Inhibitors of advanced glycosylation end products

Abstract

The present invention provides compounds of formula wherein A, B, G, R2, R6 and X are as defined herein # imgabs0 #, pharmaceutical compositions thereof, and methods for treating or inhibiting the development of AGE and / or ALE-related complications in a subject in need thereof,

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of July 31, 2020, an application number of 202080065881.9, and an invention title of "Inhibitors of Advanced Glycation End Products" (the corresponding PCT application has an application date of July 31, 2020, and an application number of PCT / US2020 / 044611).

[0002] Cross - reference to related applications

[0003] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 62 / 881,607, filed on August 1, 2019, and U.S. Provisional Patent Application No. 63 / 006,706, filed on April 7, 2020, and both applications are incorporated herein by reference in their entirety. Technical field

[0004] This application relates to the fields of chemistry, medicine, nephropathy, vascular diseases, hyperlipidemia, hyperglycemia, advanced glycation end products, diabetic complications, and advanced lipoxidation end products. Background art

[0005] Advanced glycation end products (AGEs) are carbohydrate - derived chemical modifications and cross - links that accumulate in long - lived tissue proteins during the normal aging process. The increased rate of AGE accumulation during hyperglycemia is associated with the development of long - term diabetic complications, including but not limited to retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases. In addition, AGE formation is associated with many other pathologies, such as the normal aging process, arthritis, connective tissue diseases, amyloidosis, and neurodegenerative amyloid diseases, such as Alzheimer's disease.

[0006] Advanced lipoxidation end products (ALEs) are lipid - derived chemical modifications and cross - links that also accumulate in long - lived tissue proteins during the normal aging process and are associated with hyperlipidemia, vascular diseases, and kidney diseases in both diabetic and non - diabetic animal models. It is now recognized that some compounds, such as ε N - (carboxymethyl)lysine (CML) and ε N - (carboxyethyl)lysine (CEL), may be derived from either carbohydrates or lipids and are thus named AGE / ALE. Other compounds, such as pentosidine, appear to be true AGEs, while other compounds, such as malondialdehyde - lysine (MDA - Lys) and 4 - hydroxy - 2 - nonenal - lysine (HNE - Lys), are considered ALEs and are derived entirely from lipids.

[0007] Elucidating the pathogenic mechanisms of AGE- and ALE-related complications associated with hyperglycemia and / or hyperlipidemia is crucial for developing rational therapies for treating and preventing them. However, there is currently no consensus on the relative importance of the different possible pathogenic mechanisms that may contribute to these diabetic complications.

[0008] It has recently been demonstrated that the compound pyridoxamine inhibits the formation of both AGE and ALE in vitro and can be used to treat and prevent AGE- and ALE-related complications in animal models of hyperglycemia, hyperlipidemia, and hyperglycemia-hyperlipidemia. (See, for example, U.S. Patent Serial No. 5,985,857; WO 00 / 21516; WO 00 / 23063.) Such complications include, but are not limited to, diabetic nephropathy, proteinuria, glomerular clearance disorders, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related conditions, including dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increases in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and inhibition of ultrafiltration failure and peritoneal destruction in dialysis patients.

[0009] However, there is still a need in the art for further options for treating or inhibiting the development of AGE- and ALE-related complications in patients in need, particularly those with hyperglycemia and / or hyperlipidemia. SUMMARY OF THE INVENTION

[0010] The present invention provides compounds, pharmaceutical compositions, and methods for treating or inhibiting the development of AGE- and / or ALE-related complications in a subject in need.

[0011] Accordingly, in one aspect, the present invention provides novel compounds and pharmaceutical compositions thereof as described herein. In a preferred embodiment, the method comprises administering to a subject having hyperglycemia and / or hyperlipidemia one or more compounds or pharmaceutical compositions of the present invention.

[0012] In another aspect, the present invention further provides a method for treating a disorder or inhibiting the development of a disorder, said disorder including diabetic nephropathy, proteinuria, glomerular clearance disorder, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related disorders, including dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and inhibition of ultrafiltration failure and peritoneal damage in dialysis patients. The method comprises administering to a subject in need of such treatment an effective amount of one or more compounds of the present invention as described herein or a pharmaceutically acceptable salt thereof. Detailed Description

[0013] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0014]

[0015] wherein,

[0016] X is N, N—O or CR 1 ;

[0017] G is —OH, —SH, —NH2 or —N(R G )2, wherein R G is hydrogen, (C1-C6)alkyl or —C(O)(C1-C6)alkyl;

[0018] A is

[0019]

[0020] wherein

[0021] Y is N;

[0022] Z is CH2, C(H)R A 、C(R A )2、O or NR A ;

[0023] m is 0, 1, 2 or 3;

[0024] provided that

[0025] when m is 0, Z is CH2, C(H)R A or C(R A )2, and

[0026] when m is 2, Z is O;

[0027] RA is a (C1-C6) alkyl, halogen, -OR A1 , -N(R A1 )2, -SR A1 , -S(O)R A1 , -S(O)2R A1 , -COOR A1 , -CON(R A1 )2 or -(C1-C6) alkyl-OR A1 ,

[0028] wherein R A1 is hydrogen, (C1-C6) alkyl or -C(O)(C1-C6) alkyl, or two

[0029] R A1 together with the N atom to which they are attached form a morpholinyl; and

[0030] n is 0, 1, 2, 3, 4, 5 or 6;

[0031] B has the following formula,

[0032]

[0033] wherein

[0034] ring D is (i) monocyclic, and

[0035] (ii) unsaturated or aromatic;

[0036] R C’ is hydrogen;

[0037] G 1 is O, S, N or NR N’ ;

[0038] G 2 and G 3 each independently is N, O, CR 3 , C(R 3 )2 or NR N’ , wherein each R 3 independently is -Z 3 -M-Z 4 -R Z , wherein M is -C(O)-, -C(S)-, -S(O)-, -S(O)2- or absent,

[0039] Z 3 and Z 4 independently is -O-, -S-, -N(R N3 )- or absent, wherein

[0040] R N3is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkanoyl, heterocyclic acyl, aromatic acyl, heteroaromatic acyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, wherein

[0041] R N3 is optionally substituted by one or more groups independently selected from halogen, -OH, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl or aromatic acyl;

[0042] R Z is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkynyl or -(C1-C6)haloalkyl, -(C3-C8)cycloalkyl, -(C1-C6)alkylaryl, -heterocyclic group, -aryl or -heteroaryl, wherein

[0043] R Z is optionally substituted by at least one R Z’ wherein

[0044] each R Z’ is independently -halogen, -OR, -(C1-C6)alkoxy, -C(O)OR, -C(O)R, -C(O)NR2, -S(O)2R, -OS(O)2R, -cyano, -nitro, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C8)cycloalkyl, -heterocycloalkyl or heteroaryl,

[0045] provided that when M is -S(O)-, -S(O)2- or absent, then at least one of Z 3 and Z 4 is also absent;

[0046] or two Rs 3 together are oxo;

[0047] R N’ is hydrogen or (C1-C6)alkyl;

[0048] the bonds a, b, c, d and e are independently single or double bonds,

[0049] provided that

[0050] (i) no two consecutive atoms in ring D are both oxygen;

[0051] (ii) No two consecutive bonds are double bonds;

[0052] (iii) If a or b is a double bond, then R C’ does not exist; and

[0053] (iv) If a or e is a double bond, then R N’ does not exist;

[0054] (v) If b or c is a double bond, then G 1 is not O or S;

[0055] (vi) If c or d is a double bond, then G 2 is not O;

[0056] (vii) If d or e is a double bond, then G 3 is not O;

[0057] R 1 、R 2 and R 6 are independently hydrogen, halogen, -NO2, -CN or R C ,

[0058] provided that when X = CR 1 ,

[0059] (i) R 2 、R 6 and R N1 are not phenyl;

[0060] (ii) R C is not aryl, heteroaryl, heterocyclic or (C2-C6) alkenyl

[0061] (iii) And when G 1 = N, then G2 is not O; and

[0062] (iv) Two Rs C together cannot form oxo;

[0063] And provided that when X = N, and

[0064] (i) G 1 is N, G 3 is CR 3 , and G 2 is N, and the bonds b and d are each double bonds, all of which occur simultaneously; or

[0065] (ii) G 1 is N, G 3 is C(O), G 2 is NR N’ , and the bond b is a double bond, all of which occur simultaneously;

[0066] R 2 or R 6 is not -NH-aryl or -NH-heteroaryl.

[0067] In certain embodiments, the compound of formula (I) is: wherein

[0068] Z is CH2, C(H)R A , C(R A )2 or O;

[0069] m is 0 or 2;

[0070] provided that

[0071] when m is 0, Z is CH2, C(H)R A or C(R A )2, and

[0072] when m is 2, Z is O.

[0073] In another embodiment, the present invention provides a compound of formula (I), wherein X is N and G is hydrogen.

[0074] In another embodiment, the present invention provides a compound of formula (I), wherein

[0075] B is aromatic;

[0076] G 1 is O, S, N or NR N’ ; and

[0077] G 2 and G 3 are each independently O, N or CR 3 .

