AU2008202073A1 - 1-Butyric acid derivatives and their use - Google Patents
1-Butyric acid derivatives and their use Download PDFInfo
- Publication number
- AU2008202073A1 AU2008202073A1 AU2008202073A AU2008202073A AU2008202073A1 AU 2008202073 A1 AU2008202073 A1 AU 2008202073A1 AU 2008202073 A AU2008202073 A AU 2008202073A AU 2008202073 A AU2008202073 A AU 2008202073A AU 2008202073 A1 AU2008202073 A1 AU 2008202073A1
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- cycloalkyl
- aryl
- hal
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical class CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 42
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000008030 elimination Effects 0.000 claims description 6
- 238000003379 elimination reaction Methods 0.000 claims description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 210000000845 cartilage Anatomy 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 206010036030 Polyarthritis Diseases 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 3
- 230000001028 anti-proliverative effect Effects 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 230000001613 neoplastic effect Effects 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 208000025747 Rheumatic disease Diseases 0.000 claims description 2
- 239000003435 antirheumatic agent Substances 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 238000002659 cell therapy Methods 0.000 claims description 2
- 230000007850 degeneration Effects 0.000 claims description 2
- 239000000032 diagnostic agent Substances 0.000 claims description 2
- 229940039227 diagnostic agent Drugs 0.000 claims description 2
- 230000001771 impaired effect Effects 0.000 claims description 2
- 208000014674 injury Diseases 0.000 claims description 2
- 229960000681 leflunomide Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 230000000750 progressive effect Effects 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000000552 rheumatic effect Effects 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 238000009168 stem cell therapy Methods 0.000 claims description 2
- 238000009580 stem-cell therapy Methods 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 230000008733 trauma Effects 0.000 claims description 2
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000034659 glycolysis Effects 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- ZULHCBGKPZYNNU-UHFFFAOYSA-N methyl 4-cyano-4-oxobutanoate Chemical compound COC(=O)CCC(=O)C#N ZULHCBGKPZYNNU-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- VACMTKGMNYPSRC-IHWYPQMZSA-N (Z)-2-amino-3-hydroxybut-2-enoic acid Chemical compound C\C(O)=C(\N)C(O)=O VACMTKGMNYPSRC-IHWYPQMZSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- -1 lysine Chemical class 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- QUAGSYNZLDNHFW-UHFFFAOYSA-N 4-cyano-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)C#N QUAGSYNZLDNHFW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102100027456 Cytochrome c oxidase subunit 2 Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000010454 Experimental Liver Neoplasms Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 101000725401 Homo sapiens Cytochrome c oxidase subunit 2 Proteins 0.000 description 1
- 101000605127 Homo sapiens Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 102000014171 Milk Proteins Human genes 0.000 description 1
- 108010011756 Milk Proteins Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940059756 arava Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-O cyclohexylammonium Chemical compound [NH3+]C1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-O 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000005454 flavour additive Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- SRXOJMOGPYFZKC-UHFFFAOYSA-N methyl 4-chloro-4-oxobutanoate Chemical compound COC(=O)CCC(Cl)=O SRXOJMOGPYFZKC-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000021239 milk protein Nutrition 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000019261 negative regulation of glycolysis Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
P001 Section 29 Regulation 3.2(2)
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: 1-Butyric acid derivatives and their use The following statement is a full description of this invention, including the best method of performing it known to us: P111AHAU/1107 -t- 00 Ct 1-Butyric acid derivatives and their use M Description O The invention concerns butyric acid derivatives, 00 10 pharmaceutical compounds containing such derivatives as well as uses of such derivatives for the manufacture of pharmaceutical compounds for the treatment of various illnesses.
