Hydroxamic acid derivatives, the methods for preparation thereof and pharmaceutical compositions comprising thereof, as an active ingredient

Abstract

Hydroxamic acid derivatives of the formula (I) (wherein all the symbols have the same meaning as defined in the specification.), non-toxic salts thereof or prodrugs thereof. The compounds of the formula (I) inhibit producing IL-6, so it may be used for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman's disease, atrial myxoma, diabetes mellitus, autoimmne diseases, hepatitis, colitis, graft versus host disease, infectious diseases and endometriosis.

1 . A method of inhibiting IL-6 production comprising administering to a subject in need of treatment an effective amount of a hydroxamic acid derivative of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein, R 1  is 
 (a) C1-8 alkyl,  
 (b) C2-8 alkenyl,  
 (c) C2-8 alkynyl,  
 (d) halogen,  
 (e) nitro,  
 (f) nitrile,  
 (g) trifluoromethyl,  
 (h) trifluoromethoxy,  
 (i) —OR 2 ,  
 (j) —SR 2 ,  
 (k) —NR 3 R 4 ,  
 (l) —COR 5 ,  
 (m) keto,  
 (n) Cyc1,  
 (o) C1-8 alkyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5  or Cyc1,  
 (p) —SO 2 R 10 ,  
 (q) —O—(C1-8 alkylene)—OR 11 ,  
 (r) C1-8 alkyl substituted by nitrile, —SO 2 R 10  or —O—(C1-8 alkylene)—OR 11 ,  
 (s) —O—(C1-8 alkylene)—NR 12 R 13 ,  
 (t) —S—(C1-8 alkylene)—NR 12 R 13 ,  
 (u) C1-8 alkyl substituted by —O—(C1-8 alkylene)—NR 12 R 13 — or —S—(C1-8 alkylene)—NR 12 R 13 ,  
 (v) C2-8 alkenyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5 , Cyc1, nitrile, —SO 2 R 10 , —O—(C1-8 alkylene)—OR 11 , —O—(C1-8 alkylene)—NR 12 R 13  or —S—(C1-8 alkylene)—NR 12 R 13  or  
 (w) C2-8 alkynyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5 , Cyc1, nitrile, —SO 2 R 10 , —O—(C1-8 alkylene)—OR 11 , —O—(C1-8 alkylene)—NR 12 R 13  or —S—(C1-8 alkylene)—NR 12 R 13 ;  
 R 2  is hydrogen, C1-8alkyl, C2-9 acyl or Cyc1;  
 R 3  and R 4  are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 5  is hydroxy, C1-8 alkyl, C1-8 alkoxy, —NR 6 R 7  or Cyc1;  
 R 6  and R 7  are each independently hydrogen, C1-8 alkyl or Cyc1;  
 R 10  is C1-8 alkyl or Cyc1;  
 Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom;  
 R 11  is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 12  and R 13  are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 m is 0 or an integer of 1-5;  
 ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s);  
 ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s);  
 E is a bond, —CH═CH— or —C≡C—;  
 R 8  is  
 (a) C1-8 alkyl,  
 (b) C1-8 alkoxy,  
 (c) halogen,  
 (d) nitro,  
 (e) nitrile,  
 (f) trifluoromethyl or  
 (g) trifluoromethoxy;  
 with the proviso that when E is a bond, then, optionally, R 1  and R 8 , taken together, may be C1-4 alkylene;  
 n is 0 or an integer of 1-5;  
 R 9  is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl;  
 a nontoxic salt thereof or a prodrug thereof, as an active ingredient.  
 
     
     
         2 . The method described in  claim 1 , wherein the prodrug of a compound of the formula (I) as an active ingredient is represented by a compound of the formula (IA):  
       
         
           
           
               
               
           
         
         wherein, R 14  is C1-8 alkyl substituted with C1-8 alkyl, C1-8 alkoxy, the other symbols have the same meanings as defined in  claim 1 .  
       
     
     
         3 . The method described in  claim 1 , wherein the prodrug of a compound of the formula (I) as an active ingredient is represented by comprising a compound of the formula (IB):  
       
         
           
           
               
               
           
         
         wherein, the all symbols have the same meanings as defined in  claim 1 .  
       
