WO1993013739A2 - Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues - Google Patents
Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues Download PDFInfo
- Publication number
- WO1993013739A2 WO1993013739A2 PCT/EP1993/000002 EP9300002W WO9313739A2 WO 1993013739 A2 WO1993013739 A2 WO 1993013739A2 EP 9300002 W EP9300002 W EP 9300002W WO 9313739 A2 WO9313739 A2 WO 9313739A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrrole
- methyl
- carboxyamido
- compound
- per formula
- Prior art date
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 102000015636 Oligopeptides Human genes 0.000 title description 2
- 108010038807 Oligopeptides Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- 239000003443 antiviral agent Substances 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
- 239000000126 substance Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 24
- -1 methyloxiranyl Chemical group 0.000 claims description 20
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012713 reactive precursor Substances 0.000 claims description 8
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 7
- 238000007112 amidation reaction Methods 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000013598 vector Substances 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 150000002596 lactones Chemical class 0.000 claims description 5
- 125000000466 oxiranyl group Chemical group 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002723 alicyclic group Chemical group 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 230000009089 cytolysis Effects 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 1
- 230000008707 rearrangement Effects 0.000 claims 1
- 230000003612 virological effect Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 6
- 230000001093 anti-cancer Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 0 CC[n]1c(C(NCC*(CN)=N)=O)cc(*c2cc(C(C)=N)c[n]2CC*)c1 Chemical compound CC[n]1c(C(NCC*(CN)=N)=O)cc(*c2cc(C(C)=N)c[n]2CC*)c1 0.000 description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FCDKGTXZKZEBPA-UHFFFAOYSA-N 2-[4-(2-hydroxyethylamino)anilino]ethanol Chemical compound OCCNC1=CC=C(NCCO)C=C1 FCDKGTXZKZEBPA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CBVPLFMDARRGMK-UHFFFAOYSA-N 5-methoxycarbonyl-1-methylpyrrole-3-carboxylic acid Chemical compound COC(=O)C1=CC(C(O)=O)=CN1C CBVPLFMDARRGMK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
- VONGYFFEWFJHNP-UHFFFAOYSA-N pyrrolecarboxylic acid methyl ester Natural products COC(=O)C1=CC=CN1 VONGYFFEWFJHNP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues preparation of same , and pharmaceutical compositions containing such analogues .
- the present invention relates to anticancer agents as per general formula ( I )
- n 0 or a whole number from 1 to 6
- A a single chemical bond or an alicyclic or aromatic or heterocyclic residue
- X 1 a chemical bond, the -NHCO- group or the -CONH- group
- X 2 , X 3 the -CONH- or -NHCO- group and where:
- R 1 and R 2 (equal) an oxiranomethyl or 1-aziridinomethyl or C 2 -
- R 4 is C 1 -C 4 alkyl or phenyl
- R 1 H
- the invention further refers to the process for the preparation of the aforesaid products, the pharmaceutically acceptable salts thereof, and the pharmacetical compositions containing said products.
- Dystamicin is an antibiotic already known having formula (A)
- a requisite for the therapeutic progress in this field is, therefore, the discovery of compounds having molecular characteristics increasing their selectivity in inhibiting the proliferation of viruses and tumoural cells in respect of the healthy ones.
- An object of this invention is the obtainment of anticancer and antiviral compounds and in particular of dystamicin analogues in which one or more carboxyamidic bonds has/have been replaced by a retrocarboxyamidic bond, containing new chemical modifications at the N-terminal side chain.
- the said compounds have shown a high anticancer and antiviral activity and a high selectivity in inhibiting tumoural cells and viruses in respect of healthy cells.
- the compounds as per the present invention are compounds as per general formula (I) and pharmaceutically acceptable salts thereof:
- n 0 or a whole number from 1 to 6
- A a single chemical bond or an alicyclic or aromatic or heterocyclic residue
- X 1 a single chemical bond, the -NHCO- group or the -CONH- group
- X 2 , X 3 the -CONH- or -NHCO- group and where:
- R 1 and R 2 (equal) an oxiranomethyl or 1-aziridinomethyl or C 2 -
- R 4 is C 1 -C 4 alkyl or phenyl
- R 1 H
- R 2 -CO-(CH 2 ) m -R 3 , where m is 0 or a whole number from
- R 3 halogen, oxiranyl or methyloxiranyl or azirinidyl, cyclopropyl or a C 2 -C 6 alkenyl group substituted, if required, by halogens or a ketone or an ⁇ ,(S unsaturated alicylic lactone.
