Thiazolidinone, oxazolidinone, and imidazolone derivatives for treating lower urinary tract and related disorders

1. A method for treating urinary frequency, urinary urgency, nocturia, or incontinence which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, thereof,

wherein:

Z is —S—, —S(O)—, —SO 2 —, —O— or —NR— wherein R is hydrogen, C 1 -C 6 alkyl or —CO—(C 1 -C 6 alkyl);

R 1 is hydrogen or C 1 -C 6 alkyl;

R 2 is hydrogen, fluorine, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-CO 2 H or —(C 1 -C 6 alkyl)-CO—NR 5 R 2 , wherein either (a) R 5 is hydrogen, aryl or —(C 1 C 6 alkyl)-aryl and R 6 is -L-R wherein L is a direct bond, a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group and R is hydrogen, aryl, heteroaryl, carbocyclyl or heterocyclyl or (b) R 5 and R 6 together with the nitrogen atom to which they are attached, represent a moiety -Het 1 -Het 2 , wherein Het 1 is a heterocyclyl or heteroaryl group and Het 2 is hydrogen, aryl, heteroaryl, —CH(aryl) 2 or —CH(heteroaryl) 2 ;

Y is —(CR Y 2 ) q —, —(CR Y 2 ) m , X 4 —(CR Y 2 ) n —, —(CR Y 2 ) m -A-(CR Y 2 ) m — or —(CR Y 2 ) m -A-(CR Y 2 ) p —X 3 —(CR Y 2 ) m , wherein:

p, q, m and n are each independently an integer of 0 to 4;

A is aryl, heteroaryl, carbocyclyl or heterocyclyl;

X 3 is —O—, —S—, —NR′—, —S(O)—, —SO 2 —, —O—CO—, —S—CO—, —NR′—CO, —CO—O—, —CO—S— or —CO—NR′ wherein R′ is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

X 4 is —O—, —S—, —NR′—, —S(O)— or —SO 2 — wherein R′ is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

each R y is the same or different and is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl;

R 3 is hydrogen, aryl, heteroaryl, heterocyclyl or carbocyclyl; and

R 4 is methyl, —C 1 —X 1 —Ar 1 or —C 2 —X 2 —C 3 , wherein:

C 1 is a direct bond, a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

X 1 is a direct bond when C 1 is a direct bond and, when C 1 is a C 1 -C 6 alkylene group, C 2 -C 6 alkenylene group or C 2 -C 6 alkynylene group, represents a direct bond or —O—, —S—, —NR′—, —SO—, —SO 2 —, —CO—, —CO—S—, —CO—O—, —CO—NR′—, —S—CO—, —O—CO—, —NR′—CO—, —CO—O—R″—CO—O—, —CO—NR′—R″—CO—O—, —CO—O—R″—CO—NR′—, —CO—NR′—R″—CO—NR′—, —O—CO—NR′— or —NR′—CO—O—, wherein each R′ is the same or different and represents hydrogen, phenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl and each R″ is the same or different and represents a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

Ar 1 is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-R a -, heterocyclyl-R a -, aryl-R a - or carbocyclyl-R a -, wherein Ra is a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

C 2 is a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

X 2 is a direct bond or —O—, —S—, —NR′—, —SO—, —SO 2 —, —CO—, —CO—S—, —CO—O—, —CO—NR′—, —S—CO—, —O—CO—, —NR′—CO—, —CO—O—R″—CO—O—, —CO—NR′—R″—CO—O—, —CO—O—R″—CO—NR′—, —CO—NR′—R″—CO—NR′—, —NR′—CO—O— or —O—CO—NR′—, wherein each R′ is the same or different and represents hydrogen, phenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl and each R″ is the same or different and represents a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group; and

C 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group, wherein:

the alkyl, alkylene, alkenyl, alkenylene, alkynyl and alkynylene groups and moieties in the R 1 to R 4 substituents are unsubstituted or carry-1, 2 or 3 unsubstituted substituents selected from aryl, hydroxy, C 1 -C 6 alkoxy; C 1 -C 6 alkylthio, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , halogen, cyano, nitro, —NHCO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl), —CO—O—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl) substituents; and

the aryl, heteroaryl, carbocyclyl and heterocyclyl groups and moieties in the R 1 to R 4 substituents are unsubstituted or carry 1, 2 or 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 ′ alkoxy, C 1 -C 6 alkylthio, C 3 -C 6 carbocyclyl, C 3 -C 6 carbocyclyloxy, C 3 -C 6 , Earbocyclylthio, C 2 -C 6 alkenyl, C 2 -C 6 alkenyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alknynyl, C 2 -C 6 alkynyloxy, C 2 -C 6 alkynylthio, hydroxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , cyano, nitro, —NH—CO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl), —CO—O—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl) substituents, said substituents being unsubstituted or substituted by 1, 2 or 3 further unsubstituted substituents selected from halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH—CO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl)-and —O—CO—(C 1 -C 6 alkyl) substituents.

