Imidazole compounds and their use as adenosine deaminase inhibitors

1. A compound of the formula:

wherein R 1 is aryloxy, or aryl which is optionally substituted with substituent(s);

R 2 is lower alkyl;

R 3 is hydroxy or protected hydroxy; and

-A- is lower alkylene,

or a salt thereof,

or a prodrug thereof.

2. The compound according to claim 1 , wherein

R 1 is:

aryloxy, or

aryl optionally substituted with substituent(s) selected from the group consisting of halogen; hydroxy; aryloxy; lower alkylthio; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylamino; and lower alkoxy substituted with optionally substituted amino, protected amino, halogen, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted aryl(lower)alkoxy, or optionally substituted heterocyclic group.

3. The compound according to claim 1 , wherein

R 1 is:

naphthyloxy;

phenyl substituted with substituent(s) selected from the group consisting of halogen, hydroxy, aryloxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylamino, and lower alkoxy substituted with optionally substituted amino, protected amino, halogen, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted aryl(lower)alkoxy, or optionally substituted heterocyclic group; or

naphthyl substituted with halogen.

4. The compound according to any one of claims 2 ,

wherein substituent(s) of the optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted aryl(lower)alkoxy, or optionally substituted heterocyclic group,

are each independently selected from the group consisting of aryl optionally substituted with halogen, lower alkyl or halo(lower)alkyl; halogen; aryloxy optionally substituted with halogen; heterocyclic group optionally substituted with cyano; aryloxy(lower)alkyl; aryl(lower)alkyl; aryl(lower)alkenyl; arylthio; lower cycloalkyl; lower alkylthio; heterocyclicthio optionally substituted with halogen; lower alkoxy; cyano; lower alkyl; halo(lower)alkyl; and amino optionally substituted with lower alkyl or lower alkanoyl.

5. The compound according to any one of claims 1 , wherein A is ethylene.

6. The compound according to claim 1 , wherein

R 1 is aryloxy, or aryl which is optionally substituted with substituent(s);

R 2 is methyl;

R 3 is hydroxy; and

-A- is ethylene

or a salt thereof.

7. The compound according to claim 1 selected from the group consisting of:

(1) 1-[(2S,3R)-2-benzyloxy-5-(2-(methylthio)phenyl)-3-pentyl]imidazole-4-carboxamide;

(2) 1-[(2S,3R)-2-hydroxy-5-(2-(methylthio)phenyl)-3-pentyl]imidazole-4-carboxamide;

(3) 1-[(2S,3R)-2-hydroxy-5-(2-(methylsulfinyl)phenyl)-3-pentyl]imidazole-4-carboxamide;

(4) 1-[(2S,3R)-2-hydroxy-5-(2-(methylsulfonyl)phenyl)-3-pentyl]imidazole-4-carboxamide;

(5) 1-{(2S,3R)-2-hydro):y-5-[2-(3-dimethylaminopropoxy)phenyl]3-pentyl}imidazole-4-carboxamide dihydrochloride;

(6-1) 1-{(2S,3R)-2-hydroxy-5-[2-(6-phthalimidohexyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(6-2) 1-{(2S,3R)-2-hydroxy-5-[2-(6-aminohexyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide dihydrochloride;

(7) 1-{(2S,3R)-2-hydroxy-5-[2-(2,2,2-trifluoroethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(8) 1-{(2S,3R)-2-hydroxy-5-[2-(3-(4-chlorophenyl)propoxy)-phenyl]-3-pentyl}imidazole-4-carboxamide;

(9) 1-[(2S,3R)-2-benzyloxy-5-(6-chloro-1-naphthyl)-3-pentyl]imidazole-4-carboxamide;

(10) 1-[(2S,3R)-2-hydroxy-5-(6-chloro-1-naphthyl)-3-pentyl]imidazole-4-carboxamide;

(11) 1-[(2S,3R)-2-benzyloxy-5-(7-chloro-1-naphthyl)-3-pentyl]imidazole-4-carboxamide;

(12) 1-[(2S,3R)-2-hydroxy-5-(7-chloro-1-naphthyl)-3-pentyl]imidazole-4-carboxamide;

(13) 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;

(14) 1-[(2S,3R)-2-hydroxy-5-(1-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;

(15) 1-[(2S,3R)-2-benzyloxy-5-(2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;

(16)1-[(2S,3R)-2-hydroxy-5-(2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;

(17) 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]imidazole-4-carboxamide hydrochloride;

