CA2157187A1 - Novel distamycin analogues - Google Patents
Novel distamycin analoguesInfo
- Publication number
- CA2157187A1 CA2157187A1 CA002157187A CA2157187A CA2157187A1 CA 2157187 A1 CA2157187 A1 CA 2157187A1 CA 002157187 A CA002157187 A CA 002157187A CA 2157187 A CA2157187 A CA 2157187A CA 2157187 A1 CA2157187 A1 CA 2157187A1
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- pyrrol
- carboxyamido
- chloroethyl
- bis
- 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
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical class CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- GNFWGDKKNWGGJY-UHFFFAOYSA-N propanimidamide Chemical compound CCC(N)=N GNFWGDKKNWGGJY-UHFFFAOYSA-N 0.000 claims description 29
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 25
- 239000000126 substance Substances 0.000 claims description 21
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- -1 mercaptomethyl Chemical group 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 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 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- 230000001173 tumoral effect Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 239000003085 diluting agent Substances 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims 1
- 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 101100225553 Caenorhabditis elegans epg-4 gene Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229910001868 water Inorganic materials 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-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 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- IWHSVISTOFFXOA-UHFFFAOYSA-N 4-[bis(2-chloroethyl)amino]benzoyl chloride Chemical compound ClCCN(CCCl)C1=CC=C(C(Cl)=O)C=C1 IWHSVISTOFFXOA-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 101100290380 Caenorhabditis elegans cel-1 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 206010020649 Hyperkeratosis 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
- 241001024304 Mino 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
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 230000002051 biphasic effect Effects 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 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
- 229930014626 natural product Natural products 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
-
- 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
Abstract
Described are pyrrol-amidinic compounds of general formula (I) and their pharmaceutically acceptable salts, processes for their preparation and pharmaceutical compositions containing them, useful as antitumoral.
Description
Pyrrol- ~inic compounds and their ph~ -^e7ltically acceptable salts, processes for their preparation and pharmaceutical c~ tions cont~;nin~ them.
Field of the invention The present invention refers to pyrrol-amidinic compounds of general formula (I) r~~1CI~d m 3 K Q~ H
(I) and their pharmaceutically acceptable salts wherein :
n is O or an integer ranging from 1 to 4 m is O or an integer ranging from 1 to 4 A is selected from the group consisting of cyclohexyl, p-phen.-lene, l-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine. pyrrole;
B is selected from the group consisting of : a simple chemical bonc. -CO-NH-CH(R3~ NH-CO-CH(R3)- wherein R3 is H or the side 15 ~ch~7~ of a natural alpha-aminocarboxylic acid;
X is selected from the group consisting of : -NHCO-, -CONH- and A~ D SH~
~1~7I87 wherein :
i) Rl and R2 are equal and are selected from the group consisting of : oxiranomethyl, l-aziridinomethyl, C2_4 alkyl optionally substltuted in position 2 with an OH, C2_4 alkoxy, halogen or -OSO2R4 group wherein R4 is selected from the group consisting of Cl_4 alkyl or phenyl or ii) Rl = H and R2 is as above described provided that :
when B = chemical bond, n is different from 1 when X = -CONH-, B = simple chemical bond, m is different from O
when B = -CO-NH-CH(R3)- X is different from -NHCO-when B = -~H-CO-CH(R3)- X is different from -CONH-Furthermore the invention relates to processes for the preparation of the above mentioned compounds, to their pharmacologically active salts and to pharmaceutical compositions contAin;ng them.
Prior art .~ntibiotic dystamicine is a known compound of formula (II) :
HCONH
~;~rl H H
A~',EN~:3rD Sl~
belcnging to the pyrrol-~mi~inic group and showing interesting antiviral activity, for example against the herpetic viruses and ~oloney sarcoma virus, is characterized by the ability to interact reversibly and selectlvely with DNA sequences rich in dA and dT
bases thereby interfering both in the replication and transcrlption process [see Arcamone in B. Pull~an and J. Jorterez (eds) "Molecular basis of specificity in nucleic acid - drug interaction"
369-383, lggo Kluwer Academic Publishers].
As is known, antiviral and antitumoral agents nowadays used in therapy are characterized by serious side effects, limiting their use in a large number of cases which on the contrary should take advantage from the therapy; moreover therapeutical progresses are necessary in the clinical treatment of important solid tumors, as for example pl11 m~n~ry tumors and ovarian tumors, not responding adequately to any treatment nowadays in use.
Pyrr~ mi~inic compounds having chemical structures similar to the one described in the present application, and showing antitumor and antiviral properties. are described in: EP - A - 388 948; ~P - A - 246 868; Anti-Cancer Drug Design (1986), 1. 235-244;
Bioc;-emical Pharmacology ( 1993), 45. 1536-39; J. Med. Chem. ( 1989) .
32, , ,4 - 778.
A r~uisite for the therapeutic progress in this particular field is therefore the discovery of compounds having molecular moieties alls-~ing them to increase the selectivity in inhibiting viral AM~NcED ~ET
3a 2 1 5 7 1 8 7 proliferation and the proliferation of tumoral rather than healthy ceIls.
Detailed description of the invention The present invention has the aim to render available new antitumoral and antiviral compounds and in particular compounds analogous to dystamicine containing new chemical modifications at ~r AM~NC~D ~ffEET
WO 94/20463 PCT~EP94/005~7 the N-terminal side chain level, and/or contnin;n~ a different number of pyrrolic residues if compared to the natural product.
These compounds, show a marked antitumoral and antiviral activity, as well selectivity in the inhibition of tumoral cells and viruses with respect to the healthy cells.
The compounds according to the present invention are those of general formula (I) R2~N--~(Cl~m ~ b N
~H3 n ~ ~~ 2 (I) wherein:
n, m, A, B, X, R1, R2 are as previously described, and their pharmaceutically acceptable salts.
Besides, the invention, refers to pharmaceutical compositions containing the above mentioned compounds, or pharmaceutically acceptable salts thereof formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and the like or with organic acids such as acetic, propionic, succinic, malonic, citric, ~artaric, methansulfonic, p-toluensulfonic and the like.
~ 94/20 ~ PCT~EP94/00557 According to the present invention, preferred are the ,- -ln~ of formula (I) wherein:
n is as above defined m is zero or an integer comprised between 1 and 3.
A = cyclohexyl, p-phenylene, l-methylpyrrole, th;ophpne~ thiazole, ~ ole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole.
B is a simple bond, or when it is a -C0-NH-CH(R3)- group or a -NH-C0-CH(R3)- group, R3 is preferably methyl, isobutyl, sec-butyl, hydroxymethyl, mercaptomethyl, carbamoylmethyl, benzyl, 4-hydroxybenzyl, 5-imidazolylmethyl, 2-carbamoylethyl, 2-methylthioethyl, l-hydroxyethyl, 3-~l~ni~inopropyl~ 4-aminobutyl Rl and R2 represent preferably an ethyl group, 2-hydroxyethyl, 2-chloroethyl, methansulfonylethyl.