[0078] In another embodiment, the present invention provides a compound of formula (I), wherein B is imidazolyl, oxazolyl, pyrazolyl, pyrrolyl or isoxazolyl, wherein each carbon atom is substituted by R 3 .

[0079] In another embodiment, the present invention provides a compound of formula (I), wherein B is imidazolyl, wherein each carbon atom is substituted by R 3 .

[0080] In another embodiment, the present invention provides a compound of formula (I), wherein

[0081] each R 3 is independently R Z3 , wherein

[0082] R Z3is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, where R Z3 is optionally substituted by at least one R Z3’ wherein

[0083] each R Z3’ is independently halogen, cyano, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl, where each R is independently hydrogen, (C1-C6)alkyl or (C1-C6)haloalkyl.

[0084] In another embodiment, the present invention provides a compound of formula (I), wherein

[0085] R 2 and R 6 are each independently hydrogen, halogen, -NO2, -CN or R Z6 wherein

[0086] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, where R Z6 is optionally substituted by at least one R Z6’ substituent,

[0087] wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl, where each R is independently hydrogen, (C1-C6)alkyl or (C1-C6)haloalkyl.

[0088] In another embodiment, the present invention provides a compound of formula (I), wherein

[0089] R N’ is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C3-C8)cycloalkanoyl, heterocyclic acyl, aryl acyl, heteroaryl acyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, wherein

[0090] R N' is optionally substituted by one or more substituents which are independently halogen, -OR N” 、-NR N”2, -NO2, -CN, (C1-C6) alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8) cycloalkyl or (C1-C6) haloalkyl,

[0091] wherein each R N” is independently hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0092] In another embodiment, the present invention provides a compound of formula (I), wherein A is

[0093]

[0094] wherein n is 0, 1, 2 or 3.

[0095] In another embodiment, the present invention provides a compound of formula (I), wherein A is

[0096]

[0097] In another embodiment, the present invention provides a compound of formula (I), wherein A is

[0098]

[0099] In another embodiment, the present invention provides a compound of formula (I), wherein R A is (C1-C6) alkyl, halogen or -(C1-C6) alkyl-OR A1 , wherein R A1 is hydrogen or (C1-C6) alkyl.

[0100] In another embodiment, the present invention provides a compound of formula (I), wherein R A is (C1-C6) alkyl, halogen, (C1-C6) alkyl-OR A1 or -COOR A1 , wherein R A1 is hydrogen or (C1-C6) alkyl, or two R A1 together with the N atom to which they are attached form a morpholinyl group.

[0101] In another embodiment, the present invention provides a compound of formula (I), wherein B is not aromatic, and G 1 , G 2 and G 3 are each independently O, N, CR 3 , C(R 3 )2 or N(R N’ ).

[0102] In another embodiment, the present invention provides a compound of formula (I), wherein

[0103] B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, triazolidinyl or tetrazolidinyl, wherein each carbon is substituted by two R 3 and each nitrogen is substituted by R N’ .

[0104] In another embodiment, the present invention provides a compound of formula (I), wherein

[0105] each R 3 is independently R Z3 , wherein

[0106] R Z3 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z3 is optionally substituted by at least one R Z3’ , wherein

[0107] each R Z3’ is independently -halogen, -cyano, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl.

[0108] In another embodiment, the present invention provides a compound of formula (I), wherein

[0109] R 2 and R 6 are each hydrogen, halogen, -NO2, -CN or -R Z6 , wherein

[0110] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z6 is optionally substituted by at least one R Z6’ ,

[0111] wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl,

[0112] wherein R Z6’ is optionally substituted by one or more R'.

[0113] In another embodiment, the present invention provides a compound of formula (I), wherein

[0114] each R N’ is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C3-C8)cycloalkanoyl, heterocycloacyl, aroyl, heteroaroyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, wherein

[0115] R N’ is optionally substituted with one or more substituents independently selected from halogen, -OR N” , -NR N” 2, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic, heteroaryl, (C3-C8)cycloalkyl or (C1-C6)haloalkyl,

[0116] wherein each R N” is independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl and alkoxy are optionally substituted with one or more R'.

[0117] In another embodiment, the present invention provides a compound of formula (I), wherein X is CR 1 , and G is hydrogen.

[0118] In another embodiment, the present invention provides a compound of formula (I), wherein

[0119] R 1 is -CN, -NO2, halogen, -C(O)OR 4 , -C(O)R 4 , -C(O)N(R 4 )2, -S(O)R 4 , -S(O)2R 4 or -S(O)2N(R 4 )2, wherein

[0120] each R 4 is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic, aryl or heteroaryl, wherein

[0121] R 4 is optionally substituted with at least one group, each group independently being halogen, -OH, (C1-C6)alkoxy, -C(O)R 41 , -S(O)2R 41, -OS(O)2R 41 , -CN, -NO2, (C1-C6) alkyl or (C1-C6) haloalkyl,

[0122] wherein R 41 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0123] In another embodiment, the present invention provides a compound of formula (I), wherein

[0124] B is aromatic; and

[0125] G 1 is O, S, N or NR N’ ; and

[0126] G 2 and G 3 are each independently O, N or CR 3 .

[0127] In another embodiment, the present invention provides a compound of formula (I), wherein B is imidazolyl, oxazolyl, pyrazolyl, pyrrolyl or isoxazolyl, wherein each carbon atom is substituted by R 3 substituted.

[0128] In another embodiment, the present invention provides a compound of formula (I), wherein B is imidazolyl, wherein each carbon atom is substituted by R 3 substituted.

[0129] In another embodiment, the present invention provides a compound of formula (I), wherein each R 3 is independently R Z3 , wherein

[0130] R Z3 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl, (C1-C6) alkylaryl, heterocyclic, aryl or heteroaryl, wherein R Z3 is optionally substituted by at least one R Z3’ , wherein

[0131] each R Z3’ is independently halogen, -CN, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl or heterocycloalkyl.

[0132] In another embodiment, the present invention provides a compound of formula (I), wherein

[0133] R 2 and R 6 are each hydrogen, halogen, -NO2, -CN or -R Z6 wherein

[0134] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z6 is optionally substituted by at least one R Z6’ substituent,

[0135] wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl,

[0136] wherein R Z6’ is optionally substituted by one or more R'.

[0137] In another embodiment, the present invention provides a compound of formula (I), wherein

[0138] R N’ is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C3-C8)cycloalkanoyl, heterocyclic carbonyl, arylcarbonyl, heteroarylcarbonyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, wherein

[0139] R N’ is optionally substituted by one or more substituents which are independently halogen, -OR N” , -NR N” 2, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl or (C1-C6)haloalkyl,

[0140] wherein each R N” is independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl and alkoxy are optionally substituted by one or more R'.

[0141] In another embodiment, the present invention provides a compound of formula (I), wherein B is not aromatic, and G 1 , G 2 and G 3 are each independently O, N, CR 3 , C(R 3 )2 or N(R N’)。

[0142] In another embodiment, the present invention provides a compound of formula (I) wherein B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, triazolidinyl or tetrazolidinyl, wherein each carbon is substituted with two R 3 and each nitrogen is substituted with R N’ substituted.

[0143] In another embodiment, the present invention provides a compound of formula (I) wherein

[0144] each R 3 is independently R Z3 , wherein

[0145] R Z3 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z3 is optionally substituted with at least one R Z3’ , wherein

[0146] each R Z3’ is independently halogen, -CN, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl.

[0147] In another embodiment, the present invention provides a compound of formula (I) wherein

[0148] R 2 and R 6 are each hydrogen, halogen, -NO2, -CN or -R Z6 , wherein

[0149] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z6 is optionally substituted with at least one R Z6’ substituted,

[0150] wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl,

[0151] wherein R Z6’ is optionally substituted with one or more R'.

[0152] In another embodiment, the present invention provides a compound of formula (I) wherein

[0153] Each R N’ independently is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C3-C8)cycloalkanoyl, heterocycloacyl, aroyl, heteroaroyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, wherein

[0154] R N’ is optionally substituted with one or more substituents which independently are halogen, -OR N” , -NR N” 2, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl or (C1-C6)haloalkyl,

[0155] wherein each R N” independently is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl and alkoxy are optionally substituted with one or more R'.

[0156] In another embodiment, the present invention provides a compound of formula (I), wherein the compound of formula (I) is

[0157]

[0158]

[0159]

[0160]

[0161] or a pharmaceutically acceptable salt thereof.

[0162] In another aspect, the compound provided by the present invention is:

[0163]

[0164]

[0165] or a pharmaceutically acceptable salt thereof.

[0166] In another aspect, the present invention provides a pharmaceutical composition comprising the compound as described herein and a pharmaceutically acceptable carrier.

[0167] In another aspect, the present invention provides a method for treating one or more AGE- and / or ALE-related complications or inhibiting their development in a subject in need thereof, which comprises administering to the subject one or more compounds as described herein.

[0168] In another aspect, the present invention provides a method for treating one or more AGE- and / or ALE-related complications or inhibiting their development in a subject in need thereof, which comprises administering to the subject one or more pharmaceutical compositions as described herein.