- the invention also refers to pharmaceutical compositions containing the aforesaid compounds or the pharmaceutically acceptable salts therof, based on inorganic acids, e.g. hydrochloric or hydrobromic or sulphuric or nitric acids, etc., or on organic acids, e.g. acetic or propionic or succinic or malonic or citric or tartaric or methanesulfonic or p-toluenesulfonic acids, etc.
- inorganic acids e.g. hydrochloric or hydrobromic or sulphuric or nitric acids, etc.
- organic acids e.g. acetic or propionic or succinic or malonic or citric or tartaric or methanesulfonic or p-toluenesulfonic acids, etc.
- n is as defined above
- A is a single cyclohexyl or p-phenyl or 1-methylpyrrole or thiophene or thiazole or imidazole or furan or isoxazole or oxazole or triazole or pyridine or pyrrole chemical bond
- X 1 , X 2 , X 3 are as defined above.
- the compounds as per general formula (I) may be prepared on the basis of the following processes:
- n, A. R 1 , R 2 and X 1 are as defined above, or a reactive derivative thereof, with compound as per formula (III)
- n, A, R 1 , R 2 and X 1 are as defined above, or a reactive precursor of same, with compound as per formula (V)
- reaction of compound as per formula (II) with compound as per formula (III) was conducted in the presence of condensers, such as DCC (dicyclohexyl carbodiimide) or EDC [1-(3-dimethylaminopro ⁇ yl)-3- ethylcarbodiimide hydrochloride] either in the presence or in the absence of hydroxybenzotriazole or BOP (benzotriazol)-1- yloxytris (dimethylaminophosphonium hexafluorophosphate) or a reactive derivative of (II), such as acylchloride, acylimidazole, acylazide corresponding to acid (II) or an active ester, such as 2,4,5 trichlorophenoxyester or N-oxysuccinimidoester of acid (II) or its anhydride.
- condensers such as DCC (dicyclohexyl carbodiimide) or EDC [1-(3-
- reaction of ( II) with (III) is preferably carried out at molar ratios from 1 : 1 to 1 : 3 in an inert organic solvent , such as dimethylsulphoxide , hexamethylphosphorotriamide , dimethylacetamide or preferably dimethylformamide, in the presence of a condenser of the type mentioned above and of N-hydroxybenzotriazole or BOP and in the presence of an organic base , such as triethylamine, diisopropylethylamine and 1 ,8-bis- (dimethylamino) -naphthalene.
- an inert organic solvent such as dimethylsulphoxide , hexamethylphosphorotriamide , dimethylacetamide or preferably dimethylformamide
- an organic base such as triethylamine, diisopropylethylamine and 1 ,8-bis- (dimethylamino) -naphthalene.
- the reaction temperature may range from -10 ° C to 50 °C and the reaction time from 2 to 48 hrs .
- reaction of compound as per formula (II) with compound as per formula (III) may also be conducted with a reactive derivative of compound as per formula (II) of the type mentioned above in a water- organic solvent biphasic system as for the amidation according to Schotten-Baumann, or in an organic solvent such as benzene, toluene, halogenated hydrocarbons , ethanol , methanol , tetrahydrofuran, dioxane , dimethylformamide , or in aqueous dioxane , ethanol , methanol.
- a water- organic solvent biphasic system as for the amidation according to Schotten-Baumann
- organic solvent such as benzene, toluene, halogenated hydrocarbons , ethanol , methanol , tetrahydrofuran, dioxane , dimethylformamide , or in aqueous dioxane , ethanol , methanol.
- reaction may be carried out also in the presence of an inorganic base, such as a hydroxide, a carbonate or a bicarbonate of an alkali metal , preferably sodium , potassium or barium or an organic base, such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.
- an inorganic base such as a hydroxide, a carbonate or a bicarbonate of an alkali metal , preferably sodium , potassium or barium or an organic base, such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.
- an organic base such as triethylamine, diisopropylethylamine, pyridine or N,N-dimethylaminopyridine.