Today cancer is one of the most common causes of death, and the number of cancer cases in industrialized countries is constantly on the rise. Above all this is connected with the fact that malignant tumours are an illness associated with advanced age, and thanks to the successful fight against infectious diseases more people now reach this age. Despite all the progress in diagnostic and therapeutic areas, the prospects of a successful cure for the most commonly occurring internal forms of cancers are seldom greater than 20%. At the present time, a cancerous growth can be eradicated or its growth inhibited. A reverse transformation of a tumour cell to a normal cell is not yet achievable. The most important therapeutic measures surgery and irradiation remove the cancer cells from the organism. The common current chemotherapeutic treatments of cancer, cytostatics, only lead to destruction or damage of tumour cells. The effect in most cases is not very selective, so that at the same time severe damage to healthy cells occurs. In general tumour cells have a different metabolism from healthy cells, in particular for glycolysis. Thus a change of the enzyme system involved in glycolysis and a change in NADH transport is typical for tumour cells. Among other things the activity of the enzymes 00 for glycolysis is increased. This enables rapid cell growth under the aerobic conditions typical for tumour cells. For details regarding this, please refer to E. Eigenbrodt et al., Biochemical and Molecular Aspects of Selected Cancers, Vol. 2, p. 311 ff, 1994.
State of the art The use of glucose analogues for the inhibition of glycolysis 00 10 is known from the citation E. Eigenbrodt et al., Biochemical 0 and Molecular Aspects of Selected Cancers, Vol. 2, p. 311 ff, 1994. Other approaches discussed in this source are the use of inhibitors for glycolytic isoenzymes, for example by the formation of suitable complexes or the inhibition of complex formation. The result is that tumour cells are effectively starved. A difficulty with the aforementioned compounds is that many of them are genotoxic and/or insufficiently specific for tumour cells.
In connection with a new agent against inflammatory illnesses as well as autoimmune reactions, U. Mangold et al., Eur. J.
Biochem., 266:1-9, 1999 report that these agents, namely leflunomide derivatives, also affect glycolysis.
The technical problem of the invention The present invention is based on the technical problem of preparing agents that are able to inhibit proliferation, particularly of cancer cells, and thereby inhibit the growth of neoplastic tumours and inflammations as well as exaggerated immune reactions of the body, such as septic shock, autoimmune diseases, transplant rejections as well as acute and chronic inflammation reactions, while in fact exhibiting little to no cytotoxicity toward normal cells in the blood, the immune system, and tissues.
00 For the solution of this technical problem the invention demonstrates the use of a compound of Formula I R1 R3 Formula I R C1 2 R CH -2Hb R2 R4 where a and b can be the same or different and have the values Sof 0 or 1, 00 10 where R1 -Cl-C18-alkyl, -cycloalkyl or -aryl, and 0where R2 -OX1, -SX1, -COO-, -(CH 2 )n-COOX1 or -COOX1 with Xl -Cl-C18-alkyl, -cycloalkyl or -aryl and n 1-8, where R3 -CN, -COO-, -COOX2, -CO-X2, -CO-NHX2 with X2 -Cl-C18-alkyl, -cycloalkyl or -aryl, where R4 is -NHY or -CO-NHZ with Y -CO-R (R -Cl-C18-alkyl, -cycloalkyl or -aryl or NHA, with A -Cl-C18-alkyl, -cycloalkyl or -aryl) and Z phenyl, naphthyl, phenyl substituted with -Hal and/or -0- Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl or naphthyl group substituted with -Hal and/or -O-Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl (-Hal -Cl or -Br), in which a and b correspond to the number of remaining carbon valences for C 1 and C 2 where a ring closure via R3 can occur at with the elimination of Xl in R2 and X2 in R3, or a physiologically compatible salt of such a compound for the manufacture of a pharmaceutical compound for treatment and/or prophylaxis of illnesses from the group consisting of "neoplastic tumours, inflammatory illnesses, autoimmune diseases, in particular systemic lupus erythematosus, degenerative diseases of the joints, illnesses of the rheumatic type with cartilage degeneration, all progressive forms of arthritis, in particular rheumatoid and chronic polyarthritis, joint trauma, cartilage loss due to 00 Simmobilization, septic shock, illnesses with impaired leukocyte adhesion, illnesses due to elevated TNF alpha concentrations, cachexia, Crohn's syndrome, psoriasis of the skin, Wegener's granulomatosis, rejection reactions after transplants, in particular in the course of cell therapy or stem cell therapy".