The following compounds are particl-l~rly preferred:
3-[1-Methyl-4-tl-methyl-4-t4-tN,N-bis(2-chloroethyl)amino~bPn~PnP-aminocarbonyl]pyrrol-2-caL-bo~y- ;do]pyrrol-2-carbo~y~ido]propionr idine hydrochlorate;
3-tl-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl) amino]benzeneaminocarbonyl]-pyrrol-2-carbo~ -ido]
pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carbox~ ido]
propion~mi~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzPne~minocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate;
WO 94/20463 PCT~EPg4/00557 3-tl-Methyl-4-[l-methyl-4-[4-[N~N-bis(2-chloroethyl)amino]
butPnf idQ]pyrrol-2-carboxyamido]pyrrol-2-csrboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-{4-[N,N-bis(2-chloroethyl)-amino]benzenbut~n~mi~n]pyrrol-2-c&-bo~y&~ido]pyrrol-2-csrboxy 'do]pyrrol-2-ca.l,o~ys~ido]pyrrol-2-caLLu~y~ido]propionnmi~i n~ hyd.-ochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-~1-methyl-4-[N,N-bis(2-chloroethyl)amino]ben7~nebùt~n~ ~o]pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]pyrrol-2-ca.boxy ido] pyrrol-2-ca~bGxy do]
pyrrol-2-carboxyamido]propinn~ ~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4[N,N-bis(2-chloroethyl)amino]benzyl-amino carbonyl]pyrrol-2-carbony ~o]pyrrol-2-caL-bo~y~ ;~o]propion~mi~in~ hydrochlorate;
15 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2 chloroethylamino)benzylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-ca.-bo~y ~ido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino) phenyl] et h ~n ~ inocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxa mido] propionamidine hydrochlorate;
3-~1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis (2-chloroethyl) amino]phenyl]eth~n~minocarbonyl]pyrrol-2-carboxa-mido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-~ 94/20463 PCT~EP94/00557 ';~
carboxyamido]prop;onr ~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]propylaminocarbonyl]pyrrol-2-chl-bo~y do]pyrrol-2-carboxa-mido] propisn~ ~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-tl-methyl-4-[3-[4-tN,N-bis(2-chloroethyl)amino]phenyl]propylsminocarbonyl]pyrrol-2-carboxy do]pyrrol-2-caLbo~y6~ido]pyrrol-2-carboxyamido]pyrrol-2-carboxy- do] prop;on r ~; n~ hydrochlorate;
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-tl-methyl-4-tl-methyl-4-t3-t4-tN~N-bis(2-chloroethyl)amino]phenyl]propylr ;noc~G-lyl]pyrrol-2-carbG~y do]pyrrol-2-caL-bo~y do]pyrrol-2-caLbu~y ~o]pyrrol-2-carbo~y- ido]pyrrol-2-caLboxy do]propionr '~;ne hydrochlorate;
Field of the invention The present invention refers to pyrrol-amidinic compounds of general formula (I) r~~1CI~d m 3 K Q~ H
(I) and their pharmaceutically acceptable salts wherein :
n is O or an integer ranging from 1 to 4 m is O or an integer ranging from 1 to 4 A is selected from the group consisting of cyclohexyl, p-phen.-lene, l-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine. pyrrole;
B is selected from the group consisting of : a simple chemical bonc. -CO-NH-CH(R3~ NH-CO-CH(R3)- wherein R3 is H or the side 15 ~ch~7~ of a natural alpha-aminocarboxylic acid;
X is selected from the group consisting of : -NHCO-, -CONH- and A~ D SH~
~1~7I87 wherein :
i) Rl and R2 are equal and are selected from the group consisting of : oxiranomethyl, l-aziridinomethyl, C2_4 alkyl optionally substltuted in position 2 with an OH, C2_4 alkoxy, halogen or -OSO2R4 group wherein R4 is selected from the group consisting of Cl_4 alkyl or phenyl or ii) Rl = H and R2 is as above described provided that :
when B = chemical bond, n is different from 1 when X = -CONH-, B = simple chemical bond, m is different from O
when B = -CO-NH-CH(R3)- X is different from -NHCO-when B = -~H-CO-CH(R3)- X is different from -CONH-Furthermore the invention relates to processes for the preparation of the above mentioned compounds, to their pharmacologically active salts and to pharmaceutical compositions contAin;ng them.
Prior art .~ntibiotic dystamicine is a known compound of formula (II) :
HCONH
~;~rl H H
A~',EN~:3rD Sl~
belcnging to the pyrrol-~mi~inic group and showing interesting antiviral activity, for example against the herpetic viruses and ~oloney sarcoma virus, is characterized by the ability to interact reversibly and selectlvely with DNA sequences rich in dA and dT
bases thereby interfering both in the replication and transcrlption process [see Arcamone in B. Pull~an and J. Jorterez (eds) "Molecular basis of specificity in nucleic acid - drug interaction"
369-383, lggo Kluwer Academic Publishers].
As is known, antiviral and antitumoral agents nowadays used in therapy are characterized by serious side effects, limiting their use in a large number of cases which on the contrary should take advantage from the therapy; moreover therapeutical progresses are necessary in the clinical treatment of important solid tumors, as for example pl11 m~n~ry tumors and ovarian tumors, not responding adequately to any treatment nowadays in use.
Pyrr~ mi~inic compounds having chemical structures similar to the one described in the present application, and showing antitumor and antiviral properties. are described in: EP - A - 388 948; ~P - A - 246 868; Anti-Cancer Drug Design (1986), 1. 235-244;
Bioc;-emical Pharmacology ( 1993), 45. 1536-39; J. Med. Chem. ( 1989) .
32, , ,4 - 778.
A r~uisite for the therapeutic progress in this particular field is therefore the discovery of compounds having molecular moieties alls-~ing them to increase the selectivity in inhibiting viral AM~NcED ~ET
3a 2 1 5 7 1 8 7 proliferation and the proliferation of tumoral rather than healthy ceIls.
Detailed description of the invention The present invention has the aim to render available new antitumoral and antiviral compounds and in particular compounds analogous to dystamicine containing new chemical modifications at ~r AM~NC~D ~ffEET
WO 94/20463 PCT~EP94/005~7 the N-terminal side chain level, and/or contnin;n~ a different number of pyrrolic residues if compared to the natural product.
These compounds, show a marked antitumoral and antiviral activity, as well selectivity in the inhibition of tumoral cells and viruses with respect to the healthy cells.
The compounds according to the present invention are those of general formula (I) R2~N--~(Cl~m ~ b N
~H3 n ~ ~~ 2 (I) wherein:
n, m, A, B, X, R1, R2 are as previously described, and their pharmaceutically acceptable salts.
Besides, the invention, refers to pharmaceutical compositions containing the above mentioned compounds, or pharmaceutically acceptable salts thereof formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and the like or with organic acids such as acetic, propionic, succinic, malonic, citric, ~artaric, methansulfonic, p-toluensulfonic and the like.
~ 94/20 ~ PCT~EP94/00557 According to the present invention, preferred are the ,- -ln~ of formula (I) wherein:
n is as above defined m is zero or an integer comprised between 1 and 3.
A = cyclohexyl, p-phenylene, l-methylpyrrole, th;ophpne~ thiazole, ~ ole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole.
B is a simple bond, or when it is a -C0-NH-CH(R3)- group or a -NH-C0-CH(R3)- group, R3 is preferably methyl, isobutyl, sec-butyl, hydroxymethyl, mercaptomethyl, carbamoylmethyl, benzyl, 4-hydroxybenzyl, 5-imidazolylmethyl, 2-carbamoylethyl, 2-methylthioethyl, l-hydroxyethyl, 3-~l~ni~inopropyl~ 4-aminobutyl Rl and R2 represent preferably an ethyl group, 2-hydroxyethyl, 2-chloroethyl, methansulfonylethyl.