2. The method of claim 1 , wherein R 2 represents hydrogen, fluorine, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-CO 2 H or —(C 1 -C 4 alkyl)-CONR 5 R 6 , wherein either (a) R 5 is hydrogen, aryl or —(C 1 -C 2 alkyl)-aryl and R 6 is -L-R wherein L is a direct bond or a C 1 -C 4 alkylene group and R is hydrogen, aryl, carbocyclyl, heterocyclyl or heteroaryl or (b) R 5 and R 6 , together with the nitrogen atom to which they are attached, represent a moiety -Het 1 -Het 2 , wherein Het 1 is a heterocyclyl group and Het 2 is hydrogen, aryl or —CH(aryl) 2 .

3. The method of claim 2 , wherein R 2 represents hydrogen, an unsubstituted C 1 -C 4 alkyl group, —(CH 2 ) a —CO 2 H or —(CH 2 ) b —CONR 5 R 6 wherein a and b are 1 or 2 and either (a) R 5 is hydrogen, or an unsubstituted benzyl group and R 6 is -L-R wherein L is a direct bond or an unsubstituted C 1 -C 4 alkylene group and. R is hydrogen or a phenyl, cyclohexenyl, piperidyl, pyridyl or benzimidazolylgroup which is unsubstituted or substituted by a halogen, hydroxy, —OCH 3 or —OCH 2 CH 3 substituent, or (b) R 5 and R 6 , together with the N atom to which they are attached, represent a pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl group which is unsubstituted or substituted by an unsubstituted —CHPh 2 group.

4. The method of claim 1 , wherein Ar 1 is a heteroaryl, heterocyclyl, aryl, carbocyclyl or heteroaryl-(C 1 -C 2 alkyl)-group which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 unsubstituted groups selected from halogen, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, —NR′R″ and —NH—CO—R′ wherein R′ and R″ are the same or different and are selected from hydrogen and unsubstituted C 1 -C 4 alkyl.

5. The method of claim 4 , wherein, when Ar 1 is a heteroaryl group it is a thienyl group, when Ar 1 is a heteroaryl-(C 1 -C 2 alkyl)-group it is a thienyl-methyl- or furanyl-methyl-group and when Ar is a heterocyclyl group it is a morpholinyl, 1,4-benzodioxanyl or 1,3-benzodioxanyl group.

6. The method of claim 4 , wherein Ar 1 is a pyridyl, thienyl, benzimidazolyl, furanyl-methyl-, 1,4-benzodioxanyl, phenyl, cyclohexenyl, quinolinyl, 2,3-dihydro- 1 H-indenyl, 1,3-benzodioxolyl or 1,3-benzodioxanyl group which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy, —OCH 3 , —N(CH 3 ) 2 and —NH—CO—CH 3 .

7. The method of claim 1 , wherein C 3 is a C 1 -C 4 alkyl group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted groups selected from hydroxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 and halogen.

8. The method of claim 1 , wherein the compound of formula (I) is a thiazolidinone derivative of formula (IA) or a pharmaceutically acceptable salt thereof:

wherein:

Z is —S—, —S(O)— or —S(O) 2 —;

R 2 represents hydrogen, an unsubstituted C 1 -C 4 alkyl group, —(CH 2 ) a —CO 2 H or —(CH 2 ) b —CONR 5 R 2 wherein a and b are 1 or 2 and either (a) R 5 is hydrogen or an unsubstituted benzyl group and R 6 is -L-R wherein L is a direct bond or an, unsubstituted C 1 -C 4 alkylene group and R is hydrogen or a phenyl, cyclohexenyl, piperidyl, pyridyl or benzimidazolyl group which is unsubstituted or substituted by a halogen, hydroxy, —OCH 3 or —OCH 2 CH 3 substituent, or (b) R 5 and R 6 , together with the N atom to which they are attached, represent a pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl group which is unsubstituted or substituted by an unsubstituted —CHPh 2 group;

