US2014005136A1PendingUtilityA1
Novel compounds and compositions and methods of use
Est. expiryNov 27, 2027(~1.4 yrs left)· nominal 20-yr term from priority
A61P 7/00A61P 39/02A61P 9/10A61P 9/12A61P 43/00A61P 3/10A61P 3/06A61P 9/00A61P 5/20A61P 25/00A61P 19/02A61P 13/12A61P 17/06A61P 13/04A61P 19/00A61P 19/06A61K 31/7056C07H 19/06A61K 31/7068A61K 31/7072C07D 249/14A61K 31/7076A61K 31/4196C07D 249/12C07H 7/02A61K 45/06C07H 19/16C07D 235/28
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Claims
Abstract
Described herein are compounds useful in the modulation of blood uric acid levels, formulations containing them and methods of using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant levels of uric acid.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula (III), or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof:
wherein
X is CH or N;
W is O, S, S(O), S(O) 2 , NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH 2 ;
R 1 is H, Cl, Br, I, NH 2 , methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF 3 , CHF 2 or CH 2 F;
R 3 and R 3′ are independently selected from H and lower alkyl, or R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;
R 2 is selected from the group consisting of (a), (b), (c) and (d):
wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
Q and Q′ are independently selected from N and CH;
R P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;
R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF 3 , NH 2 and NHCH 3 ;
R 11 is Cl, Br, I, CH 3 , CF 3 , methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and
R 12 , R 13 , R 14 and R 15 are independently H or methyl.
2 . The compound of claim 1 , wherein:
X is N.
3 . The compound of claim 1 , wherein:
W is S or O.
4 . The compound of claim 1 , wherein:
R 2 is
5 . The compound of claim 4 , wherein:
represents a carbon-carbon double bond; and R P is cyclopropyl.
6 . The compound of claim 1 , wherein:
X is N; W is S; and R 1 is Cl, Br, I, optionally substituted methyl, CF 3 , CHF 2 or CH 2 F.
7 . The compound of claim 1 , wherein:
R 3 and R 3′ are not H.
8 . The compound of claim 1 , wherein:
R 3 and R 3′ are H.
9 . The compound of claim 1 , wherein:
R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O.
10 . The compound of claim 1 , wherein:
R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring.
11 . A compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B , or pharmaceutically acceptable salt, solvate, or tautomer thereof:
wherein,
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , SR 3a , NR 4a R 4b , at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation; or
R 2a is —[C(R 5a )(R 5b )] m R 5c ;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or
R 3a is —[C(R 5a )(R 5b )] n R 5c ;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or
R 4b is —[C(R 5a )(R 5b )] n R 5c , wherein
each R 5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
each R 5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
R 5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
wherein L is a bond, —C(O)—, —S(O), or —S(O) 2 ;
y 1 is 0, 1, 2 or 3;
Y is OH, OMe, COOH, SO 3 H, OSO 3 H, OS(O) 2 NH 2 , P(O)(OH) 2 , OP(O)(OH) 2 , OP(O)(OH)(O—C 1-4 alkyl) or NY 2 Y 3 Y 4 ; wherein
Y 2 and Y 3 are each independently hydrogen or methyl; or
Y 2 and Y 3 are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and
Y 4 is an electron pair or an oxygen atom;
m is 1, 2, 3, 4;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and wherein if R 2a is —[C(R 5a )(R 5b )] m R 5c then at least one of R 5a , R 5b and R 5c is not hydrogen.
12 . The compound of claim 11 , wherein:
R 1a is at least one amino acid.
13 . The compound of claim 11 , wherein:
R 1a is a peptide.
14 . The compound of claim 11 , wherein:
R 1a is a lipid.
15 . The compound of claim 11 , wherein:
R 1a is a phospholipid.
16 . The compound of claim 11 , wherein:
R 1a is a glycoside.
17 . The compound of claim 11 , wherein:
R 1a is a nucleoside.
18 . The compound of claim 11 , wherein:
R 1a is a nucleotide.
19 . The compound of claim 11 , wherein:
R 1a is an oligonucleotide.
20 . The compound of claim 11 , wherein:
R 1a is polyethylene glycol.
21 . The compound of claim 11 , wherein:
R 1a is a combination of one or more groups selected from at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, and polyethylene glycol.