SSome of the substances falling under the aforementioned definition are known and familiar in other contexts. Other 00 10 substances falling under the aforementioned definition, Showever, are new. Therefore the invention includes further compounds according to Formula I R1 R3 Formula I C' C2Hb R2 R4 where a and b can be the same or different and have the values of 0 or 1, where R1 -C1-C18-alkyl, -cycloalkyl or -aryl, and where R2 -OX1, -SX1, -COO-, -(CH 2 )n-COOXl or -COOX1 with X1 -Cl-C18-alkyl, -cycloalkyl or -aryl and n 1-8, where R3 -CN, where R4 is -NHY or -CO-NHZ with Y -CO-R (R -Cl-C18-alkyl, -cycloalkyl or -aryl or NHA, with A -Cl-C18-alkyl, -cycloalkyl or -aryl) and Z phenyl, naphthyl, phenyl substituted with -Hal and/or -0- Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl or naphthyl group substituted with -Hal and/or -O-Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl (-Hal -Cl or -13r), in which a and b correspond to the number of remaining carbon valences for C 1 and C 2 or a physiologically compatible salt of such a compound 00 Finally the invention covers a pharmaceutical composition containing a compound with the formula R1 R3 Formula I R C1H;2-Hb R R2 R4 p where a and b can be the same or different and have the values Sof 0 or 1, Swhere R1 -Cl-C18-alkyl, -cycloalkyl or -aryl, and 00 10 where R2 -OX1, -SX1, -COO-, (CH 2 -COOX1 or -COOX1 with 0 X1 -Cl-C18-alkyl, -cycloalkyl or -aryl and n 1-8, where R3 -CN, -COO-, -COOX2, -CO-X2, -CO-NHX2 with X2 -Cl-C18-alkyl, -cycloalkyl or -aryl, where R4 is -NHY or -CO-NHZ with Y -CO-R (R -Cl-C18-alkyl, -cycloalkyl or -aryl or NHA, with A -Cl-C18-alkyl, -cycloalkyl or -aryl) and Z phenyl, naphthyl, phenyl substituted with -Hal and/or -0- Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl or naphthyl group substituted with -Hal and/or -0-Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl (-Hal -Cl or whereby a and b correspond to the number of remaining carbon valences for C 1 and C 2 where a ring closure via R3 can occur at C with the elimination of Xl in R2 and X2 in R3, or a physiologically compatible salt of such a compound as well as at least one physiologically compatible inactive ingredient and/or vehicle.
It is self-evident that in some cases various stereoisomers of compounds corresponding to Formula I can exist (especially enantiomers and diastereomers), which are all objects of the invention. The term "alkyl" encompasses linear and branched 00 alkyl groups. The term "cycloalkyl" also encompasses cycloalkyl groups with linear or branched alkyl substituents.
The term aryl also includes aryl groups where there may be alkyl substituents that are alkyl or cycloalkyl.
Surprisingly it was found that such 1-butyric acid derivatives of the general Formula I are able, depending on the dose, to inhibit the proliferation of cancer cells in therapeutically relevant concentrations in vitro. In the range of dosages 00 10 investigated no cytotoxic effect was determined. Thus Scompounds of the general Formula I have an antiproliferative effect, that is, the propagation of tissues is slowed down.
For example in chronic polyarthritis, excessive growth of the synovial sheath, which increases almost like a tumour, penetrates into the joint and with the progress of the illness destroys the cartilage and bone. The antiproliferative effect of the compounds corresponding to Formula I of the invention causes an immediate slowing of the growth as well as a decrease of the so-called systemic inflammation activity and in fact for all proliferation processes having to do with the inflammation, wound healing or regeneration. Thus, due to their pharmacological properties, the compounds in accordance with the invention are likewise outstandingly suited for treatment and prevention of the other previously listed illnesses. The aforementioned medical definitions and terms can be found in the Roche Lexikon Medizin (Roche Medical Lexicon), 4 th Edition, Munich 1999.
Furthermore the invention concerns a diagnostic agent containing at least one compound corresponding to Formula I for the detection of illnesses such as those mentioned above, for which purpose a cell or cell culture to be tested is brought into contact with such a compound and evaluated appropriately. Refer to Example 2 for this.
00 O Embodiments of the invention Within the scope of the invention there are various, nonrestrictive embodiments possible. Thus a pharmaceutical composition corresponding to the invention can have several different compounds meeting the aforementioned definition.