- a reactive precursor of compound as per formula (IV) may be e. g. compound having formula (VI)
- the reaction of an isocyanate as per formula (IV) with an amidino acid as per formula (V) is preferably conducted with an acylazide as per formula (VI) as a reactive precursor of an isocyanate as per formula (IV).
- the reaction may be carried out in an aromatic hydrocarbon as solvent, such as for example benzene or toluene at 50°C-100°C for 5-20 hrs.
- a molar quantity of an organic base e.g. triethylamine. pyridine, and the like, may be utilized in the reaction to salify an acid as per formula (V).
- the process of formation of an isocyanate from a reactive precursor, e.g. an acylazide is well known in organic chemistry (cf. Curtius's reaction).
- An azide as per formula (VI) may be prepared by causing to react compound as per formula (II) with diphenylphosphorazide or sodium azide (NaN 3 ).
- R 5 is a typical protective group of carboxylic acids, such as methyl, ethyl, t-butyl, benzyl, 2-trimethylxylylethyl, 2,2,2- trichloroethyl.
- the hydrolysis of compound as per formula (VII) may be performed according to the methods and procedures known in organic chemisty, as, for instance, referred to in T.W. Greene, Protective Groups in Organic Synthesis, J. Wiley and Sons, Interscience Publishers, 1981.
- compound as per formula (II), where X 1 , n and A are as defined above and R 1 and R 2 are equal and stand for a C 2 -C 4 alkyl group substituted in position 2 by a halogen or an -OSO 2 R 4 group, where R 4 is as defined above may be prepared, if preferred so, by causing compound as per formula (II), where X 1 , n and A are as defined above and R 1 and R 2 are equal and stand for a C 2 -C 4 alkyl group substituted in position 2 by a hydroxy group, to react with a halogenating agent, e.g.
- a halogenating agent e.g.
- R 5 is as defined above.
- An acid reactive derivative as per formula (VIII) may be the same as that reported hereinabove for compound as per formula (II) and the reaction may be carried out under conditions analogous to those reported for the amidation of compound as per formula (II) with compound as per formula (III).
- R 1 , R 2 and R 5 are as defined above, are either known [cf. e.g. J. Med. Chem., 32, 774 (1989)] or prepared on the basis of standard procedures starting from known compounds.
- n, A, and R 5 are as defined above.
- compound as per formula (IV) may be prepared from a corresponding reactive precursor as per formula (VI) on the basis of Curtius's reaction.
- An acylazide as per formula (VI) may be prepared from the corresponding acid as per formula (II) on the basis of the methods described in Tetr., 30, 2151 (1974).
- R 6 is a protective group for a carboxylic acid, such as for example 2,2,2 trichloroethyl, benzyl, phenacyl, and the like, and X 3 is as already defined.
- the R 6 group may be removed e.g. with Zn in acetic acid or by catalytic hydrogenation on Pd/C in H 2 O, MeOH, EtOH, formic acid and their mixtures.
- a reactive derivative of compound (XV) may be of the same type as those reported for compounds as per formula (II) and the amidation reaction between (XV) and (XVI) may be carried out as reported above for the reaction between compounds as per formulas (II) and (III).
- Compounds as per formulas (XV) and (XVI) may be prepared as disclosed in the applicant's Italian Patent N. 22154 dated 22nd Nov. 1990 and referred to here for reference.
- a reactive precursor of compound ( XVII ) may be a compound as per formula (XIX)
- R 6 is as defined above .
- reaction of an isocyanate as per formula (XVII) with an acid as per formula (XVIII) may preferably be conducted using an azide as per formula (XIX) as reactive precursor of (XVII) under conditions analogous to those reported above for the reaction of compound as per formula (VI) with compound as per formula (V) .
- the present invention further refers to pharmaceutical compositions containing as active ingredient a compound as per formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable vector or diluent.
- a therapeutically effective amount of compound as per formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vector.
- the vectors used may be the traditional ones and the compositions may be formulated according to the usual methods .
- the compounds as per the present invention are useful for the therapeutic treatment of humans and animals .
- the compounds as per the Invention are useful as antitumoural and/or antiviral agents when administered in therapeutically effective amounts , e.g. an adequate dosage for adult administration may range from 0.1 to 100 mg approx. pro dose from 1 to 4 times /day.