22 . The compound of claim 21 , wherein:
the one or more R 1a groups are covalently linked.
23 . The compound of claim 21 , wherein:
the one or more R 1a groups form a conjugate.
24 . The compound of claim 11 , wherein:
R 1a is OR 2a .
25 . The compound of claim 24 , wherein:
R 2a is substituted C 1 -C 4 alkyl or optionally substituted C 5 -C 10 alkyl.
26 . The compound of claim 24 , wherein:
R 2a is a pharmaceutically acceptable cation.
27 . The compound of claim 24 , wherein:
R 2a is a pharmaceutically acceptable cation selected from Li + , Na + , K + , Mg ++ , Ca ++ or a protonated amine.
28 . The compound of claim 24 , wherein:
R 2a is —[C(R 5a )(R 5b )] m R 5c .
29 . The compound of claim 28 , wherein:
R 5a is hydrogen, R 5b is hydrogen and R 5c is not hydrogen.
30 . The compound of claim 28 , wherein:
R 5c is at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, or polyethylene glycol.
31 . The compound of claim 11 , wherein:
R 1a is SR 3a .
32 . The compound of claim 31 , wherein:
R 3a is optionally substituted C 1 -C 10 alkyl.
33 . The compound of claim 31 , wherein:
R 3a is —[C(R 5a )(R 5b )] n R 5c .
34 . The compound of claim 33 , wherein:
R 5a is hydrogen, R 5b is hydrogen and R 5c is not hydrogen.
35 . The compound of claim 33 , wherein:
R 5c is at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, or polyethylene glycol.
36 . The compound of claim 11 , wherein:
R 1a is NR 4a R 4b .
37 . The compound of claim 36 , wherein:
R 4a is hydrogen.
38 . The compound of claim 36 , wherein:
R 4b is optionally substituted alkyl.
39 . The compound of claim 36 , wherein:
R 4b is —[C(R 5a )(R 5b )] n R 5c .
40 . The compound of claim 39 , wherein:
R 5a is hydrogen, R 5b is hydrogen and R 5c is not hydrogen.
41 . The compound of claim 39 , wherein:
R 5c is at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, or polyethylene glycol.
42 . The compound of claim 39 , wherein:
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , NR 4a R 4b , at least one amino acid, a peptide, or a glycoside;
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.
43 . A method for decreasing uric acid levels in one or more tissues or organs, blood, serum, urine, or combinations thereof of an individual in need of decreased uric acid levels, comprising administering to the individual a uric acid level decreasing amount of:
(i) a compound of formula (I); or (ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B ; (iii) a compound of formula (III); or (iv) a combination thereof;
wherein
X is CH or N;
W is O, S, S(O), S(O) 2 , NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH 2 ;
R 1 is H, Cl, Br, I, NH 2 , methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF 3 , CHF 2 or CH 2 F;
R 3 and R 3′ are independently selected from H and lower alkyl, or R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;
R 2 is selected from the group consisting of (a), (b), (c) and (d):
wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
Q and Q′ are independently selected from N and CH;
R P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;
R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF 3 , NH 2 and NHCH 3 ;
R 11 is Cl, Br, I, CH 3 , CF 3 , methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and
R 12 , R 13 , R 14 and R 15 are independently H or methyl;
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , SR 3a , NR 4a R 4b at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation; or
R 2a is —[C(R 5a )(R 5b )] m R 5c ;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or
R 3a is —[C(R 5a )(R 5b )] n R 5c ;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or
R 4b is —[C(R 5a )(R 5b )] n R 5c , wherein
each R 5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
each R 5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
R 5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
wherein L is a bond, —C(O)—, —S(O), or —S(O) 2 ;
y 1 is 0, 1, 2 or 3;
Y is OH, OMe, COOH, SO 3 H, OSO 3 H, OS(O) 2 NH 2 , P(O)(OH) 2 , OP(O)(OH) 2 , OP(O)(OH)(O—C 1-4 alkyl) or NY 2 Y 3 Y 4 ; wherein
Y 2 and Y 3 are each independently hydrogen or methyl; or
Y 2 and Y 3 are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and
Y 4 is an electron pair or an oxygen atom;
m is 1, 2, 3, 4;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and wherein if R 2a is —[C(R 5a )(R 5b )] m R 5c then at least one of R 5a , R 5b and R 5c is not hydrogen;
R 4 is H, lower alkyl, lower alkenyl or lower alkynyl;
R 5 , R 5′ , R 6 , R 6′ and R 7 are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF 3 , CHF 2 , CH 2 F, NH 2 , NHR′, NR′R″, OR′, SR′, C(O)R′, CO 2 H, a salt of CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, a salt of SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl or a heterocycle, wherein
R′ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl)(C 1-3 alkyl), CONHC 1-3 alkyl, aryl or a heterocycle;
R″ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CONHC 1-3 alkyl, aryl or a heterocycle; or
R′ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;
or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.