Y is a direct bond or a group of formula —(CR y 2 )—, —(CH 2 ) m O(CH 2 )—, -A- or -A-X 3 —(CH 2 ) m , wherein R Y is hydrogen, —CH 3 , —CH 2 —CH 3 or an unsubstituted phenyl group, wherein no more than one R Y group is phenyl; A is a phenyl, pyridyl or pyrrolyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from —CH 3 , —CH 2 —CH 3 , —OCH 3 , —OCH 2 —CH 3 , halogen and hydroxy; X 3 is —O—, —SO 2 — or NH—CO—; and m is 0 or 1;

R 3 is hydrogen or a phenyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl or 2,3-dihydrobenzofuran group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 allcylthio, C 2 -C 4 alkenyloxy, C 3 -C 6 carbocyclyloxy, —NHCO-Me and —N(CH 3 ) 2 , the substituents on R 3 being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy;

R 4 is an unsubstituted methyl group or is —C 1 —X 1 —Ar 1 or —C 2 —X 2 —C 3 , wherein:

C 1 is —(CH 2 )—, —(CH 2 ) 2 — or —(CH 2 ) 3 —;

X 1 is a direct bond or is —O—, —S—, —S—CO— or —O—CO—;

Ar 1 is a phenyl, pyridyl, thienyl, benzimidazolyl, furanyl-methyl-, cyclohexenyl, quinolinyl, 2,3-dihydro-1H-indenyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl or 1,4-benzodioxanyl group, which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy; —OCH 3 , —N(CH 3 ) 2 and —NH—CO—CH 3 ;

C 2 is a straight chain unsubstituted C 1 -C 4 alkylene group;

X 2 is a direct bond or is or is —O—, —S—, —CO—O— or —NH—CO—O; and

C 3 is C 1 -C 4 alkyl group which is unsubstituted or substituted on a primary carbon atom with either (a) one hydroxy or (b) 1, 2 or 3 halo substituents.

9. The method of claim 8 wherein, when Ar 1 is a pyridyl or benzimidazolyl group it is attached via a carbon atom.

10. The method of claim 8 , wherein Ar 1 is a phenyl, thienyl, furanylmethyl-, 1,3-benzodioxanyl or 1,4-benzodioxanyl group, which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy, —OCH 3 , —N(CH 3 ) 2 and —NH—CO—CH 3 .

11. A method for treating urinary frequency, urinary urgency, nocturia, or incontinence which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I′) or a pharmaceutically acceptable salt thereof,

wherein:

Z is —S—, —S(O)—, —SO 2 —, —O— or —NR— wherein R is hydrogen, C 1 -C 6 alkyl or —CO—(C 1 -C 6 -alkyl);

R 1 is hydrogen or C 1 -C 6 alkyl;

R 2 is hydrogen, fluorine, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-CO 2 H or —(C 1 -C 6 alkyl)-CO—NR 5 R 6 , wherein either (a) R 5 is hydrogen, aryl or —(C 1 C 6 alkyl)-aryl and R 6 is -L-R wherein L is a direct bond, a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group and R is hydrogen, aryl, heteroaryl, carbocyclyl or heterocyclyl or (b) R 5 and R 6 , together with the nitrogen atom to which they are attached, represent a moiety —Het 1 -Het 2 , wherein Het 1 is a heterocyclyl or heteroaryl group and Het 2 is hydrogen, aryl, heteroaryl, —CH(aryl) 2 or —CH(heteroaryl) 2 ;

R 3 is —SCQ 3 or —OCQ 3 wherein Q is halogen; and

R 4 is methyl, —C 1 —X 1 —Ar 1 or —C 2 —X 2 —C 3 , wherein

C 1 is a direct bond, a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

X 1 is a direct bond when C 1 is a direct bond and, when C 1 is a C 1 -C 6 alkylene group, C 2 -C 6 alkenylene group or C 2 -C 6 alkynylene group, represents a direct bond or —O—, —S—, —NR′—, —SO—, —SO 2 —, —CO—, —CO—S—, —CO—O—, —CO—NR′—, —S—CO—, —O—CO—, —NR′—CO—, —CO—O—R″—CO—O—, —CO—NR′—R″—CO—O—, —CO—O—R″—CONR′—, —CO—NR′—R″—CO—NR′—, —OCO—NR′— or —NR′—CO—O— wherein each R′ is the same or different and represents hydrogen, phenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl and each R″ is the same or different and represents a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