The following compounds are particl-l~rly preferred:
3-[1-Methyl-4-tl-methyl-4-t4-tN,N-bis(2-chloroethyl)amino~bPn~PnP-aminocarbonyl]pyrrol-2-caL-bo~y- ;do]pyrrol-2-carbo~y~ido]propionr idine hydrochlorate;
3-tl-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl) amino]benzeneaminocarbonyl]-pyrrol-2-carbo~ -ido]
pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carbox~ ido]
propion~mi~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzPne~minocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate;
WO 94/20463 PCT~EPg4/00557 3-tl-Methyl-4-[l-methyl-4-[4-[N~N-bis(2-chloroethyl)amino]
butPnf idQ]pyrrol-2-carboxyamido]pyrrol-2-csrboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-{4-[N,N-bis(2-chloroethyl)-amino]benzenbut~n~mi~n]pyrrol-2-c&-bo~y&~ido]pyrrol-2-csrboxy 'do]pyrrol-2-ca.l,o~ys~ido]pyrrol-2-caLLu~y~ido]propionnmi~i n~ hyd.-ochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-~1-methyl-4-[N,N-bis(2-chloroethyl)amino]ben7~nebùt~n~ ~o]pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]pyrrol-2-ca.boxy ido] pyrrol-2-ca~bGxy do]
pyrrol-2-carboxyamido]propinn~ ~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4[N,N-bis(2-chloroethyl)amino]benzyl-amino carbonyl]pyrrol-2-carbony ~o]pyrrol-2-caL-bo~y~ ;~o]propion~mi~in~ hydrochlorate;
15 3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2 chloroethylamino)benzylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-ca.-bo~y ~ido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino) phenyl] et h ~n ~ inocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxa mido] propionamidine hydrochlorate;
3-~1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis (2-chloroethyl) amino]phenyl]eth~n~minocarbonyl]pyrrol-2-carboxa-mido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-~ 94/20463 PCT~EP94/00557 ';~
carboxyamido]prop;onr ~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]propylaminocarbonyl]pyrrol-2-chl-bo~y do]pyrrol-2-carboxa-mido] propisn~ ~ine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-tl-methyl-4-[3-[4-tN,N-bis(2-chloroethyl)amino]phenyl]propylsminocarbonyl]pyrrol-2-carboxy do]pyrrol-2-caLbo~y6~ido]pyrrol-2-carboxyamido]pyrrol-2-carboxy- do] prop;on r ~; n~ hydrochlorate;
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-tl-methyl-4-tl-methyl-4-t3-t4-tN~N-bis(2-chloroethyl)amino]phenyl]propylr ;noc~G-lyl]pyrrol-2-carbG~y do]pyrrol-2-caL-bo~y do]pyrrol-2-caLbu~y ~o]pyrrol-2-carbo~y- ido]pyrrol-2-caLboxy do]propionr '~;ne hydrochlorate;
3-tl-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzyl carbo~yr ~o]pyrrol-2-carboxyamido]pyrrol-2-carboxy- do]propion~ ;~;ne hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-tN,N-bis(2-chloroethyl)amino]benzylcarbo~y do]pyrrol-2-carbo~y ~o]pyrrol-2-carboxyamido]pyrrol-2-carboxy ;~o]pyrrol-2-carboxyr i~o]
propionr i~i ne hydrochlorate;
3-[1-Methyl-4-tl-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]ethylcarboxyamido3pyrrol-2-carboxyamido]pyrrol-2-carboxy-amido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis - (2-chloroethyl)amino]phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-~ ~ ~ 8 ca ~o~y~ido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-me~hyl-4-[1-methyl-4-[N,g-[4-EN,N-bis(2-chloro-ethyl)amino]benzoyl]glycylamino]pyrrol-2-carbG~y ~o]pyrrol-2-c&~-bo~y do]pyrrol-2-carbo~y do]propionr i~inP hydrochlorate;
3-~1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycylamino]-pyrrol-2-ca~o~y do]pyrrol-2-carbo~y ~o]pyrrol-2-ca~-~o~y ~o]pyrrol-2-calbo~y ;do]propi on~ ine hydrochlorate;
Compounds of general formula (I) can be prepared according to the following processes:
a) reacting the ~ nd of fo. 1~ (III) Rl~
N-A-(CH2)m-B-COOH
(III) wherein B is a chemical bond or the -CONHCH(R3)- group wherein R3 is as above defined, and m, A, Rl and R2 are as above defined, or a reactive derivative thereof, with a compound of formula (IV) _ CH3 `~ --P H2 (IV) 94/204K3 ~ PCTAEP94/00557 . 9 ~ ~
wherein p is an integer comprised between 2 and 6, thereby obt~ining the compounds of formula (I) wherein X = -CONH-, B is a ~'~ c~1 bond or the -CO-NH-CH(R3)- group and m, n, A, B, Rl, R2 and R3 are as above defined;
a') reacting the compound of formula (V) Rl / N A (CH2)m B NH2 (V) wherein B is a chemical bond or the -NHCOCH(R3)- group, wherein R3 is as above defined, and m, A, R1 and R2 are as above defined, with a c ,_~tn~ of formula (VI) HOOC~
~N ~NH
_ CH3 1 --PH2 (VI) wherein p is an integer comprised between 2 and 6, thereby obt~ining the compounds of formula (I) wherein X = -NHCO-, B is a chemical bond or the -~'H-CO-CH(R3)- group and m, n, A, B, R1, R2 and R3 are as above defined;
WO 94/20463 PCT~EP94/00557 b) reacting the compound of formula (VII) A (CH2~X
N~--COOH
~H (VII) wherein m, A, X, R1 and R2 are as above defined, with a compound of formula (IV) HOOC~
~N ~N~
(IV) wherein p is an integer comprised between 1 and 5, thereby obt~inin~ the compounds of formula (I) wherein B is a chemic~l bond and m, n, A, X, R1 and R2 are as above defined.
The amidation reactions of the compound of formula (III) with a compound of formula (IV) wherein p is an integer comprised between 2 and 6, of the compound of formula (V), wherein Rl, R2, A, m and B
are as previously defined, with the compound of formula (VI), wherein p is comprised between 2 and 6, and of the compound of formula (VIIj, wherein R1, R2, A, m, X are as above defined, with a compound of formula (IV) wherein p is an integer comprised between 1 and 5, can be carried out in the presence of co~Pncing agents as ~ 94/20463 ~ ~ ~ PCT~EPg4/00557 8~
DCC (dicyclnhpyylcarbo~ de) or EDC [l-dimethyl r~i n~propyl)-3-~ ethylcarbo~ de hydrochlorate] and poss~hly in the presence of hydroxybenzotriazole or BOP (benzotriazol-1-iloxy(dimethylaminophncphonit '~ fluoride ph~sph~te) or by using a reactive derivative of the acids (TTT) and (IV) as for example an acylchloride, an acyl~ ole, an acyl~7i~e or an active ester, such as 2,4,5 trichlororh~l~o~yester or N-oxysllcc;ni ~n~cter, or an anhy~.-ide thereof.