44 . The method of claim 43 , wherein the reduction in uric acid levels results in a reduction in hypertension or cardiovascular events.
45 . The method of claim 43 , comprising administering one or more metabolites of a compound of formula (I).
46 . The method of claim 43 , wherein the compound of formula (I) is 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof:
47 . The method of claim 43 , wherein the compound of formula (III) is 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof:
48 . The method of claim 43 , comprising administering a compound of formula (I), or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.
49 . The method of claim 43 , comprising administering a compound of formula (II), wherein the compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B , or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.
50 . The method of claim 43 , comprising administering a compound of formula (III), or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.
51 . The method of claim 43 , wherein the individual has been diagnosed with, is suspected of having, or is predisposed to develop a cardiovascular disease, renal disease, high blood pressure, hyperlipidemia, impaired fasting glucose, metabolic syndrome, prehypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria, proteinuria, kidney disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral artery disease, carotid artery disease, coronary artery disease, endothelial dysfunction, oxidative stress, elevated renin levels, elevated endothelin levels, elevated C-reactive protein levels, or combinations thereof.
52 . The method of claim 43 , wherein the individual the individual has been diagnosed with, is suspected of having, or is predisposed to develop gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
53 . The method of claim 43 , wherein the individual has been diagnosed with, is suspected of having, or is predisposed to develop a cardiovascular disorder.
54 . The method of claim 43 , wherein the individual has been diagnosed with, is suspected of having, or is predisposed to develop an aneurysm; angina; atherosclerosis; a stroke; cerebrovascular disease; congestive heart failure; coronary artery disease; and/or a myocardial infarction.
55 . The method of claim 43 , wherein the individual has been diagnosed with, is suspected of having, or is predisposed to develop diabetes.
56 . The method of claim 43 , wherein the individual has been diagnosed with, is suspected of having, or is predisposed to develop Type I diabetes and/or Type II diabetes.
57 . The method of claim 43 , wherein the individual has been diagnosed with, is suspected of having, or is predisposed to develop metabolic syndrome.
58 . The method of claim 43 , further comprising administering a second agent effective for the treatment of the gout.
59 . The method of claim 58 , wherein the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof.
60 . The method of claim 58 , wherein the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.
61 . A method of treating or preventing a condition characterized by abnormal tissue or organ levels of uric acid in an individual comprising administering to the individual an effective amount of:
(i) a compound of formula (I); or (ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B ; or (iii) a compound of formula (III); or (iv) a combination thereof;
wherein
X is CH or N;
W is O, S, S(O), S(O) 2 , NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH 2 ;
R 1 is H, Cl, Br, I, NH 2 , methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF 3 , CHF 2 or CH 2 F;
R 3 and R 3′ are independently selected from H and lower alkyl, or R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;
R 2 is selected from the group consisting of (a), (b), (c) and (d):
wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
Q and Q′ are independently selected from N and CH;
R P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;
R 8 , R 9 and R 19 are independently selected from H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF 3 , NH 2 and NHCH 3 ;
R 11 is Cl, Br, I, CH 3 , CF 3 , methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and
R 11 , R 13 , R 14 and R 15 are independently H or methyl;
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , SR 3a , NR 4a R 4b at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation; or
R 2a is —[C(R 5a )(R 5b )] m R 5c ;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or
R 3a is —[C(R 5a )(R 5 )] n R 5c ;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or
R 4b is —[C(R 5a )(R 5b )] n R 5c , wherein
each R 5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
each R 5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
R 5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
