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US 7,074,799 B2Granted
Substituted quinazolin-4-ylamine analogues
AssigneeNeurogen Corporation
InventorsRajagopal Bakthavatchalam, Charles A. Blum, Harry Brielmann, Timothy M. Caldwell, Stephane De Lombaert, Kevin J. Hodgetts, Xiaozhang Zheng
Life of this patent
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Abstract
Substituted quinazolin-4-ylamine analogues are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.
Claims59
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherin:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkanone, C2-C8alkenyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar2 is a 5- to 7-membered aromatic heterocycle, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- Ar1 is a 5- to 10-membered aromatic carbocycle or heterocycle, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl).
27 more elements
A compound according to 2, wherein W and Y are each CH and Z is N, or wherein W and Z are each CH and Y is N.
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkanone, C2-C8alkenyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently chosen from phenyl and 5- and 6-membered aromatic heterocycles, optionally substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- and
- R7 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, mono- or di(C1-C8alkyl)amino or a 3- to 10-membered heterocycle, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, C1-C6alkyl, C1-C8alkoxy, C2-C8alkyl ether, haloC1-C8alkyl and haloC1-C8alkoxy.
27 more elements
A compound according to 11, wherein W and Y are each CH and Z is N, or wherein W and Z are each CH and Y is N.
A method for reducing calcium conductance of a cellular capsaicin receptor, comprising contacting a cell expressing a capsaicin receptor with at least one compound or salt of the formula:
- wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, amido, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- and thereby reducing calcium conductance of the capsaicin receptor.
27 more elements
A method for inhibiting binding of vanilloid ligand to a capsaicin receptor in vitro, the method comprising contacting capsaicin receptor with at least one compound or salt of the formula:
- wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- under conditions and in an amount sufficient to detectably inhibit vanilloid ligand binding to capsaicin receptor.
27 more elements
A method for treating a condition responsive to capsaicin receptor modulation in a patient, wherein the condition is selected from (i) exposure to capsaicin, pain, asthma, chronic obstructive pulmonary disease, itch, urinary incontinence, and cough, the method comprising administering to the patient a pharmaceutical composition comprising a capsaicin receptor modulatory amount of at least one compound or salt of the formula:
- wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl) and a physiologically acceptable carrier or excipient;
- wherein the compound or salt is a capsaicin receptor antagonist and has an IC50 value of 1 micromolar or less in a VR1-mediated calcium mobilizatoin assay;
- wherein the compound or salt is a capsaicin receptor antagonist and has an IC50 value of 1 micromolar or less in a VR1-mediated calcium mobilization assay;
- and thereby alleviating the condition in the patient.
29 more elements
A method for treating pain in a patient, comprising administering to a patient suffering from pain a pharmaceutical composition comprising a capsaicin receptor modulatory amount of at least one compound or salt of the formula:
- wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 1 0-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl) and a physiologically acceptable carrier or excipient;
- wherein the compound or salt is a capsaicin receptor antagonist and had and IC50 value of 1 micromolar or less in a VR1-mediated calcium mobilization assay;
- and thereby alleviating pain in the patient.
28 more elements
A method for treating itch in a patient, comprising administering to a patient a pharmaceutical composition comprising a capsaicin receptor modulatory amount of a compound or salt of the formula:
- wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 1 0-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl) and a physioloigically acceptable carrier or excipient;
- wherein the compound or salt is a capsaicin receptor antagonist and has an IC50 value of 1 micromolar or less in a VR1-mediated calcium mobilization assay;
- and thereby alleviating itch in the patient.
28 more elements
A method for treating cough in a patient, comprising administering to a patient a pharmaceutical composition comprising a capsaicin receptor modulatory amount of a compound or salt of the formula:
- wherein:
- V and X are N;
- W, Y and Z are each independently N or CR1, with the proviso that exactly one of W, Y, and Z is N;
- U is CR2;
- R1 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, amino, C1-C8alkyl, haloC1-C8alkyl, C1-C8alkoxy, haloC1-C8alkoxy and mono- and di-(C1-C8alkyl)amino;
- R2 is:
- (i) hydrogen, halogen or cyano;
- (ii) C2-C8alkanoyl or C3-C8alkanone, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (iii) a group of the formula —Rc-M-A-Ry, wherein:
- Rc is C0-C3alkyl;
- M is a bond, N(Rz), S, SO2, (C═O)pN(Rz), N(Rz)(C═O)p, SO2N(Rz), or N(Rz)SO2, wherein p is 0 or 1;
- A is a bond or C1-C8alkyl, optionally substituted with from 1 to 3 substituents independently selected from Rd;
- and
- Ry and Rz, if present, are:
- (a) independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C6-C10arylC0-C8alkyl, a 4- to 10-membered carbocycle, or joined to Rc to form a 4- to 10-membered carbocycle, wherein each Ry and Rz is independently unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- or
- (b) joined to form a 4- to 10-membered heterocycle that is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rd;
- wherein Rd is independently selected at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkylthio, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl);
- Ar1 and Ar2 are independently selected from 5- to 10-membered aromatic carbocycles and heterocycles, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from groups of the formula LRa;
- L is independently selected at each occurrence from a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)m—, —NRx—, —C(═O)NHRx—, —NHRxC(═O)—, —NRxS(O)m—, —S(O)mNRx— and —N[S(O)mRx]S(O)m—;
- wherein m is independently selected at each occurrence from 0, 1 and 2;
- and Rx is independently selected at each occurrence from hydrogen and C1-C8alkyl;
- Ra is independently selected at each occurrence from:
- (i) hydrogen, halogen, cyano and nitro;
- and
- (ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C2-C8alkyl ether, 3- to 10-membered heterocycles, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C1-C6alkyl, each of which is unsubstituted or substituted with from 1 to 9 substituents independently selected from Rb;
- and
- Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkyl ether, hydroxyC1-C8alkyl, haloC1-C8alkyl, phenyl, phenyl(C1-C8alkyl), mono- and di-(C1-C6alkyl)amino, (SO2)C1-C8alkyl, 5- to 7-membered heterocycle and (5- to 7-membered heterocycle)(C1-C8alkyl) and a physiologically acceptable carrier or excipient;
- wherein the compound or salt is a capsaicin receptor antagonist and has an IC50 value of 1 micromolar or less in a VR1-mediated calcium mobilization assay;
- and thereby alleviating cough in the patient.
28 more elements
Dependencies are inferred from the claim text.