Preferably the above defined ~ t~ on reactions are carried out using molar ratio of from 1:1 to 1:3 in an inert organic solvent for example dimethyl sulfoxide. hexamethyl phosphotriamide, dimethylacetamide, or preferably ~ l fo. ~e in the pres~nce of a con~nsing agent as above described and of N-hy~-u~ybenzotriazole or BOP and in the presence of an organic base as triethylamine, diisopropylethylamine and 1,8-bis(dimethylamino)-naphth~l~ne.
The reaction temperature may be comprised between -lO C and 5O C
and the time required for the reaction ranges from 2 to 48 hours.
The reaction of the compound of foL .l~ (III) or the compound of formula (VII) with the compound of fo. l~ (IV) may be csrried out using a reactive derivative of the compound of formula (III) or of the compound of formula (VII) of the above mentioned type, and therefore accompliching the reaction in a biphasic system water-organic solvent as Schotten-B~I ~nn amidation or in an organic WO 94/20463 ~ PCT~EP94/00557 solvent as for example a hydro~yde, a carbonate or a bicarbonate of an ~lkaline metal, preferably sodium, potassium, barium or an organic ba e as triethylamine, diisopropyl~ ne, pyridine or N,N
dimethylaminopyridine.
The reaction is usually conducted at room temperature and the time required for the reaction varies from 2 to 24 hours.
In the process (a), the compounds of formula (III) wherein B is a chemical bond and m, A, Rl and R2 are as above defined, namely the compounds of formula (VIII) Rl\
N-A-(CH2)m~CH
(VIII) either are already commercially av~ hle or they are prepared by conventional processes of the organic chemistry, starting from known compounds as reported for example in J. Med. Chem. 32, 774 (1989) or J. Org. Chem. 26, 4996 or in J. Med. Chem. 33, 1177 ( 1990) .
In the process (a) a compound of formula (III) wherein B is the group -CO-NH-CH(R3)- and m, A, Rl, R2 and R3 are as above defined, can be prepared by the hydrolysis of the compounds of formula (IX) Rl~ .
N-A-(CH2)m-CO-NH-CH(R3)-COORs R2 (IX) ~ 94l20463 - PCT~EP94100557 13 S71~7 wherein A, m. Rl, R2, R3 are as above defined and R5 is a protecting group characteristic of the carboxylic group of n9~ c as methyl, ethyl, t-butyl, benzyl, trimethylsilyl, the hydrolysis of the compound of formula (IX) can be carried out following the ~nown methods and processes of the organic chemistry as for example reported in T. W. Greene Protective groups in Organic Synthesis Wiley Interscience Pu~li cnti on 1981.
A compound of formula (IX) wherein A, m, Rl, R2 R3 and R5 are ~c above defined, can be prepared by rescting a ~ d of foL 1~
(VIII) wherein A, m, Rl and R2 are as above defined or its reactive derivative with a compound of fo. 1l ~ (X) H2N-CH(R3)-COORs (X) wherein R3 and R5 have the above defined -~nin~, A reactive compound of an acid of formula (VIII) can be the same already reported in the present application for the compound of formula (III) or for the compound of formula (VII) and the reaction can be accomplished under similar conditions to those reported for the amidation reaction of a compound of formula (III) or a compound of formula (VII) with a compound of formula (IV).
The compounds of formula (X) either are commercially available or can be prepared by the conventional processes starting from the - corresponding aminoacids as described for example in E. Gross, J.
Meienhofer, The Peptides V. 3, p. 102-132, 1981. .~c~ ;c Press.
W O 94/20463 ~ PCT~EP94/00557 ; 14 In the process (a') a compound of formula (V) wherein B is a chemical bond snd m, A, R1 snd R2 are as above defined, nsmely compounds of formula (XI) Rl~
N-A-(CH2)m-NH2 (XI) either are commercially available or are prepared by the conventional processes of the organic chemistry as ,-e~o,-ted for example in J. Med. Chem. 33, 112 (199O).
In the process (a') a compound of fo. -l~ (V) wherein B is the group -NHCOCH(R3) wherein m, A, R1, R2 and R3 are as above defined, can be prepared by hydrolysis of the c ,_ ~ of formula (XII) N-A-(cH2)m-NH-co-cH(R3)-NHR6 (XII) wherein A, m, R1, R2, R3 are as above defined and R6 is a protecting group characteristic of the smino group of ~mino~ c as trifluoroacetyl, benzyloxycsrbonyl. tertbutyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and trityl, the hydrolysis of the compound of formula (XII) can be carried out following the methods and processes known in the organic chemistry as for example reported in T. W. Greene Protective group in Organic Synthesis 94/20463 ~ PCT~EP94100557 -, Wiley Interscience Publication 1981.
A compound having formula (XII) wherein A, m, R1, R2, R3 and R6 are as above defined can be prepared by reacting a compound of fG. 1 (XI) wherein A, m, R1 and R2 are as above defined, with a c _ of formula (XIII) Hooc-cH(R3)-NHR6 (XIII) wherein R3 and R6 are as above defined, or with its reactive derivative.
A reactive derivative of an acid of formula (XIII) can be the same as reported in this application for the compound having fo~
(III) or for the compound having formula (VII) and the reaction can be carried out under similar conditions to those reported for the amidation reaction of a compound of fo. 1~ (III) or a c .- ~ of formula (VII) with a compound of fo, l~ (IV).
The compounds of formula (XIII) either are commercially avAil~hle or are prepared by conventional procedures, startin~ from aminoacids as described for example in E. Gross, J. ~ei~nhofer, The Peptides V. 3, p. 102-132, 1981, Ac~ ic Press.
In the process (b), a compound of formula (VII) wherein m, A, X, R1 and R2 are as above defined, can be prepared as described in the ZO International Patent applicstion No. WO 93/13739 published on 22nd July 1993 in the name of the same applicant and herein reported by reference.
WO 94/20463 ~ PCT~EP94/00557 ~ ~ 16 In the processes (a) and (b) a compound of formula (IV) either is a commercially av~ h]e compound or can be prepared by the known methods tGazzetta Chimica It~ n~ 99, 632 (1969)].
In the process (a') a compound of fo. -lA (VI) can be prepared according to the methods described in the International Patent application No. W0 93/13739 p-~hl i che~ on 22nd July 1993 in the name of the same applicant and herein reported by reference.
The compounds of the present invention have antitumoral and antiviral activity, in particular they show high cytotoxicity levels against the tumoral cel 1~ r lines.
Moreover the present invention relates to pharmaceutical c~,~sitions comprising as active principle a compound of general for .l~ (I) or a pharmaceutically acceptable salt thereof with a pha.- --eutically acceptable vehicle or ~il u~n t .
A therapeutically effective amount of the compound of formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vehicle. Conventional vehic~es can be used and the ~ .itions can be prepared using the conventional techniques. The compounds according to the present invention are useful for human and animal therapeutical treatment.
In particular, the compounds according to the present invention are useful as antitumoral and / or antiviral agents when ~i ni ctered to patients in a therapeutically effective amount, for example a suitable dosage for the a~in; ctation to adult patients can vary 25 from about O.1 and 100 mg per unitary dose from one to 4 times a 94l204C3 , PCTAEP94/00557 day.