wherein L is a bond, —C(O)—, —S(O), or —S(O) 2 ;
y 1 is 0, 1, 2 or 3;
Y is OH, OMe, COOH, SO 3 H, OSO 3 H, OS(O) 2 NH 2 , P(O)(OH) 2 , OP(O)(OH) 2 , OP(O)(OH)(O—C 1-4 alkyl) or NY 2 Y 3 Y 4 ; wherein
Y 2 and Y 3 are each independently hydrogen or methyl; or
Y 2 and Y 3 are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and
Y 4 is an electron pair or an oxygen atom;
m is 1, 2, 3, 4;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and wherein if R ea is —[C(R 5a )(R 5b )] m R 5c then at least one of R 5a , R 5b and R 5c is not hydrogen;
R 4 is H, lower alkyl, lower alkenyl or lower alkynyl;
R 5 , R 5′ , R 6 , R 6′ and R 7 are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF 3 , CHF 2 , CH 2 F, NH 2 , NHR′, NR′R″, OR′, SR′, C(O)R′, CO 2 H, a salt of CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, a salt of SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl or a heterocycle, wherein
R′ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl)(C 1-3 alkyl), CONHC 1-3 alkyl, aryl or a heterocycle;
R″ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CONHC 1-3 alkyl, aryl or a heterocycle; or
R′ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;
or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.
62 . The method of claim 61 , wherein the condition is gout, a recurrent gout attack, gouty arthritis, hyperuricaemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
63 . The method of claim 61 , wherein the condition is gout.
64 . The method of claim 61 , further comprising administering a second agent effective for the treatment of the gout.
65 . The method of claim 64 , wherein the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof.
66 . The method of claim 64 , wherein the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.
67 . A method of treating or preventing cancer which also maintains uric acid levels at pretreatment levels or causes a decrease in uric acid levels, comprising administering:
a) an effective amount of an anticancer agent; b) a uric acid level maintaining or lowering amount of:
(i) a compound of formula (I); or
(ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B ; or
(iii) a compound of formula (III); or
(iv) a combination thereof;
wherein
X is CH or N;
W is O, S, S(O), S(O) 2 , NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH 2 ;
R 1 is H, Cl, Br, I, NH 2 , methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF 3 , CHF 2 or CH 2 F;
R 3 and R 3′ are independently selected from H and lower alkyl, or R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;
R 2 is selected from the group consisting of (a), (b), (c) and (d):
wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
Q and Q′ are independently selected from N and CH;
R P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;
R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF 3 , NH 2 and NHCH 3 ;
R 11 is Cl, Br, I, CH 3 , CF 3 , methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and
R 12 , R 13 , R 14 and R 15 are independently H or methyl;
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , SR 3a , NR 4a R 4b at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation; or
R 2a is —[C(R 5a )(R 5b )] m R 5c ;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or
R 3a is —[C(R 5a )(R 5b )] n R 5c ;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or
R 4b is —[C(R 5a )(R 5b )] n R 5c , wherein
each R 5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
each R 5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
R 5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
wherein L is a bond, —C(O)—, —S(O), or —S(O) 2 ;
y 1 is 0, 1, 2 or 3;
Y is OH, OMe, COOH, SO 3 H, OSO 3 H, OS(O) 2 NH 2 , P(O)(OH) 2 , OP(O)(OH) 2 , OP(O)(OH)(O—C 1-4 alkyl) or NY 2 Y 3 Y 4 ; wherein
Y 2 and Y 3 are each independently hydrogen or methyl; or
Y 2 and Y 3 are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and
Y 4 is an electron pair or an oxygen atom;
m is 1, 2, 3, 4;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and wherein if R 2a is —[C(R 5a )(R 5b )] m R 5c then at least one of R 5a , R 5b and R 5c is not hydrogen;
R 4 is H, lower alkyl, lower alkenyl or lower alkynyl;
R 5 , R 5′ , R 6 , R 6′ and R 7 are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF 3 , CHF 2 , CH 2 F, NH 2 , NHR′, NR′R″, OR′, SR′, C(O)R′, CO 2 H, a salt of CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, a salt of SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl or a heterocycle, wherein
R′ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl)(C 1-3 alkyl), CONHC 1-3 alkyl, aryl or a heterocycle;
R″ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CONHC 1-3 alkyl, aryl or a heterocycle; or
R′ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;
or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.