Ar 1 is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-Y—, heterocyclyl-Y—, aryl-Y— or carbocyclyl-Y—, wherein each Y is the same or different and represents a C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene group;

C 2 is a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group;

X 2 is a direct bond or —O—, —S—, —NR′—, —SO—, —SO 2 —, —CO—, —CO—S—, —CO—O—, —CO—NR′—, —S—CO—, —O—CO—, —NR′—CO—, —CO—O—R″—CO—O—, —CO—NR′—R″—CO—O—, —CO—O—R″—CO NR′—, —OCO—NR′— or NR′—CO—O-wherein each R′ is the same or different and represents hydrogen, phenyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl and each R″ is the same or different and represents a C 1 -C 6 alkylene group, a C 2 -C 6 alkenylene group or a C 2 -C 6 alkynylene group; and

C 3 is a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group or a C 2 -C 6 alkynyl group,

wherein:

the alkyl, alkylene, alkenyl, alkenylene, alkynyl and allcynylene groups and moieties in the R 1 to R 4 substituents are unsubstituted or carry 1, 2 or 3 unsubstituted substituents selected from aryl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , halogen, cyano, nitro, —NHCO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl), —CO—O—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl);

the aryl and heteroaryl groups and moieties in the R 1 to R 4 substituents are unsubstituted or carry 1, 2 or 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, hydroxy, C 1 -C 4 alkylenedioxy —NH 2 , —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , cyano, nitro, NH—CO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl), —CO—O—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl) substituents, said substituents being unsubstituted or substituted by 1, 2 or 3 further unsubstituted substituents selected from halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NH—CO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl); and

the carbocyclyl and heterocyclyl groups and moieties in the R 1 to R 4 substituents are unsubstituted or carry 1, 2 or 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, hydroxy, C 1 -C 4 alkylenedioxy, —NH 2 , NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , cyano, nitro, oxo, —NH—CO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl), —CO—O—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl) substituents, said substituents being unsubstituted or substituted by 1, 2 or 3 further unsubstituted substituents selected from halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C′ 1 -C 2 alkyl) 2 , —NH—CO—(C 1 -C 6 alkyl), —CO—NH—(C 1 -C 6 alkyl) and —O—CO—(C 1 -C 6 alkyl).

12. The method of claim 11 , wherein C 2 is unsubstituted or carries one substituent at the carbon atom α to the moiety X 2 or, where X 2 is a direct bond, to the moiety C 3 , which substituent is selected from hydroxy, halogen, C 1 -C 2 alkoxy, —NH 2 , NH(C 1 -C 2 alkyl), —N(C 1 -C 2 alkyl) 2 and —NHCO—(C 1 -C 2 alkyl).

13. The method of claim 12 , wherein said substituent is hydroxy or —NHCOCH 3 .

14. The method of claim 11 , wherein X 2 is a direct bond or is —O—, —S—, —NR′—, —CO—S—, —CO—O—, —CO—NR′— or —CO—NR′—R″—CO—O— wherein each R′ is the same or different and is hydrogen, —CH 3 or —CH 2 CH 3 and R″ is —CH 2 — or —CH 2 —CH 2 —.

15. The method of claim 11 , wherein C 3 is unsubstituted or substituted by one, two or three substituents selected from hydroxy, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 and halogen.

16. The method of claim 11 , wherein the compound of formula (I′) is a compound of formula (Ia′)

wherein:

Z is —S—, —S(O)— or —S(O) 2 —;

R 2 is hydrogen, an unsubstituted C 1 -C 4 alkyl group, —(CH 2 ) a -CO 2 H or —(CH 2 ) b —CONR 5 R 6 wherein a and b are 1 or 2 and either (a) R 5 is hydrogen or an unsubstituted benzyl group and R 2 is -L-R wherein L is a direct bond or an unsubstituted C 1 -C 4 alkylene group and R is hydrogen or a phenyl, cyclohexenyl, piperidyl, pyridyl or benzimidazolyl group which is unsubstituted or substituted by a halogen, hydroxy, —OCH 3 or —OCH 2 CH 3 substituent, or (b) R 5 and R 2 , together with the N atom to which they are attached, represent a pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl group which is unsubstituted or substituted by an unsubstituted —CHPh 2 group;

R 4 is an unsubstituted methyl group or is —C 1 —X 1 —Ar 1 or —C 2 —X 2 —C 3 .