Moreover, a pharmaceutical composition corresponding to the invention can additionally contain at least one active Singredient that is different to the compound defined by 00 10 Formula I. Such a case is a combination preparation. The 0 various active ingredients in this can be prepared in a single pharmaceutical form, that is, the active ingredients are mixed together in the administration form. However, it is also possible to prepare the various active ingredients in physically separate administration forms of the same of different types. Preferred active ingredients in this regard are so-called immune modulators like leflunomide (Arava®), Methotrexate or antirheumatic agents.
It is preferable that the compounds according to the invention have the following groups: R1 methyl or ethyl, R2 -OX, -COO-, or COOX with X1 H, methyl or ethyl, R3 -CN, -COOH, -COO-, or COX2, -CO-NHX2 or a ring closure via R3 to with the elimination of X1 in R2 and X2 in R3, R4 is -NHY with Y H or -COR (R methyl, ethyl or -NHA with A H, methyl or ethyl) or CO-NHZ with Z -Br, -Cl, -0-C1 and/or -0-Br substituted phenyl.
Particularly appropriate examples of compounds falling under Formula I are explained below.
Compound 1: R1 methyl, R2= -OH, R3 -CN, R4 -NH 2 a b 0 Compound 2: 00 RI methyl, R2 -OH, R3 =COOH, R4 -NI1 2 a =b =0 Compound 3: R1 methyl, R2 -OH, R3 -CN, R4 =-NHY, a =b =0 Compounds 4 6: Ri methyl, R2= -OH, R3 R4 =-CO-NH-C 6
H
4 F meta)
-CO-NH-C
6
H
3 Br 2 ortho, meta), or C 6
H
4 O(_l para) a b =0 Compound 7: R1 methyl, R2 -OH, R3 -CN, R4 -CO--NH-Z, a =b =0 00 10 Compound 8: R1 methyl, R2 -OH, R3 -CN, R4 -NH 2 a b =0 Compound 9: R1 R2 -COO-methyl, R3 -CN, R4 a b =0 Compound Ri R2 -COO-, R3 -COOH, R4 a 1, b =0 Compound 11: R1 R2 -COO-, R3 -COOH, R4 -NH-CO-NH 2 a =b 1 Compound 12: R1 R2 -COO-, R3 -COOH, R4 NH 2 a =b =1 Compound 13: R1 R2 -CH 2 -COO-methyl, R3 -CN, R4 a 1, b 0 Compound 14: R1 R2 =-OXi, R3 =-CO-X2, R4 NH 2 a b Xl and X2 eliminated Compound R1 R2 -COOH, R3 =-COOH, R4 -NH--CO-NH 2 a =b 1 Compound 16: Ri R2 -OXi, R3 =-CO-NHX2, R4 =NH 2 a b 1, Xl and X2 eliminated Most particularly preferable are those compounds according to Formula I that show (oxo-enol) tautomerism, such as the methyl ester of 4-cyano-4-oxo-butyric acid (Compound 9, earlier: carbomethoxypropionyl cyanide).- 00
OCH,
O ^N 0 0 Counter-ions which come into question for ionic compounds in accordance with Formula I are, for example, Na+, Li+, S 5 cyclohexylammonium or basic amino acids (such as lysine, 0 arginine, ornithine, glutamine). The pharmaceuticals 00 0 manufactured with compounds in accordance with the invention Scan be administered orally, intramuscularly, periarticularly, intraarticularly, intravenously, intraperitonealy, subcutaneously or rectally. The invention concerns the processes for the manufacture of pharmaceuticals which are characterized in that they contain at least one compound according to Formula I with a pharmaceutically suitable and physiologically compatible carrier and perhaps additional active ingredients, additives or auxiliary materials in an appropriate administration form. Suitable solid or liquid galenic preparations or formulations are, for example, granulates, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions as well as preparations with a protracted release of the active ingredient, in the manufacture of which typical auxiliary materials such as carriers, disintegrants, binding agents, coatings, swelling agents, lubricants or grease, flavour additives, sweeteners, solubilizers find use. Auxiliary materials named are magnesium carbonate, titanium dioxide, lactose, mannite and other sugars, talc, milk protein, gelatine, starch, cellulose and its derivatives, animal and vegetable oils such as cod-liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycols and solubilizers such as sterile water and single or multi-functional alcohols such as glycerine.
00 O Preferably the pharmaceuticals are manufactured and administered in dosage units, each unit: containing as the active component a particular dose of the compound corresponding to the invention as represented by Formula I.
For solid dosage units such as tablets, capsules, coated pills or suppositories this dose can consist of 1 to 1000 mg, with to 300 mg preferred, and for injection solutions in ampules the dose can be 0.3 to 300 mg, with 10 to 100 mg preferred.
00 10 For treatment of an adult patient weighing between 50 and 100 Skg, for example weighing 70 kg, daily doses of 20 to 1000 mg of the active ingredient, preferably 100 to 500 mg, are indicated. In some circumstances, however, higher or lower daily doses can also be applied. The administration of the daily dosage can occur as a single application of a single dosage unit, but it can also occur with several smaller dosage units as well as multiple administrations of divided doses at particular intervals.
The invention is explained in more detail in the following sections using examples intended solely to illustrate the embodiments.
Example 1 The compound carbomethoxypropionyl cyanide was synthesized according to the method described by Q. Tang and S. Sen (Tetrahedron Letters 39 1998, pp 2249-2252). Typically 1.5 g mmol) carbomethoxypropionyl chloride was added to a solution of 1.79 g CuCN (20 mmol) in 10 ml acetonitrile. The mixture was refluxed for 30 minutes and after cooling to room temperature concentrated with the rotary evaporator. The residue was dissolved in ether, and the ether solution was filtered. After removal of the solvent a slightly yellow oil remained (yield 0.95 g, 67% theoretical); IR (cm1) 2225, 1727.
00 0 Example 2 The Novikoff hepatoma cells used came from the tumour bank of the Deutsches Krebsforschungszentrum (German Cancer Research Centre) in Heidelberg (Cancer Research 1951, 17, 1010). Each cm 2 culture flask was seeded with 100,000 cells. The substance pertaining to the invention from Example 1, Lcycloserine or dehydrothreonine was dissolved in a solvent Ssuited for use in cell cultures, such as water, dilute 00 10 ethanol, dimethyl sulfoxide or similar and added in increasing concentrations to the culture medium. For example Lcycloserine (Compound 16) or dehydrothreonine (Compound 2) was used in a concentration range from 80 pM to 5000 pM, carbomethoxypropionyl cyanide (Compound 13) in a concentration range of 100 pM to 300 pM. After four days of cultivation the cell count in each flask was measured. The results are shown in Figures 1 and 2. A dosage-dependent inhibition of proliferation can be seen in comparison to the control sample which has no added compound according to the invention.
Example 3 The investigation of the effects of carbomethoxypropionyl cyanide (CMPC) on the metabolism of the Novikoff cells showed that CMPC greatly inhibits the glycolysis rate, as shown in Figure 3.
Claims (8)
1. The use of a compound according to Formula I Formula I RI R3 SC1Ha^.C2Hb SR2 R4 0 where a and b can be the same or different and have the values 00 10 of 0 or 1, 0 where R1 -Cl-C18-alkyl, -cycloalkyl or -aryl, and where R2 -OX1, -SX1, -COO-, -(CH 2 )n-COOX1 or -COOX1 with Xl -Cl-C18-alkyl, -cycloalkyl or -aryl and n 1-8, where R3 -CN, -COO-, -COOX2, -CO-X2, -CO-NHX2 with X2 -Cl-C18-alkyl, -cycloalkyl or -aryl, where R4 is -NHY or -CO-NHZ with Y -CO-R (R Cl-C18-alkyl, -cycloalkyl or -aryl or -NHA, with A Cl-C18-alkyl, -cycloalkyl or -aryl) and Z phenyl, naphthyl, phenyl substituted with -Hal and/or -0- Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl or naphthyl group substituted with -Hal and/or -0-Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl (-Hal -Cl or in which a and b correspond to the number of remaining carbon valences for C' and C 2 in which a ring closure via R3 can occur at with the elimination of X1 in R2 and X2 in R3, or a physiologically compatible salt of such a compound for the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of illnesses from the group consisting of "neoplastic tumours, inflammatory illnesses, autoimmune diseases, in particular systemic lupus erythematosus, degenerative diseases of the joints, illnesses of the rheumatic type with cartilage degeneration, all progressive forms of arthritis, in particular' rheumatoid and chronic polyarthritis, joint trauma, cartilage loss due to 00 3 immobilization, septic shock, illnesses with impaired Sleukocyte adhesion, illnesses due to elevated TNF alpha concentrations, cachexia, Crohn's syndrome, psoriasis of the skin, Wegener's granulomatosis, rejection reactions after transplants, in particular in the course of cell therapy or stem cell therapy".
2. Compound according to Formula I R1 R3 00 10 Formula I R 1 R3 SC' H b Ci R2 R4 where a and b can be the same or different and have the values of 0 or 1, where R1 -Cl-C18-alkyl, -cycloalkyl or -aryl, where R2 -OX1, -SX1, -COO-, -(CH 2 )n-COOX1 or -COOX1 with Xl -Cl-C18-alkyl, -cycloalkyl or -aryl and n 1-8, where R3 -CN, where R4 is -NHY or -CO-NHZ with Y -CO-R (R -Cl-C18-alkyl, -cycloalkyl or -aryl or NHA, with A -Cl-C18-alkyl, -cycloalkyl or -aryl) and Z phenyl, naphthyl, phenyl substituted with -Hal and/or -0- Hal and/or C1-C18-alkyl, -cycloalkyl or -aryl or naphthyl group substituted with -Hal and/or -0-Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl (-Hal -Cl or -Br), in which a and b correspond to the number of remaining carbon valences for C 1 and C 2 or a physiologically compatible salt of such a compound.
3. Pharmaceutical composition containing a compound according to the formula R1 R3 Formula I C'H^z--CZHb R2 R4 00 t where a and b can be the same or different and have the values of 0 or 1, where R1 -Cl-C18-alkyl, -cycloalkyl or -aryl, where R2 -OX1, -SX1, -COO-, -(CH 2 )n-COOX1 or -COOX1 with M Xl -C1-C18-alkyl, -cycloalkyl or -aryl and n 1-8, 0 where R3 -CN, -COO-, -COOX2, -CO-X2, -CO-NHX2 with 0 X2 -Cl-C18-alkyl, -cycloalkyl or -aryl, 00 10 where R4 is -NHY or -CO-NHZ with SY -CO-R (R Cl-C18-alkyl, -cycloalkyl or -aryl or -NHA, with A -Cl-C18-alkyl, -cycloalkyl or -aryl) and Z phenyl, naphthyl, phenyl substituted with -Hal and/or -0- Hal and/or -Cl-C18-alkyl, -cycloalkyl or -aryl or naphthyl group substituted with -Hal and/or -0-Hal and/or Cl-C18-alkyl, -cycloalkyl or -aryl (-Hal -Cl or in which a and b correspond to the number of remaining carbon valences for C' and C 2 where a ring closure via R3 can occur at C 1 with the elimination of X1 in R2 and X2 in R3, or a physiologically compatible salt of such a compound as well as at least one physiologically compatible auxiliary and/or carrier substance.
4. A pharmaceutical composition according to claim 3 which contains in addition at least one active ingredient differing from the compounds corresponding to Formula I, preferably leflunomide (raaf Methotrexate or antirheumatic agents.
5. The use of a compound or pharmaceutical composition according toone of the claims 1 to 4, where R1 methyl or ethyl, R2 -OX1, -COO-, or -COOX1 with X1 methyl or ethyl, R3 -CN, -COOH, -COO-, -COX2, -CO-NHX2 with a ring closure via R3 to with the elimination of X1 in R2 and X2 in R3, 00 O R4 is -NHY with Y H or -COR (R methyl, ethyl or -NHA with A H, methyl or ethyl) or CO-NHZ with Z -Br, -Cl, -0-C1 and/or -0-Br substituted phenyl.
6. A compound according to Formula I and one of the claims 1 to 4, characterized in that it has an anti- proliferative effect.
S7. A compound according to Formula I and claim 6, 00 10 characterized in that has the effect of inhibiting Sinflammation.