68 . A pharmaceutical composition comprising:
(i) a compound of formula (I); or (ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B ; or (iii) a compound of formula (III); or (iv) a combination thereof;
wherein
X is CH or N;
W is O, S, S(O), S(O) 2 , NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH 2 ;
R 1 is H, Cl, Br, I, NH 2 , methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF 3 , CHF 2 or CH 2 F;
R 3 and R 3′ are independently selected from H and lower alkyl, or R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;
R 2 is selected from the group consisting of (a), (b), (c) and (d):
wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
Q and Q′ are independently selected from N and CH;
R P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;
R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF 3 , NH 2 and NHCH 3 ;
R 11 is Cl, Br, I, CH 3 , CF 3 , methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and
R 12 , R 13 , R 14 and R 15 are independently H or methyl;
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , SR 3a , NR 4a R 4b at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation; or
R 2a is —[C(R 5a )(R 5b )] m R 5c ;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or
R 3a is —[C(R 5a )(R 5b )] n R 5c ;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or
R 4b is —[C(R 5a )(R 5b )] n R 5c , wherein
each R 5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
each R 5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
R 5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
wherein L is a bond, —C(O)—, —S(O), or —S(O) 2 ;
y 1 is 0, 1, 2 or 3;
Y is OH, OMe, COOH, SO 3 H, OSO 3 H, OS(O) 2 NH 2 , P(O)(OH) 2 , OP(O)(OH) 2 , OP(O)(OH)(O—C 1-4 alkyl) or NY 2 Y 3 Y 4 ; wherein
Y 2 and Y 3 are each independently hydrogen or methyl; or
Y 2 and Y 3 are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and
Y 4 is an electron pair or an oxygen atom;
m is 1, 2, 3, 4;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and wherein if R 2a is —[C(R 5a )(R 5b )] m R 5c then at least one of R 5a , R 5b and R 5c is not hydrogen;
R 4 is H, lower alkyl, lower alkenyl or lower alkynyl;
R 5 , R 5′ , R 6 , R 6′ and R 7 are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF 3 , CHF 2 , CH 2 F, NH 2 , NHR′, NR′R″, OR′, SR′, C(O)R′, CO 2 H, a salt of CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, a salt of SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl or a heterocycle, wherein
R′ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl)(C 1-3 alkyl), CONHC 1-3 alkyl, aryl or a heterocycle;
R″ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CONHC 1-3 alkyl, aryl or a heterocycle; or
R′ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;
or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof; and
(v) optionally one or more pharmaceutically acceptable carriers.
69 . The composition of claim 68 , further comprising a second agent effective for the treatment of the gout.
70 . The composition of claim 69 , wherein the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof.
71 . The composition of claim 69 , wherein the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.
72 . A method of reducing serum uric acid levels in an individual, comprising administering:
(i) a compound of formula (I); or (ii) a compound of formula (II), wherein the compound of formula (II) is a 3-substituted-5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole wherein the substituent at the 3-position is —R B ; or (iii) a compound of formula (III); or (iv) a combination thereof;
wherein
X is CH or N;
W is O, S, S(O), S(O) 2 , NH, N (optionally substituted alkyl), NC(O)(optionally substituted alkyl) or CH 2 ;
R 1 is H, Cl, Br, I, NH 2 , methyl, ethyl, n-propyl, i-propyl, optionally substituted methyl, optionally substituted ethyl, optionally substituted n-propyl, optionally substituted i-propyl, CF 3 , CHF 2 or CH 2 F;
R 3 and R 3′ are independently selected from H and lower alkyl, or R 3 and R 3′ together with the carbon to which they are attached form a 4-, 5-, or 6-membered ring, optionally containing 1 or 2 heteroatoms selected from N, S and O;