(18) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-chlorophenoxy)ethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(19) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-chlorophenylthio)ethoxy)phenyl]3-pentyl}imidazole-4-carboxamide;

(20) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-chlorophenylsulfonyl)ethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(21) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(3,4-dichlorobenzyloxy)ethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(22) 1-{(2S,3R)-2-hydroxy-5-[2-(4-phenylbenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(23) 1-{(2S,3R)-2-hydroxy-5-[2-(3,4-dichlorobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(24) 1-{(2S,3R)-2-hydroxy-5-[2-(4-phenoxybenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(25) 1-{(2S,3R)-2-hydroxy-5-[2-(2-naphthylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(26) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(1-methyl-1-phenylethyl)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(27) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(2-pyridyl)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(28) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(4-fluorophenoxy)benzyloxy)phenyl]3-pentyl}imidazole-4-carboxamide;

(29) 1-{(2S,3R)-2-hydroxy-5-[2-(3-(phenoxymethyl)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(30) 1-{(2S,3R)-2-hydroxy-5-[2-(4-isopropylbenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(31) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(2-cyano-1-pyrrolyl)-3-fluorobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(32) 1-{(2S,3R)-2-hydroxy-5-[2-(5-(4-tert-butylphenyl)-1,2,4-oxadiazol-3-ylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(33) 1-{(2S,3R)-2-hydroxy-5-[2-(4-chlorobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(34) 1-{(2S,3R)-2-hydroxy-5-[2-(4-bromobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(35) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(E)-styrylbenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(36) 1-{(2S,3R)-2-hydroxy-5-[2-(4-phenylthiobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(37) 1-{(2S,3R)-2-hydroxy-5-[2-(4-cyclohexylbenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(38) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-(trifluoromethyl)phenyl)-4-thiazolylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(39) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(methylthio)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(40) 1-{(2S,3R)-2-hydroxy-5-[2-(3-bromobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(41) 1-{(2S,3R)-2-hydroxy-5-[2-(4-bromo-2-fluorobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(42) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(1,2,3-thiadiazol-4-yl)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(43) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(N-methylpropionylamino)-4-thiazolylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(44) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(2-thienylthio)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(45) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(5-chloro-2-thienylthio)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(46) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(2-thienyl)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(47) 1-{(2S,3R)-2-hydroxy-5-[2-(4-methoxybenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(48) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(3-thienyl)-2-thienylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(49) 1-{(2S,3R)-2-hydroxy-5-[2-(4-cyanobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(50) 1-{(2S,3R)-2-hydroxy-5-[2-(3,5-dibromobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(51) 1-{(2S,3R)-2-hydroxy-5-[2-(5-bromo-2-thienylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(52) 1-{(2S,3R)-2-hydroxy-5-[2-(5-(4-fluorophenyl)-2-thienylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(53) 1-{(2S,3R)-2-hydroxy-5-[2-(3,5-bis(trifluoromethyl)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(54) 1-{(2S,3R)-2-hydroxy-5-[2-(3,5-dimethoxybenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(55) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-biphenylyloxy)ethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(56) 1-{(2S,3R)-2-hydroxy-5-[2-(5-(2-thiazolylthio)-2-thienylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(57) 1-{(2S,3R)-2-hydroxy-5-[2-(4-ethoxybenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(58) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-biphenylyl)ethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(59) 1-{(2S,3R)-2-hydroxy-5-[2-(3,5-dimethylbenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(60) 1-[(2S,3R)-5-(2-benzyloxy-4-fluorophenyl)-2-tert-butyldimethylsilyloxy-3-pentyl]imidazole-4-carboxamide;

(61) 1-[(2S,3R)-5-(2-benzyloxy-4-fluorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;

(62) 1-[(2S,3R)-5-(2-hydroxy-4-fluorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;

(63) 1-{(2S,3R)-2-hydroxy-5-[4-fluoro-2-(4-(2-thienylthio)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(64) 1-{(2S,3R)-2-hydroxy-5-[2-(4-bromobenzyloxy)-4-fluorophenyl]-3-pentyl}imidazole-4-carboxamide;

(65) 1-[(2S,3R)-5-(2-benzyloxy-4-chlorophenyl)-2-tert-butyldimethylsilyloxy-3-pentyl]imidazole-4-carboxamide;

(66) 1-[(2S,3R)-5-(2-benzyloxy-4-chlorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;

(67) 1-[(2S,3R)-5-(2-hydroxy-4-chlorophenyl)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;