     
     
         4 . A hydroxamic acid derivative of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein, R 1  is 
 (a) C1-8 alkyl,  
 (b) C2-8 alkenyl,  
 (c) C2-8 alkynyl,  
 (d) halogen,  
 (e) nitro,  
 (f) nitrile,  
 (g) trifluoromethyl,  
 (h) trifluoromethoxy,  
 (i) —OR 2 ,  
 (t) —SR 2 ,  
 (k) —NR 3 R 4 ,  
 (l) —COR 5 ,  
 (m) keto,  
 (n) Cyc1,  
 (o) C1-8 alkyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5  or Cyc1,  
 (p) —SO 2 R 10 ,  
 (q) —O—(C1-8 alkylene)—OR 11 ,  
 (r) C1-8 alkyl substituted by nitrile, —SO 2 R 10  or —O—(C1-8 alkylene)—OR 11 ,  
 (s) —O—(C1-8 alkylene)—NR 12 R 13 ,  
 (t) —S—(C1-8 alkylene)—NR 12 R 13 ,  
 (u) C1-8 alkyl substituted by —O—(C1-8 alkylene)—NR 12 R 13 — or —S—(C1-8 alkylene)—NR 12 R 13 ,  
 (v) C2-8 alkenyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5 , Cyc1, nitrile, —SO 2 R 10 , —O—(C1-8 alkylene)—OR 11 , —O—(C1-8 alkylene)—NR 12 R 13  or —S—(C1-8 alkylene)—NR 12 R 13  or  
 (w) C2-8 alkynyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5 , Cyc1, nitrile, —SO 2 R 10 , —O—(C1-8 alkylene)—OR 11 , —O—(C1-8 alkylene)—NR 12 R 13  or —S—(C1-8 alkylene)—NR 12 R 13 ,  
 R 2  is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 3  and R 4  are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 5  is hydroxyl, C1-8 alkyl, C1-8 alkoxy, —NR 6 R 7  or Cyc1;  
 R 6  and R 7  are each independently hydrogen, C1-8 alkyl or Cyc1;  
 R 10  is C1-8 alkyl or Cyc1;  
 Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom;  
 R 11  is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 12  and R 13  are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 m is 0 or an integer of 1-5;  
 ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s);  
 ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s);  
 E is a bond, —CH═CH— or —C≡C—;  
 R 8  is  
 (a) C1-8 alkyl,  
 (b) C1-8 alkoxy,  
 (c) halogen,  
 (d) nitro,  
 (e) nitrile,  
 (f) trifluoromethyl or  
 (g) trifluoromethoxy;  
 with the proviso that when E is a bond then, optionally, R 1  and R 8 , taken together, is C1-4 alkylene optionally;  
 n is 0 or an integer of 1-5;  
 R 9  is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl;  
 with the proviso that when E is —CH═CH— or —C≡C—, ring A is C3-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom;  
 with the proviso that a compound wherein R 1  is  
 (a) C1-8 alkyl,  
 (b) C2-8 alkenyl,  
 (c) C2-8 alkynyl,  
 (o) C1-8 alkyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5  or Cyc1,  
 (u) C1-8 alkyl substituted by —O—(C1-8 alkylene)—NR 12 R 13 — or —S—(C1-8 alkylene)—NR 12 R 13 ,  
 (v) C2-8 alkenyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5 , Cyc1, nitrile, —SO 2 R 10 , —O—(C1-8 alkylene)—OR 11 , —O—(C1-8 alkylene)—NR 12 R 13  or —S—(C1-8 alkylene)—NR 12 R 13 , or  
 (w) C2-8 alkynyl substituted by —OR 2 , —SR 2 , —NR 3 R 4 , —COR 5 , Cyc1, nitrile, —SO 2 R 10 , —O—(C1-8 alkylene)—OR 11 , —O—(C1-8 alkylene)—NR 12 R 13  or —S—(C1-8 alkylene)—NR 12 R 13 ;  
 R 2  is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 3  and R 4  are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 5  is hydroxyl, C1-8 alkyl, C1-8 alkoxy, —NR 6 R 7  or Cyc1;  
 R 6  and R 7  are each independently hydrogen, C1-8 alkyl or Cyc1;  
 R 10  is C1-8 alkyl or Cyc1;  
 Cyc1 is morpholine, piperidine or piperazine;  
 R 11  is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 R 12  and R 13  are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1;  
 m is an integer of 1-5;  
 ring A is a benzene ring;  
 ring B is a benzene ring;  
 E is a bond, —CH═CH— or —C≡C—;  
 R 8  is  
 (a) C1-8 alkyl,  
 (b) C1-8 alkoxy,  
 (c) halogen,  
 (d) nitro,  
 (e) nitrile,  
 (f) trifluoromethyl or  
 (g) trifluoromethoxy,  
 with the proviso that when E is a bond then, optionally, R 1  and R 8 , taken together, is C1-4 alkylene;  
 n is 0 or an integer of 1-5;  
 R 9  is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, is excluded;  
 a nontoxic salt thereof or a prodrug thereof.  
 