[0169] In one embodiment, the one or more AGE- and / or ALE-related complications are selected from the group consisting of: accelerated protein aging, retinopathy, nephropathy, proteinuria, glomerular clearance disorder, neuropathy, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis, cardiovascular disease, neurodegenerative amyloid disease, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue disease, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, hypertension; and dialysis-related conditions selected from the group consisting of: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and ultrafiltration failure and peritoneal damage in dialysis patients.

[0170] In another aspect, the present invention provides a method for treating one or more conditions selected from the group consisting of: diabetic nephropathy, proteinuria, glomerular clearance disorder, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue disease, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related conditions including: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and inhibiting ultrafiltration failure and peritoneal damage in dialysis patients, wherein the method comprises administering to a subject in need of such treatment an effective amount of a compound as described herein.

[0171] In another aspect, the present invention provides a method for treating one or more disorders selected from the group consisting of or inhibiting the development thereof: diabetic nephropathy, proteinuria, glomerular clearance disorder, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related disorders including: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and inhibition of ultrafiltration failure and peritoneal damage in dialysis patients, wherein the method comprises administering to a subject in need of such treatment an effective amount of a pharmaceutical composition as described herein.

[0172] In another aspect, the present invention provides a pharmaceutical composition comprising one or more compounds of the present invention as disclosed above and a pharmaceutically acceptable carrier. Preferred embodiments of the pharmaceutical composition are described below.

[0173] In another aspect, the present invention provides a method for treating one or more AGE- and / or ALE-related complications or inhibiting the development thereof in a subject in need thereof, which comprises administering to a subject in need thereof one or more compounds or pharmaceutical compositions of the present invention. As used herein, the phrase "AGE- and / or ALE-related complications" includes but is not limited to accelerated protein aging, retinopathy, nephropathy, proteinuria, glomerular clearance disorder, neuropathy, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis, cardiovascular disease, and neurodegenerative amyloid diseases (such as Alzheimer's disease), diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, oxidative stress-related conditions, and hypertension; and dialysis-related disorders including: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and inhibition of ultrafiltration failure and peritoneal damage in dialysis patients.

[0174] In another aspect, the present invention provides a method for treating one or more of the following conditions or inhibiting their development: diabetic nephropathy, proteinuria, glomerular clearance disorder, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, oxidative stress-related conditions, and hypertension; and dialysis-related conditions including: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and inhibition of ultrafiltration failure and peritoneal damage in dialysis patients, wherein the method comprises administering to a subject in need of such treatment an effective amount of one or more compounds of the present invention or a pharmaceutically acceptable salt thereof.

[0175] In a preferred embodiment, the method is for treating a patient suffering from hyperlipidemia and / or hyperglycemia or their complications, or for inhibiting the development of complications caused by hyperlipidemia and / or hyperglycemia, such as those described above.

[0176] Although the method in this aspect of the present invention is not limited by a specific mechanism, it is believed that the compounds of the present invention can be used to treat these complications or inhibit their development based on their ability to inhibit AGE and / or ALE formation, and thus inhibit the development or progression of complications associated with AGE and / or ALE accumulation.

[0177] Definitions

[0178] As used herein, "treat" or "treating" means accomplishing one or more of the following: (a) reducing the severity of a condition; (b) limiting or preventing the development of the symptomatic characteristics of one or more conditions being treated; (c) inhibiting the worsening of the symptomatic characteristics of one or more conditions being treated; (d) limiting or preventing the recurrence of the one or more conditions in a patient previously suffering from the one or more conditions; and (e) limiting or preventing the recurrence of symptoms in a patient previously having symptoms of the one or more conditions.

[0179] As used herein, the term "inhibit the development of" means preventing or minimizing the development of a condition or complication in an individual at risk of developing the condition or complication.

[0180] As used herein, the term "absent" means that the group is replaced by a single bond. If replacing a group with a bond results in two moieties both defined as bonds being connected, then the -bond-bond- group is understood to be reduced to a single bond.

[0181] As used herein, the term "alkenyl" means a straight-chain or branched-chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0182] As used herein, the term "alkoxy" means an alkyl as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0183] As used herein, the term "alkyl" means a straight-chain or branched-chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0184] As used herein, the term "alkanoyl" means an alkyl as defined herein attached to the parent molecular moiety through a carbonyl as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, and 1-oxopentyl.

[0185] As used herein, the term "alkoxycarbonyl" means an alkoxy as defined herein attached to the parent molecular moiety through a carbonyl as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

[0186] As used herein, the term "alkynyl" means a straight-chain or branched-chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0187] As used herein, the term "aryl" means phenyl or bicyclic aryl or tricyclic aryl. Bicyclic aryl is naphthyl, or phenyl fused to cycloalkyl, or phenyl fused to cycloalkenyl. Bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic aryl. Representative examples of bicyclic aryl include, but are not limited to, indanyl, indenyl, naphthyl, dihydronaphthyl, and tetrahydronaphthyl. Tricyclic aryl is anthracene or phenanthrene, or bicyclic aryl fused to cycloalkyl, or bicyclic aryl fused to cycloalkenyl, or bicyclic aryl fused to phenyl. Tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the tricyclic aryl. Representative examples of tricyclic aryl rings include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

[0188] As used herein, the term "arylalkoxycarbonyl" means arylalkoxy as defined herein, which is attached to the parent molecular moiety through a carbonyl as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphthalen-2-ylmethoxycarbonyl.

[0189] As used herein, the term "arylalkyl" means aryl as defined herein, which is attached to the parent molecular moiety through an alkyl as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthalen-2-ylethyl.

[0190] As used herein, the term "aroyl" means aryl as defined herein, which is attached to the parent molecular moiety through a carbonyl as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

[0191] As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group containing 3 to 8 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0192] As used herein, the term "cycloalkanoyl" means cycloalkyl as defined herein, which is attached to the parent molecular moiety through a carbonyl as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and cyclohexylcarbonyl.

[0193] As used herein, the term "halo" or "halogen" means -Cl, -Br, -I, or -F.

[0194] As used herein, the term "haloalkyl" means at least one halogen as defined herein, which is attached to the parent molecular moiety through an alkyl as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

[0195] As used herein, the term "heteroaryl" means a monocyclic heteroaryl or a bicyclic heteroaryl. A monocyclic heteroaryl is a 5- or 6-membered ring. The 5-membered ring contains two double bonds and one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6-membered ring contains three double bonds and one, two, three, or four nitrogen atoms. The 5- or 6-membered heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryls include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. A bicyclic heteroaryl includes a monocyclic heteroaryl fused to a phenyl, a monocyclic heteroaryl fused to a cycloalkyl, a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The bicyclic heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryls include, but are not limited to, benzimidazolyl, benzofuryl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furanopyridyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thiophenopyridyl.

[0196] As used herein, the term "heteroaroyl" means a heteroaryl as defined herein, which is attached to the parent molecular moiety through a carbonyl as defined herein. Representative examples of heteroaryl carbonyls include, but are not limited to, furan-3-ylcarbonyl, 1H-imidazol-2-ylcarbonyl, 1H-imidazol-4-ylcarbonyl, pyridine-3-ylcarbonyl, 6-chloropyridine-3-ylcarbonyl, pyridine-4-ylcarbonyl, (6-(trifluoromethyl)pyridine-3-yl)carbonyl, (6-(cyano)pyridine-3-yl)carbonyl, (2-(cyano)pyridine-4-yl)carbonyl, (5-(cyano)pyridine-2-yl)carbonyl, (2-(chloro)pyridine-3-yl)carbonyl, pyrimidine-5-ylcarbonyl, pyrimidine-2-ylcarbonyl, thiophene-2-ylcarbonyl, and thiophene-3-ylcarbonyl.

[0197] As used herein, the term "heterocycle" means a monocyclic and 3-, 4-, 5-, 6- or 7-membered ring containing at least one heteroatom independently selected from O, N and S. A 3- or 4-membered ring contains 1 heteroatom selected from O, N and S. A 5-membered ring contains zero or one double bond and one, two or three heteroatoms selected from O, N and S. A 6- or 7-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from O, N and S. The heterocycle is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thianyl and trithianyl.

[0198] As used herein, the term "heterocyclic acyl" means a heterocycle as defined herein attached to the parent molecular moiety through a carbonyl group as defined herein.

[0199] "Oxidative stress" is defined as a specific increase in reactive oxygen species and derived free radicals. Oxidative stress-related conditions include, but are not limited to, atherosclerosis, ischemia-reperfusion injury, inflammatory diseases such as arthritis, cancer, exposure to ionizing radiation and / or chemotherapeutic agents, adult respiratory distress syndrome (ARDS) of the lung, myocardial infarction and stroke, pancreatitis or intestinal ulcers, and aging. (See, e.g., U.S. Patent Nos. 5,700,654 and 5,462,946).

[0200] As used herein, the term "oxide" means an -O moiety; for example, as is well known to those skilled in the art, the attachment of an oxide group to nitrogen forms an N-oxide compound. In such compounds, the oxygen bears a formal negative charge and the nitrogen bears a formal positive charge, and thus the net charge of the entire compound is zero.

[0201] As used herein, the term "oxo" means a =O moiety.

[0202] Pharmaceutical Compositions and Administration

[0203] The compounds of the present invention can be administered alone or in combination, usually in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and contain at least one active compound.