3-[1-Methyl-4-tl-methyl-4-[1-methyl-4-[1-methyl-4-t4-[N,N-bis(2-chloroethyl)amino]benzenbut~n~ ;~n]pyrrol-2-c & ~o~y do]pyrrol-2-cal~o~y i~o]pyrrol-2-carbo~n~ido]pyrrol-2-ca~ y do]propiona-midine hydrochlorate (I, X ~ -CONH-, A = p-phenylene, B z O m = 3, n = 2, Rl = R2 = 2-chloroethyl).
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-tN,N-bis(2-chloroethyl)amino]benzylcarbo~y do]pyrrol-2-carbo~y ~o]pyrrol-2-carboxyamido]pyrrol-2-carboxy ;~o]pyrrol-2-carboxyr i~o]
propionr i~i ne hydrochlorate;
3-[1-Methyl-4-tl-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]ethylcarboxyamido3pyrrol-2-carboxyamido]pyrrol-2-carboxy-amido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis - (2-chloroethyl)amino]phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-~ ~ ~ 8 ca ~o~y~ido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-me~hyl-4-[1-methyl-4-[N,g-[4-EN,N-bis(2-chloro-ethyl)amino]benzoyl]glycylamino]pyrrol-2-carbG~y ~o]pyrrol-2-c&~-bo~y do]pyrrol-2-carbo~y do]propionr i~inP hydrochlorate;
3-~1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycylamino]-pyrrol-2-ca~o~y do]pyrrol-2-carbo~y ~o]pyrrol-2-ca~-~o~y ~o]pyrrol-2-calbo~y ;do]propi on~ ine hydrochlorate;
Compounds of general formula (I) can be prepared according to the following processes:
a) reacting the ~ nd of fo. 1~ (III) Rl~
N-A-(CH2)m-B-COOH
(III) wherein B is a chemical bond or the -CONHCH(R3)- group wherein R3 is as above defined, and m, A, Rl and R2 are as above defined, or a reactive derivative thereof, with a compound of formula (IV) _ CH3 `~ --P H2 (IV) 94/204K3 ~ PCTAEP94/00557 . 9 ~ ~
wherein p is an integer comprised between 2 and 6, thereby obt~ining the compounds of formula (I) wherein X = -CONH-, B is a ~'~ c~1 bond or the -CO-NH-CH(R3)- group and m, n, A, B, Rl, R2 and R3 are as above defined;
a') reacting the compound of formula (V) Rl / N A (CH2)m B NH2 (V) wherein B is a chemical bond or the -NHCOCH(R3)- group, wherein R3 is as above defined, and m, A, R1 and R2 are as above defined, with a c ,_~tn~ of formula (VI) HOOC~
~N ~NH
_ CH3 1 --PH2 (VI) wherein p is an integer comprised between 2 and 6, thereby obt~ining the compounds of formula (I) wherein X = -NHCO-, B is a chemical bond or the -~'H-CO-CH(R3)- group and m, n, A, B, R1, R2 and R3 are as above defined;
WO 94/20463 PCT~EP94/00557 b) reacting the compound of formula (VII) A (CH2~X
N~--COOH
~H (VII) wherein m, A, X, R1 and R2 are as above defined, with a compound of formula (IV) HOOC~
~N ~N~
(IV) wherein p is an integer comprised between 1 and 5, thereby obt~inin~ the compounds of formula (I) wherein B is a chemic~l bond and m, n, A, X, R1 and R2 are as above defined.
The amidation reactions of the compound of formula (III) with a compound of formula (IV) wherein p is an integer comprised between 2 and 6, of the compound of formula (V), wherein Rl, R2, A, m and B
are as previously defined, with the compound of formula (VI), wherein p is comprised between 2 and 6, and of the compound of formula (VIIj, wherein R1, R2, A, m, X are as above defined, with a compound of formula (IV) wherein p is an integer comprised between 1 and 5, can be carried out in the presence of co~Pncing agents as ~ 94/20463 ~ ~ ~ PCT~EPg4/00557 8~
DCC (dicyclnhpyylcarbo~ de) or EDC [l-dimethyl r~i n~propyl)-3-~ ethylcarbo~ de hydrochlorate] and poss~hly in the presence of hydroxybenzotriazole or BOP (benzotriazol-1-iloxy(dimethylaminophncphonit '~ fluoride ph~sph~te) or by using a reactive derivative of the acids (TTT) and (IV) as for example an acylchloride, an acyl~ ole, an acyl~7i~e or an active ester, such as 2,4,5 trichlororh~l~o~yester or N-oxysllcc;ni ~n~cter, or an anhy~.-ide thereof.
Preferably the above defined ~ t~ on reactions are carried out using molar ratio of from 1:1 to 1:3 in an inert organic solvent for example dimethyl sulfoxide. hexamethyl phosphotriamide, dimethylacetamide, or preferably ~ l fo. ~e in the pres~nce of a con~nsing agent as above described and of N-hy~-u~ybenzotriazole or BOP and in the presence of an organic base as triethylamine, diisopropylethylamine and 1,8-bis(dimethylamino)-naphth~l~ne.
The reaction temperature may be comprised between -lO C and 5O C
and the time required for the reaction ranges from 2 to 48 hours.
The reaction of the compound of foL .l~ (III) or the compound of formula (VII) with the compound of fo. l~ (IV) may be csrried out using a reactive derivative of the compound of formula (III) or of the compound of formula (VII) of the above mentioned type, and therefore accompliching the reaction in a biphasic system water-organic solvent as Schotten-B~I ~nn amidation or in an organic WO 94/20463 ~ PCT~EP94/00557 solvent as for example a hydro~yde, a carbonate or a bicarbonate of an ~lkaline metal, preferably sodium, potassium, barium or an organic ba e as triethylamine, diisopropyl~ ne, pyridine or N,N
dimethylaminopyridine.
The reaction is usually conducted at room temperature and the time required for the reaction varies from 2 to 24 hours.
In the process (a), the compounds of formula (III) wherein B is a chemical bond and m, A, Rl and R2 are as above defined, namely the compounds of formula (VIII) Rl\
N-A-(CH2)m~CH
(VIII) either are already commercially av~ hle or they are prepared by conventional processes of the organic chemistry, starting from known compounds as reported for example in J. Med. Chem. 32, 774 (1989) or J. Org. Chem. 26, 4996 or in J. Med. Chem. 33, 1177 ( 1990) .
In the process (a) a compound of formula (III) wherein B is the group -CO-NH-CH(R3)- and m, A, Rl, R2 and R3 are as above defined, can be prepared by the hydrolysis of the compounds of formula (IX) Rl~ .
N-A-(CH2)m-CO-NH-CH(R3)-COORs R2 (IX) ~ 94l20463 - PCT~EP94100557 13 S71~7 wherein A, m. Rl, R2, R3 are as above defined and R5 is a protecting group characteristic of the carboxylic group of n9~ c as methyl, ethyl, t-butyl, benzyl, trimethylsilyl, the hydrolysis of the compound of formula (IX) can be carried out following the ~nown methods and processes of the organic chemistry as for example reported in T. W. Greene Protective groups in Organic Synthesis Wiley Interscience Pu~li cnti on 1981.
A compound of formula (IX) wherein A, m, Rl, R2 R3 and R5 are ~c above defined, can be prepared by rescting a ~ d of foL 1~
(VIII) wherein A, m, Rl and R2 are as above defined or its reactive derivative with a compound of fo. 1l ~ (X) H2N-CH(R3)-COORs (X) wherein R3 and R5 have the above defined -~nin~, A reactive compound of an acid of formula (VIII) can be the same already reported in the present application for the compound of formula (III) or for the compound of formula (VII) and the reaction can be accomplished under similar conditions to those reported for the amidation reaction of a compound of formula (III) or a compound of formula (VII) with a compound of formula (IV).