     
     
         5 . The prodrug of a compound of the formula (I) described in  claim 4 , which is represented by the formula (IA):  
       
         
           
           
               
               
           
         
         wherein, R 14  is C1-8 alkyl substituted with C1-8 alkyl, C1-8 alkoxy, the other symbols have the same meaning as defined in  claim 4 .  
       
     
     
         6 . The prodrug of a compound of the formula (I) described in  claim 4 , which is represented by the formula (IB):  
       
         
           
           
               
               
           
         
         wherein, the all symbols have the same meaning as defined in  claim 4 .  
       
     
     
         7 . The compound described in  claim 4 , wherein E is a bond and ring A is C3-15 mono-, bi- or tri-carbocyclic ring.  
     
     
         8 . The compound described in  claim 4 , wherein E is a bond and ring A is 5-18 membered mono-, bi-, or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or sulfur atom(s).  
     
     
         9 . The compound described in  claim 4 , wherein E is —CH═CH— or —C≡C— and ring A is C3-7 mono-carbocyclic ring.  
     
     
         10 . The compound described in  claim 4 , wherein E is —CH═CH— or —C≡C— and A is 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one nitrogen atom and/or one sulfur atom.  
     
     
         11 . The compound described in  claim 4 , which is 
 (1) N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide,    (2) N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide,    (3) N-hydroxy-6-(4-cyclohexylphenyl)-6-hydroxyhexanamide,    (4) N-hydroxy-6-(4-(4-methylphenyl)phenyl)-6-hydroxyhexanamide,    (5) N-hydroxy-6-(4-(4-methoxyphenyl)phenyl)-6-hydroxyhexanamide,    (6) N-hydroxy-6-(4-(trans-4-propylcyclohexyl)phenyl)-6-hydroxyhexanamide,    (7) (R)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide,    (8) (S)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide,    (9) N-hydroxy-6-(4-(benzofuran-2-yl)phenyl)-6-hydroxyhexanamide,    (10) N-hydroxy-6-(4-(pyridin-4-yl)phenyl)-6-hydroxyhexanamide,    (11) N-hydroxy-6-(4-(pyridin-3-yl)phenyl)-6-hydroxyhexanamide,    (12) N-hydroxy-6-(4-(2-chlorophenyl)phenyl)-6-hydroxyhexanamide,    (13) N-hydroxy-6-(4-(3-chlorophenyl)phenyl)-6-hydroxyhexanamide,    (14) N-hydroxy-6-(4-(4-bromophenyl)phenyl)-6-hydroxyhexanamide,    (15) N-hydroxy-6-(4-(thiophen-2-yl)phenyl)-6-hydroxyhexanamide,    (16) N-hydroxy-6-(4-(furan-2-yl)phenyl)-6-hydroxyhexanamide,    (17) N-hydroxy-6-(4-(1,3-dioxy-2,3-dihydroinden-5-yl)phenyl)-6-hydroxyhexanamide,    (18) N-hydroxy-6-(4-(4-methylthiophenyl)phenyl)-6-hydroxyhexanamide,    (19) N-hydroxy-6-(4-(naphthalen-1-yl)phenyl)-6-hydroxyhexanamide,    (20) N-hydroxy-6-(4-(naphthalen-2-yl)phenyl)-6-hydroxyhexanamide,    (21) N-hydroxy-6-(4-(4-acetylphenyl)phenyl)-6-hydroxyhexanamide,    (22) N-hydroxy-6-(4-(4-hydroxyphenyl)phenyl)-6-hydroxyhexanamide,    (23) N-hydroxy-6-(4-(dibenzofuran-4-yl)phenyl)-6-hydroxyhexanamide,    (24) N-hydroxy-6-(4-(2-methoxyphenyl)phenyl)-6-hydroxyhexanamide,    (25) N-hydroxy-6-(4-(3-methoxyphenyl)phenyl)-6-hydroxyhexanamide,    (26) N-hydroxy-6-(4-(4-trifluoromethylphenyl)phenyl)-6-hydroxyhexanamide,    (27) N-hydroxy-6-(4-(4-t-butylphenyl)phenyl)-6-hydroxyhexanamide,    (28) (R)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (29) (R)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (30) (R)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide,    (31) (R)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide,    (32) (R)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (33) N-hydroxy-6-(4-(trans-4-butylcyclohexyl)phenyl)-6-hydroxyhexanamide,    (34) N-hydroxy-6-(4-(trans-4-hydroxycyclohexyl)phenyl)-6-hydroxyhexanamide,    (35) N-hydroxy-6-(4-cyclopentylphenyl)-6-hydroxyhexanamide,    (36) N-hydroxy-6-[4-(morpholin-4-yl)phenyl]-6-hydroxyhexanamide,    (37) N-hydroxy-6-[3-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide,    (38) N-hydroxy-6-[2-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide,    (39) N-hydroxy-6-[4-((1E)-2-phenylvinyl)phenyl]-6-hydroxyhexanamide,    (40) N-hydroxy-6-[4-((1E)-2-(pyridin-4-yl)vinyl)phenyl]-6-hydroxyhexanamide,    (41) N-hydroxy-6-[4-((1E)-2-(pyridin-2-yl)vinyl)phenyl]-6-hydroxyhexanamide,    (42) N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyheptanamide,    (43) N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxy-7-octenamide,    (44) N-hydroxy-6-(4-biphenyl)-6-hydroxyheptanamide,    (45) (+)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide,    (46) (−)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide,    (47) (R)-N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide,    (48) (R)-N-hydroxy-6-[4-(4-methylphenyl)phenyl]-6-hydroxyhexanamide,    (49) (R)-N-hydroxy-6-[4-(3-methylphenyl)phenyl]-6-hydroxyhexanamide,    (50) (R)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (51) (R)-N-hydroxy-6-[4-(2-phenylethynyl)phenyl]-6-hydroxyhexanamide,    (52) (R)-N-hydroxy-6-[4-(benzothiophen-2-yl)phenyl]-6-hydroxyhexanamide,    (53) (R)-N-hydroxy-6-[4-(4-(cyanomethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (54) (R)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyhexanamide,    (55) (R)-N-hydroxy-6-[4-(4-propylphenyl)phenyl]-6-hydroxyhexanamide,    (56) (R)-N-hydroxy-6-[4-(4-biphenyl)phenyl]-6-hydroxyhexanamide,    (57) (R)-N-hydroxy-6-[4-(1-methylpiperidin-4-yl)phenyl]-6-hydroxyhexanamide,    (58) (R)-N-hydroxy-6-[4-(indol-2-yl)phenyl]-6-hydroxyhexanamide,    (59) (R)-N-hydroxy-6-[4-(4-cyanophenyl)phenyl]-6-hydroxyhexanamide,    (60) (R)-N-hydroxy-6-[4-phenyl-2-methylphenyl]-6-hydroxyhexanamide,    (61) (R)-N-hydroxy-6-(4-cycloheptylphenyl)-6-hydroxyhexanamide,    (62) (R)-N-hydroxy-6-(9,10-dihydrophenanthren-2-yl)-6-hydroxyhexanamide,    (63) (R)-N-hydroxy-6-[4-(1-ethoxycarbonylpiperidin-4-yl)phenyl]-6-hydroxyhexanamide,    (64) (R)-N-hydroxy-6-[4-(4-(N-methylcarbamoyl)phenyl)phenyl]-6-hydroxyhexanamide,    (65) (R)-N-hydroxy-6-(4-cyclohexylphenyl)-6-hydroxyhexanamide,    (66) (R)-N-hydroxy-6-[4-(5-hydroxybenzofuran-2-yl)phenyl]-6-hydroxyhexanamide,    (67) (R)-N-hydroxy-6-[4-(2-(4-methylphenyl)ethynyl)phenyl]-6-hydroxyhexanamide,    (68) (R)-N-hydroxy-6-[4-((1E)-2-(4-methylphenyl)vinyl)phenyl]-6-hydroxyhexanamide,    (69) (R)-N-hydroxy-6-[4-(4-trifluoromethoxyphenyl)phenyl]-6-hydroxyhexanamide,    (70) (R)-N-hydroxy-6-[4-(4-ethylthiophenyl)phenyl]-6-hydroxyhexanamide,    (71) (R)-N-hydroxy-6-[4-(4-methoxyphenyl)phenyl]-6-hydroxyhexanamide,    (72) (R)-N-hydroxy-6-[4-(4-(1-methylethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (73) (R)-N-hydroxy-6-[4-(4-(N,N-dimethylcarbamoylmethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (74) (R)-N-hydroxy-6-[4-(benzothiazol-2-yl)phenyl]-6-hydroxyhexanamide,    (75) (R)-N-hydroxy-6-[4-(4-(methoxymethoxymethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (76) (R)-N-hydroxy-6-[4-(6-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (77) (R)-N-hydroxy-6-[4-(6-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (78) (R)-N-hydroxy-6-[4-(4-methoxymethylphenyl)phenyl]-6-hydroxyhexanamide,    (79) (R)-N-hydroxy-6-[4-(5-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (80) (R)-N-hydroxy-6-[4-(4-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (81) (R)-N-hydroxy-6-[4-(4-hydroxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (82) (R)-N-hydroxy-6-[4-(6-hydroxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (83) (R)-N-hydroxy-6-[4-((1E)-2-(4-methylthiophenyl)vinyl)phenyl]-6-hydroxyhexanamide,    (84) (R)-N-hydroxy-6-[4-(5-methoxybenzofuran-2-yl)phenyl]-6-hydroxyhexanamide,    (85) (R)-N-hydroxy-6-[4-(5-methylthiobenzofuran-2-yl)phenyl]-6-hydroxyhexanamide,    (86) (R)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (87) (R)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethoxy)phenyl)phenyl]-6-hydroxyhexanamide,    (88) (R)-N-hydroxy-6-[4-(4-(2-(diethylamino)ethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (89) (R)-N-hydroxy-6-[4-(4-(2-hydroxyethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (90) (S)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide,    (91) (S)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide,    (92) (S)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (93) (S)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (94) (S)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (95) (R)-N-hydroxy-6-[4-(4-(dipropylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (96) (R)-N-hydroxy-6-(5-phenylthiophen-2-yl)-6-hydroxyhexanamide,    (97) (R)-N-hydroxy-6-(5-phenylbenzofuran-2-yl)-6-hydroxyhexanamide,    (98) (R)-N-hydroxy-6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanamide,    (99) (R)-N-hydroxy-6-[4-(4-carboxyphenyl)phenyl]-6-hydroxyhexanamide,    (100) (R)-N-hydroxy-6-[4-(4-methylsulfonylphenyl)phenyl]-6-hydroxyhexanamide,    (101) (R)-N-hydroxy-6-[4-(4-hydroxymethylphenyl)phenyl]-6-hydroxyhexanamide,    or a nontoxic salt thereof.    
     
     
         12 . The compound described in  claim 5 , which is: 
 (1) N-(1-methoxy-1-methyl)ethoxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide,    (2) N-(1-methoxy-1-methyl)ethoxy-6-(4-(benzofuran-2-yl)phenyl)-6-hydroxyhexanamide,    (3) (R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (4) (R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide,    (5) (R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide,    (6) (R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide,    (7) (R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (8) (R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(dipropylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide,    (9) N-methoxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide,    or a nontoxic salt thereof.    
     
     
         13 . The compound described in  claim 6 , which is 
 (1) (R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(5-methylbenzoxazol-2-yl)phenyl]pentan-1-ol,    (2) (R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-methylthiophenyl)phenyl]pentan-1-ol,    (3) (R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-(dimethylaminomethyl)phenyl)phenyl]pentan-1-ol,    or a nontoxic salt thereof.