- X 3 -CONH-) (190 mg; 0.469 mM), 63 mg of N- hydroxybenzotriazole (H0BT) (0.469 mM), 103 mg of 1,8-bis- (dimethylamino)-naphthalene (0.480 mM) and by subsequent additions [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (162 mg; 0.848 mM) .
- H0BT N- hydroxybenzotriazole
- EDC 1,8-bis- (dimethylamino)-naphthalene
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93902141A EP0623023A1 (en) | 1992-01-10 | 1993-01-04 | Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI92A000021 | 1992-01-10 | ||
ITMI920021A IT1262921B (en) | 1992-01-10 | 1992-01-10 | ANALOGUE AGENTS ANALOGUES OF PYROL-AMIDINE OLIGOPEPTIDES BACK TO PREPARATION PROCESSES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1993013739A2 true WO1993013739A2 (en) | 1993-07-22 |
WO1993013739A3 WO1993013739A3 (en) | 1993-11-25 |
Family
ID=11361495
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/000002 WO1993013739A2 (en) | 1992-01-10 | 1993-01-04 | Retroreverse pyrrole-amidino oligopeptide anticancer agent analogues, preparation of same, and pharmaceutical compositions containing such analogues |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0623023A1 (en) |
AU (1) | AU3347893A (en) |
IT (1) | IT1262921B (en) |
WO (1) | WO1993013739A2 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994020463A1 (en) * | 1993-03-01 | 1994-09-15 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Novel distamycin analogues |
WO1994025436A1 (en) * | 1993-04-26 | 1994-11-10 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Distamycin a derivatives as anti-malarial agents |
EP0719765A2 (en) * | 1994-12-27 | 1996-07-03 | Mitsui Toatsu Chemicals, Inc. | Phenylbenzimidazole derivatives |
EP0776891A1 (en) | 1995-11-29 | 1997-06-04 | Mitsui Toatsu Chemicals, Incorporated | Pyrrolylbenzimidazole derivatives |
WO1998021202A1 (en) * | 1996-11-11 | 1998-05-22 | Pharmacia & Upjohn S.P.A. | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
US6555693B2 (en) | 2000-03-16 | 2003-04-29 | Genesoft, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
US6794378B2 (en) * | 1999-07-01 | 2004-09-21 | Ajinomoto Co., Inc. | Heterocyclic compounds and medical use thereof |
US7078536B2 (en) | 2001-03-14 | 2006-07-18 | Genesoft Pharmaceuticals, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
US7122626B2 (en) | 2001-04-26 | 2006-10-17 | Genesoft Pharmceuticals, Inc. | Halogen-substitued thienyl compounds |
US7129214B2 (en) | 2002-12-10 | 2006-10-31 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
US7265129B2 (en) | 2002-10-25 | 2007-09-04 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
US7348427B2 (en) | 2001-06-13 | 2008-03-25 | Genesoft Pharmaceuticals, Inc. | Antipathogenic benzamide compounds |
US7498349B2 (en) | 2002-08-02 | 2009-03-03 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
Citations (5)
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FR4158M (en) * | 1963-07-26 | 1966-05-16 | ||
DE3623853A1 (en) * | 1985-07-16 | 1987-01-29 | Erba Farmitalia | DISTAMYCINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
DE3623880A1 (en) * | 1985-07-16 | 1987-01-29 | Erba Farmitalia | POLY-4-AMINOPYRROL-2-CARBOXAMIDO DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
EP0246868A1 (en) * | 1986-05-20 | 1987-11-25 | FARMITALIA CARLO ERBA S.r.l. | Site specific alkylating agents |
EP0388948A1 (en) * | 1989-03-23 | 1990-09-26 | FARMITALIA CARLO ERBA S.r.l. | Acryloyl substituted pyrrole derivatives |
-
1992
- 1992-01-10 IT ITMI920021A patent/IT1262921B/en active IP Right Grant
-
1993
- 1993-01-04 WO PCT/EP1993/000002 patent/WO1993013739A2/en not_active Application Discontinuation
- 1993-01-04 AU AU33478/93A patent/AU3347893A/en not_active Abandoned