(68) 1-{(2S,3R)-2-hydroxy-5-[4-chloro-2-(5-bromo-2-thienylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide;

(69) 1-[(2S,3R)-2-tert-butyldimethylsilyloxy-5-(2-phenoxyphenyl)-3-pentyl]imidazole-4-carboxamide;

(70) 1-[(2S,3R)-2-hydroxy-5-(2-phenoxyphenyl)-3-pentyl]imidazole-4-carboxamide hydrochloride;

(71) 1-[(2S,3R)-2-tert-butyldimethylsilyloxy-5-(2-(dimethylamino)phenyl)-3-pentyl]imidazole-4-carboxamide; and

(72) 1-[(2S,3R)-2-hydroxy-5-(2-(dimethylamino)phenyl)-3-pentyl]imidazole-4-carboxamide.

8. The compound according to claim 1 , selected from the group consisting of:

(8) 1-{(2S,3R)-2-hydroxy-5-[2-(3-(4-chlorophenyl)propoxy)-phenyl]-3-pentyl}imidazole-4-carboxamide;

(10) 1-[(2S,3R)-2-hydroxy-5-(6-chloro-1-naphthyl)-3-pentyl]imidazole-4-carboxamide;

(16) 1-[(2S,3R)-2-hydroxy-5-(2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;

(18) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-chlorophenoxy)ethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(19) 1-{(2S,3R)-2-hydroxy-5-[2-(2-(4-chlorophenylthio)ethoxy)phenyl]3-pentyl}imidazole-4-carboxamide;

(44) 1-{(2S,3R)-2-hydroxy-5-[2-(4-(2-thienylthio)benzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(50) 1-{(2S,3R)-2-hydroxy-5-[2-(3,5-dibromobenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(51) 1-{(2S,3R)-2-hydroxy-5-[2-(5-bromo-2-thienylmethyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride;

(54) 1-{(2S,3R)-2-hydroxy-5-[2-(3,5-dimethoxybenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride; and

(57) 1-{(2S,3R)-2-hydroxy-5-[2-(4-ethoxybenzyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide hydrochloride.

9. A pharmaceutical composition comprising:

the compound of claim 1 and

a pharmaceutically acceptable carrier or excipient.

10. A pharmaceutical composition having an adenosine deaminase inhibiting activity, which comprises:

the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

11. A method for inhibiting adenosine deaminase activity (ADA) or for elevating adenosine concentration, which comprises administering the compound of claim 1 to a mammal.

12. A process for producing the compound of claim 1 , comprising any of the following steps (1) to (4):

(1) reacting a compound of formula (III):

 with a compound of formula (IV):

 wherein R 1 , R 2 , R 3 , and A are as defined above, and X 1 is hydroxy or a leaving group, provided that R 3 is not hydroxy;

(2) reacting a compound of formula (V):

R 1 —OH  (V)

 wherein R 1 is as defined above, with a compound of formula (VI):

 wherein R 2 , R 3 , and A are as defined above, and X 2 is hydroxy or a leaving group, provided that R 3 is not hydroxy;

(3) reacting a compound of formula (I-1):

 wherein R 1 , R 2 , and A are as defined above, and R 2 is hydroxy protective group, with a deprotecting agent; or

(4) reacting a compound of formula (VII):

 wherein R 2 and R 3 are as defined above and X 3 is hydrogen or halogen, with a compound of formula (VIII):

R 4 X 4   (VIII)

 wherein X 4 is a leaving group and R 4 is lower alkyl substituted with optionally substituted amino, protected amino, halogen, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted aryl(lower)alkoxy or optionally substituted heterocyclic group; wherein substituent(s) of the optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted aryl(lower)alkoxy, and optionally substituted heterocyclic group, are each independently selected from the group consisting of aryl optionally substituted with halogen, lower alkyl or halo(lower)alkyl; halogen; aryloxy optionally substituted with halogen; aryl(lower)alkyl; heterocyclic group optionally substituted with cyano; aryloxy(lower)alkyl; aryl(lower)alkenyl; arylthio; lower cycloalkyl; lower alkylthio; heterocyclicthio optionally substituted with halogen; lower alkoxy; cyano; lower alkyl; halo(lower)alkyl; and amino optionally substituted with lower alkyl or lower alkanoyl.

13. A method for for preparing a composition comprising admixing the compound of claim 1 with a pharmaceutically acceptable excipient or carrier.