The compounds of formula (X) either are commercially available or can be prepared by the conventional processes starting from the - corresponding aminoacids as described for example in E. Gross, J.
Meienhofer, The Peptides V. 3, p. 102-132, 1981. .~c~ ;c Press.
W O 94/20463 ~ PCT~EP94/00557 ; 14 In the process (a') a compound of formula (V) wherein B is a chemical bond snd m, A, R1 snd R2 are as above defined, nsmely compounds of formula (XI) Rl~
N-A-(CH2)m-NH2 (XI) either are commercially available or are prepared by the conventional processes of the organic chemistry as ,-e~o,-ted for example in J. Med. Chem. 33, 112 (199O).
In the process (a') a compound of fo. -l~ (V) wherein B is the group -NHCOCH(R3) wherein m, A, R1, R2 and R3 are as above defined, can be prepared by hydrolysis of the c ,_ ~ of formula (XII) N-A-(cH2)m-NH-co-cH(R3)-NHR6 (XII) wherein A, m, R1, R2, R3 are as above defined and R6 is a protecting group characteristic of the smino group of ~mino~ c as trifluoroacetyl, benzyloxycsrbonyl. tertbutyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and trityl, the hydrolysis of the compound of formula (XII) can be carried out following the methods and processes known in the organic chemistry as for example reported in T. W. Greene Protective group in Organic Synthesis 94/20463 ~ PCT~EP94100557 -, Wiley Interscience Publication 1981.
A compound having formula (XII) wherein A, m, R1, R2, R3 and R6 are as above defined can be prepared by reacting a compound of fG. 1 (XI) wherein A, m, R1 and R2 are as above defined, with a c _ of formula (XIII) Hooc-cH(R3)-NHR6 (XIII) wherein R3 and R6 are as above defined, or with its reactive derivative.
A reactive derivative of an acid of formula (XIII) can be the same as reported in this application for the compound having fo~
(III) or for the compound having formula (VII) and the reaction can be carried out under similar conditions to those reported for the amidation reaction of a compound of fo. 1~ (III) or a c .- ~ of formula (VII) with a compound of fo, l~ (IV).
The compounds of formula (XIII) either are commercially avAil~hle or are prepared by conventional procedures, startin~ from aminoacids as described for example in E. Gross, J. ~ei~nhofer, The Peptides V. 3, p. 102-132, 1981, Ac~ ic Press.
In the process (b), a compound of formula (VII) wherein m, A, X, R1 and R2 are as above defined, can be prepared as described in the ZO International Patent applicstion No. WO 93/13739 published on 22nd July 1993 in the name of the same applicant and herein reported by reference.
WO 94/20463 ~ PCT~EP94/00557 ~ ~ 16 In the processes (a) and (b) a compound of formula (IV) either is a commercially av~ h]e compound or can be prepared by the known methods tGazzetta Chimica It~ n~ 99, 632 (1969)].
In the process (a') a compound of fo. -lA (VI) can be prepared according to the methods described in the International Patent application No. W0 93/13739 p-~hl i che~ on 22nd July 1993 in the name of the same applicant and herein reported by reference.
The compounds of the present invention have antitumoral and antiviral activity, in particular they show high cytotoxicity levels against the tumoral cel 1~ r lines.
Moreover the present invention relates to pharmaceutical c~,~sitions comprising as active principle a compound of general for .l~ (I) or a pharmaceutically acceptable salt thereof with a pha.- --eutically acceptable vehicle or ~il u~n t .
A therapeutically effective amount of the compound of formula (I) according to the invention is combined with an inert and pharmaceutically acceptable vehicle. Conventional vehic~es can be used and the ~ .itions can be prepared using the conventional techniques. The compounds according to the present invention are useful for human and animal therapeutical treatment.
In particular, the compounds according to the present invention are useful as antitumoral and / or antiviral agents when ~i ni ctered to patients in a therapeutically effective amount, for example a suitable dosage for the a~in; ctation to adult patients can vary 25 from about O.1 and 100 mg per unitary dose from one to 4 times a 94l204C3 , PCTAEP94/00557 day.
3-[1-Methyl-4-tl-methyl-4-[1-methyl-4-[1-methyl-4-t4-[N,N-bis(2-chloroethyl)amino]benzenbut~n~ ;~n]pyrrol-2-c & ~o~y do]pyrrol-2-cal~o~y i~o]pyrrol-2-carbo~n~ido]pyrrol-2-ca~ y do]propiona-midine hydrochlorate (I, X ~ -CONH-, A = p-phenylene, B z O m = 3, n = 2, Rl = R2 = 2-chloroethyl).
4-[Bis(2-chloroethyl)amino~b~ 7~Pbutanoylchloride (801 mg, 2.49 mmoles), (obt~ined by the correspon~ing ca~Lo~ylic acid VIII, (A =
p-phenylene, m = 3, R1 = R2 = 2-chloroethyl) (75O mg, 2.49 mmoles) by treatment with SOCl2 (1.2 ml) in tetrahydrofuran (25 ml) under reflux), are ~iscolved in 25 ml anhydrous tetrahydrofuran and added to a solution of 3-[1-Methyl-4-[1-methyl-4-~1-methyl-4-(1-methyl-4-aminopyrrole-2-carboxyamido)pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate tIV, p = 4) (327 mg, 0.51 mmoles), [Gazzetta Chimica It~ n~, 99, 632 (1969)] and sodium bicarbonate (90 mg, 1.11 mmoles) in 40 ml water.
~fter one hour stirring st room temperature, the reaction mixture is evaporated to dryness and the residue is separated by chromatography on silica gel (eluent CHC13/MeOH 7/3) thus obt~in;ne 276 mg I (X = -CONH-, A = p-phenylene, B = O, m = 3, n = 2, R1 = R2 = 2-chloroethyl) (yield 60 %).
-W O 94/20463 PCT~EW4/00557 H-NMR (DMS0-d6), d : 1.82 (m, 2H), 2.25 (t, 2H), 2.45 (t, 2H), 2.64 (t, 2H), 3.50 (m, 2H), 3.70 (s, 8H), 3.82 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 6.69 (d, 2H), 6.90 (d, lH), 6.97 (d, lH), 7.04 (d, 2H), 7.08 (bs, 2H), 7.15 (d, lH), 7.18 (d, lH), 7.22 (bs, 2H). 8.19 (t, lH), 8.57 (bs,2H), 8.95 (bs, 2H), 9.76 (s,lH), 9.90 (m,3H)-The following compound of formula (I) is also obtained by an analogous proce~s:
3-~l-Methyl-4-tl-methyl-4-[4-~N,N-bis(2-chloroethyl)amino]be but~nFImido]pyrrol-2-ca.bu~.y do]pyrrol-2-caLLo~y r~n] propiona-midine hydrochlorate (I, X - -CONH-, A = p-phenylene, B = 0, m ~ 3, n ~ O, Rl ~ R2 = 2-chloroethyl).
lH-NMR (DMS0-d6), d : 1.80 (m, 2H), 2.24 (t, 2H), 2.50 (t, 2H), 2.62 (t, 2H), 3.50 (m, 2H), 3.70 (s, 8H), 3.81 (s, 3H), 3.83 (s, 3H), 6.68 (d, 2H), 6.87 (d, lH), 6.92 (d, lH), 7.04 (d, 2H), 7.13 (d, lH), 7.16 (d, lH), 8.18 (t, lH), 8.65 (bs, 2H), 8.94 (bs, 2H), 9.75 (s, lH), 9.83 (s, lH).
3-rl-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl~amino3benzen~ i~ocarbonyl]pyrrol-2-caL-bo~y -ido]pyrrol-2-carboxyamido]pyrrol-Z-carboxyamido]pyrrol-2-carbo~y ido] propio-namidine hydrochlorate (I, X = -NHC0-, A = p-phenylene, B z 0, m = 0, n = 2, Rl = R2 = 2-~ 0 94/20463 , I 8 7 PCT~EPg4/00557 chloroethyl).
(337 mg, o.84 mmoles) of 1-Methyl-4-~4-[N,N-bis(2-chloroethyl)-amino]b~n~nPminocarbonyl] pyrrol-2-c~,~ohylic acid chloride (VII, A = p-phenylene, X = -NHCO-, m - O, Rl = R2 = 2-chloroethyl), (obtained by treatment of the carboxylic acid VII (A ~ p-phenylene, X = -NHCO-, m = O, Rl = R2 = 2-chloroethyl) (322 mg, o.84 l~) with SOC12 (4.2 mmoles) ~i~solved in CH2C12 and in the pr~nre of dimethylfor de), are dissolved in 10 ml tetrahydrofursn and added to a mixture of N-deformyldystamicine (221 mg, 0.42 mmoles) 10 and diisopropylethylamine (0.3 ml, 2.1 mmoles) in anhydrous EtOH (5 ml) .
The mixture is maintained 30 minutes under stirring at room t~ ture, then ethylacetate is added up to the precipitation of the raw product, which after separation by HPLC (H20/CH3CN/CF3COOH
15 56/44/0.1) gives 162 mg of I (X = -NHCO-, A = p-phenylene, B = O, m = O, n = 2, Rl = R2 = 2-chloroethyl), (yield 45 %).
H-NMR (DMSO-d6), d : 2.60 (t, 2H), 3.50 (m, 2H), 3.70 (s. 8H), 3.81 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.74 (d, 2H), 6.96 (d, lH), 7.08 (s, 2H), 7.18 20 (d, 2H), 7.25 (d, lH), 7.28 (d, lH), 7.42 (d, lH), 7.54 (d, 2H), 7.69 (d, lH), 8.17 (t, lH), 8.50 (bs, 2H), 8.59 (bs, 2H), 9.49 (s, lH), 9.88 (s, lH), 9.94 (s, lH), 10.09 (s, lH)-The following compound of formula (I) is also obtained by an WO 94/20463 PCT~EP9S/00557 ~ 20 analogous process:
3~ Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]b~n7Pnr 'noc~rbonyl]pyrrol-2-c~ y do]pyrrol-2-ca~bo~y ~o]pyrrol-2-carbo~y~ido]pyrrol-2-5 C&~o~y ~o]pyrrol-2-car~y~ido] propionr ~ine hydrochlorate (I, X = -NHC0-, A = p-phenylene, B = O, m = O, n = 3, Rl = R2 = 2-chloroethyl).
H-NMR (DMS0-d6), d : 2.60 (t, 2H), 3.50 (m, 2H), 3.70 (s. 8H), 3-81 (s, 3H), 3.85 (s, 3H). 3.87 (s, 6H), 3-92 10 (s, 3H), 6.72 (d, 2H), 6.95 (d, lH), 7.07 (m, 3H), 7.16 (d, lH), 7.21 (d, lH), 7.23 (d, lH), 7.26 (d, lH), 7.41(d, lH), 7.52 (d, 2H), 7.68 (d, lH), 8.18 (t, lH), 8.47 (bs, 2H), 8.89 (bs, 2H), 9.48 (s, lH), 9.88 (s, lH) 9.90 (s, lH), 9.93 (s, lH), 10.09 (s, lH) N-[4-~N,N-bis(2-chloroethyl)amino]benzoyl]glycine (III, A = p-phenylene, m = 0, Rl = R2 = 2-chloroethyl, B = -CONHCH(R3)-, R3 =
H) A mixture composed by glycine (600 mg, 8 mmoles), 20 bis(trimethylsilyl)acetamide (3.25 g, 16 mmoles), and trimethylsilylchloride (0.2 ml, 1.6 mmoles) in CH2Cl2 (20 ml) is kept under reflux for 2 hours.
After cooling to room temperature, (3 g, 10.8 mmoles) of 4-[N,N-bis(2-chloroethyl)amino]benzoylchloride are added to the reaction ~0 94/20463 1S7187 PCT/EP94/00557 mixture, which is maintained under stirring at 40 C.
After 2 hours, the mixture is acidified with lN HCl and extracted with CH2C12; the organic extracts are coll ected and extracted on their turn with an aqueous solution of NaHC03, and the basic phase, 5 after acidification with lN HCl i~ extracted with CH2Cl2 thus obt~;nine after evaporation of the organic phase, 1.32 g of III (A
= p-phenylene, m = O, R1 = R2 = 2-chloroethyl. B = -CONHCH(R3)-, R3 = H), (yield 52 ,X) lH-NMR (DMSO-d6), d: 3.78 (m, 8H), 3.88 (d. 2H), 6.78 10 (d, 2H). 7.72 (d. 2H), 8.46 (t. lH).
BAI~LE 4 3-[1-Methyl-4-~1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycylamino]pyrrol-2-ca~l~o~y 'do]pyrrol-2-carl~o~y ~o]pyrrol-2-cE~ G~y do]propion~ 13in~ hydrochlorate 15 (I, X = -CONH-, A ~ p-phenylene, B z -CO~;n(R3)-, R3 = H, m = O, n 1, R1 = R2 = 2-chloroethyl).
308 mg (0.58 mmoles) N-deformyldystamicine, 136 mg (1 mmole) N-hydroxybenzotriazole (HOBT), 182 mg (0.85) mmoles 1,8-bis-(dimethylamino)-naphthalene and 191 mg (0.11 mmoles) [1-(3-20 dimethylaminopropyl)-3-ethylcarbodiimide ( EDC ) are added to a solution of 270 mg, (0.85 mmoles) III (A = p-phenylene, m = O, R1 =
R2 = 2-chloroethyl, B = -CONHCH(R3) -, R3 = H ), prepared as described in example 3 and dissolved in anhydrous dimethylformamide (45 ml).