[0204] The compounds of the present invention can be administered as the sole active pharmaceutical agent, or they can be used in combination with one or more other compounds for practicing the methods of the present invention, said compounds including but not limited to pyridoxamine, aminoguanidine, the compounds disclosed in WO2004 / 019889 (including but not limited to BST 4996, BST 4997 and BST-146); agents that promote blood glucose control, such as insulin, metformin and thiazolidinediones; and antihypertensive drugs, such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), endothelin receptor antagonists and renin inhibitors. When administered in combination, the therapeutic agents can be formulated as separate compositions to be given at the same time or at different times, or the therapeutic agents can be given as a single composition.

[0205] The compounds can be made in solid form (including granules, powders or suppositories) or in liquid form (e.g., solutions, suspensions or emulsions). The compounds of the present invention can be applied in various solutions and can be subjected to conventional pharmaceutical operations, such as sterilization and / or can contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifying agents, buffering agents, etc.

[0206] The compounds of the present invention can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. As used herein, the term parenteral includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular or intrathecal injection or infusion techniques, etc. In addition, a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable carrier is provided. One or more compounds of the present invention can be present in combination with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and other active ingredients if desired. The pharmaceutical composition containing the compound of the present invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0207] Compositions intended for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and in order to provide palatable formulations, such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preservatives. Tablets contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques. In some cases, such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained long-term action. For example, delayed release materials such as glyceryl monostearate or glyceryl distearate may be employed.

[0208] Preparations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin); or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0209] Aqueous suspensions contain the active material admixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and acacia; dispersing or wetting agents may be naturally occurring phosphatides (such as lecithin), or condensation products of ethylene oxide with fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (such as heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (such as polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (such as polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (such as sucrose or saccharin).

[0210] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0211] Dispersible powders and granules suitable for the preparation of aqueous suspensions provide, by the addition of water, an active ingredient admixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are illustrated by those already mentioned above. Additional excipients may also be present, such as sweetening agents, flavoring agents, and coloring agents.

[0212] The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifying agents may be naturally occurring gums such as gum arabic or tragacanth; naturally occurring phospholipids such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan monooleate); and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents and flavoring agents.

[0213] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations may also contain demulcents, preservatives, flavoring agents, and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile non-volatile oil is conventionally employed as a solvent or suspending medium. For this purpose, any mild non-volatile oil may be employed, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid have been found useful in the preparation of injectables.

[0214] The compounds and pharmaceutical compositions of the invention may also be administered in the form of suppositories, for example, for rectal administration of drugs. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature and liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0215] The compounds and pharmaceutical compositions of the invention may be administered parenterally in a sterile medium. Depending on the vehicle and the concentration used, the drug may either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents may be dissolved in the vehicle.

[0216] Dose levels on the order of about 0.01 mg to about 50 mg per kilogram of body weight per day, more preferably about 0.1 mg to about 50 mg per kilogram of body weight per day, and even more preferably about 0.1 mg to about 20 mg per kilogram of body weight per day can be used to treat the above-mentioned conditions. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Dosage unit forms will generally contain from about 1 mg to about 500 mg of the active ingredient.

[0217] Administer a pharmaceutical composition containing the compounds described herein to an individual in need thereof. In a preferred embodiment, the subject is a mammal; in a more preferred embodiment, the subject is a human. In therapeutic applications, the composition is administered in an amount sufficient to effect the methods of the invention. The effective amount for these uses depends on a variety of factors, including but not limited to the nature of the compound (specific activity, etc.), the route of administration, the stage and severity of the disorder, the body weight and general health of the subject, and the judgment of the prescribing physician. The active compounds are effective over a wide range of doses. However, it should be understood that the amount of the compound actually administered will be determined by the physician in view of the relevant circumstances described above. Accordingly, the above dosage ranges are not intended to limit the scope of the invention in any way.

[0218] For administration to non-human mammals, the composition can also be added to animal feed or drinking water. It may be convenient to formulate these animal feed and drinking water compositions so that the animal ingests an appropriate amount of the composition in one meal or in a day. It is also convenient to add the composition as a premix to the feed or drinking water.

[0219] Preparation of the compounds of the invention

[0220] The compounds and methods of the invention will be better understood in connection with the following synthetic schemes, which illustrate methods by which the compounds of the invention can be prepared. Starting materials can be obtained from commercial sources or prepared by established literature methods known to those of ordinary skill in the art.

[0221] The reactions are carried out in a solvent suitable for the reagents and materials used and are applicable to the transformations being effected. Those skilled in the art of organic synthesis will understand that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require judgment to modify the order of synthetic steps or to select a particular process scheme over another in order to obtain the compounds required by the invention.

[0222] It should also be recognized that another major consideration in any synthetic route planning in this field is the wise selection of protecting groups for protecting the reactive functional groups present in the compounds described in the present invention. An authoritative explanation that describes many alternatives for trained practitioners is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999). Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC), trimethylsilylethanesulfonamide (SES), benzyloxycarbonyl (CBZ), and benzyl (Bn) protecting groups.

[0223] The present invention provides the following embodiments including, but not limited to:

[0224] 1. A compound of the following formula or a pharmaceutically acceptable salt thereof,

[0225]

[0226] wherein,

[0227] X is N, N-O or CR 1 ;

[0228] G is -OH, -SH, -NH2 or -N(R G )2, where R G is hydrogen, (C1-C6) alkyl or -C(O)(C1-

[0229] C6) alkyl;

[0230] A is

[0231]

[0232] where

[0233] Y is N;

[0234] Z is CH2, C(H)R A , C(R A )2, O or NR A ;

[0235] m is 0, 1, 2 or 3;

[0236] provided that

[0237] when m is 0, Z is CH2, C(H)R A or C(R A )2, and

[0238] when m is 2, Z is O or NR A ;

[0239] RA is a (C1-C6) alkyl, halogen, -OR A1 , -N(R A1 )2, -SR A1 , -S(O)R A1 , -S(O)2R A1 , -COOR A1 , -CON(R A1 )2 or -(C1-C6) alkyl-OR A1 ,

[0240] wherein R A1 is hydrogen, (C1-C6) alkyl or -C(O)(C1-C6) alkyl, or two R A1 together with the N atom to which they are attached form a morpholinyl group; and

[0241] n is 0, 1, 2, 3, 4, 5 or 6;

[0242] B has the following formula,

[0243]

[0244] wherein

[0245] ring D is (i) monocyclic, and

[0246] (ii) unsaturated or aromatic;

[0247] R C’ is hydrogen;

[0248] G 1 is O, S, N or NR N’ ;

[0249] G 2 and G 3 each independently is N, O, CR 3 , C(R 3 )2 or NR N’ , wherein each R 3 independently is -Z 3 -M-Z 4 -R Z , wherein M is -C(O)-, -C(S)-, -S(O)-, -S(O)2- or absent,

[0250] Z 3 and Z 4 independently are -O-, -S-, -N(R N3 )- or absent, wherein

[0251] R N3is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkanoyl, heterocyclic acyl, aryl acyl, heteroaryl acyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, where

[0252] R N3 is optionally substituted with one or more groups independently selected from halogen, -OH, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl or aryl acyl;

[0253] R Z is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkynyl or -(C1-C6)haloalkyl, -(C3-C8)cycloalkyl, -(C1-C6)alkylaryl, -heterocyclic group, -aryl or -heteroaryl, where R Z is optionally substituted with at least one R Z’ substituent, where

[0254] each R Z’ is independently selected from -halogen, -OR, -(C1-C6)alkoxy, -C(O)OR, -C(O)R, -C(O)NR2, -S(O)2R, -OS(O)2R, -cyano, -nitro, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C8)cycloalkyl, -heterocycloalkyl or heteroaryl,

[0255] provided that when M is -S(O)-, -S(O)2- or absent, Z 3 and Z 4 at least one of which is also absent;

[0256] or two Rs 3 together are oxo;

[0257] R N’ is hydrogen or (C1-C6)alkyl;

[0258] bonds a, b, c, d and e are independently single or double bonds,

[0259] provided that

[0260] (i) no two consecutive atoms in ring D are both oxygen;

[0261] (ii) no two consecutive bonds are both double bonds;

[0262] (iii) If a or b is a double bond, then R C’ does not exist; and

[0263] (iv) If a or e is a double bond, then R N’ does not exist;

[0264] (v) If b or c is a double bond, then G 1 is not O or S;

[0265] (vi) If c or d is a double bond, then G 2 is not O;

[0266] (vii) If d or e is a double bond, then G 3 is not O;

[0267] R 1 、R 2 and R 6 are independently hydrogen, halogen, -NO2, -CN or R C ,

[0268] provided that when X = CR 1 ,

[0269] (i) R 2 , R 6 and R N1 are not phenyl;

[0270] (ii) R C is not aryl, heteroaryl, heterocyclic or (C2-C6) alkenyl

[0271] (iii) and G 1 = N together, then G2 is not O; and

[0272] (iv) Two R C together cannot form oxo;

[0273] and provided that when X = N, and

[0274] (i) G 1 is N, G 3 is CR 3 , and G 2 is N, and the bonds b and d are each double bonds, all of which occur simultaneously; or

[0275] (ii) G 1 is N, G 3 is C(O), G 2 is NR N’ , and the bond b is a double bond, all of which occur simultaneously;

[0276] R2 or R 6 is not -NH-aryl or -NH-heteroaryl.

[0277] 2. The compound according to Embodiment 1, wherein X is N and G is -OH.

[0278] 3. The compound according to Embodiment 2, wherein

[0279] B is aromatic; and

[0280] G 1 is O, S, N or NR N’ ; and

[0281] G 2 and G 3 are each independently O, N or CR 3 .

[0282] 4. The compound according to Embodiment 3, wherein B is imidazolyl, oxazolyl, pyrazolyl, pyrrolyl or isoxazolyl, wherein each carbon atom is substituted by R 3 substituted.

[0283] 5. The compound according to Embodiment 4, wherein B is imidazolyl, wherein each carbon atom is substituted by R 3 substituted.

[0284] 6. The compound according to Embodiment 4 or 5, wherein

[0285] each R 3 is independently R Z3 , wherein

[0286] R Z3 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z3 is optionally substituted by at least one R Z3’ , wherein

[0287] each R Z3’ is independently halogen, cyano, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl, wherein each R is independently hydrogen, (C1-C6)alkyl or (C1-C6)haloalkyl.

[0288] 7. The compound according to Embodiment 5, wherein

[0289] R 2 and R 6Each is hydrogen, a halogen, -NO2, -CN or R Z6 , wherein

[0290] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z6 is optionally substituted by at least one R Z6’ , wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl, wherein each R is independently hydrogen, (C1-C6)alkyl or (C1-C6)haloalkyl.

[0291] 8. The compound according to embodiment 5, wherein

[0292] R N’ is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C3-C8)cycloalkanoyl, heterocyclic carbonyl, arylcarbonyl, heteroarylcarbonyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, wherein

[0293] R N' is optionally substituted by one or more groups which are independently halogen, -OR N” , -NR N” 2, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl or (C1-C6)haloalkyl,

[0294] wherein each R N” is independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0295] 9. The compound according to embodiment 5, wherein A is

[0296]

[0297] wherein n is 0, 1, 2 or 3.

[0298] 10. The compound according to embodiment 5, wherein A is

[0299]

[0300] 11. The compound according to embodiment 5, wherein A is

[0301]

[0302] 12. The compound according to any one of Embodiments 9-11, wherein R A is (C1-C6) alkyl, halogen or -(C1-C6) alkyl-OR A1 , wherein R A1 is hydrogen or (C1-C6) alkyl.

[0303] 13. The compound according to Embodiment 2, wherein B is not aromatic, and G 1 , G 2 and G 3 are each independently O, N, CR 3 , C(R 3 )2 or N(R N’ ).

[0304] 14. The compound according to Embodiment 13, wherein

[0305] B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, triazolidinyl or tetrazolidinyl, wherein each carbon is substituted by two R 3 , and each nitrogen is substituted by R N' .

[0306] 15. The compound according to Embodiment 14, wherein

[0307] each R 3 is independently R Z3 , wherein

[0308] R Z3 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl, (C1-C6) alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z3 is optionally substituted by at least one R Z3’ , wherein

[0309] each R Z3’ is independently -halogen, -cyano, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl or heterocycloalkyl.

[0310] 16. The compound according to Embodiment 14, wherein

[0311] R 2 and R 6 are each hydrogen, halogen, -NO2, -CN or -R Z6 , wherein

[0312] R Z6 is a (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C8) cycloalkyl, (C1-C6) alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z6 is optionally substituted by at least one R Z6’ wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6) alkyl or (C1-C6) haloalkyl,

[0313] wherein R Z6' is optionally substituted by one or more R'.

[0314] 17. The compound according to embodiment 14, wherein

[0315] each R N' is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkanoyl, (C3-C8) cycloalkyl, aryl, heteroaryl, (C3-C8) cycloalkanoyl, heterocyclic acyl, aryl acyl, heteroaryl acyl, (C1-C6) alkoxycarbonyl or aryl (C1-C6) alkoxycarbonyl, wherein

[0316] R N' is optionally substituted by one or more groups independently selected from halogen, -OR N” 、-NR N” 2, -NO2, -CN, (C1-C6) alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8) cycloalkyl or (C1-C6) haloalkyl,

[0317] wherein each R N” is independently hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl and alkoxy are optionally substituted by one or more R'.

[0318] 18. The compound according to embodiment 14, wherein A is

[0319]

[0320] wherein n is 0, 1, 2 or 3.

[0321] 19. The compound according to embodiment 18, wherein A is

[0322]

[0323] 20. The compound according to embodiment 14, wherein A is

[0324]

[0325] 21. The compound according to any one of Embodiments 18 - 20, wherein R A is (C1 - C6) alkyl, halogen or -(C1 - C6) alkyl - OR A1 , wherein R A1 is hydrogen or (C1 - C6) alkyl.

[0326] 22. The compound according to Embodiment 1, wherein X is CR 1 , and G is hydrogen.

[0327] 23. The compound according to Embodiment 22, wherein

[0328] R 1 is -CN, -NO2, halogen, -C(O)OR 4 , -C(O)R 4 , -C(O)N(R 4 )2, -S(O)R 4 , -S(O)2R 4 or -S(O)2N(R 4 )2, wherein

[0329] each R 4 is independently hydrogen, (C1 - C6) alkyl, (C2 - C6) alkenyl, (C3 - C8) cycloalkyl, (C1 - C6) alkylaryl, heterocyclic group, aryl or heteroaryl, wherein

[0330] R 4 is optionally substituted by at least one group, each group independently being halogen, -OH, (C1 - C6) alkoxy, -C(O)R 41 , -S(O)2R 41 , -OS(O)2R 41 , -CN, -NO2, (C1 - C6) alkyl or (C1 - C6) haloalkyl,

[0331] wherein R 41 is hydrogen, (C1 - C6) alkyl, (C1 - C6) haloalkyl, (C1 - C6) alkoxy, (C3 - C8) cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0332] 24. The compound according to Embodiment 23, wherein

[0333] B is aromatic; and

[0334] G 1 is O, S, N or NR N’ ; and

[0335] G 2 and G 3 each independently is O, N or CR 3 .

[0336] 25. The compound according to embodiment 24, wherein B is imidazolyl, oxazolyl, pyrazolyl, pyrrolyl or isoxazolyl, and each carbon atom is substituted by R 3 substituted.

[0337] 26. The compound according to embodiment 25, wherein B is imidazolyl, and each carbon atom is substituted by R 3 substituted.

[0338] 27. The compound according to embodiment 26, wherein

[0339] each R 3 is independently R Z3 , wherein

[0340] R Z3 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, and R Z3 is optionally substituted by at least one R Z3’ , wherein

[0341] each R Z3’ is independently halogen, -CN, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl.

[0342] 28. The compound according to embodiment 26, wherein

[0343] R 2 and R 6 each is hydrogen, halogen, -NO2, -CN or -R Z6 , wherein

[0344] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, and R Z6 is optionally substituted by at least one R Z6’ , and each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl,

[0345] wherein R Z6'Optionally substituted by one or more R'.

[0346] 29. The compound according to embodiment 27, wherein

[0347] R N’ is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkanoyl, (C3-C8) cycloalkyl, aryl, heteroaryl, (C3-C8) cycloalkanoyl, heterocycloacyl, arylcarbonyl, heteroarylcarbonyl, (C1-C6) alkoxycarbonyl or aryl(C1-C6) alkoxycarbonyl, wherein

[0348] R N' is optionally substituted by one or more groups independently being halogen, -OR N” 、-NR N” 2, -NO2, -CN, (C1-C6) alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8) cycloalkyl or (C1-C6) haloalkyl,

[0349] wherein each R N” is independently hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl and alkoxy are optionally substituted by one or more R'.

[0350] 30. The compound according to embodiment 26, wherein A is

[0351]

[0352] wherein n is 0, 1, 2 or 3.

[0353] 31. The compound according to embodiment 30, wherein A is

[0354]

[0355] 32. The compound according to embodiment 26, wherein A is

[0356]

[0357] 33. The compound according to any one of embodiments 30-32, wherein R A is (C1-C6) alkyl, halogen or (C1-C6) alkyl-OR A1 wherein R A1 is hydrogen or (C1-C6) alkyl.

[0358] 34. The compound according to embodiment 23, wherein B is not aromatic, and G 1 、G2 and G 3 each independently is O, N, CR 3 , C(R 3 )2 or N(R N’ ).

[0359] 35. The compound according to embodiment 34, wherein B is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, triazolidinyl or tetrazolidinyl, wherein each carbon is substituted by two R 3 and each nitrogen is substituted by R N' .

[0360] 36. The compound according to embodiment 35, wherein

[0361] each R 3 is independently R Z3 , wherein

[0362] R Z3 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z3 is optionally substituted by at least one R Z3’ , wherein

[0363] each R Z3’ is independently halogen, -CN, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl.

[0364] 37. The compound according to embodiment 35, wherein

[0365] R 2 and R 6 are each hydrogen, halogen, -NO2, -CN or -R Z6 , wherein

[0366] R Z6 is (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, wherein R Z6 is optionally substituted by at least one R Z6’ , wherein each R Z6’ is independently halogen, -OR, -C(O)OR, -C(O)R, (C1-C6)alkyl or (C1-C6)haloalkyl,

[0367] wherein R Z6 ' is optionally substituted by one or more R'.

[0368] 38. The compound according to embodiment 35, wherein

[0369] each R N' is independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C3-C8)cycloalkanoyl, heterocycloacyl, aroyl, heteroaroyl, (C1-C6)alkoxycarbonyl or aryl(C1-C6)alkoxycarbonyl, where R N' is optionally substituted with one or more substituents independently selected from halogen, -OR N” , -NR N” 2, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl or (C1-C6)haloalkyl,

[0370] where each R N” is independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where the alkyl and the alkoxy are optionally substituted with one or more R'.

[0371] 39. The compound according to embodiment 35, wherein A is

[0372]

[0373] where n is 0, 1, 2 or 3.

[0374] 40. The compound according to embodiment 39, wherein A is

[0375]

[0376] 41. The compound according to embodiment 35, wherein A is

[0377]

[0378] 42. The compound according to any one of embodiments 39-41, wherein R A is (C1-C6)alkyl, halogen or -(C1-C6)alkyl-OR A1 , where R A1 is hydrogen or (C1-C6)alkyl.

[0379] 43. The compound according to any one of embodiments 1-41, wherein R A is (C1-C6)alkyl, halogen, (C1-C6)alkyl-OR A1 or -COORA1 , wherein R A1 is hydrogen or (C1-C6) alkyl, or two R A1 together with the N atom to which they are attached form a morpholinyl group.

[0380] 44. A compound according to any one of embodiments 1-43, wherein

[0381] Z is CH2, C(H)R A , C(R A )2 or O;

[0382] m is 0 or 2;

[0383] provided that when m is 0, Z is CH2, C(H)R A or C(R A )2, and when m is 2, Z is O.

[0384] 45. The compound according to embodiment 1, which is

[0385]

[0386]

[0387]

[0388]

[0389] or a pharmaceutically acceptable salt thereof.

[0390] 46. A compound, which is:

[0391]

[0392]

[0393] or a pharmaceutically acceptable salt thereof.

[0394] 47. The compound according to any one of embodiments 1-46, which is in the form of a pharmaceutically acceptable salt.

[0395] 48. The compound according to any one of embodiments 1-46, which is in the form of a zinc (Zn 2+ ) salt.

[0396] 49. The compound according to embodiment 48, wherein the zinc salt is ZnCl2, ZnBr2, ZnI2, Zn(NO3)2, ZnSO4, Zn3(PO4)2 or Zn(OH)2.

[0397] 50. A compound according to embodiment 48 or 49, wherein the compound complexes with Zn in a 1:1 stoichiometry 2+ complex.

[0398] 51. A compound according to embodiment 48 or 49, wherein the compound complexes with Zn in a 2:1 stoichiometry 2+ complex.

[0399] 52. A compound according to embodiment 48 or 49, wherein the compound complexes with Zn in a 3:1 stoichiometry 2+ complex.

[0400] 53. A compound according to any one of embodiments 1 - 46, which is in the form of a sodium (Na + ), potassium (K + ), calcium (Ca 2+ ) or magnesium (Mg 2+ ) salt.

[0401] 54. A pharmaceutical composition comprising a compound according to any one of embodiments 1 - 53 and a pharmaceutically acceptable carrier.

[0402] 55. A method for treating one or more AGE - and / or ALE - related complications or inhibiting their development in a subject in need thereof, comprising administering to the subject one or more compounds according to any one of embodiments 1 - 53 or one or more pharmaceutical compositions according to embodiment 54.

[0403] 56. The method according to embodiment 55, wherein the one or more AGE - and / or ALE - related complications are selected from the group consisting of: accelerated protein aging, retinopathy, nephropathy, proteinuria, glomerular clearance disorder, neuropathy, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis, cardiovascular disease, neurodegenerative amyloid disease, diabetes - related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue disease, amyloidosis, obesity - related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, hypertension; and dialysis - related conditions selected from the group consisting of: dialysis - related cardiac morbidity and mortality, dialysis - related amyloidosis, dialysis - related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and ultrafiltration failure and peritoneal damage in dialysis patients.

[0404] 57. A method for treating one or more conditions selected from the group consisting of or inhibiting the development thereof: diabetic nephropathy, proteinuria, glomerular clearance disorder, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related conditions including: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients, and ultrafiltration failure and peritoneal damage in dialysis patients, wherein the method comprises administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of embodiments 1-53 or one or more pharmaceutical compositions according to embodiment 54.

[0405] Example

[0406] The method of the present invention is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures and compounds described therein.

[0407] General procedure: Proton nuclear magnetic resonance spectra (1H NMR) were recorded and analyzed using a Varian 200 (200 MHz) NMR system. Chemical shift (δ) values are expressed in ppm (parts per million) relative to tetramethylsilane as an internal standard: s, singlet; p, pentet; m, multiplet; br, broad singlet. HPLC separation was used to determine the purity of the target compound. HPLC analysis was performed on an Eclipse XDB-phenyl column on an Agilent technologies 1260 infinity system. The absorbance (254 nm) peak area of the main peak compared to other peaks was used to determine the purity. Using EC-C18 chromatographic column, on Finnigan LCMS analysis was performed on an LCQ LC / MS system. The following conditions were used for LC-MS analysis: Solvent A: aqueous solution of 0.1% TFA, Solvent B: ACN solution of 0.1% TFA; Flow rate: 0.50 ml / min; Gradient: Solvent A (95%, 0 - 0.5 min), Solvent A (95% - 50%, 0.5 - 5 min), Solvent B (50%, 5 - 10 min), Solvent B (50% - 95%, 10 - 12 min), Solvent B (95%, 12 - 13 min). All solvents were purchased from Sigma - Aldrich Co. or Fisher Scientific Inc. or Alfa Aesar and used as received. Pyridoxal hydrochloride, methyl azetidine - 3 - carboxylate hydrochloride, and 1 - methylpiperazine were purchased from Combiblocks Inc. Morpholine, pyrrolidine, glyoxal, and ammonium hydroxide solution were purchased from Sigma - Aldrich. 15N - ammonium hydroxide (3.3 M) was purchased from Cambridge Isotope Laboratories.

[0408] Overview: Based on the chemical reactions shown in Scheme 1 below, milligram quantities of four compounds 4, 5, 8, and 9 were prepared. From these four compounds, two compounds (5 and 8) were synthesized on a 25 g scale, and 15N - labeled compounds 13 and 14 (Figure 1) were also synthesized. The synthetic schemes and experimental procedures for synthesizing the final compounds from the previously synthesized intermediates are shown below.

[0409] Scheme 1. Synthetic scheme for synthesizing compounds 4, 5, 8, and 9.

[0410]

[0411] 15 Structures of 15N - labeled compounds 13 and 14

[0412]

[0413] Pyridoxal hydrochloride 1 was treated with glyoxal (40%) and ammonium hydroxide (28%) at room temperature to obtain imidazole derivative 2. It was then treated with a toluene solution of thionyl chloride under reflux conditions to obtain imidazole derivative 3. Imidazole derivative 3 was treated with N - methylpiperazine, morpholine, and pyrrolidine at room temperature to obtain the final compounds 4, 5, and 9, respectively. To obtain the final compound 8, imidazole derivative 3 was first treated with methyl azetidine - 3 - carboxylate hydrochloride in the presence of triethylamine at room temperature, and the resulting methyl ester derivative 7 was then hydrolyzed to obtain azetidine - 3 - carboxylic acid methyl ester 8.

[0414] Using the above synthetic route, two compounds (5 and 8) were synthesized on a 25 g scale. For the synthesis of compounds 5 and 8 15N-labeled compound (Scheme 2), pyridoxal hydrochloride 1 was treated with glyoxal (40%) and 15 N-ammonium hydroxide (3.3 M) at room temperature to obtain imidazole derivative 10. It was then treated with a toluene solution of thionyl chloride under reflux conditions to obtain imidazole derivative 11. Then it was treated with morpholine at room temperature to obtain the final compound 14. To obtain the final compound 13, first imidazole derivative 11 was treated with methyl azetidine-3-carboxylate hydrochloride in the presence of triethylamine at room temperature, and then the obtained methyl ester derivative 12 was hydrolyzed to give 15 N-labeled azetidine-3-carboxylic acid derivative 13.

[0415] Scheme 2. Synthesis 15 Synthetic scheme of N-labeled compounds 13 and 14.

[0416]

[0417] All four compounds 4, 5, 8, and 9 were purified by column chromatography and their free bases were obtained, except for compound 8 which was obtained in the form of its HCl salt. The scale-up of compounds 5 and 8 was also successfully completed. Compound 8 was purified by crystallization during its scale-up. 15N-labeled compound 14 as the free base and 13 as the HCl salt were also successfully synthesized and purified by column chromatography.

[0418] Synthesis of imidazole derivative 2 (PTG-4997, CV-10206).

[0419]

[0420] To a solution of pyridoxal hydrochloride 1 (1 equivalent) in methanol (12 volumes) cooled to 5 °C using an NaCl / ice bath was added a glyoxal solution (40%, 4 volumes). Then an aqueous ammonia solution (28%, 4 volumes) was added dropwise while maintaining the temperature between 5 °C and 10 °C. The initially pale yellow homogeneous mixture turned red. After complete addition, the mixture was stirred at 5 °C for an additional 4 hours and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was filtered to remove some solid particles present and the methanol was evaporated at 35 °C. The aqueous layer was extracted six times with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate. Evaporation of the solvent gave the crude compound which was stirred with a 1:1 mixture of ethyl acetate and diethyl ether for 40 minutes. The resulting solid was filtered, washed with diethyl ether and dried to give the imidazole derivative 2 as a light brown solid. Yield: 33%; 1H NMR (200 MHz, CD3OD): δ = 2.51 (s, 3H, CH3), 4.70 (s, 2H, CH2), 7.32 - 7.35 (m, 2H, Ar), 7.84 (s, 1H, Ar). LCMS (ESI): m / z calculated for C10H11N3O2 + H+ [M + H+]: 206.1; found: 206.1. HPLC purity: 92.4% (at 254 nm).

[0421] Synthesis of imidazole derivative 3 (PTG - 520, CV - 10223)

[0422]

[0423] To a solution of imidazole derivative 2 (1 equivalent) in toluene (20 volumes) was added thionyl chloride (5 volumes) and the mixture was refluxed for 2 hours. The reaction mixture was cooled to 0 °C and filtered, washed with cold toluene to give the imidazole derivative 3 as a brown solid which was used without further purification. Yield: 83%; 1H NMR (200 MHz, CD3OD): δ = 2.79 (s, 3H, CH3), 4.81 (s, 2H, CH2), 7.92 (s, 2H, Ar), 8.58 (s, 1H, Ar).

[0424] Synthesis of imidazole derivatives 4, 5 and 9.

[0425]

[0426] General procedure for the synthesis of final compounds 4, 5, and 9: To a solution of imidazole derivative 3 (1 equiv) in dichloromethane (42 vol) was added N-methylpiperazine or morpholine or pyrrolidine (10 equiv), and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and dissolved in dichloromethane. The dichloromethane solution was washed with water and brine solution and dried over sodium sulfate. The solvent was concentrated, and the residue was purified using Combiflash Rf (dichloromethane solution of 0%-5% methanol), and the fractions containing the pure product (TLC) were combined and evaporated to afford the pure products 4, 5, and 9.

[0427] N-methylpiperazine derivative 4 (CV-10191, PTG-605). Light brown solid; yield: 28.4%; 1H NMR (200 MHz, CDCl3): δ = 2.31 (s, 3H, CH3), 2.40 - 2.80 (br s, 11H, (CH2)4, CH3), 3.63 (s, 2H, CH2), 7.14 (s, 1H, Ar), 7.24 - 7.25 (m, 1H, Ar), 7.87 (s, 1H, Ar). LCMS (ESI): m / z calculated for C 15 H 21 N5O+H + [M+H + calculated: 288.2; found: 288.2. HPLC purity: 99.5% (at 254 nm).

[0428] N-morpholine derivative 5 (CV-10192, PTG-630). Light brown solid; yield: 45%; 1H NMR (200 MHz, CDCl3): δ = 2.56 (s, 3H, CH3), 2.64 (br s, 4H, (CH2)2), 3.66 (s, 2H, CH2), 3.77 (br s, 4H, (CH2)2), 7.16 (s, 1H, Ar), 7.25 - 7.26 (m, 1H, Ar), 7.89 (s, 1H, Ar). LCMS (ESI): m / z calculated for C14H18N4O2+H+ [M+H+]: 275.1; found: 275.2. HPLC purity: 96.3% (at 254 nm).

[0429] N-Pyrrolidine derivative 9 (CV-10215, PTG-650). Light brown solid; yield: 47%; 1H NMR (200 MHz, CDCl3): δ = 1.85 - 1.91 (m, 4H, (CH2)2), 2.56 (s, 3H, CH3), 2.67 (br s, 4H, (CH2)2), 3.73 (s, 2H, CH2), 7.12 - 7.13 (m, 1H, Ar), 7.23 - 7.26 (m, 1H, Ar), 7.90 (s, 1H, Ar). LCMS (ESI): m / z calculated for C14H18N4O + H+ [M + H+]: 259.3; found: 259.2. HPLC purity: 95.0% (at 254 nm).

[0430] Synthesis of azetidine-3-carboxylic acid derivative 8:

[0431]

[0432] To a solution of imidazole derivative 3 (1 equiv) in dichloromethane (40 vol) was added methyl 3-azetidinecarboxylate (1.5 equiv), triethylamine (8 equiv), and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and dissolved in dichloromethane. The organic layer was washed with water and brine solution and dried over sodium sulfate. The solvent was concentrated and the residue was purified using Combiflash Rf (dichloromethane solution of 0% - 5% methanol), and the fractions containing the pure product (TLC) were combined and evaporated to give pure product 7.

[0433] Methyl 3-azetidinecarboxylate derivative 7 (PTG-641, CV-10224). Brown gel; yield: 41%; 1H NMR (200 MHz, CDCl3): δ = 2.45 (s, 3H, CH3), 3.28 - 3.64 (m, 5H, (CH2)2, CH), 3.72 (s, 3H, CH3), 4.94 (br s, 1H, NH), 7.30 - 7.31 (m, 2H, Ar), 7.87 (s, 1H, Ar). LCMS (ESI): m / z calculated for C15H18N4O3 + H+ [M + H+]: 303.3; found: 303.1.

[0434] To a solution of methyl 3-azetidinecarboxylate derivative 7 (1 equiv) in THF-water (1:1) (24 vol mixture) was added 2N NaOH (2 equiv) solution, and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and dissolved in water and acidified to pH 4 - 5. The mixture was concentrated and the residue was purified using Combiflash Rf (chloroform:methanol:water - 16:6:1), and the fractions containing the pure product (TLC) were combined and evaporated to afford the pure product 8. In the scale-up of this product, the crude residue was purified by treatment with 1:1 water-methanol, the solid formed was filtered, washed with methanol and dried.

[0435] Azetidine-3-carboxylic acid derivative 8 (CV-10193, PTG-640). Pale yellow solid; yield: 66%; 1H NMR (200 MHz, D2O): δ = 2.59 (s, 3H, CH3), 3.62 (p, 1H, CH), 4.14 - 4.38 (m, 4H, (CH2)2,), 4.50 (s, 2H, CH2), 7.51 (m, 2H, Ar), 7.89 (s, 1H, Ar). LCMS (ESI): m / z calculated for C14H16N4O3 + H+ [M + H+]: 289.1; found: 289.1.

[0436] 15 Synthesis of N-labeled compounds 13 and 14.

[0437]

[0438] The 15N-labeled compounds of compounds 13 and 14 were synthesized as given in Scheme 2 below.

[0439] Imidazole derivative 10: To a solution of pyridoxal hydrochloride 1 (1 equiv) in methanol (12 vol) cooled to 5 °C using an NaCl / ice bath was added glyoxal solution (40%, 4 vol). Then, 15Solution of N-ammonium hydroxide (3.3 M, 10 volumes), maintaining the temperature between 5 °C and 10 °C. The initially pale yellow homogeneous mixture turned red. After the addition was complete, the mixture was stirred for an additional 4 hours at 5 °C, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the methanol was evaporated at 35 °C. The aqueous layer was extracted six times with ethyl acetate. The combined organic layers were washed with water, brine, and dried over sodium sulfate. Evaporation of the solvent gave the crude compound, which was stirred with a 1:1 mixture of ethyl acetate and diethyl ether for 40 minutes. The resulting solid was filtered, washed with diethyl ether, and dried to obtain the imidazole derivative 10 as a light brown solid. Yield: 26.5%; 1H NMR (200 MHz, CD3OD): δ = 2.49 (s, 3H, CH3), 4.71 (s, 2H, CH2), 7.30 - 7.35 (m, 2H, Ar), 7.85 (s, 1H, Ar). LCMS (ESI): m / z calculated for C 10 H 11 NN 15 2O2 + H+ [M + H+]: 208.1; found: 208.1.

[0440] Imidazole derivative 11. Thionyl chloride (5 volumes) was added to a solution of imidazole derivative 10 (1 equivalent) in toluene (20 volumes), and the mixture was refluxed for 2 hours. The reaction mixture was cooled to 0 °C and filtered, washed with cold toluene, to obtain imidazole derivative 11 as a brown solid, which was used without further purification. Yield: 38%; 1H NMR (200 MHz, CD3OD): δ = 2.63 (s, 3H, CH3), 4.54 (s, 2H, CH2), 7.60 (s, 2H, Ar), 8.02 (s, 1H, Ar). LCMS (ESI): m / z calculated for C 10 H 10 NN 15 2O + H+ [M + H+]: 226.1; found: 226.1.

