a disease mediated by the P2X3 and/or P2X2/3 receptor antagonist, wherein the method comprises administering to a subject in need thereof a pharmaceutical composition, the pharmaceutical composition comprises a prophylactically or therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier, wherein the compound has the following structure:
11. The method according to claim 10 , wherein the disease is selected from the group consisting of a urinary tract disease selected from reduced bladder capacity, frequent micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity; pain disease selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine and cluster headaches, nerve injury, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury and pain associated with irritable bowel syndrome; cardiovascular system disease; respiratory disease selected from chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disease selected from irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic, and pain associated with gastrointestinal distension.
12. The method according to claim 1 , wherein R 1 and R 4 together form —NHCH 2 CH 2 —O—CH 2 CH 2 —.
13. The method according to claim 7 , wherein the pharmaceutical composition is in the form of a solid, semi-solid, liquid, or gas preparation.
14. The method according to claim 8 , wherein the cardiovascular system disease is hypertension.
15. The method according to claim 8 , wherein the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome.
16. The method according to claim 9 , wherein the cardiovascular system disease is hypertension.
17. The method according to claim 9 , wherein the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome.
18. The method according to claim 10 , wherein the pharmaceutical composition is in the form of a solid, semi-solid, liquid, or gas preparation.
19. The method according to claim 11 , wherein the cardiovascular system disease is hypertension.
20. The method according to claim 11 , wherein the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome.