IL145957A - Pharmaceutical composition comprising an agent which binds with 3-deoxyglucosone - Google Patents
Pharmaceutical composition comprising an agent which binds with 3-deoxyglucosoneInfo
- Publication number
- IL145957A IL145957A IL145957A IL14595701A IL145957A IL 145957 A IL145957 A IL 145957A IL 145957 A IL145957 A IL 145957A IL 14595701 A IL14595701 A IL 14595701A IL 145957 A IL145957 A IL 145957A
- Authority
- IL
- Israel
- Prior art keywords
- group
- lysine
- compounds
- glycated
- agent
- Prior art date
Links
- UHPMJDGOAZMIID-UHFFFAOYSA-N 3-deoxyglucosone Natural products OCC1OC(O)C(=O)CC1O UHPMJDGOAZMIID-UHFFFAOYSA-N 0.000 title claims description 72
- ZGCHLOWZNKRZSN-NTSWFWBYSA-N 3-deoxyglucosone Chemical compound OC[C@@H](O)[C@@H](O)CC(=O)C=O ZGCHLOWZNKRZSN-NTSWFWBYSA-N 0.000 title claims description 71
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 116
- 239000003795 chemical substances by application Substances 0.000 claims description 40
- 108090000623 proteins and genes Proteins 0.000 claims description 23
- 102000004169 proteins and genes Human genes 0.000 claims description 22
- SRZFVMRRVYUWSA-UHFFFAOYSA-N FL3P Natural products NCCCCC(NCC(=O)C(OP(=O)(O)O)C(O)C(O)CO)C(=O)O SRZFVMRRVYUWSA-UHFFFAOYSA-N 0.000 claims description 21
- 239000002243 precursor Substances 0.000 claims description 16
- 108091005996 glycated proteins Proteins 0.000 claims description 15
- 230000005740 tumor formation Effects 0.000 claims description 14
- 108010004903 glycosylated serum albumin Proteins 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 108010007622 LDL Lipoproteins Proteins 0.000 claims description 7
- 102000007330 LDL Lipoproteins Human genes 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000004048 modification Effects 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 108010088751 Albumins Proteins 0.000 claims description 4
- 102000009027 Albumins Human genes 0.000 claims description 4
- IGRMTQMIDNDFAA-UWVGGRQHSA-N Lys-His Chemical group NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IGRMTQMIDNDFAA-UWVGGRQHSA-N 0.000 claims description 4
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 4
- 108010054155 lysyllysine Proteins 0.000 claims description 4
- 108010017384 Blood Proteins Proteins 0.000 claims description 2
- 102000004506 Blood Proteins Human genes 0.000 claims description 2
- 102000003839 Human Proteins Human genes 0.000 claims description 2
- 108090000144 Human Proteins Proteins 0.000 claims description 2
- -1 aminosubstituted imidazoles Chemical class 0.000 description 92
- 125000000217 alkyl group Chemical group 0.000 description 67
- 150000003839 salts Chemical class 0.000 description 56
- 125000004432 carbon atom Chemical group C* 0.000 description 51
- 229910052739 hydrogen Inorganic materials 0.000 description 46
- 239000001257 hydrogen Substances 0.000 description 46
- 239000002253 acid Substances 0.000 description 43
- 150000007857 hydrazones Chemical class 0.000 description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
- 125000003277 amino group Chemical group 0.000 description 34
- 239000004472 Lysine Substances 0.000 description 32
- 125000003545 alkoxy group Chemical group 0.000 description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 30
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 29
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 28
- 125000003118 aryl group Chemical group 0.000 description 28
- 235000018977 lysine Nutrition 0.000 description 28
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 27
- 230000000875 corresponding effect Effects 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 24
- 125000005843 halogen group Chemical group 0.000 description 23
- 150000002431 hydrogen Chemical class 0.000 description 23
- 230000037361 pathway Effects 0.000 description 22
- 125000001424 substituent group Chemical group 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- BFSYFTQDGRDJNV-AYHFEMFVSA-N fructosyllysine Chemical compound OC(=O)[C@@H](N)CCCCNCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BFSYFTQDGRDJNV-AYHFEMFVSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 17
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 16
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 235000000346 sugar Nutrition 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 14
- 235000005911 diet Nutrition 0.000 description 14
- 230000037213 diet Effects 0.000 description 14
- 125000001153 fluoro group Chemical group F* 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 150000007522 mineralic acids Chemical class 0.000 description 13
- 150000007524 organic acids Chemical class 0.000 description 13
- 125000001246 bromo group Chemical group Br* 0.000 description 12
- 125000001309 chloro group Chemical group Cl* 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 125000002346 iodo group Chemical group I* 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 238000011084 recovery Methods 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 11
- 239000008103 glucose Substances 0.000 description 11
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 10
- PVPTUASRAVWKGX-UHFFFAOYSA-N 1,2-dihydrotriazol-3-amine Chemical compound NN1NNC=C1 PVPTUASRAVWKGX-UHFFFAOYSA-N 0.000 description 9
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 9
- 108700040099 Xylose isomerases Proteins 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 210000003734 kidney Anatomy 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 239000006188 syrup Substances 0.000 description 9
- 235000020357 syrup Nutrition 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 230000013595 glycosylation Effects 0.000 description 8
- 238000006206 glycosylation reaction Methods 0.000 description 8
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 8
- 125000003944 tolyl group Chemical group 0.000 description 8
- 125000005023 xylyl group Chemical group 0.000 description 8
- 239000005715 Fructose Substances 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 230000018109 developmental process Effects 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 239000011593 sulfur Substances 0.000 description 7
- 229930091371 Fructose Natural products 0.000 description 6
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 150000001243 acetic acids Chemical class 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 150000002689 maleic acids Chemical class 0.000 description 6
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 6
- 235000011007 phosphoric acid Nutrition 0.000 description 6
- 150000003016 phosphoric acids Chemical class 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- LXFQSRIDYRFTJW-UHFFFAOYSA-M 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S([O-])(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-M 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 150000008163 sugars Chemical class 0.000 description 5
- 206010038389 Renal cancer Diseases 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000012752 auxiliary agent Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical compound O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 201000010174 renal carcinoma Diseases 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- DDGHBOLOCQWPKE-UHFFFAOYSA-N 1,3-thiazole;hydrobromide Chemical compound [Br-].C1=CSC=[NH+]1 DDGHBOLOCQWPKE-UHFFFAOYSA-N 0.000 description 3
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 3
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 3
- 108010053754 Aldehyde reductase Proteins 0.000 description 3
- 102100027265 Aldo-keto reductase family 1 member B1 Human genes 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N alpha-ketodiacetal Natural products O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000000711 cancerogenic effect Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 235000020940 control diet Nutrition 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229940015043 glyoxal Drugs 0.000 description 3
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 230000037353 metabolic pathway Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 description 2
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 238000003691 Amadori rearrangement reaction Methods 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 description 2
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- 108010015038 LDL glycosylated lipoproteins Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
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- 125000004414 alkyl thio group Chemical group 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
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- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 238000001784 detoxification Methods 0.000 description 2
- 125000004989 dicarbonyl group Chemical group 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 102000035122 glycosylated proteins Human genes 0.000 description 2
- 108091005608 glycosylated proteins Proteins 0.000 description 2
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
A PHARMACEUTICAL COMPOSITION COMPRISING AN AGENT WHICH BINDS WITH 3 - DEOXYGLUCOSONE im i ya -3 ivypnon tm> o>b>0Qn jrinpn η>νηη , FIELD OF THTC yNVR nO The present invention relates to new therapeutic use of various known classes of compounds that have the ability to complex or otherwise bind to reactive carbonyl moieties of compounds formed from the cleavage of early stage glycosylation products. These compounds have been reported to be effective for treatment of various disease states, including retinopathy, cataracts, diabetic kidney disease, glomerulosclerosis, peripheral vascular disease, arteriosclerosis obliterans, peripheral neuropathy, stroke, hypertension, atherosclerosis, osteoarthritis, periarticular rigidity, loss of elasticity and wrinkling of skin, stiffening of joints, and glomerulonephritis. More specifically, it has now been discovered that the compounds described hereinbelow, because of their effectiveness in binding such reactive arbonyl-containing compounds, are also useful in reducing a susceptibility to tumor formation, as well as in preventing or delaying the onset of tumor formation.
It is to be noted that only subject matter embraced in the scope of the claims appended hereto, whether in the manner defined in the claims or in a manner similar thereto and involving the main features as defined in the claims , is intended to be included in the scope of the present invention, while subject matter described and exemplified to provide background and better understanding of the invention, is not intended for inclusions as part of the present invention.
BACKGROUND OF THE PRIOR ART The role of 3-DG and related metabolites in contributing to human disease has been previously investigated as will be appreciated from a review of the patents listed below. The listed patents are generally directed to compositions and methods for inhibiting non-enzymatic protein aging. The compositions described in these patents comprise various active agents which have in common the capability of inhibiting the formation of advanced glycosylation end products (AGEs) of target proteins by reacting with carbonyl compounds, such as glycoaldehyde, glyceraldehyde or 3-deoxyglucosone, formed from the cleavage of Amadori or other "early glycosylation product(s)", as defined in those patents. The compounds described in the listed patents presumably act by complexing 3DG, thereby preventing its reaction with proteins, one of the irreversible steps of AGE-protein fonnation. The disclosures provided in the listed patents do not suggest the possibility of inhibiting the formation of 3DG. They focus exclusively on complexing this toxic molecule. Certain of the compounds described in the listed patents, for example, U.S. Patent No. 5,262,152, are o-effect amines, which are known to react with dicarbonyl compounds, such as 3DG. See, W.P. Jencks, 3"1 ed., McGraw Hill, New York.
U.S. Patent No. Active A^ent ,698,563 to Wagle et al. bis(guanylhydrazones) ,661,139 to Lankin et al. bis-2-(aryl) hydrazones ,565,261 to Cerarni et al. thiazolium compounds ,612,332 to Wagle et al. di- or tri-aminoguariidines ,534,540 to Ulrica and Wagle substituted or unsubstituted tetrarnic and tetronic acids ,476,849 to Ulrich et al amino-benzoic acids and derivatives ,128,360 to Cerami et al aminoguanidine ,468,777 to France et al cysteine and cysteine derivatives ,358,960 to Ulrich etal aminosubstituted imidazoles ,334,617 to Ulrich et al amino acids ,318,982 to Ulrich et al 1,2,4-uiazoles ,272,165 to Ulrich et al 2-alkylidene-ammoguanidines ,262, 152 to Ulrich et al amidrazones and derivatives ,258,381 to Ulrich et al 2-substituted-2-imidazolines ,243,071 to Ulrich et al 2-alkyUdene-aminoguanidies ,221,683 to Ulrich et al diaminopyridine compounds ,130,324 to Ulrich et al 2- kyUdene-anunoguaiudines ,114,943 by Ulrich et al amino-substituted pyrimidines Another approach to reducing the deleterious health effects of glycated protein, as manifested in diabetic complications, involves the administration of antibodies or other immunoreactive substances which specifically bind to glycated albumin or its cellular receptor, or to glycated low-density lipoprotein (LDL). See, for example, U.S. Patents Nos. 5,223,392, 5,494,791 and 5,518,720 to M. CoLai. One such antibody is characterized as specifically binding to an epitope present on glycated albumin but not present on non-glycated albumin or other human protein. A representative antibody of this kind is known as A717, which is produced by cell line ATCC HB 9596. Another antibody useful for this purpose is one which reacts immunospecifically with an epitope comprising N-deoxyfructosyllysine, which is present in glycated LDL, but not in unglycated LDL or in other glycated or unglyca ed plasma proteins, the epitope being present in apolipoprotein B of glycated LDL.
Methods for monitoring metabolic control in diabetic patients by measurement of glycosylation end-products are known. The concentration of glycosylated hemoglobin is known to reflect mean blood glucose concentration during the preceding several weeks. U.S. Patent 4,371,374, issued to A. Cerami et al., describes a method for monitoring glucose levels by quantitation of the degradation products of glycosylated proteins, more specifically non-enzymatically glycosylated amino acids and peptides, in urine. This method purports to utilize the affinity of alkaline boronic acids for forming specific complexes with the coplanar cis-diol groups found in glycosylation end-products to separate and quantitate such end-products.
U.S. Patent 4,761,368 issued to A Cerami describes the isolation and purification of a chromophore present in browned polypeptides, e.g., bovine serum albumin and poly-L-lysine. The chromophore, 2-(2-furoyl)-4(5)-2(furoyl)- lH-imidazole (FFI) is a conjugated heterocycle derived from the condensation of two molecules of glucose with two lysine-derived amino groups. This patent further describes the use of FFI in a method for measuring "aging" (the degree of advanced glycosylation) in a protein sample wherein the sample "age" is - 4 - 145 ,957/2 determined by measuring the amount of the above-described chromophore in the sample and then comparing this measurement to a standard (a protein sample having an amount of FFI which has been correlated to the "age" of the sample).
The disclosures of all of the above-mentioned patents are incorporated by reference in the present specification, as though set forth herein in fulL As can be appreciated from the foregoing summary of the prior art, although a number of therapeutic agents have been proposed for treating various disease states in which there is evidence that one or more early glycosylarion products having an etiologic effect, it is not believed that such agents have previously been proposed for use in reducing a susceptibility to, or preventing or delaying the onset of rumor formation.
SUMMARY OF THE INVENTION The present invention arose, in part, from the discovery of a metabolic pathway that involves the enzyme-mediated conversion of fructose lysine (FL) to fructose-lysine-3-phosphate (FL3P) and produces relatively high concentrations of 3-deo yglucosone (3DG) in organs affected by diabetes- See International Patent Application WO 98/33492, published August 6, 1998, the entire disclosure of which is incorporated by reference in the present specification as though set forth herein in full. Further research into the biochemical function of this newly discovered pathway tends to indicate that it also has a role in the etiology of tumor formation. It is now suspected that this pathway contributes to the development of tumor formation, particularly renal cell carcinoma. 4a 145, 957/1 This discovery has found practical application in the present invention which, in one aspect provides use of an agent which is effective to bind a substance selected from the group of 3-Deoxyglucosone (3DG) and at least one precursor of 3DG for the manufacture of a medicament capable of reducing a susceptibility to tumor formation in a subject, caused by the presence in said subject of a substance selected from the group of 3DG and at least one precursor of 3DG, substantially as described in the specification, said agent being either (I) a compound selected form the group consisting of those having Formulas I-XVIII, as set forth in the foregoing specification and aminoguanidine , or (ii) a monoclonal antibody which specifically binds an epitope that is found in native glycated albumin that has been subjected to no artificial modification, but that is not found on unglycated albumin, said epitope occurring at boy lys-lys and lys-his sequences, said antibody specifically binding more than one of said sequences located at residues selected form the group consisting of lysine-199, lysine-281, lysine-439 and lysine-525, and said antibody being insignificantly reactive with other proteins.
According to another aspect, this invention provides a pharmaceutical composition for reducing a susceptibility to tumor formation in a subject caused by the presence in said subject of a substance selected from the group of 3-deoxyglucosone (3DG) and at least one precursor of 3DG comprising an agent which is effective to bind said 3DG or said 3DG precursor said agent being either (I) a compound selected form the group consisting of those having Formulas I-XVIII, as set forth in the foregoing specification and aminoguanidine, or (ii) a monoclonal antibody which specifically binds an epitope that is found in native - 145 ,957/2 glycated albumin that has been subjected to no artificial modification, but that is not found on unglycated albumin, said epitope occurring at boy lys-lys and lys-his sequences, said antibody specifically binding more than one of said sequences located at residues selected form the group consisting of lysine-199, lysine-281, lysine-439 and lysine-525, and said antibody being insignificantly reactive with other proteins.
RTEF DESCRIPTION OF DRAWINGS FIGURE I illustrates the reactions involved in the lysine recovery pathway. r> T AILED DESCRIPTION OF THE INVENTION The following definitioiis are provided to facilitate understanding of the present invention, as described in further detail hereinbelow I. Glycated-L sine Residues - The expression "glycated lysine residues", as used herein, refers to the modified lysine residue of a stable adduct produced by the reaction of a reducing sugar and a lysme^ontaining protein.
The majority of protein lysine residues are located on the surface of proteins as expected for a positively charged amino acid. Thus, lysine residues on proteins which come in contact with serum, or other biological fluids, can freely react with sugar molecules in solution. This reaction occurs in multiple stages. The initial stage involves the formation of a Schiff base between the lysine free amino group and the sugar keto-group. This initial product then undergoes the Amadori rearrangement, to produce a stable ketoamine compound This series of reactions can occur with various sugars. When the sugar involved is glucose, the initial Schiffbase product will involve imine formation between the aldehyde moiety on C-l of the glucose and the lysine €-amino group. The Amadori rearrangement will result in formation of lysine coupled to the C-l carbon of fructose, 1-deoxy-l- (e-arninolysine)-fructose, herein referred to as tructose-lysine or FL.
Similar reactions will occur with other aldose sugars, for example galactose and ribose (Dills, Am. J. Clin. Nutr., 58: S779 (1993)). For the purpose of the present invention, the early products of the reaction of any reducing sugar and the e-amino residue of protein lysine are included within the meaning of glycated-lysine residue, regardless of the exact structure of the modifying sugar molecule.
Also, the terms glycated-lysine residue, glycated protein and glycosylated protein or lysine residue are used interchangeably herein, which is consistent with current usage in scientific journals where such expressions are often used interchangeably. 2. Fructose-lysine - The term "fructose-lysine" (FL) is used herein to signify any glycated-lysine, whether incorporated in a protein peptide or released from a protein/peptide by proteolytic digestion. This term is specifically not limited to the chemical structure commonly referred to as fructose-lysine, which is reported to form from the reaction of protein lysine residues and glucose. As noted above, lysine amino groups can react with a wide variety of sugars. Indeed, one report indicates that glucose is the least reactive sugar out of a group of sixteen (16) different sugars tested (Burin et al., Science, 213: 222 (1981)). Thus, tagatose-lysine formed from galactose and lysine, analogously to glucose, is included wherever the term fructose-lysine is mentioned in this description, as is - the condensation product of all other sugars, whether naturally-occurring or not. It will be understood from the description herein that the reaction between protein-lysine residues and sugars involves multiple reaction steps. The final steps in this reaction sequence involve the crosslinking of proteins and the production of multimeric species, known as AGE-proteins, some of which are fluorescent. Proteolytic digestion of such modified proteins does not yield lysine covalentiy linked to a sugar molecule. Thus, these species are not included within the meaning of "fructose-lysine", as that term is used herein. 3. Fructose-lysine-3-phosphate - This compound is formed by the enzymatic transier of a high e crgy phosphate group from ATP to FL. The term fructose-lysine-3 -phosphate (FL3P), as used herein, is meant to include all phosphorylated fructose-lysine moieties that can be enzymatically formed whether free or protein-bound. 4. Fmctose-lysine-3-phosphate kinase - This term refers to one or more proteins which can enzymatically convert FL to FL3P, as defined above, when additionally supplied with a source of high energy phosphate. . 3-DeoxygIucosone - 3-Deoxyglucosone (3DG) is the l,2-dicarbonyl-3-deoxysugar (also known as 3-deoxyhexulosone) which is formed upon breakdown of FL3P to yield free lysine and inorganic phosphate. For purposes of the present description, the term 3-deoxyglucosone is intended to include all possible dicarbonyl sugars which are formed upon breakdown of FL3P, having the broad definition of FL3P stated above. 6. FL3P Lysine Recovery Pathway - A lysine recovery pathway exists in human kidney, and possibly other tissues, which regenerates unmodified lysine as a free amino acid or incorporated in a polypeptide chain. As explained below, the metabolites produced by this pathway induce a susceptibility to carcinoma. 7. "Early glycosylation product(s)" - This term is intended to encompass any and all early glycosylation products with which the compounds described below are capable of reacting, including, without limitation, early glycosylation products with carbonyl moieties that are involved in the formation of advanced glycosylation end products and that are bound by interaction with the compounds described below. Such products may comprise reactive carbonyl moieties of Amadori products or their further condensation, dehydration and/or rearrangement products, which may condense to form advanced giycosylation end products. Also, reactive carbonyl compounds, containing one or more carbonyl moieties (such as glycoladehyde, glyceraldehyde or 3DG) may form from the cleavage of Amadori or other giycosylation end products, and by subsequent reactions with an amine or Amadori products, may form carbonyl-containing advanced giycosylation products such as alkylformyl-glycosylpyrroles. 8. "Susceptible test animal" - As used herein this expression refers a strain of laboratory animals which, due to the presence of certain genetic mutations have a higher propensity towards malignant transformation and tumor formation. The Eker rat, which has a mutation in the tuberous sclerous gene (Tsc-2), is one example of such a susceptible test animal. One of ordinary skill in the art is no doubt aware of a variety of other laboratory rat or mouse strains with increased propensity for tumor formation. The phrase "similar susceptible test animal" refers to animals of a comparable genetic background which are used as control, untreated animals.
The present invention evolved from the discovery of a previously unknown metabolic pathway, referred to herein as the FL3P lysine recovery pathway, which produces 3DG in an enzyme-catalyzed reaction. This enzymatic pathway is capable of enzymatic inhibition, thereby reducing the production of toxic 3DG.
Previously, it had been generally accepted that the origin of 3DG in vivo was from the decomposition of proteins containing glycated lysine residues. It had also been commonly believed that these glycated-lysines could not be used as an amino acid source. Additional extensive laboratory investigation has now shown that this previous belief was incorrect. See, WO 98/33492, supra.
The reaction steps involved in this newly discovered metabolic pathway are presented in Figure 1. In the first step, fructose-Iysine and ATP react to form FL3P and ADP in a reaction catalyzed by FL3P kinase. Phosphorylation occurs on the 3-position of the fructose moiety, leading to destabilization of the 9 - 145 ,957/2 fructoselysine molecule. The resulting FL3P then decomposes to form 3DG, inorganic phosphate, and unmodified, free, reusable lysine, which is available for utilization in protein synthesis. Aldehyde reductase detoxifies 3DG by reduction to 3 -deoxy fructose (3DF), which is excreted in urine.
FL3P is not stable in aqueous solution. It rapidly degrades to form 3DG, lysine and inorganic phosphcte. This reaction also occurs in vivo. It is not currently know if the degradation of FL3P that occurs in vivo is a spontaneous or enzyme catalyzed reaction. It is strongly suspected, however, that enzymatic catalysis is involved, as the production of 3DG from fructose* lysine occurs very rapidly in intact kidney.
Although Figure 1 illustrates the FL3P lysine recovery pathway using the most prevalent glycated-lysine, Le., fructose-lysine, it will be readily apparent to those skilled in the art that a wide variety of similar molecules can flux through this pathway. Indeed, the substrate selectivity of the FL3P lysine recovery pathway is quite broad, thus warranting the broad definition of the terms given above.
Additional experiments have shown that the lysine recovery pathway is found in a wide variety of warm-blood vertebrate species, including-sheep, pig, dog, rabbit, cow, mice and chicken. This pathway is also present in humans. See, WO 98/33492, supra. The ubiquitous presence of the FC3P lysine recovery pathway can be understood, given mat lysine is an essential amino acid which is present in relatively low concentrations in most foods. In addition, an appreciable percentage of the lysine residues in food will exist in the glycated form and the proportion of this modified lysine will increase when the food is cooked. Since these glycated lysine residues can not be utilized for protein synthesis, a recovery pathway for lysine is of great utility and affords a selective advantage to organisms which possess it.
A method of reducing susceptibility to tumor formation in a patient associated with the intake of glycated protein is the subject of related published international application no. WO00/24405, the entire disclosure of which is incorporated by reference in the present specification as though set forth herein in full. That method comprises the administration of a pharmaceutical composition which contains ah active compound having inhibitory activity for the enzymatic conversion of f uctose-lysine to FL3P. Another aspect of that invention concerns a method of preventing or delaying the onset of tumor formation caused by the formation of AGE-proteins, which comprises administering a therapeutic amount of an agent that inhibits production of 3DG.
In accordance with the present invention, other approaches for reducing a susceptibility to tumor formation, and for preventing or delaying the onset of tumor formation have been devised. One such approach involves administering an agent which is effective to bind 3DG in the system of a subject undergoing treatment in accordance with this invention, The agents which are suitable for this purpose are described hereinbelow. These agents are small molecules that are effective in b ding 3DG, irrespective of whether the 3DG is biochemically formed by the subject, e.g., via the FL3P lysine recovery pathway, or is present in food or beverage ingested by the subject which raises endogenous levels of 3DG.
Another approach entails binding of substrates that function as precursors of 3DG, for example, FL or analogous compounds that are metabolized in vivo to form 3DG. This method is preferably carried out using an immunoreactive agent that specifically binds 3DG precursors in vivo.
Representative examples of such immunoreactive agents include the monoclonal antibody produced by cell line ATCC HB 9596, which specifically binds an epitope present on glycated albumin. Substrates which may be bound in this manner so as to interfere with the production of 3DG include any of the phosphorylated fructose-lysine moieties, whether free or protein-bound, that can be enzymatically produced in the system of a subject undergoing treatment. Antibodies may be generated, using well-known procedures, to a variety of substrates that may vary by size, including, without limitation, amino acid-fragments, peptide-lysine fragments, polypeptide fragments, and the like.
The agents involved in the lysine recovery pathway have been identified in other tissues besides kidney, specifically red blood cells, lens, and peripheral nerve tissues. These agents are also found in pancreas tissue.
Compounds which may be used in the practice of this invention include one or more (i.e., combinations) of the following: H ¾N C— N— C— NR,Ra 0) NH NH wherein R, and R2 are independently hydrogen, lower alkyl, lower alkoxy or an aiyl group; or together with the nitrogen atom form a heterocyclic ring containing from 1 to heteroatoms and 2 to 6 carbon atoms, the second of said heteroatoms being selected from the group consisting of nitrogen, oxygen and sulfur, and their biocompatible and pharmaceutically acceptable acid addition salts.
The lower alkyl groups in the compounds of Formula (I) contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof. The lower alkoxy groups have 1-6 carbon atoms and include methoxy, ethoxy, propoxy, butoxy, penthyloxy, hexyl oxy and branched chain isomers thereof. The aryl groups include both substituted and unsubstituted phenyl and pyridyl groups. Typical aryl group substituents are those such as lower alkyl groups, fluoro, chloro, bromo and iodo atoms.
Of the compounds encompassed by Formula I, certain combinations of substituents are preferred. For instance, when R, is a hydrogen atom, then R2 is preferably hydrogen or an aryl group.
When R, and R2 are both alkyl groups, then the compounds having identical R, and R2 alkyl groups are preferable.
When R, and Rj together with the nitrogen atom form a heterocyclic ring containing from 1 to 2 heteroatoms, said heteroatoms being selected from the group consisting of nitrogen, oxygen and sulfur, the preferred heterocyclic rings will be rnorpholino, piperazinyl, piperidinyl and thiomorpholino, with the rnorpholino being most preferred.
Representative of the compounds of formula (I) are: diamide; imidodicarbonimidic diamide; N-phenylin-idodicaxbonimidic diamide; ^aminniTninnmethyl)^mnr hnh'riftP-a hfiyiT Tri»miHft; N ancdnoiminoroerayl)^ N-(ammom inomethyl)- -methyl- 1 -piperazmecaAojdimdamide; N-(ammoimmomemyl)-l-piperidmecarboxim^ N^aminoiminomethy 1)- 1 -pynOUdmecarboximidamide; diamide; N,N-di-n-hexyliinidodicarboiiimid c diamide; N,N-di-n-pen1ylin^dodicarboniinidic diamide; N,NHd-n-burylinu^odicarbonimidic diamide; NjN-dipropylinndoGlcarboniinidic diamide; N,N^emylimidodicarbonimidic diamide; and the pharmaceutically acceptable acid addition salts thereof; wherein Z is N or CH-; X, Y and Q axe each independently a hydrogen, amino, heterocyclo, amino lower alkyl, lower alkyl or hydroxy group; and R3 is hydrogen or an amino group; and their corresponding 3-oxides; an their biocompatible and pharmaceutically acceptable salts. he compounds of Fonnula II wherein the X, Y or Q substituenl is on a nitrogen of the ring exist as tautomers, i.e., 2-hydroxypyrinndhie can exist also as 2(lH)-pyrirnidine. Both forms may be used in practicing this invention.
The lower alkyl groups of the compounds of formula II contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof. The heterocycylic groups of the compounds of formula II contain rom 3-6 carbon atoms and are exemplified by groups such as pyirolidinyl, 2-methylpyrrolidinyl, piperidinol, 2-methylpiperidino morpholino, end hexamethyleneamino.
The "floating" X, Y, Q and HR3 bonds in Formula II indicate that these variants can be attached to the ring structure at any available carbon juncture. The hydroxy variant of X, Y and Q can also be present on a nitrogen atom.
Of the compounds encompassed by Formula Π, certain combinations of substituents are preferred. For instance, compounds having R3 as hydrogen, as a CH group, and at least one of X, Y or Q as another amino group, are preferred. The group of compounds where R3 is hydrogen, Z is a CH group and one of X or Y is an amino lower alkyl group are also preferred. Another preferred group of compounds is those where R is hydrogen and Z is N (nitrogen). Certain substitution patterns are preferred, i.e., the 6-position (TUPAC numbering, Z.dbd-CH) is preferably substituted, and most preferably by an amino or a nitro containing group. Also preferred are compounds where two or more of X, Y and Q are other than hydrogen.
Representative of the compounds of formula II are: 2-hyd^a2ino-4-hydroxy'6-memylpyrimiduie; 4,5-diaminopyrimidine; 4- amLno-5-aminomethyI-2-methylpyrimidine; 6^piperidino)-2,4-diaminopyrimidm 3-oxide; 3 -amino-6-methyl- 1 ,2 ,4-triaz_n-5(2H)-one; 4,6-diaiiunopyrimidine; 4,5,6-trianiinopyriinidine; 4,5^.irmno-6«hyclrox> yrirriidme: 2,4,5-triarn--ao-6-hyQroxypyiM-idine; ,6-diariiino-2,4-axhyroxypyrirnidine; 4, 5 niiamino-2 -met y Ipyrimidine; 4,5Hdiamino-2,6^dimethylpyrirnio¼ 4,5-dianuno-2-hydroxy-pyi½uaTne; 2- hydrazinopyrLTTidine; 4,6Kiimethyl-2-hydra-dnc^yriini 3- hydrazino-l ,2,4-triazine; 3-hy(kazino-5-hya^oxy-l^,4-triazine; - hydrazino-S-h o^o -l^j^fcriazi e; and .6- diamiiio-3-hydroxy-l,2,4-tria2ine; Rs H NH I I I on) Χ,-C N -N - C- NHR, wherein R„ is hydrogen or acyl; is hydrogen or lower alkyl; X, is a substituent selected from the group consisting of lower alkyl, carboxy, carboxymethyi, or a phenyl or pyridyl group, optionally substituted by halogen, lower alkyl, hydroxy lower alkyl, hydroxy, or acetylamino - 15 - with the proviso that when X is a phenyl or pyridyl group, optionally substituted, then R2 is hydrogen and their biocompatible and pharmaceutically acceptable acid addition salts.
The lower alk l groups in the compounds of Formula HI contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof. The halo variants can be fluoro, chloro, bromo or iodo substituents.
Equivalent to the compounds of Formula III for the purpose of this invention are the biocompatible and pharmaceutically acceptable salts thereof.
Such salts can be derived from a variety of organic and inorganic acids including but not limited to methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
Of the compounds encompassed by Formula III, certain substituents are preferred. For instance, R4 is preferably a methyl group and X, is preferably a phenyl or substituted phenyl group.
Representative of the compounds of Formula III are: N-acetyl-2^henylmemylene)hydra2mecarboximidaanide; 2^henyImemylene)hydrazinecarboximidarrii'de; 2-(2,6^chlorophenylmemylene)hydra-^ pyridoxal guanylhydrazone; pyridoxal phosphate guanywydrazone; 2-( 1 -methy lethy Uckne)hydrazinecarboximidamide; pyruvic acid guanylhydrazone-, 4-acetamidobenza dehyde guanylhydrazone; 4-acetamidobenzaldehyde N-acetylguanylhydrazone; acetoacetic acid guanylhydrazone; and the biocompatible and pharmaceutically acceptable salts thereof; Rs N R, I 1 (IV).
H2N-N - C - Ra wherein is hydrogen or a lower alk l group, or a phenyl group, optionally substituted by 1-3 halo, amino, hydroxy or lower alkyl groups; R7 is hydrogen, a lower alkyl group, or an amino group and R„ is hydrogen or a lower alkyl group; their biocompatible and pharmaceutically acceptable acid addition salts.
The lower alkyl groups in the compounds of Formula IV contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof. The halo variants can be fluoro, chloro, bromo or iodo substituents. Where the phenyl ring is substituted, the point or points of substitution may be ortho meta or para to the point of attachment of the phenyl ring to the straight chain of the molecule.
Equivalent to the compounds of Formula IV for the purpose of this invention are the biocompatible and pharmaceutically acceptable salts thereof. Such salts can be derived from a variety of organic and inorganic acids including but not limited to methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
Of the compounds encompassed by Formula IV, certain substituents are preferred. For instance, R« is preferably a methyl or ethyl group.
Representative of the compound of Formula IV are: emanimidic acid hydrazide; ethanehydrazonic acid hydrazide; N-memylethanirnidic acid hydrazide; ewanimidic acid 1-methylhydrazide; formamidrazone (methaniidic acid hydrazide); propanimidic acid hydrazide; benzimidic acid, hydrazide; benzimidic acid, 1-methylhydrazide; propanehydrazonic acid nydrazide; - 17 - n-butanehydrazonic acid hydrazide; 4-memylbenzarnidrazone; N-methylbexu»necarbojcirnidic acid hydrazide; beiuenecarboximidic acid 1-methylhydrazide; 3-chlorobenzamidrazone; 2- fluorobeiizamidrazorie; 3- fluorobenzamidrazone; 4- fluorobenzarnidrazone; 2-hydioxybenzanudrazone; 3- hydroxybenzamidrazone, 4- hydroxy beiizarmdrazone : 2-aminobenzamidrazone; benzenecarboh5'drazonic acid hydrazide; benzenecarbohydrazonic acid 1-methylhydrazide; and the biocompatible and-pharmaceutically acceptable salts thereof; wherein 1¾ and R,0 are independently hydrogen, hydroxy, lower alkyl or lower alkoxy; with the proviso that the "floating" amino group is adjacent to the fixed amino group; their biocompatible and pharmaceutically acceptable acid addition - 18 - salts.
The lower alk l groups of the compounds of Formula V contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof. Likewise, the lower alkoxy groups of the compounds of formula V contain 1-6 carbon atoms and include methoxy, ethoxy, propoxy, butoxy pentoxy, h?xoxy, and the corresponding branched chain isomers thereof.
Equivalent to the compounds of Formula V for the purpose of this invention are the biocompatible and pharmaceutically acceptable salts thereof. Such salts can be derived from a variety of organic and inorganic acids mcluding but not limited to methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
Of the compounds encompassed by Formula V, certain substituents are preferred. For instance, when R, is hydrogen then R,0 is preferably also hydrogen.
Representative of the compounds of Formula V are: 2,3-diammop ridine; - memyl-2,3-diammopyridine; 4-memyl-2,3-diarninopvridine; 6- memyl-2,3-pyridmem*armne; 4,6-dimemyl-2^-pyridiriedianiine; 6-ethoxy-2,3-diaminopyridine; 6-dimemylammo-2,3-diammopyridine; diethyl 2-(2,3-diamino-6-pyridyI)malonate; 6(4-methyl- 1 -pyperazmy l)-2,3-pyridmediarnine; 6-(memyltMo)-5-(trirluoromemyl)-2,3-pyridmediamine; trifiuoromemyl)-2,3-pyridinediamine; 6-(2,2,2-trifluoremoxy)-5-(trifluoro 6-cWoro-5-(trifluoromethyl)-2,3-pyridinedianune; -bromo-4-6^methyl-2^-pyridiiiedian3ine; " 5-methoxy-6- methylthio)-2,3-pyridinediamine; - bromo- -methyl-2,3 -pyridinediamine; trifluoromethyl-2^-pyridinediamine; 6- bromo-4-methyl-2,3-pyridinedxan?ine; -bro .no -6-methy 1-2,3 -pyridinedi amine ; 6-methoxy-3a4-pyridinediairiine; 2-methoxy-3>4-pyiidinediaminR; -methyl-3,4-pyridinedian.ine; -methoxy-3s4-pyridinedi amine; -bromo-3,4-pyridkediamine; 2,3,4-pyridmetriainine; 4,6 iimet-iyl-2J ,5-py-idinetriainine; 2,3 ,5-pyridinetrianiiiie; 4-methy 1-2,3 ,6-pyiidinetriamine; 4-(methylthio)-2,3 ,6-pyridinetriarnine; 4~ethoxy-2,3 ,6-pyridinetriamine; 3A5-pyri(iinetriamine; 4- methoxy-2,3-pyridinediamine; and the biocompatible and pharmaceutically acceptable salts thereof; wherein n is 1 or 2; R, , is an amino group or a hydroxyethyl group; and R,2 is an amino, a hydroxyalkylamino, a lower alkyl group or a group of the formula alk-Ya wherein aU is a lower alkyiene group and Ya is selected from the group consisting of hydroxy, lower alkoxy, lower alkylthio, lower alk lamino and heterocyclic groups containing 4-7 ring members and 1-3 heteroatoms; with the proviso that when Ru is a hydroxyethyl group then R12 is an amino group; their biocompatible and pharmaceutically acceptable acid addition salts.
The lower alkyl, lower alkyiene and lower alkoxy groups referred to herein contain 1-6 carbon atoms and include methyl, methylene, methoxy, ethyl, ethylene, ethoxy, propyl, propylene, propoxy, butyl, butylene, butoxy, pentyl, pentylene, pentyloxy, hexyl, hexylene, hexyloxy and the corre^onding branched chain isomers thereof. The heterocyclic groups referred to herein include 4-7 membered rings having at least one and up to 3 heteroatoms therein. Representative heterocyclic groups are those such as morpholino, piperidino, piperazino, methylpiperazino, and hexamethylenimino.
Equivalent to the compounds of Formula I for the purpose of this invention are the biocompatible and pharmaceutically acceptable salts thereof. Such salts can be derived from a variety of organic and inorganic acids including but not limited to, methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
Of the compounds encompassed by Formula VI, certain combinations of substituents are preferred. For instance, when R,, is a hydroxyethyl group, then Rl2 is an amino group. When Rn is an amino group, then R,2 is preferably a hydroxy lower alkylamino, a lower alkyl group or a group of the formula alk-Y, wherein alk is a lower alkyiene group and Y is selected from the group consisting of hydroxy, lower alkoxy, lower alkylthio, lower - 21 - alkylamino and heterocyclic groups containing 4-7 ring members and 1-3 heteroatoms.
Representative of the compounds of Formula VI are; l-amino-2-[2-(2-hydroxyeuiyl)hydra2-iio]-2-imi 1 -amino-2-(2-hydroxyethylainmo)-2-imidazoline; 1 -(2-hydroxyemyl)-2-hydia2ino- 1 ,4,5,6-tetiahy lropyrimidine; 1 -(2-hydroxyemyl)2-hydrazino-2 -imidazoline; l-aiirino~2-(P-{4-morpholino)eftyl]am 1 -amino-2^[3-(4-moi3jholmo)piopyl] 1 -arnino-2-(X3-(4-methylpiperaz - 1 -yl)propyI]-aiiuno)iinidazoline; 1 -amino-2-([3 -(dimemylanamo)propyl]amuio)iniidazolm^ 1 -amino-2-[(3 -ethoxypropyl)ammo]imidazoline; 1 -amino-2-([3-(l -inTidazolyl)piOpyl]animo)inudazoline; 1 -amino-2-(2-metfaoxyethylaimno)-2-imidazoIiiie; l-aimtto- -(3-isopropoxypropylammo)-2-^ 1 -amino-2-[3-(l -piperidmo)propylarnmo)miidazoline; l-aim o-2-P-2Hiimem l 3-(di e ^ 1 -ammo-2-(neopentylammo)-2-miidazoUne; and the biocompatible and pharmaceutically acceptable salts thereof; wherein R,3 is a hydrogen or an amino group; R14 and R,5 are independently an amino group, a hydrazino group, a lower alkyl group, or an aryl group; with the proviso that one of R,3, R„ and RIS must be an amino or a hydrazino group; and their biologically or pharmaceutically acceptable acid or - 22 - alkali addition salts.
The lower alkyl groups referred to above preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof.
The aryl groups encompassed by the Formula VII are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g. tolyl and xylyl, and phenyl substituted by 1 -2 halo, hydroxy or lower alkoxy groups.
The halo atoms in the Formula VII may be fluoro, chloro, bromo or iodo. The lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, n-propoxy, isopropoxy and the like.
For the purposes of this invention equivalent to the compounds of Formula VII are the biologically and pharmaceutically acceptable acid addition salts thereof. Such acid addition salts may be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
Of the compounds encompassed by Formula VII, certain combinations of substituents are preferred. For instance, when R13 is hydrogen, then , is preferably an amino group. When R14 is a hydrazino group, then R is preferably an amino group.
Representative of the compounds of Formula VII are: 3,5-o amino-l ,2,4-lriazole; 4- amino-3-hydrazino-5-methyl-l ,2,4-triazole; 3 ,4-diamino-5-methyl- 1 ,2,4-triazole; 4H-1 ,2,4-triazo W-amine; 3,5-dimemyl-4H-l,2,4-tria2ol-4-amine; 3 ,5-diethyl-4H~ 1 ,2,4-triazol-4-amine; 3,5-dipropyI-4H-l ,2,4-triazol-4-amine; 3,5-dibutyMH-l,2,4-triazoI-4-amine; 375-dihexyI^H-l,234-tria2ol-4-amine; 3-methyl-4H-l ,254-triazol-4-ainine,- 3 -methyl-5-phenyl-4H- 1 ,234-triazol-4-amine; 3- pentyl-5-phenyl-4H- 1 ,2,4-triazol- 4· amine; 4H-1 -2,4-triazoIe-3,4-diainine; -(l^ylpropylHH-l,2s4-tiiazole ,4^iaii-ine; 5-isopropy H,iA4-triazole ,4-diainine -EQethyMH-l^,4-triazole-3.4^amine -propyl-4H-l,2,4-triazole- 3,4-diamine; -cyclohexyl-4Hr 1 ,2,4-triazole-3 ,4-diamine; 4- amino-3 ,5-djhy drazino-4H- 1 ,2,4-triazole; 4-amino-3 -hydrazino-5 -phenyl-4H- 1 ,2,4-triazole; 4-amino-3-hydra2ino-5-ethyl-4H-l,2,4-triazole; 3-ammo-5-hydrazino-l,2,4-triazole; 3-(2-c orophenyl)-5-hydiazino-l,234-triazole; 3-(l-ethylpropyl 5-hydra^o-lA4-triazole; 4H-l,2,4-triazol-4~amine; lH-triazole-L,5-diainine; 1 H-triazole-U3-diainine; 1 H- 1 ,2,4-ttiazol-3-amine; 1 ,5-bis(4-chlorophenyl)-lH- 1 ,2,4-triazol-3-amine ; l,5-bis(4-fluorophenyl lH-l,2,4-tiiazol-3-aniine; l,5-bis(4-methoxyphenyl)-lH-l,2,4-triazol-3-amiiie 1 ,5-diet yl- 1 H- i ,2,4-triazol-3-amine; 1 ,5-dimethyl-l H-l ,2,4-tria2»I-3-amine; 1 ,5-diphenyl- 1 H- 1 ,2,4-tri-uaDW-amine; 1 -(4-chloropheny 1)- 1 H-l ,2,4-triazol-3-amine; 1 -ethyl- 1 H- 1 ,2,4-triazol-3-amine; 1-methyl-lHrl ,2,4-triazol-3-amine; 1 -propyl-lH-1 ,2 ,4-triazol-3-amine; -(l^thyl-l-methyipropyl)-lH-l^,4-triazol-3-amiiie -(l -methylethyl)- 1H- 1 ,2,4-tria2ol-3-amine; -(2-methylpropyl)-l H- 1 ,2,4-tria20 W-amine; -(4-chlorophenyI l -(4-fluorophenyl)-lH-l-2,4-triazol-3-anjiije; -(4-chlorophenyl)-l -(4-methylphenyl>lH-l .254-triazol-3-amine; -{4-methoxyphenyl)-lH-1.2,4-triazol-3-a-aiine; -(3-methylphenyl)-lH-l^,4-triazol -ainine; -(4-methylphenyl)- 1 H- 1 ^,4-triazol-3-amine; -butyl- 1 H- i -2,4-triazol -3-amine; -ethyl- 1 H-l ,2,4-triazol-3-amine; -ethyl- 1 -methyl- 1 H- 1 ,2,4-triazol-3 -amine; -hexyl-lH-l,2,4-triazol-3-amine; -methyl-lH-l,2,4-triazol-3-amine; -pentyl-lH- 1 ,2,4-triazol-3 ►amine; -propyl-lH-l,2,4-triazol-3-amine; and -(4-chloropheny l)-3-hydrazino-2-methyl-2H- 1 ,2,4-triazole; (VIII) wherein R,6 is hydrogen or an amino group; R,7 is an amino group or a guanidino group when R,6 is hydrogen; or R,7 is an amino group when R16 is an amino group; R18 and R19 are independently hydrogen, hydroxy, a lower alk l group, a lower alkoxy group, or an aryl group; and their biologically or pharmaceutically acceptable acid or alkali addition salts.
The lower alkyl groups in the compounds of Formula VIII preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched chain isomers thereof The lower alkoxy groups likewise contain 1-6, and preferably 1-3, carbon atoms, and are illustrated by methoxy, ethoxy, n-propoxy, isopropoxy and the like. The aryl groups encompassed by the above formula are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy or lower alkoxy groups.
The halo atoms in the above Formula VHI may be fluoro, chloro, bromo or iodo.
The biologically or pharmaceutically acceptable salts of the compounds of Formula VIII are those tolerated by the mammalian body and include acid addition salts derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, sulfamic, citric, lactic, malefc, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
Of the compounds encompassed by Formula VIII, certain substituent are preferred. For instance, the compounds wherein R,7 is an amino group are a preferred group.
Representative of the compounds of Formula VIII are: 2-guamd obenzimidazole; 1 ,2-diaminobenzimidazoie; 1,2-diaminobenainidazole hydrochloride; 2-arnmobenzimidazole; 2-aminobenzimidazole-5-01 ; 4.5- dimethyl-2-aminoben2-imidazole; 4.6- dicUoro-2-aminobenzimidazole; 4,6^methyI-2-aminobenzunidazole; 4,7-dimethoxy-2-aininoben2imida2ole; 4.7- dimethyl-2-anjinobei--0niidazo!e-, 4- cMoro-2-aminobenzimidazoIe; S,6-(ii hloro-2-aminobeii2iinidazole,-5,6^ethoxy-2«aminobenHmidazole; 5,6Hdimetboxy-2-aininoben7imidazx)le; 5,6^methyl-2-aminobeiizimidazole; - butyl-2-aminobenzimida2ole; -pTOpyl-2-aminobeii2iinidazole; -ethyl-2-aiTunobeazdniidazole; -methyl-2-aminobenzimidazole; -cWoro-2-aininoben2imida2ole; -fluoro-2-aininobenzimidazole; S-methoxy-2~aminoben7irnidazole; -chloi -6-methyl-2-arniiiobenzimidazoIe; 5^bJoro^-fluoro-2-aminobeiiziniida2ole; -methyl-2-guanidinobeiizimidazole; 4,6-dimethyl-2-guanidinobenzimidazole; ,6-
The acyl groups referred to herein are residues of lower alkyl, aryl and heteroaryl carboxylic acids containing 2-10 carbon atoms. They are typified by acetyl, propionyl, butanoyl, valeryl, hexanoyl and the corresponding higher chain and branched chain analogs thereof. The acyl radicals may also contain one or more double bonds and/or an additional acid functional group e.g., glutaryl or succinyl.
The amino acids utilized herein can possess either the L&D; stereochemical configuration or be utilized as mixtures thereof. However, the L-configuration is preferred.
Equivalent to the compounds of Formula DC for the purposes of this invention are the biocompatible and pharmaceutically acceptable salts thereof. Such salts can be derived from a variety of inorganic and organic acids such as methanesulfonic, hydrochloric, toluenesulfonic, sulfuric, maleic, acetic, phosphoric and related acids.
Representative compounds of the compounds of Formula DC are: lysine; 2,3-diaminosuccinic acid; cysteine and the biocompatible and - 28 - pharmaceutically acceptable salts thereof. wherein 22 and are independently, hydrogen, an amino group or a mono- or di-amino lower alkyl group; Rw and are independently hydrogen, a lower alkyl group, an aryl group; or an acyl group with the proviso one of and must be an amino group or an mono- or di amino lower alkyl group; and their biologically orphannaceutically acceptable acid or alkali addition salts.
The lower alkyl groups of the compounds of Formula X contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof. The mono-or di-amino alkyl groups are lower alkyl groups substituted in the chain by one or two amino groups.
The aryl groups referred to herein encompass those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy and lower alkoxy groups. The acyl groups referred to herein are residues of lower alkyl, aryl and heteroaryl carboxylic acids containing 2-10 carbon atoms. They are typified by acetyl, propionyl, butanoyl, valeryl, hexanoyl and the corresponding higher chain and branched chain analogs thereof. The acyl radicals may also contain one or more double bonds and/or an additional acid functional group, e.g., glutaryl or succinyl.
The heteroaryl groups referred to above encompass aromatic heterocyclic groups containing 3-6 carbon atoms and one or more heteroatoms - 29 - such as oxygen, nitrogen or sulfur.
The halo atoms in the above Formula X may be fluoro, chloro, bromo and iodo. The lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, propoxy, isopropoxy and the like. The term biologically or pharmaceutically acceptable salts refers to salts which are tolerated by the mammalian body and are exemplified by acid addition salts derived f om a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, glucomic, ascorbic and related acids.
Of the compounds encompassed by Formula X, certain combinations of substituents are preferred. For instance, when and are both amino groups, then Rj4 and are preferably both hydrogen atoms. When or Ri3 is amino group and one of or is an aryl group, the other of and is preferably hydrogen.
Representative compounds of Formula X are: 1 ,2-diamino-4-phenyl[lH]imidazole; 2-aminoimidazole sulfate; 1 ,2-cliarmnoimidazole; 1 ^,3-a1aminopropyl)imidazole trihydrochloride; 4,5-diphenylimidazole- 1 ^-diamine; 4-(4-bromopheny l)imidazole- 1 ,2-diarnine; 4-(4-cMorophenyl)imidazole- 1 ^-ciiamme; 4-(4-hexylphenyl)imidazole-l ^-dLiamine; 4-(4-memoxyphenyl)imidazole- 1,2-diamine; 4-phenyl-5-propy -imidazole- 1 ,2-chamine; 1 -armnoimidazole; 1 -amino- -methylimida2ole; 1- arrdno^(2-methylphenyI)imidazole; 2- aminoimidazole; 4-(2,4-dichlorophenyl)-2-aminoimidazole; 4-(4-methoxyphenyl)-2-an3dnoin-idazoie; 4-(4-ethoxyphenyl)-2-aiiiinoimidazole; 4-(4-fluorophenyl)-2-aminoimidazole; 4-(4-bromophenyl)-2-amiiioimida2ole; 4-butyl-2-aminoimidazole; -ethyl-2-aminoimidazole; -methyl-2-aminoiinidazole; -phenyl-2-an-inoirnida2ole; -propyl-2-aminoimidazole; 1 -(3-aniinopropyl)inudazDle; 1 -(3-amino- 1 -met y lpropyl)iinidazole; 1 -(3-aiJiinopropyl)4-5-dimethylimidazole; 1 -(3-aminopropyl)4-methylimidazole; l-(3-ai3n-aiopropyl)4-phraylimida2ole; 1^3-aminopropyl)5-inethyM-phenyliiiiida2ole; 1 - (2-aminoethyl)iraida2ole; - (aminomethyl)iin dazole; -(-uninomethyl)-4-methyliiTiidazole; -(3-aminopropyi)imidazole; -(3-aminopropyl)^5-dimethylimidazole; -(3-aminopropyl)^methyUmidazole; 1,2 ^iamiao^methylimidazole l^-diaimno^,5^imethylimida2ole; and 1.2^iamino^methyl-5-acetylimidazole; wherein R26 is a hydroxy, lower alkoxy, amino, amino lower alkoxy, mono-lower alkylamino lower alkoxy, di-lower alkylamino lower alkoxy or hydrazino group, or a group of the formula — NR-g R30s wherein R29 is hydrogen or lo er alkyl, and R30 is an alkyl group of 1-20 carbon atoms, an aryl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, cycloloweralkyl group or a heterocyclic group containing 4-7 ring members and 1-3 heteroatoms; or 2 and R30 together with the nitrogen form a morpholino, piperidinyl, or piperazinyl group; or when R^ is hydrogen, then R30 can also he a hydroxy group; R^ is 0-3 amino or nitro groups, and/or a hydrazino group, a hydrazinosulfonyl group, a hydroxyethylamino"or an arnidino group; R2g is hydrogen or one or two fluoro, hydroxy, lower alkoxy, carboxy, loweralkylamino, dilower alkylamino or a hydroxyloweralkylamino groups; with the proviso that when R2fi is hydroxy or lower alkoxy, then R27 is a non-hydrogen substituent with the further proviso that when RM is hydrazino, then there must be at least two non-hydrogen substituents on the phenyl ring; and with the further proviso that when R2g is hydrogen, then R30 can also be an arninoimino, guanidyl, aminoguanidinyl or cuaminoguanidyl group; their pharmaceutically acceptable salts and hydrates.
The lower alkyl groups of the compounds of Formula XI contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyL, hexyl, and the corresponding branched-chain isomers thereof. The cycloalkyl groups contain 4-7 carbon atoms and are exemplified by groups such as cyclobutyl, cyclopentyl, cyclohexyl, 4-methyIcyclohexyrand cycloheptyl groups.
The heterocyclic groups of the compounds of Formula XI include 4-7 membered rings having at least one and up to 3 heteroatoms, e.g., oxygen, nitrogen, or sulfur, therein, and including various degrees of unsaturation.
Representatives of such heterocyclic groups are those such as morpholino, piperidino, homopiperidino, piperazino, rnethylpiperazino, hexamethylenirnino, pyridyl, methylpyridyl, imidazolyi, pyrrolidinyl, 2,6-dimethylmorpholino, furfural, 1,2,4-triazoyIyl, thiazolyl, thiazolinyl, methylthiazolyl, and the like.
Equivalent to the compounds of Formula XI for the purposes of this invention are the biocompatit/lc and pharmaceutically acceptable salts and hydrates thereof. Such salts can be derived from a variety of organic and inorganic acids, mcluding, but not limited to, methanesulfonic, hydrochloric, hydrobromic, hydroiodic, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
When the compounds of Formula XI contain one or more asymmetric carbon atoms, mixtures of enantiomers, as well as the pure (R) or (S) enantiomeric form can be utilized in the practice of this invention.
Of the compounds encompassed by Formula XI, certain combinations of substituents are preferred. For instance, when R, is a hydroxy, then j is preferably one or two amino groups, or a single hydrazino or a single hydrazino-sulfonyl group. When R, is hydroxy and is a single amino group or a single hydrazino group, the Rj substituent is preferably para to the carboxy substituent When R is hydroxy and is two amino groups, they are preferably meta and para to the carboxy substituent. When R, is hydroxy and R2 is a single hydrazino-sulfonyl group, then the Rj substituent is preferably meta to the carboxy substituent.
When R, is a dialk l aminolower alkoxy group, then R2 is preferably a single amino group.
When R, is a carboxylower alkylamino group, then ¾ is preferably a single amino group.
In addition, compounds having a 3,4-diamino-, 3-hydroxy-4-amino-, 3-amino-4-hydroxy-, 3,5-diamino-4-hydroxy-, 3,5-diamino-4-alkoxy- or 2,3-diamino-5-fluoro substituent pattern on the phenyl ring are highly preferred.
Representative compounds of the present invention are: -(cyclohexylarnino-carbonyI)-o-ph.enyrene diamine hydrochloride; -aminobeiizhydra2ide; ,4-diaminobenzhydra2ade; -(n-butylamino-carbonyl)-0-phenylene-dianiine dihydrochloride; -(ethylajm_moH:arbonyI)-o-phcnylene-diamine dihydrochloride; -carbamoyl-o-phenyiene diamine hydrochloride; -hydroxybenzhydrazide; - amino-4-hydroxybenzoic acid; - arnino-3-hydroxybenzoic acid; -amino-4-hydroxybenzhy drazide; - arnino-4-hydroxybenzhydrazide dihydrochloride; . - aniidinobenzamide hydrochloride; -(morpholino-carbc^yl)^-phenylene-diarnine hydrochloride; -[(4-morphoh^o)hydraziiio-carbonyl]-c-phenylenediam -( 1 -piperidiny laniino-carbonyI)→3-phenylenediarniQe dihydrochloridi .4- diamino-3-hydroxybenzoic acid; acid; -amino-3-hydroxybeiizoic acid; -an-ino-3-hydroxybenzamide; .5- diamino-2-hydroxybenzoic acid; ,4nliaminoberizarnide; ,4-diaminobenzhydrazide; ,4^iamino-N,N-bis( 1 -methylethyl)benzamide; ,4-diamino-N,N-diethylbenzarnide; ,4-diarnino-N,N-dipropylbenzamide; ,4-diamino-N-(2-fiiranylmethyl)benzamide ,4^iarnino-N-(2-methy lpropyl)benzamide; ,4-diamino-N-{4,5-dihydro-2-thiazolyl)benzamide; ,4-diarruno-N-(5-methyl-2-thiazoly berizarnide; ,4-diamino-N^6-methoxy-2-benzothiazolyl)berizamide; ,4-diammo-N^6-methoxy-8 i^ ,4-diamiiw-N-(6-meth 1-2-pyridmy l)beiizamide; 34-diamino-N-( 1 H-benzimidazol-2-y l)benzamide; ,4^iarnino-N-(2-pyridiny l)benzamide; ,4-diamino-N-(2-thi£i2olyl)benzamide; s4-diamino-N-(4-pyrIdiny l)benzamide; ,4-diamino-N-butylbenzamide; ,4^ianiino-N^clohexyIb€iizamide; ,4-diamino-N-cyclopenty lbenzamide; A^anuno-N-decylbenzamide; ,4-diamino-^N-niethylbeiizainide; ,4-diamino-N>ocly lbenzamide; s4niiaimno-N-pentylbeiizamide; ,4-diamino-N-pheny lbenzamide; -atnino-4-hydi xybenzamide; - aniino^hydroxy-N-octylbenzamide; - (diethylainjno-carbonyl)^-phenylene di-unine; -(tert-bu ylairi-no-carbonyl) )^henylene diamm^ -isobutylamino-carbonyl)-o-phenylene diamine; -(neopcntylami-ao-carbonyl)-o-phenylene diamine; -(dipropylamino-carbonyl)-o-phenylene diamine; -(n-hexylamino-carbonyl)-o-phenylene diamine; -(n-decyianiino-carbonyl)-o-phenyIene diairiine; -(n-dodecylamino-carbonyl)-o-phenylene diamine; -(l-hexadecylamino-carbonyl)-o-phenylene diamine; -(octadecy 1 amino-carbony I)-o-pheny lene diamine; -(hydroxylamino-carbonyl)-o-phenylene diamine; -(2-hydroxyethylamino-carbonyl)-o-phenylene diamine; -[(2-hydroxyethylaniino)ethylamino-carbonyl]o-phenylene diai^ - [(2-hy droxy ethy loxy)ethylamino-carbonyl]-o-phen lene diamine; -(6-hydroxyhexylamino-carbonyl)-o-phenylene diamine; -(3~ethoxypropylamino-carbonyl)-o-phenylene diamine; -(3-isopropoxypropylamino-carbonyl)-o-phenylene diamine; -(3^imemylaii-½opropyl-mimo-cai onyl)^-phenylene diamine; -(N ,Ν ,2,2-tetramethyl- 1 ,3 -propanoamino-carbonyl)-o-phenylene diamine; -[4^2-ammoethyl)morphoIino-carbonyI]-o-phenylene diamine; -IN-(3-ammopropyl)pytro]idmo-(.acbonyl]^-ph^ -[3 N-piperid o)propylam o ^onyI^ -[3 4-memylpiperazmyl)propylam o^ -(3-imidazoylpropylamm<>-carbonyl)-o-phenylene diamm -(3-phenylprop3'lamino-carbonyl)-o-phenylene diamine; -[2-( ,N^ethyiammo)emylamino- arbonyl]-o-phenylene diamine; -(imidazolylainino-carbonyl)-o-phenylene diamine; -(pyrrolidinyl-carbonyl)-o-phenylene diamine; ^iperidino-carbonyl)-o-phenylene diamine; -(l -methylpiperazinyl-carbonyl)-o-pheny lene diamine; ^2,6-dimemylmoxpholini carbonyl)-o-phenylene diamine; -(pyiTolidin- 1 -y lamino-carbony l)»o-phenylene diamine; -(homopiperidin-l-ylamino-carbonyI)-o-phenylene cn'amine; -(4-methylpiperazin.e- 1 -ylamino-carbonyl)-o-phenylene diamine; -(l ,2,4-triazol-l-ylamino-carbonyl)-o-phenylene diamine; -(guanidinyl-carbonyl)-o-phenylene diamine; H;g addmylamino-carbonyl)-o-phenylene diamine; ammogAj^dmylamino-carbonyl)-o-phenylene diamine; -(diaminoguanidinylamino-carbonyl)-o-phenylene diamine; -hydroxy^^diemylamino-carbonyl)aniline; -hydroxy^-(tertbutylamino-carbonyl)aniline; - 36 - -hydroxy^-(isobutylamino-carbonyl)aniline; -hydroxy-4-(neopentyIamino-carbonyl)aniline; -hydroxy^^dipropylamino-carbonyl)aiuline; -hy
The lower alkyl groups of the compounds of Formula XII contain 1 -6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof. Likewise, the lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and include methoxy, ethoxy, isopropoxy, propoxy and the like. The hydroxy lower alkyl groups include primary, secondary and tertiary alcohol substituent patterns.
The aryl groups of the compounds of Formula ΧΕΓ encompass those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy and lower alkoxy groups.
The halo atoms in the above Formula XII may be fluoro, chloro, bromo and iodo.
The term biologically or pharmaceutically acceptable salts refers to salts which are tolerated by the mammalian body and are exemplified by acid addition salts derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic and related acids.
Of the compounds encompassed by Formula XH, certain substituents are preferred. For instance, the compounds wherein R32 is hydroxy and R33 is an amino group are preferred.
Representative of the compounds of Formula XII are : 3,4-diaminopyrazole; 3 ,4-diamino-5-hydroxy pyrazole; 3,4-cuamino-5-methylpyrazoIe 3 ,4-diamino-5-methoxypyrazole; 3,4-diamino-5-phenylpyrazole; 1 -methy 1 -hydroxy-4,5-diaminopyrazoIe; 1 -(2-hydroxyethyl)-3-hydroxy-4,5-diaminopyrazole; l-(2-hydroxyemyl)-3-phenyl-4,5-diammopyrazole; l-(2-hydroxyethyl) -methyl- ,5-diaminopyrazole; l^-hydroxyethyl -S-^aiimopyrazole; l-(2-hydroxypropyl)-3-hydroxy^,5-diaminopyrazole; 3-amino-5-hydroxypyrazole; and l-(2-hydroxy-2-meAylpropyl)-3-hydroxy^ and their biologically and pharmaceutically acceptable acid addition salts; wherein is oxygen or nitrogen; R3< is hydrogen, lower alkyl or aryl; R3S is hydrogen, lower alkyl, lower alkenyl, aryl, or hydroxy lower alkyl; R36 is hydrogen, hydroxy, lower alkyl, aryl, halo, lower alkanoyl, or aryl lower alkyl; and their biologically or pharmaceutically acceptable salts with organic or inorganic bases.
The lower alkyl groups of the compounds of Formula ΧΙΠ contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof. Similarly, the lower alkenyl groups referred to contain 2-6 carbon atoms and include ethenyl, propenyl and the like. The - 42 - lower alkanoyl groups likewise contain 2-6 carbon atoms and are exemplified by acetyl, propionyl and the like.
The aryl groups of the compounds of Formula XIII encompass those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and phenyl substituted by 1-2 halo, hydroxy and lower alkoxy groups.
The halo atoms in the above in Formula ΧΙΠ may be fluoro, chloro, bromo and iodo. The lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, propoxy, isopropoxy and the like.
The term biologically or pharmaceutically acceptable salts refers to salts which are tolerated by the mammalian body and are exemplified by salts derived from a variety of organic and inorganic bases such as amines, e.g., procaine, or Ν,Ν'-dibenzylemylenediamine, or alkali or alkaline-earth metal salts, e.g., potassium or sodium hydroxide, calcium hydroxide, and the like. Thus formed are the amine salts or the corresponding alkali or alkaline-earth metal salts.
Of the compounds encompassed by Formula XIII, certain patterns of substituents are preferred. For instance, when R3(5 is lower alkanoyl, then R¾ and R3J are preferably hydrogen, lower alkyl or phenyl. Also preferred are the compounds wherein R¾, R35 and R3S are all hydrogen, or those wherein R3fi is hydrogen- Representative of the compounds of Formula ΧΠΙ are: 2,4-pyrrolidinedione; 2,4(3H,5H)-furandione (tetronic acid); -ethyl-2,4(3H,5H)-furandione; -memyl-2,4(3H,5H)-furandione; -propyl-2,4(3H,5H)-mrandione; ,5-dimemyl-2,4(3H,5H)-furandione; -hexyl-5-methyl-2,4(3H,5H)-furandione; -ethylidene-2,4(3H,5H)-furandione; 3-butyl-2,4(3H,5H)-rurandione; 3-benzyI-2,4(3H,5H)-furandione; 3-ethyl-2,4(3H,5H)-furandione; 43 3-hyciToxy-2,4(3H,5H)-fuiaadione; 3-isobutyl-2,4(3H,5H)-furandione; 3 -isopentyl-2 ,4(3 H,5H)-furandione; 3-methyl-2,4(3H,5H)-furandione; 3-ethyl-5-methyl-2,4(3H,5H)-furandione; 3,5-fIiinethyl-2,4(3H-5H)-furandione; 3 ,5-diphenyl-2,4(3H,5H)-furandione; 3-methyl-5-(2-methyl-2-propenyI 2,4(3H,5H)-fi-raiidione; 3-propyl-2,4(3H,5H)-fmaiidione; 3-tert-biityI-2.4(3H,5H)-furandione; 3-fluoro-5-(4-methoxyphenyl)-2,4(3H,5H)-flirandione; 3-hydroxy-5-methyl-2,4(3H,5H)-fiaandione; 3-hydroxy-5-phenyl-2,4(3H,5H)-furandione,- 3-acetyl-2,4(3H,5H)-l irandione; S-acetyl-^S-dimelh W^CSHjSH^fiirandione; 3-acetyl-5-ethyl-2.4(3H,5H)-fi-randione; 3-acetyl-5-methyl'2,4(3H,5H)-fuiandione; (5R)-3-acetyl-5-methyl-2,4 3H,5H)-furandione; (5S>3-acetyl-5-me l-2,4(3H,5H)-furandione; 3-acetyl-5-phenyl-2,4(3H,5H)-furandione; (tetramic acid) -(l-hydroxyethyl)-2 pyrrolidinedioiie; -(l -methyletliyI)-2,4-pyTroUdinedione; (S)-5-(l-methylethyl)-2,4-pyiTolidinedione; -(l-methylpropyl)-2,4-pyTTolidinedione; (.+- -4-(2-methylpropyl)-2,4-pyTrolidinedione; -(2-methylpentyl)-2,4-pyiroU(iinedione; (.+--)-5-(2-methylpropyl)-2,4-pyrrolidinedione; (.+-.)-5-(2-phenylethyl)-2,4-pyrrolidinedione; (.+-.)-5-(3-methylbutyl)-2,4-pynOlidinedione; -ethyl-2,4-pyrrolidinedione; -hexyl-2,4-pyrrolidineclione; -meth.yl-2,4-pyrrolidinedione; -phenyl-2,4-pyrroIidinedione; 3-ethyl-5-phenyl-l-p--tolyl-2.4-pyrrolidinedione; 3-acetyl-l,5-dimemyl-2,4-pyrroIidinedione; 3,5-dietb.yl-5-phenyl-2,4-pyrrolidinedione; 3,5-dimethyl-5-p-toIyl-2,4-pyTrolidinedione; S^-dicnethyl-S-phenyl^^pyTrolidinedione; and 3^thyl-5-methyl-5-phenyl-2,4-pyiToUdinedione; H2N-NRao-C(= 39)-NR37R38 (XIV) wherein R37 is a lower alkyl group, or a group of the forrnula-NR41R,2 wherein is hydrogen, and R,,2 is a lower alkyl group or a hydroxy(lower)alkyl group; or R4 , and R42 together with the nitrogen atom are a heterocyclic group containing 4-6 carbon atoms and, in addition to the nitrogen atom, 0-1 oxygen, nitrogen or sulfur atoms; R38 is hydrogen or an amino group; R39 is hydrogen or an amino group; R,0 is hydrogen or a lower alkyl group; with the proviso that at least one of R3g, R39, and R_,0 is other than hydrogen; and with the further proviso that K and ¾β cannot both be amino groups; their pharmaceutically acceptable acid addition salts.
The lower alkyl groups of die compounds of Formula XIV contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the conresponding branched-chain isomers thereof.
The heterocyclic groups formed by the N-Re, R^ group are 4-7 membered rings having at 0-1 additional heteroatoms, e.g., oxygen, nitrogen, or sulfur, therein, and including various degrees of unsaturation. Representatives of - 45 - such heterocyclic groups are those such as morpholino, piperidino, hexahydroazepino, piperazino, methylpiperazino, hexamethylenimino, pyridyl, methylpyridyl, imidazolyl, pyrrolidinyl, 2,6-dimethylmorpholino, 1.2,4-triazoylyl, thiazolyl, thiazolinyl, and the like.
Equivalent to the compounds of Formula XIV for the purposes of this invention are the biocompatible and pharmaceutically acceptable salts thereof. Such salts can be derived from a variety of organic and inorganic acids, including, but not limited to, methanesulfonic, hydrochloric, hydrobromic, hydroiodic, toluenesulfonic, sulfuric, maleic, acetic and phosphoric acids.
When the compounds of Formula XIV contain one or more asymmetric carbon atoms, mixtures of enantiomers, as well as the pure (R) or (S) enantiomeric form can be utilized in the practice of this invention.
Of the compounds encompassed by Formula XTV, certain combinations of substituents are preferred. For instance, compounds wherein R37 is a heterocylic group, and particularly a morpholino or a hexahydroazepino group, are highly preferred.
Representative of the compounds of Formula XTV are: 2-(2-hydroxy-2-memylpropyl)hyo^razmecarboximidic hydrazide; N-(4-mo^hoHno)hydrazinecarho¾iTnidarnide; 1 -methy l-N-(4-morpholino)hydrazmecarboximidarnide; 1- memyl-N-(4-piperidmo)hydrazmecarboxiniidamide; 1 -( -hexahydroazepino)hy drazm^ N,N-dimethylcarbonimidic dihydrazide; 1 -methylcarbonimidic dihydrazide; 2- (2-hydroxy-2-memylpropyl)carbohydrazonic dihydrazide; and N-ethylcarbonimidic dihydrazide; (R43HN=)CR44-W-CR45(=NHR43) (XV) wherein ¾3 is pyridyl, phenyl or a carboxylic acid substituted phenyl group of the formula wherein R<6 is hydrogen, lower alkyl or a warer-solubilizing ester moiety; W is a carbon-carbon bond or an alkylene group of 1-3 carbon atoms, is a lower alkyl. aryl, or heteroaiyl group and R<, is hydrogen, a lower alkyl, aryl or heteroaryl group; and their biologically or pharmaceutically acceptable acid addition salts.
The lower alkyl groups of the compounds of Formula XI preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo, hydroxy, amino or lower alkylamino groups.
The alkylene groups of the compounds of Formula XV likewise can be straight or branched chain, and are thus exemplified by ethylene, propylene, butylene, pentylene, hexylene, and their corresponding branched chain isomers.
In the R groups which are a carboxylic acid substituted phenyl group of the formula: C-0 — R44 47 - wherein is hydrogen, lower alkyl or a water-solubilizing ester moiety, the water solubilizing ester moiety can be selected from a variety of such esters known in the art. Typically, these esters are derived from dialkylene or trialkylene glycols or ethers thereof, dihydroxyalkyl groups, arylalkyl group, e.g., nitrophenylalkyl and pyridylalkyl groups, and carboxylic acid esters and phosphoric acid esters of hydroxy and carboxy-substituted alkyl groups. Particularly preferred water-solubilizing ester moieties are those derived from 2,3-dihydroxypropane, and 2-hydroxyethylphosphate.
The aryl groups encompassed by the above Formula XV are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and are optionally substituted by 1-2 halo, nitro, hydroxy or lower alkoxy groups.
Where the possibility exists for substitution of a phenyl or aryl ring, the position of the substituents may be ortho, meta, or para to the point of attachment of the phenyl or aryl ring to the nitrogen of the hydrazine group.
The halo atoms in the above Formula XV may be fluoro, chloro, bromo or iodo. The lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoy, n-propoxy, isopropoxy and the like.
The heteroaryl groups in the above Formula XV contain 1-2 heteroatoms, i.e., nitrogen, oxygen or sulfur, and are exemplified by furyl, pyrrolinyl, pyridyl, pyrirr nyl, thienyl, quinolyl, and the corresponding alkyl substituted compounds.
For the purposes of this invention equivalent to the compounds of Formula XV are the biologically and pharmaceutically acceptable acid addition salts thereof. Such acid addition salts may be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, methanesulfonic and related acids. - 48 Of the compounds encompassed by Formula XV, certain substituents are preferred. For instance, the compounds wherein W is a carbon-carbon bond, R„4 is a methyl group and ¾5 is hydrogen are preferred.
Representative of the compounds of Formula XV are: methyl glyoxai bis-(2-bydra2ino-benzoic acid)hydrazone; methyl glyoxai bis-(dimethyl 2-hydrazinobenzoate) hydrazone; methyl glyoxai bis-(pheny ydrazme)hydrazone; methyl glyoxai bis-(dimethyl 2-hydrazmobenzoate) hydrazone; methyl glyoxai bis-(4-hydLtazinobenzoic acid)hydrazone; methyl glyoxai bis-(dimethyl 4-hycirazinobenzoate)hydrazone; methyl glyoxai bis-(2-pyridyl)hydrazone; methyl glyoxai bis-(diethylene glycol methyl ether-2-hydrazinobenzoate) hydrazone; methyl glyoxai bis-[l-(2,3-dihydroxvpropane)-2-hydrazmebenzoate]hydra∞ne methyl glyoxai bis-[l-(2-hydroxyemane)-2-hy
The lower alkyl groups of the compounds of Formula XVI preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo hydroxy, amino or lower alkylamino groups.
The alkylene groups of the compounds of Formula XVI likewise can be straight or branched chain, and are thus exemplified by ethylene, propylene, butylene, pentylene, hexylene, and their corresponding branched chain isomers.
The aryl groups encompassed by the above Formula XVI are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g. tolyl and xylyl, and are optionally substituted by 1-2 halo, hydroxy or lower alkoxy groups.
The halo atoms in the above Formula XVI may be fluoro, chloro, bromo or iodo. The lower alkoxy groups contain 1-6, and preferably 1-3, carbon atoms and are illustrated by methoxy, ethoxy, n-propoxy, isopropoxy and the like.
The heteroaryl groups in the above Formula XVI contain 1 -2 heteroalorns, i.e. nitrogen, oxygen or sulfur, and are exemplified by be furyl, pyrrolinyl, pyridyl, pyrimidinyl, thienyl, quinolyl, and the corresponding alkyl substituted compounds.
For the purposes of this invention equivalent to the compounds of Formula XVI are the biologically and pharmaceutically acceptable acid addition salts thereof. Such acid addition salts may be derived from a variety of organic and inorganic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, methanesulfonic and related acids.
Of the compounds encompassed by Formula XVI, certain substituents are preferred. For instance, the compounds wherein R,8 and R 9 are together an alkylene group of 2-3 carbon atoms are preferred. The compounds wherein Rj2 and RS3 together are a butylene, ethylene, or an ethenylene group and those wherein and R53 are both methyl or furyl groups are also highly preferred.
Representative of the compounds of Formula XVI are: methyl glyoxal bis(guanylhydrazone); methyl glyoxal bis(2-hyci-¾zmo-2'imidazoline-hyclrazone); terephthaldicarboxaldehyde bis(2-hydrazino-2-imidazoline hydrazone); terephaldicarboxaldehyde bis(guanylhydrazone); phenyl glyoxal bis(2-hydrazmo-2-in dazoline hydrazone); furyl glyoxal bis(2 -hydra .dno-2-imidazolijae hydrazone); methyl glyoxal bis>l-(2-hydroxyetfayl)-2-hydrazmo-2-irnidazolme hydrazone!; methyl glyoxal bis>H2-hydroxyetoyl>2¾drazmo-l,^ hydrazone!; phenyl glyoxal bis(guanylhydrazone); phenyl glyoxal bis>1^2-hydroxyemyl)-2-hydrazmo-2-irnidazoline hydrazone!; furyl glyoxal bis>H2-hydroxyemyl)-2-hydMzmo-2-iirdl-(2-hydroxyethyl)-2-hydrazmo-l,4,5,6-tetrahydropyrimi^ hydrazone!; furyl glyoxal bis>l-(2-hydroxyethyl)-2-hydrazmo-l,4,5,6-tetrahydropyri^ hydrazone!; 2.3- butanedione bis(2-hydrazmo-2-imidazoline hydrazone); 1.4- cy clohexane dione bis(2-hydrazko-2-imidazoIine hydrazone! ; o-phthalic dicarboxaldehyde bi.3(2-hydrazmo-2-imida2»line hydrazone); 2.3- naphthalene dialdehyde bis(2-hycirazino-2-in-idazoline hydrazone); 1 ,2-cyclohexanedione bis(2-hydrazino-2-irnidazoline hydrazone); 2.4- pentanedione bis(2-hydra2iao-2-imidazoline hydrazone); furyl bis(2-hydrazino-2-irnidazoIine hydrazone); 1,4-benzoquinone bis(2-hydrazino-2--midazoline hydrazone); methyl glyoxal bis(2-hydrazino-l,4,5,6-tetrahydropyrirnidine hydrazone); methyl glyoxal bis)N-(2,2-dimethyl-3-dimethylaminopropyl)hydrazm carboximidamide hydrazone!; methyl glyoxal bis>N-3-dimeuiylaniinopropyl)hydrazinecarboximidamide hydrazone!; methyl glyoxal bis{N- 2-( -mo ho^no)ethyl!hydΓazinecaΓboxίmidamide hydrazone}; and methyl glyoxal bis{N->3-(4-methyIpiperazin-l-yl)propyl!hydrazine - 52 - carboximidamide hydrazone}; furyl glyoxal bis (guanyl hydrazone)dihydxochloride dihydrate; 2,3-pentanedione bis(2-tetrahydropyrimidine)hydrazone dihydrobromide; 1.2- cycIohexanedione bis(2-teti^ydropyrirnidine)hydrazone dihydrobromide; 2.3- hexanedione bis(2-tetrahydropyrixnidine)hydrazone dihydrobromide; 1,3-diacetyl bis(2-tetrahydropyrimidine)hydrazone dihydrobromide; 2.3- butanedione bisC2-tetrahydTopyrirrddine)hydrazene dihydrobromide; 2,6-diacerylpyridllne-bis-(2-hydra-d-M-2-m^ hydra2one)dihydrobromide; 2,6-diacerylpyridme-bis-(grianylhydr^ 2,6-pyridine cUcartoxaldehyde-bis-(2-hyd hydrazone)dihydrobromide tnhydrate); 2,6-pyridine dicarboxaldehyde-bis(guanyl hydrazone)dihydrochloride; 1.4- diacetyl benzene-bis-(2-hy(lrazino-2-iinidazoline hyd^azone)dihydrobrornide dihydrate; 1,3-diacetyl bexizene-bis-(2-hydraano 2-irm^ dihydrobromide; 1.3- diacetyI benzene-bis(guanyl)-hydrazone dihydrochloride; isophthalaldehyde-bis-(2-hydramo-2-i^ isophthalaldehyde-bis-(guanyl)hydrazone dihydrochloride; 2,6-diacetylaniIine bis-(guanyl)hydrazone dihydrochloride; 2,6-diacetyl aniline bis-(2-hydjazmo-2-iimdazolme)hyclra2one dihydrobromide; 2.5- diacetylthiophene bis(guanyl)hydrazone dihydrochloride; 2,5-diacetylthiophene bis-(2-hydra2ino-2-iir-idazolme)hycira2orie dihydrobromide; 1.4- cyclohexanedione bis(2-tetrahydropyrimidine)hydxazoiie dihydrobromide; 3,4-hexanedionB bis(2-tetrahydropyrmTidine)hydrazone dihydrobromide; methyl glyoxal-bis-(4-amino-3-hydrazmo-l ^ dihydrochloride; methyl glyoxal-bis-(4-armno-3-hydra2^^ dihydrochloride; 2,3 -pen1-Medione-bis-(2-hydra-dno-3 -imidazole dihydrobromide; 2,3-hexanedione-bis-(2-hydrazmo-2-imida2oline)hydrazone dihydrobromide; 3-ethyl-254-pentane dione-bis^2-hydra.dno-2-im^ dihydrobromide; methyl glyoxal-bis-(4-aminc-3-hydrazino-5-ethyl- 1 ,2,4-triazole)hydrazone dih drochloride; methyl glyoxal-bi-H4-amino-3-hydrazino-5-isopropy dihy drochloride; methyl glyoxal-bis-(4-amino-3-hy drazino-5-cy clopropyl- 1 ,2,4-triazole)hy drazone dihydrochlori methyl glyoxal-bis^4-acruno-3-hydra2ino-5-cyclobutyl-l ^,4-uiazole)hydrazone dihydrochlorid l,3-cyclohexanedione-bi-3-(2-hydra2mo-2-imida2oline)hydrazone dihydrobromide; 3,5^iaceryl-l,4-
The lower alkyl groups of the compounds of Formula XVII contain 1-6 carbon atoms and include methyl, ethyl, propyl, butyl, pentyl, hexyl, and the corresponding branched-chain isomers thereof. The lower alkynyl groups contain from 2 to 6 carbon atoms. Similarly, the lower alkoxy groups contain from I to 6 carbon atoms, and include methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy, and the corresponding branched-chain isomers thereof. These groups are optionally substituted by one or more halo, hydroxy, amino or lower alkylamino groups.
The lower ac lox (1 o wer)alky 1 grotips encompassed by the above Formula XVII include those wherein the acy loxy portion contain from 2 to 6 carbon atoms and the lower alkyl portion contains from 1 to 6 carbon atoms.
Typical acy loxy portions are those such as acetoxy or ethanoyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, and the corresponding branched chain isomers thereof. Typical lower alkyl portions are as described hereinabove. The aryl groups encompassed by the above formula are those containing 6-10 carbon atoms, such as phenyl and lower alkyl substituted-phenyl, e.g., tolyl and xylyl, and are optionally substituted by 1-2 halo, hydroxy, lower alkoxy or di ower)alkylammo groups. Preferred aryl groups are phenyl, methoxyphenyt and 4-bromophenyl groups.
The halo atoms in the above Formula XVII may be fluoro, chloro, bromo or iodo.
For the purposes of this invention, the compounds of Formula XVII are formed as biologically and pharmaceutically acceptable salts. Use ul salt forms are the halides, particularly the bromide and chloride, tosylate, rnethanesulfonate, and mesitylenesulfonate salts. Other related salts can be formed using similarly non-toxic, and biologically and pharmaceutically acceptable anions.
Of the compounds encompassed by Formula XVII, certain substituents are preferred. For instance, the compounds wherein j4 or R55 are lower alkyl groups are preferred. Also highly preferred are the compounds wherein Ya is a 2-phenyl-2-oxoethyl or a 2-[4'-bromophenyl]-2-oxoethyl group.
Representative of the compounds of Formula XVII are: - 55 - -aminothiazolium mesitylenesulfonate; -aiiuno^,5-dime hylaminothiazolium mesitylenesulfonate; .3- diaminothiazolinium mesitylenesulfonate; -(2-memoxy-2-oxoemyl mia2oIium bromide; -(2-methoxy-2^xoethyl)^,5-dimethylthiazolium bromide; -(2-memoxy«2-oxoemyl)- -methylthiazolium bromide; -(2-phenyI-2-oxoemyl)^methylthi2olium bromide; -(2-phenyl-2-oxoemyl)^^-xoemyl)^memyl-5 2-hydroxyemyl)tbiazolium bromi -(2-phenyl-2-oxoemyl)^memyl-5-(2-hydroxyemyl)tliiazouum broim -[2-(4'-bromophenyl)-2 3xoemyl]^memyl-5-(2-hydroxyemyl)l-iiazoli .4- dimethyl-5-(2-hydroxy et3ayl)thiazolium iodide; ^thyl-5-(2-hydroxyemyl)^-memylthiazolium bromide; -ben-tyl-5^2-hydroxye1iiyl)^memyltliiazoUum cU -(2-memoxy-2-oxoemyl)benzotHazolium bromide; -(2-phenyl-2-oxoemyl)berizothiazolium bromide; -[2-(4¾romophenyl)-2^xoemyl]ben20thiazolium bromide; -(carboxymemyl)beri2»thiazolium bromide; -(diamino)benzothiazolium mesitylenesulfonate; -(2-amino-2-oxoethyl)thiazolium bromide; -(2-amino-2-oxoethyl)-4-methy lthiazolium bromide; -(2-amino-2-oxoethyl -5-methylthiazolium bromide; -(2-arnino-2-oxoethyl)4,5-dimethy lthiazolium bromide; -(2-amino-2- oxoethyl) benzothiazolium bromide; -(2-amino-2- oxoethyl) 4-methyl-5 2-hydroxyei3iyl)thiazolivim bromide; -amino-5-(2-hydroxyethyl)- -methylthiazolium mesitylenesulfonate; -(2-methyl-2-oxoethyl)tbiazolium chloride; -ammo^-methyl-5-(2-acetoxyethyl)thia2olium mesitylenesulfonate; -(2-phenyl-2-oxoethyl)thiazolium bromide; -(2-methoxy-2-oxoethyl)^methyl-5-(2-acetoxyethyl)i azoUurn bromide; -(2-amino-2^xoethyl)^-memyl-5-(2-acetoxy -ammo-3-(2-methoxy-2-oxoemyl)thiazoliiim bromide; -amino-3-(2-methoxy-2-oxoetiiyl)ben^t& -aimno-3-(2-ainino-2^xoethyl)thiazoliuiri bromide; - axnino-3-(2-amino-2-oxoethyl)beiLzothiazoliurn bromide; - [2-(4'-methoxyphenyl)-2-oxoethyl]-tbiazolinium bromide; -[2-(2^4'Hdimemoxyphcnyl)-2-oxoethyl]-thiazolinium b^^ -[2-(4'-fluorophenyl)-2H3xoethyl]-thiazoliriium bromide; -[2-(2^4'-o fluorophenyl)-2H3xoemyl]-trda2»lmiiim bromide; . -[2-(4'-diemylaminophenyl)-2^xoe yl]-t^ -propaigyl-thiazoliiiium bromide; -propargyl^methylthiazolinium bromide; -propargyl-5-methyltliiazoliDium bromide; -propargy ,5-cl-methylthia2ol-j-ium bromide; and -propargyM-methyl-5^-hydroxyemyl)-tliiazoliiiium bromide; - 57 - wherein R,7 is OH, NHCONR^, or N-CCNR^R^; Re, and R«2 are each independently selected from the group consisting of hydrogen; CH0 alkyl, straight or branched chain; aryl C alkyl; and mono- or disubstituted aryl CM alkyl where the substituents are fluoro, chloro, bromo, iodo or C 0 alkyl, straight or branched chain; Rsg and are each independently selected from the group consisting of hydrogen, amino, and mono- or di-substituted amino where the substituents are CM0 alkyl, straight or branched chain C^, cycloalkyl; provided that R| and Rj may not both be amino or substituted amino; and Rio is hydrogen, trifluoromethyl; fluoro; chloro; bromo; or iodo; or a pharmaceutically acceptable salt thereof.
The compounds to be used in the methods of this invention also include so-called nutraceuticals, for example, certain amino acids, vitamins or the like which are effective when adrninistered individually, but preferably in combination, to bind to or otherwise interfere with the production of 3DG.
Representative examples of such substances are Vitamin C and lysine.
The methods of the present invention may also be practiced using antibodies or other immunoreactive substances that are capable of binding to 3DG precursors. These include, without limitation, the antibodies described in the above-mentioned U.S. Patents Nos. 5,223,392, 5,494,791 and 5,518,720.
Pharmaceutical preparations which may be used in practicing the method of the present invention comprise one or more of the agents described above, as the active ingredient, in combination with a pharmaceutically acceptable carrier medium or auxiliary agent.
These ingredients may be prepared in various forms for administration, including both liquids and solids. Thus, the preparation may be in the form of tablets, caplets, pills or dragees, or can be filled in suitable containers, such as capsules, or, in the case of suspensions, filled into bottles. As used herein, "pharmaceutically acceptable carrier medium" includes any and all solvents, - 58 - diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Representative examples of suitable carrier media include gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or the like. Remington's Pharmaceutical Sciences. Fifteenth Edition, E.W. Martin (Mack Publishing Co., Easton, PA 1975) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the enzyme inhibitors of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical preparation, its use is contemplated to be within the scope of this invention.
In the pharmaceutical preparations of the invention, the active agent(s) may be present in an amount of at least 0.01% and generally not more than 10% by weight, based on the total weight of the preparation, including carrier medium and/or auxiliary agent(s), if any. Preferably, the proportion of active agent varies between 1.0% - 5.0% by weight of the composition.
Anti-hypertensive drugs, including particularly the angiotensin-converting enzyme (ACE) inhibitors, may also be included as supplementary active agents in the pharmaceutical preparations of this invention.
Auxiliary agents, such as compounds that will protect the active agent from acid destruction in the stomach or facilitate the absorption of the active compound into the bloodstream can also be incorporated into the pharmaceutical preparation, if necessary or desirable. Such auxiliary agents may include, for example, complexing agents such as borate or other salts which partially offset the acid conditions in the stomach, and the like. Absorption can be increased by delivering the active compound as the salt of a fatty acid (in those cases where the active compound contains one or more basic functional groups).
The compounds of the invention, along with any supplementary active irigredient(s) may be administered, using any amount and any route of administration effective for binding to glycated protein, in vivo. Thus, the expression "therapeutically effective amount", as used herein, refers to an amount of the therapeutic agent which is at once non-toxic and sufficient to provide the desired reduction in susceptibility to carcinoma associated with the intake of glycated protein. The exact amount required may vary, depending on the species, age, and general condition of the patient, the particular therapeutic agent and its mode of administration, and the like.
The agents used in the method of the invention are preferably formulated in dosage form for ease of aclministration and uiuforrnity of dosage. Dosage unit form as used herein refers to a physically discrete unit of the therapeutic agent appropriate for the patient to be treated. Each dosage should contain the quantity of active material calculated to produce the desired therapeutic effect either as such, or in association with the selected pharmaceutical carrier medium. Typically, the small molecule agents used in practicing this invention will be administered in dosage units containing from about 25 mg to about 2500 mg of the compound, per dose, with a range of about 250 mg to about 750 mg being preferredL The agents of the invention may be administered orally, parenterally, such as by intramuscular injection, intraperitoneal injection, intravenous infusion or the like, depending on the stability of the selected compounds to the various physiological conditions encounted in each route of administration. The small molecule agents may be administered orally or parenterally at dosage levels of about 1 mg to about 50 mg and preferably from about 10 mg to about 25 mg/kg, of patient body weight per day, one or more times a day, to obtain the desired therapeutic effect. Orally active agents are particularly preferred, provided the oral dose is capable of generating blood and/or target tissue levels of the above-described agents that are therapeutically active.
The normal concentration of immunoreactive agent used in the methods of this invention, including antibodies and antibody fragments, will be - 60 - from about 1.0 mg and about 10 mg. These will typically be administered by intravenous or intraarterial infusion.
The compounds of the invention will typically be administered once per day or up to four times per day, depending upon the specific agent chosen. The exact regimen for administration of the compounds described herein will necessarily be dependent on the needs of the individual subject undergoing treatment, the type of therapy administered and the judgment of the attending physician. As used herein, the term "subject" includes both humans and animals.
While it is known that 3DG is an endogenously produced reactive dicarbonyl correlated with numerous pathologic conditions, it is not widely known that 3DG is present in various foodstuffs, the ingestion of which contributes to endogenous levels of 3DG. Examples of a number of commercial 3DG-containing syrups and a soft drink, along with the 3DG content thereof is presented in the following table.
TABLE 1 High Fructose Com Syrup #1 2.65 πιοΐϋ^ High Fructose Com Syrup #2 2.26 umols/g Karo® Pancake Syrup 380 nmols/g aro® Light Syrup 340 nmols/g Crystal Light Syrup (Acme) 57 nmols/g Aunt Jemima® Pancake Syrup 360 nmols/g Pepsi Cola® 0.54 m The production of high fructose com syrup involves treating a solution of glucose with xylose isomerase. 3DG is produced as a by-product of this process. Furthermore, while catalyzing the reversible interconversion of D-x lose and D-xylulose, xylose isomerase (XI) has been observed by 13C-NMR spectroscopy to produce D-lyxose and 3-deoxy-D-xyIosone (3-deoxy-D-glycero - 61 - pentose-2-ulose).
High fructose com syrup solutions having reduced 3DG content may be obtained by treatment with an adsorbent resin or other suitable separation medium capable of selectively binding 3DG.
From preliminary observations on the ratios of 3DG and 3DF in the urine of diabetics and non-diabetics, diabetics appear to have reduced ability to detoxify 3DG of either endogenous or exogenous origin as well as a higher flux through the pathways that generate 3DG. These two factors combine to produce higher urinary concentrations of 3DG in diabetics (Lai et al., Arch. Biochem. and Biophys., 342(1): 254-60 (1997). See also the above-mentioned, published international patent application, WO 98/33492.
Although diabetic patients have significantly more 3DG in serum than do non-diabetic patients (12.78 ± 2.49 μΜ versus 1.94 + 0.17 u ) (Toshimitsu Niwa et al.a Nephron, 6JJ: 438 (1 95)), this compound is also found in healthy individuals. The body has developed clearance mechanisms for this molecule. One of these reactions is catalyzed by aldehyde reductase which detoxifies 3DG by reducing it to 3-deoxyfhictose (3DF) which is efficiently excreted in the urine (Takahashi et al., Biochem., 3 ,: 1433 (1995)). Another detoxification reaction oxidizes 3DG to 3-deoxy«2»ketogluconic acid (DGA_ by oxoaldehyde dehydrogenase (Fujii et al., Biochem. Biophys. Res. Comm.. 21_0: 852 (1995)).
Results of studies to date show that the efficiency of at least one of these enzymes, aldehyde reductase, is adversely affected in diabetes. When isolated from normal rat liver, a fraction of this enzyme is partially glycated on lysines 67, 84 and 140 and has low catalytic efficiency when compared with the normal, unmodified enzyme (Takahashi et al., Biochem., 34: 1433 (1995)). Since diabetic patients have higher ratios of glycated proteins than normoglycemic individuals they are likely to have both higher levels of 3DG and a reduced ability to detoxify this reactive molecule by reduction to 3DF. The ingestion of exogenous 3DG found in foodstuffs therefore represents an additional risk factor for the - 62 - development and progression of complications in diabetic patients. Even in a clinically healthy individual, sufficient amounts of 3DG may exceed the physiologic capacity for detoxification. Thus, consumption of exogenous 3DG in foodstuffs is a risk factor for healthy individuals for the development of 3DG-related diseases and conditions.
The following examples are provided to describe the invention in further detail. These examples are provided for illustrative purposes only, and should in no way be construed as limiting the invention. All temperatures given in the examples are in degrees centigrade unless otherwise indicated.
EXAMPLE 1 CARCINOGENIC EFFECTS OF FRUCTOSELYSINE PATHWAY To investigate the carcinogenic potential of metabolites formed in the fructoselysine pathway, experiments have been conducted on a strain of rats with a high susceptibility to kidney carcinomas. Four rats were put on a glycated protein diet and three rats on a control diet, After ten weeks on the diet, the animals were sacrificed and their kidneys examined. In all four animals on the diet, kidney carcinomas of size greater than 1mm were found, whereas no lesions this large were found in the control animals. The probability of this happening by chance is less than 2%, The data show that the elevated 3DG levels caused by the excess iructoselysine coming from the glycated protein in the animals diet found in the kidney tubular cells (known to be the cell of origin of most kidney carcinomas) can interact with the cellular DNA leading to a variety of mutagenic and ultimately carcinogenic events. The foregoing data indicate that this process is important in the development of human cancers in the kidney and elsewhere.
EXAMPLE 2 DIETARY EFFECTS OF GLYCATED PROTEIN DIET ON RENAL CELL CARCINOMA IN SUSCEPTD3LE RATS In additional experiments assessing the relationship between a glycated protein diet and renal cell carcinoma, twenty-eight rats with a mutation making them susceptible to the development of kidney carcinoma were divided into two cohorts. One cohort was fed a glycated protein diet: the other cohort was on a control diet. The glycated protein diet consisted of a standard nutritious diet to which 3% glycated protein had been added. The glycated protein was made by mixing together casein and glucose (2: 1) adding water (2X the weight of the dried material) and baking the mixture at 60 °C for 72 hours. The control was prepared in the same way except that no water was used and the casein and glucose were not mixed prior to baking. Rats were placed on the diets immedu-tely following weaning at three weeks of age and maintained on the diets ad libitum for the next 16 weeks. The animals were then sacrificed, the kidneys fixed and nemotoxylin and eosin sections were made. These were examined for lesions by a trained pathologist. Four types of lesions were identified. These included: cysts, very small collections of tumor-like cells, typically less than 10 cells; small tumors, 0.5 mm or less, and tumors greater than 0.5 mm: For every type, more lesions were observed in the animals on the glycated diet than on the control diet as shown in the following table.
To summarize the results, the average number of lesions per kidney - 64 - section was computed for each diet These were 0.82 ± 0.74 and 2.43 ± 2.33 in the control and glycated diet, respectively. The likelihood of this happening by chance is about 2 in 100,000.
These results provide strong support for the premise that effects of the lysine recovery pathway, the discovery of which underlie the present invention, extend to causing mutations, and thus are an etiologic factor in the development of carcinoma, as well. These results provide a basis for the development of therapeutic methods and agents to counteract this pathway in order to reduce cancer in the kidney as well as i other organs where this pathway produces similar effects.
While certain embodiments of the present invention have been described and/or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to the particular embodiments described and/or exemplified, but is capable of considerable variation and modification without departure from the scope of the appended claims.
Claims (12)
1. Use of an agent which is effective to bind a substance selected from the group of 3-Deoxyglucosone (3DG) and at least one precursor of 3DG for the manufacture of a medicament capable of reducing a susceptibility to tumor formation in a subject, caused by the presence in said subject of a substance selected from the group of 3DG and at least one precursor of 3DG, substantially as described in the specification, said agent being either (I) a compound selected form the group consisting of those having Formulas I-XVIII, as set forth in the foregoing specification and aminoguanidine , or (ii) a monoclonal antibody which specifically binds an epitope that is found in native glycated albumin that has been subjected to no artificial modification, but that is not found on unglycated albumin, said epitope occurring at boy lys-lys and lys-his sequences, said antibody specifically binding more than one of said sequences located at residues selected form the group consisting of lysine-199, lysine-281, lysine-439 and lysine-525, and said antibody being insignificantly reactive with other proteins .
2. Use of an agent according to claim 1 , wherein the tumor is renal cell carcinoma.
3. Use of an agent according to claim 1 , wherein said agent binds 3DG.
4. . Use of an agent according to claim 1 , wherein said monoclonal antibody binds a 3DG precursor.
5. Use of an agent according to claim 4 , wherein said precursor is Fructose-lysine-3-phosphate . 66 145,957/3
6. Use of an agent according to claim , wherein said precursor is glycated protein .
7. Use of an agent according to claim 6 , wherein said precursor is glycated albumin.
8. Use of an agent according to claim 7 , wherein said Immunoreactive agent binds the glycated albumin epitope bound by the monoclonal antibody produced by cell line ATCC HB 9596.
9. Use of an agent according to claim 8 , wherein said immunoreactive agent is a monoclonal antibody that specifically binds to an epitope present on glycated albumin, but not present on non-glycated albumin or other human proteins .
10. Use of an agent according to claim 6, wherein said precursor is glycated low density lipoprotein.
11. Use of an agent according to claim 10, wherein said Immunoreactive substance is a monoclonal antibody that specifically binds an epitope comprising N-deoxyfructosyllysine, said epitope being present in glycated low density lipoprotein, but not present in unglycated low density lipoprotein or in other glycated or unglycated plasma proteins , wherein said epitope is present in a polipoprotein B of glycated low density lipoprotein .
12. A pharmaceutical composition for reducing a susceptibility to tumor formation in a subject caused by 67 145,957/2 the presence in said subject of a substance selected from the group of 3-deoxyglucosone (3DG) and at least one precursor of 3DG comprising an agent which is effective to bind said 3DG or said 3DG precursor said agent being either (I) a compound selected form the group consisting of those having Formulas I -XVI I I , as set forth in the foregoing specification and aminoguanidine , or (ii) a monoclonal antibody which specifically binds an epitope that is found in native glycated albumin that has been subjected to no artificial modification, but that is not found on unglycated albumin, said epitope occurring at boy lys-lys and lys-his sequences, said antibody specifically binding more than one of said sequences located at residues selected form the group consisting of lysine-199, lysine-281, lysine-439 and lysine-525, and said antibody being insignificantly reactive with other proteins. For the Applicant WOLFF, BREG MAN AND GOLLER
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PCT/US2000/010071 WO2000062626A1 (en) | 1999-04-15 | 2000-04-17 | Method for reducing a susceptibility to tumor formation induced by 3-deoxyglucosone and precursors thereof |
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US6290929B1 (en) * | 2000-07-28 | 2001-09-18 | The Procter & Gamble Company | Cancer treatment |
SE523153C2 (en) * | 2000-12-28 | 2004-03-30 | Gambro Lundia Ab | Method of detoxification of medical solution |
US7622117B2 (en) | 2002-04-17 | 2009-11-24 | Dynamis Therapeutics, Inc. | 3-deoxyglucosone and skin |
US9051583B2 (en) | 2011-12-19 | 2015-06-09 | Northwestern University | Modified silica shell particles, and methods of making and using the same |
AR108671A1 (en) * | 2016-06-03 | 2018-09-12 | Enlibrium Inc | IMIDODICARBONIMIDIC DIAMIDE ANALOGS |
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US5334617A (en) * | 1984-03-19 | 1994-08-02 | The Rockefeller University | Amino acids useful as inhibitors of the advanced glycosylation of proteins |
US5100919A (en) * | 1984-03-19 | 1992-03-31 | The Rockefeller University | Biguanides and derivatives thereof as inhibitors of advanced glycosylation of a target protein |
US5468777A (en) * | 1984-03-19 | 1995-11-21 | The Rockefeller University | Method and agents for preventing and reversing the staining of teeth |
US5114943A (en) * | 1984-03-19 | 1992-05-19 | The Rockefeller University | Amino-substituted pyrimidines, derivatives and methods of use therefor |
US5258381A (en) * | 1984-03-19 | 1993-11-02 | The Rockefeller University | 2-substituted-2-imidazolines |
US5130324A (en) * | 1984-03-19 | 1992-07-14 | The Rockefeller University | 2-alkylidene-aminoguanidines and methods of use therefor |
US5272165A (en) * | 1984-03-19 | 1993-12-21 | The Rockefeller University | 2-alkylidene-aminoguanidines and methods of use therefor |
US5262152A (en) * | 1984-03-19 | 1993-11-16 | The Rockefeller University | Amidrazones and derivatives thereof |
US5476849A (en) * | 1984-03-19 | 1995-12-19 | The Rockefeller University | Methods for glycosylation inhibition using amino-benzoic acids and derivatives |
US4665192A (en) * | 1984-03-19 | 1987-05-12 | The Rockefeller University | 2-(2-furoyl)-4(5)-2(furanyl)-1H-imidazole |
US5358960A (en) * | 1984-03-19 | 1994-10-25 | The Rockefeller University | Method for inhibiting advanced glycosylation of proteins using aminosubstituted imidazoles |
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US5318982A (en) * | 1984-03-19 | 1994-06-07 | The Rockefeller University | Inhibition of the advanced glycosylation of proteins using substituted-1,2,4-triazoles |
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US5223392A (en) * | 1988-01-25 | 1993-06-29 | Exocell, Inc. | Monoclonal antibodies against glycated albumin, hybrid cell lines producing these antibodies, and use therefore |
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US5518720A (en) * | 1992-12-30 | 1996-05-21 | Exocell, Inc. | Treatment of complications of diabetes with substances reactive with the fructosyl-lysine structure in glycated albumin |
US5500439A (en) * | 1993-12-09 | 1996-03-19 | Alteon Inc. | Aminopyrazoles |
US5661139A (en) * | 1995-01-13 | 1997-08-26 | Alteon Inc. | Bis-(2-aryl) hydrazones |
US5698563A (en) * | 1995-01-13 | 1997-12-16 | Alteon Inc. | Bis- hydrazones! |
US5656261A (en) * | 1995-01-18 | 1997-08-12 | The Picower Institute For Medical Research | Preventing and reversing advanced glycosylation endproducts |
US5850840A (en) * | 1995-11-15 | 1998-12-22 | Alteon Inc. | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
CN1211321A (en) * | 1995-12-26 | 1999-03-17 | 皮考瓦医疗研究院 | Methods for measurment and treatment predicated on presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
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US6004958A (en) * | 1997-02-05 | 1999-12-21 | Fox Chase Cancer Center | Compounds and methods for therapeutic intervention in preventing diabetic complications and procedures for assessing a diabetic's risk of developing complications and determining the efficacy of therapeutic intervention |
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