[0441] 15 Synthesis of N-labeled compound 14: Morpholine (10 equivalents) was added to a solution of imidazole derivative 11 (1 equivalent) in dichloromethane (50 volumes), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and dissolved in dichloromethane. The organic layer was washed with water and brine solution, and dried over sodium sulfate. The solvent was concentrated, and the residue was purified using Combiflash Rf (dichloromethane solution of 0% - 5% methanol), and the fractions containing the pure product (TLC) were combined and evaporated to afford the pure product 14.

[0442] 15 N-morpholine derivative 14 (CV-10212, of PTG-63015 N - derivative). Light yellow gel; Yield: 62.7%; 1H NMR (200 MHz, CDCl3): δ = 2.56 (s, 3H, CH3), 2.65 (br s, 4H, (CH2)2), 3.66 (s, 2H, CH2), 3.77 (br s, 4H, (CH2)2), 7.14 - 7.19 (m, 1H, Ar), 7.23 - 7.30 (m, 1H, Ar), 7.89 (s, 1H, Ar). LCMS (ESI): m / z calculated for C 14 H 18 N2 15 N2O2 + H + [M + H + calculated: 277.3; found: 277.2. HPLC purity: 94.0% (at 254 nm).

[0443] Synthesis of 15N - labeled azetidine - 3 - carboxylic acid derivative 13

[0444] To a dichloromethane solution of imidazole derivative 11 (1 equiv.), methyl 3 - azetidinecarboxylate (1.5 equiv.) and triethylamine (8 equiv.) were added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and dissolved in dichloromethane. The organic layer was washed with water and brine solution and dried over sodium sulfate. The solvent was concentrated and the residue was purified using Combiflash Rf (dichloromethane solution of 0% - 5% methanol), and the fractions containing the pure product (TLC) were combined and evaporated to give the pure product 12.

[0445] Methyl 3 - azetidinecarboxylate derivative 12. Brown gel; Yield: 45%; 1H NMR (200 MHz, CDCl3): δ = 2.55 (s, 3H, CH3), 3.25 - 3.40 (m, 1H, CH), 3.53 - 3.57 (m, 4H, (CH2)2), 3.69 - 3.74 (m, 5H, CH3, CH2), 7.22 - 7.26 (m, 2H, Ar), 7.91 (s, 1H, Ar). LCMS (ESI): m / z calculated for C15H18N4O3 + H+ [M + H+]: 305.1; found: 305.1.

[0446] To a solution of methyl 3-azetidinecarboxylate derivative 12 (1 equiv) in THF-water (1:1) was added 2N NaOH (2 equiv) solution, and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and dissolved in water and acidified to pH 4-5. The mixture was concentrated and the residue was purified using Combiflash Rf (chloroform:methanol:water - 16:6:1), and the fractions containing the pure product (TLC) were combined and evaporated to afford the pure product 13.

[0447] 15 N-labeled azetidine-3-carboxylic acid derivative 13 (CV-10213, 15 N-labeled derivative): pale yellow solid; yield: 66%; 1 H NMR (200 MHz, D2O): δ = 2.58 (s, 3H, CH3), 3.25 - 3.42 (m, 1H, CH), 4.18 - 4.40 (m, 4H, (CH2)2,), 4.59 (s, 2H, CH2), 7.41 - 7.45 (m, 2H, Ar), 7.79 (s, 1H, Ar). LCMS (ESI): calcd for C 14 H 16 15 N2N2O3 + H + [M + H + m / z: 291.1; found: 291.1. HPLC purity: 91.4% (at 254 nm).

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof, wherein, X is N, N-O or CR 1 ; G is -OH, -SH, -NH2 or -N(R G )2, where R G is hydrogen, (C1-C6) alkyl or -C(O)(C1-C6) alkyl; A is where Y is N; Z is CH2, C(H)R A , C(R A )2, O or NR A ; m is 0, 1, 2 or 3; provided that When m is 0, Z is CH2, C(H)R A or C(R A )2, and When m is 2, Z is O or NR A ; R A is a (C1-C6) alkyl, halogen, -OR A1 , -N(R A1 )2, -SR A1 , -S(O)R A1 , -S(O)2R A1 , -COOR A1 , -CON(R A1 )2 or -(C1-C6) alkyl-OR A1 , wherein R A1 is hydrogen, (C1-C6)alkyl or -C(O)(C1-C6)alkyl, or two Rs A1 together with the N atom to which they are attached form a morpholinyl group; and n is 0, 1, 2, 3, 4, 5 or 6; B has the following formula, where ring D is (i) monocyclic, and (ii) unsaturated or aromatic; R C’ is hydrogen; G 1 is O, S, N or NR N’ ; G 2 and G 3 each independently is N, O, CR 3 , C(R 3 )2 or NR N’ , where each R 3 is independently -Z 3 -M-Z 4 -R Z , where M is -C(O)-, -C(S)-, -S(O)-, -S(O)2- or absent Z 3 and Z 4 independently is -O-, -S-, -N(R N3 )- or does not exist, where R N3 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)haloalkyl, (C1-C6)alkanoyl, (C3-C8)cycloalkanoyl, heterocyclic acyl, aroyl, heteroaroyl, (C1-C6) alkoxycarbonyl or aryl (C1-C6) alkoxycarbonyl, where R N3 Optionally substituted by one or more groups independently selected from halogen, -OH, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, -NO2, -CN, (C1-C6)alkyl, aryl, heterocyclic group, heteroaryl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6) alkanoyl or aroyl; R Z is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkynyl or -(C1-C6)haloalkyl, -(C3-C8)cycloalkyl, -(C1-C6)alkylaryl, -heterocyclic group, -aryl or -heteroaryl, wherein R Z optionally substituted by at least one R Z’ wherein Each R Z’ is independently - halogen, -OR, -(C1-C6) alkoxy, -C(O)OR, -C(O)R, -C(O)NR2, -S(O)2R, -OS(O)2R, - cyano, - nitro, -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C8) cycloalkyl, - heterocycloalkyl or heteroaryl, provided that when M is -S(O)-, -S(O)2- or absent, at least one of Z 3 and Z 4 is also absent; Or two Rs 3 Combined together are oxo; R N’ is hydrogen or a (C1-C6) alkyl group; the bonds a, b, c, d and e are independently a single bond or a double bond, provided that (i) no two consecutive atoms in ring D are both oxygen; (ii) no two consecutive bonds are both double bonds; (iii) If either a or b is a double bond, then R C’ does not exist; and (iv) If a or e is a double bond, then R N’ does not exist; (v) If b or c is a double bond, then G 1 is not O or S; (vi) If c or d is a double bond, then G 2 is not O; (vii) If d or e is a double bond, then G 3 is not O; R 1 , R 2 and R 6 are independently hydrogen, halogen, -NO2, -CN or R C , The condition is that when X = CR 1 when (i)R 2 、R 6 and R N1 are not phenyl; (ii)R C is not aryl, heteroaryl, heterocyclic or (C2-C6) alkenyl (iii) and G 1 =N together, then G2 is not O; and (iv) Two Rs C together cannot form an oxo; and provided that when X = N, and (i) G 1 is N, G 3 is Cr 3 , and G 2 is N, and the bonds b and d are each double bonds, all of which occur simultaneously; or (ii) G 1 is N, G 3 is C(O), G 2 is NR N’ , and the bond b is a double bond, all occurring simultaneously; R 2 or R 6 is not -NH-aryl or -NH-heteroaryl.

2. The compound according to claim 1, wherein X is N and G is -OH.

3. The compound according to claim 2, wherein B is aromatic; and G 1 is O, S, N or NR N’ ; and G 2 and G 3 each independently is O, N or CR 3 .

4. The compound according to claim 3, wherein B is imidazolyl, oxazolyl, pyrazolyl, pyrrolyl or isoxazolyl, and each carbon atom is substituted by R 3 substituted.

5. The compound according to claim 4, wherein B is imidazolyl, and each carbon atom is substituted by R 3 substituted.

6. The compound according to claim 4 or 5, wherein Each R 3 is independently R Z3 wherein R Z3 is hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (C1-C6)alkylaryl, heterocyclic group, aryl or heteroaryl, where R Z3 is optionally substituted by at least one R Z3’ and wherein Each R Z3’ is independently halogen, cyano, -OR, -C(O)OR, -C(O)R, -C(O)NR2, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or heterocycloalkyl, where each R is independently hydrogen, (C1-C6)alkyl or (C1-C6)haloalkyl.

7. A compound which is: or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier.

9. A method for treating one or more AGE- and / or ALE-related complications or inhibiting their development in a subject in need thereof, which comprises administering to the subject one or more compounds according to any one of claims 1-7 or one or more pharmaceutical compositions according to claim 8.

10. A method for treating one or more conditions selected from the group consisting of: diabetic nephropathy, proteinuria, glomerular clearance disorder, retinopathy, neuropathy, atherosclerosis, diabetes-related hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion and hypertension; and dialysis-related conditions including: dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increase in peritoneal permeability in dialysis patients, progression of renal failure in dialysis patients and ultrafiltration failure and peritoneal damage in dialysis patients, wherein the method comprises administering to a subject in need of such treatment an effective amount of one or more compounds according to any one of claims 1-7 or one or more pharmaceutical compositions according to claim 8.

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