R 2 is selected from the group consisting of (a), (b), (c) and (d):
wherein
represents a carbon-carbon single bond or a carbon-carbon double bond;
Q and Q′ are independently selected from N and CH;
R P is methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl;
R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CH 3 , CF 3 , CFH 2 , CF 2 H, ethyl, i-propyl, cyclopropyl, methoxy, OH, OCF 3 , NH 2 and NHCH 3 ;
R 11 is Cl, Br, I, CH 3 , CF 3 , methoxy, i-propyl, cyclopropyl, tert-butyl, cyclobutyl or methyl; and
R 12 , R 13 , R 14 and R 15 are independently H or methyl;
R B is —SCH 2 C(═O)R 1a , —SCH 2 -tetrazolyl, —SCH 2 C(═O)NHOH, —SCH 2 C(═O)O-alkyl-OC(═O)R 3a , —SCH 2 C(═O)O-alkyl-OC(═O)OR 3a , —SCH 2 C(═O)O-alkyl-OC(═O)NR 4a R 4b , or —SCH 2 C(Oalkyl) 3 ;
R 1a is OR 2a , SR 3a , NR 4a R 4b at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, or a combination thereof, wherein
R 2a is substituted C 1 -C 4 alkyl, optionally substituted C 5 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or
R 2a is a pharmaceutically acceptable cation; or
R 2a is —[C(R 5a )(R 5b )] m R 5c ;
R 3a is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; or
R 3a is —[C(R 5a )(R 5b )] n R 5c ;
R 4a is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and
R 4b is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; or
R 4b is —[C(R 5a )(R 5b )] n R 5c , wherein
each R 5a is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
each R 5b is independently hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di-(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
R 5c is hydrogen, halogen, cyano, nitro, at least one amino acid, a peptide, a lipid, a phospholipid, a glycoside, a nucleoside, a nucleotide, oligonucleotide, polyethylene glycol, -L-OH, -L-SH, -L-NH 2 , substituted -L-C 1 -C 3 alkyl, optionally substituted -L-C 4 -C 9 alkyl, optionally substituted L-C 2 -C 5 alkenyl, optionally substituted L-C 2 -C 5 alkynyl, optionally substituted L-C 2 -C 5 heteroalkyl, optionally substituted -L-C 3 -C 7 cycloalkyl, optionally substituted L-C 3 -C 7 cycloalkenyl, optionally substituted -L-C 3 -C 7 heterocycloalkyl, optionally substituted -L-C 1 -C 4 haloalkyl, optionally substituted -L-C 1 -C 4 alkoxy, optionally substituted -L-C 1 -C 4 alkylamine, optionally substituted -L-di(C 1 -C 4 )alkylamine, optionally substituted -L-C 5 -C 7 aryl, optionally substituted -L-C 5 -C 7 heteroaryl,
wherein L is a bond, —C(O)—, —S(O), or —S(O) 2 ;
y 1 is 0, 1, 2 or 3;
Y is OH, OMe, COOH, SO 3 H, OSO 3 H, OS(O) 2 NH 2 , P(O)(OH) 2 , OP(O)(OH) 2 , OP(O)(OH)(O—C 1-4 alkyl) or NY 2 Y 3 Y 4 ; wherein
Y 2 and Y 3 are each independently hydrogen or methyl; or
Y 2 and Y 3 are taken together with the nitrogen to which they are attached to form a five or six membered ring that optionally contains an oxygen atom or a second nitrogen atom; and
Y 4 is an electron pair or an oxygen atom;
m is 1, 2, 3, 4;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
and wherein if R 2a is —[C(R 5a )(R 5b )] m R 5c then at least one of R 5a , R 5b and R 5c is not hydrogen;
R 4 is H, lower alkyl, lower alkenyl or lower alkynyl;
R 5 , R 5′ , R 6 , R 6′ and R 7 are independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, substituted methyl, substituted ethyl, substituted n-propyl, substituted i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, CF 3 , CHF 2 , CH 2 F, NH 2 , NHR′, NR′R″, OR′, SR′, C(O)R′, CO 2 H, a salt of CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, a salt of SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl or a heterocycle, wherein
R′ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl)(C 1-3 alkyl), CONHC 1-3 alkyl, aryl or a heterocycle;
R″ is H, C 1-3 alkyl, substituted C 1-3 alkyl wherein said substituents are selected from CF 3 , OH, OC 1-3 alkyl, COC 1-3 alkyl, COOH, COOC 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , CONHC 1-3 alkyl, aryl or a heterocycle; or
R′ and R″ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring;
or a metabolite, pharmaceutically acceptable salt, solvate, ester, tautomer or prodrug thereof.Cited by (0)
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