- 1993-01-04 EP EP93902141A patent/EP0623023A1/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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FR4158M (en) * | 1963-07-26 | 1966-05-16 | ||
DE3623853A1 (en) * | 1985-07-16 | 1987-01-29 | Erba Farmitalia | DISTAMYCINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
DE3623880A1 (en) * | 1985-07-16 | 1987-01-29 | Erba Farmitalia | POLY-4-AMINOPYRROL-2-CARBOXAMIDO DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
EP0246868A1 (en) * | 1986-05-20 | 1987-11-25 | FARMITALIA CARLO ERBA S.r.l. | Site specific alkylating agents |
EP0388948A1 (en) * | 1989-03-23 | 1990-09-26 | FARMITALIA CARLO ERBA S.r.l. | Acryloyl substituted pyrrole derivatives |
Non-Patent Citations (1)
Title |
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Dialog Information Services, file 155, Medline, Dialog accession no. 07972172, Medline accession no.92110172, Pezzoni G. et al: "Biological profile of FCE 24517, a novel benzoyl mustard analogue of distamycin A", Br J Cancer Dec 1991, 64 (6) p1047-50 * |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994020463A1 (en) * | 1993-03-01 | 1994-09-15 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Novel distamycin analogues |
WO1994025436A1 (en) * | 1993-04-26 | 1994-11-10 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Distamycin a derivatives as anti-malarial agents |
US5670534A (en) * | 1993-04-26 | 1997-09-23 | A. Menarini Industrie Farmaceutice Reunite S.R.L. | Distamycin a derivatives as anti-malarial agents |
EP0719765A2 (en) * | 1994-12-27 | 1996-07-03 | Mitsui Toatsu Chemicals, Inc. | Phenylbenzimidazole derivatives |
EP0719765A3 (en) * | 1994-12-27 | 1997-02-19 | Mitsui Toatsu Chemicals | Phenylbenzimidazole derivatives |
US5821258A (en) * | 1994-12-27 | 1998-10-13 | Mitsui Chemicals, Inc. | Phenylbenzimidazole derivatives |
EP0776891A1 (en) | 1995-11-29 | 1997-06-04 | Mitsui Toatsu Chemicals, Incorporated | Pyrrolylbenzimidazole derivatives |
US5808087A (en) * | 1995-11-29 | 1998-09-15 | Mitsui Chemicals, Inc. | Sulfonium salts of pyrrolylbenzimidazoles |
WO1998021202A1 (en) * | 1996-11-11 | 1998-05-22 | Pharmacia & Upjohn S.P.A. | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
US6153642A (en) * | 1996-11-11 | 2000-11-28 | Pharmacia & Upjohn S.P.A. | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents |
US6794378B2 (en) * | 1999-07-01 | 2004-09-21 | Ajinomoto Co., Inc. | Heterocyclic compounds and medical use thereof |
US6555693B2 (en) | 2000-03-16 | 2003-04-29 | Genesoft, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
US7301037B2 (en) | 2000-03-16 | 2007-11-27 | Genesoft, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
US7078536B2 (en) | 2001-03-14 | 2006-07-18 | Genesoft Pharmaceuticals, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
US7122626B2 (en) | 2001-04-26 | 2006-10-17 | Genesoft Pharmceuticals, Inc. | Halogen-substitued thienyl compounds |
US7498405B2 (en) | 2001-04-26 | 2009-03-03 | Genesoft Pharmaceuticals, Inc. | Halogen-substituted thienyl compounds |
US7348427B2 (en) | 2001-06-13 | 2008-03-25 | Genesoft Pharmaceuticals, Inc. | Antipathogenic benzamide compounds |
US7498349B2 (en) | 2002-08-02 | 2009-03-03 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
US7265129B2 (en) | 2002-10-25 | 2007-09-04 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
US7129214B2 (en) | 2002-12-10 | 2006-10-31 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
US7642245B2 (en) | 2002-12-10 | 2010-01-05 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
Also Published As
Publication number | Publication date |
---|---|
IT1262921B (en) | 1996-07-22 |
WO1993013739A3 (en) | 1993-11-25 |
ITMI920021A1 (en) | 1993-07-10 |
AU3347893A (en) | 1993-08-03 |
EP0623023A1 (en) | 1994-11-09 |
ITMI920021A0 (en) | 1992-01-10 |
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