8. A diagnostic agent containing at least one compound according to Formula I and claim 1.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10112924A DE10112924A1 (en) | 2001-03-13 | 2001-03-13 | 1-butanoic acid derivatives, pharmaceutical compositions containing such derivatives and uses of such derivatives |
| DE10112924.6 | 2001-03-13 | ||
| DE10112925A DE10112925A1 (en) | 2001-03-13 | 2001-03-13 | Use of sugar phosphates, sugar phosphate analogs, amino acids, amino acid analogs for modulating transaminases and / or the association p36 / malate dehydrogenase |
| AU2002256665A AU2002256665A1 (en) | 2001-03-13 | 2002-03-13 | 1-Butyric acid derivatives and their use |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002256665A Division AU2002256665A1 (en) | 2001-03-13 | 2002-03-13 | 1-Butyric acid derivatives and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2008202073A1 true AU2008202073A1 (en) | 2008-05-29 |
Family
ID=39491489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2008202073A Abandoned AU2008202073A1 (en) | 2001-03-13 | 2008-05-09 | 1-Butyric acid derivatives and their use |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2008202073A1 (en) |
-
2008
- 2008-05-09 AU AU2008202073A patent/AU2008202073A1/en not_active Abandoned
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI97891C (en) | Process for the preparation of acyl derivatives of 2'-deoxyguanocin | |
| MX2011001426A (en) | Methods of treating thalassemia. | |
| WO2009117985A1 (en) | Pirinixic acid derivatives as prostglandin e2 synthesis inhibitors for treating inflammatory diseases | |
| US9301968B2 (en) | Therapeutic agent for inflammatory diseases, containing adenosine N1-oxide as an effective ingredient | |
| US20120156137A1 (en) | Composition for treatment of atopic dermatitis comprising glucosamine and derivatives thereof and a method for treatment of atopic dermatitis using them | |
| DE69620233T2 (en) | OXIDIZED GLUTATHION AS A MEANS TO IMPROVE THE ENDOGENIC PRODUCTION OF CYTOKINES AND HAEMATOPOIETIC FACTORS | |
| CA2193551C (en) | Eliminating agent for activated oxygen and free radicals | |
| ES2383005T3 (en) | Medications for glomerular diseases | |
| PT2120919E (en) | New combination for use in the treatment of inflammatory disorders | |
| EP0292660B1 (en) | Alkylidenedithiobis (substituted) phenols for inhibiting interleukin-1 release and for alleviating interleukin-1 mediated conditions | |
| RU2108100C1 (en) | Immunomodulating agent | |
| US20060014709A1 (en) | Drug or cosmetic | |
| AU2008202073A1 (en) | 1-Butyric acid derivatives and their use | |
| US20100256230A1 (en) | 1-butane acid derivatives, pharmaceutical compositions containing said derivatives and the use thereof | |
| JP4382354B2 (en) | 1-butanoic acid derivatives and uses thereof | |
| EP0551180B1 (en) | Use of bucillamine for the manufacture of a medicament for the treatment of cystinuria | |
| KR100912735B1 (en) | Composition for the anti-inflammatory and analgesia comprising rutin-contained Sophora japonica extract | |
| CN113262218B (en) | Use of isothiocyanate compounds | |
| KR102141035B1 (en) | Colon targeting composition for preventing or treating inflammatory bowel diseases | |
| JPS62263127A (en) | Remedy for tumor by self-derived lak cell, interleukin-2 andornithine decarboxylase inhibitor | |
| AU2002363318B2 (en) | Compounds and methods for treating transplant rejection | |
| US20230111232A1 (en) | Pharmaceutical composition for preventing or treating rheumatoid arthritis and health functional food | |
| KR20020009636A (en) | Remedies for arthrosis deformans | |
| CN1212620A (en) | Mercapto derivatives as inhibitors of cyclooxygenases | |
| EP0297842A2 (en) | Uses of a substituted 2-phenoxyphenylacetic acid as an immunosuppressant drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC1 | Assignment before grant (sect. 113) |
Owner name: WARBURG GLYCOMED GMBH Free format text: FORMER APPLICANT(S): PROTAGEN AG |
|
| MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application |