25 The reaction mixture is maintained under stirring at room WO 94/20463 PCT~EP94/00557 temperature for one hour, then ethylacetate is added up to precipitation o~ the raw product, which after chromatography on silica gel (eluent CH2Cl2/anhydrous EtOH/H2O 65/35/2) gives 275 mg of I (X - -CONH-, A = p-phenylene, B ~ -CONHCH(R3)-, R3 ~ H, m - O.
n = 1. Rl = R2 = 2-chloroethyl) (yleld 60 %) H-NMR (DMSO-d6), d : 2.64 (t, 2H), 3.50 (m, 2H), 3.78 (s, 8H), 3.82 (s, 3H), 3.84 (s, 6H), 3.97 (d, 2H), 6.78 (d, 2H), 6.91 (s. 2H), 7.O4 (d. lH), 7.14 (d, lH), 7.18 (d. lH), 7.21 (d, lH), 7.78 (d, 2H), 8.21 (t, lH), 8.52 (t, lH), 8.78 (bs, 2H), 9.O4 (bs, 2H), 9.89 (s, 2H), 9.95 (8, lH).
p-phenylene, m = 3, R1 = R2 = 2-chloroethyl) (75O mg, 2.49 mmoles) by treatment with SOCl2 (1.2 ml) in tetrahydrofuran (25 ml) under reflux), are ~iscolved in 25 ml anhydrous tetrahydrofuran and added to a solution of 3-[1-Methyl-4-[1-methyl-4-~1-methyl-4-(1-methyl-4-aminopyrrole-2-carboxyamido)pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate tIV, p = 4) (327 mg, 0.51 mmoles), [Gazzetta Chimica It~ n~, 99, 632 (1969)] and sodium bicarbonate (90 mg, 1.11 mmoles) in 40 ml water.
~fter one hour stirring st room temperature, the reaction mixture is evaporated to dryness and the residue is separated by chromatography on silica gel (eluent CHC13/MeOH 7/3) thus obt~in;ne 276 mg I (X = -CONH-, A = p-phenylene, B = O, m = 3, n = 2, R1 = R2 = 2-chloroethyl) (yield 60 %).
-W O 94/20463 PCT~EW4/00557 H-NMR (DMS0-d6), d : 1.82 (m, 2H), 2.25 (t, 2H), 2.45 (t, 2H), 2.64 (t, 2H), 3.50 (m, 2H), 3.70 (s, 8H), 3.82 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 6.69 (d, 2H), 6.90 (d, lH), 6.97 (d, lH), 7.04 (d, 2H), 7.08 (bs, 2H), 7.15 (d, lH), 7.18 (d, lH), 7.22 (bs, 2H). 8.19 (t, lH), 8.57 (bs,2H), 8.95 (bs, 2H), 9.76 (s,lH), 9.90 (m,3H)-The following compound of formula (I) is also obtained by an analogous proce~s:
3-~l-Methyl-4-tl-methyl-4-[4-~N,N-bis(2-chloroethyl)amino]be but~nFImido]pyrrol-2-ca.bu~.y do]pyrrol-2-caLLo~y r~n] propiona-midine hydrochlorate (I, X - -CONH-, A = p-phenylene, B = 0, m ~ 3, n ~ O, Rl ~ R2 = 2-chloroethyl).
lH-NMR (DMS0-d6), d : 1.80 (m, 2H), 2.24 (t, 2H), 2.50 (t, 2H), 2.62 (t, 2H), 3.50 (m, 2H), 3.70 (s, 8H), 3.81 (s, 3H), 3.83 (s, 3H), 6.68 (d, 2H), 6.87 (d, lH), 6.92 (d, lH), 7.04 (d, 2H), 7.13 (d, lH), 7.16 (d, lH), 8.18 (t, lH), 8.65 (bs, 2H), 8.94 (bs, 2H), 9.75 (s, lH), 9.83 (s, lH).
3-rl-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl~amino3benzen~ i~ocarbonyl]pyrrol-2-caL-bo~y -ido]pyrrol-2-carboxyamido]pyrrol-Z-carboxyamido]pyrrol-2-carbo~y ido] propio-namidine hydrochlorate (I, X = -NHC0-, A = p-phenylene, B z 0, m = 0, n = 2, Rl = R2 = 2-~ 0 94/20463 , I 8 7 PCT~EPg4/00557 chloroethyl).
(337 mg, o.84 mmoles) of 1-Methyl-4-~4-[N,N-bis(2-chloroethyl)-amino]b~n~nPminocarbonyl] pyrrol-2-c~,~ohylic acid chloride (VII, A = p-phenylene, X = -NHCO-, m - O, Rl = R2 = 2-chloroethyl), (obtained by treatment of the carboxylic acid VII (A ~ p-phenylene, X = -NHCO-, m = O, Rl = R2 = 2-chloroethyl) (322 mg, o.84 l~) with SOC12 (4.2 mmoles) ~i~solved in CH2C12 and in the pr~nre of dimethylfor de), are dissolved in 10 ml tetrahydrofursn and added to a mixture of N-deformyldystamicine (221 mg, 0.42 mmoles) 10 and diisopropylethylamine (0.3 ml, 2.1 mmoles) in anhydrous EtOH (5 ml) .
The mixture is maintained 30 minutes under stirring at room t~ ture, then ethylacetate is added up to the precipitation of the raw product, which after separation by HPLC (H20/CH3CN/CF3COOH
15 56/44/0.1) gives 162 mg of I (X = -NHCO-, A = p-phenylene, B = O, m = O, n = 2, Rl = R2 = 2-chloroethyl), (yield 45 %).
H-NMR (DMSO-d6), d : 2.60 (t, 2H), 3.50 (m, 2H), 3.70 (s. 8H), 3.81 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.74 (d, 2H), 6.96 (d, lH), 7.08 (s, 2H), 7.18 20 (d, 2H), 7.25 (d, lH), 7.28 (d, lH), 7.42 (d, lH), 7.54 (d, 2H), 7.69 (d, lH), 8.17 (t, lH), 8.50 (bs, 2H), 8.59 (bs, 2H), 9.49 (s, lH), 9.88 (s, lH), 9.94 (s, lH), 10.09 (s, lH)-The following compound of formula (I) is also obtained by an WO 94/20463 PCT~EP9S/00557 ~ 20 analogous process:
3~ Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]b~n7Pnr 'noc~rbonyl]pyrrol-2-c~ y do]pyrrol-2-ca~bo~y ~o]pyrrol-2-carbo~y~ido]pyrrol-2-5 C&~o~y ~o]pyrrol-2-car~y~ido] propionr ~ine hydrochlorate (I, X = -NHC0-, A = p-phenylene, B = O, m = O, n = 3, Rl = R2 = 2-chloroethyl).
H-NMR (DMS0-d6), d : 2.60 (t, 2H), 3.50 (m, 2H), 3.70 (s. 8H), 3-81 (s, 3H), 3.85 (s, 3H). 3.87 (s, 6H), 3-92 10 (s, 3H), 6.72 (d, 2H), 6.95 (d, lH), 7.07 (m, 3H), 7.16 (d, lH), 7.21 (d, lH), 7.23 (d, lH), 7.26 (d, lH), 7.41(d, lH), 7.52 (d, 2H), 7.68 (d, lH), 8.18 (t, lH), 8.47 (bs, 2H), 8.89 (bs, 2H), 9.48 (s, lH), 9.88 (s, lH) 9.90 (s, lH), 9.93 (s, lH), 10.09 (s, lH) N-[4-~N,N-bis(2-chloroethyl)amino]benzoyl]glycine (III, A = p-phenylene, m = 0, Rl = R2 = 2-chloroethyl, B = -CONHCH(R3)-, R3 =
H) A mixture composed by glycine (600 mg, 8 mmoles), 20 bis(trimethylsilyl)acetamide (3.25 g, 16 mmoles), and trimethylsilylchloride (0.2 ml, 1.6 mmoles) in CH2Cl2 (20 ml) is kept under reflux for 2 hours.
After cooling to room temperature, (3 g, 10.8 mmoles) of 4-[N,N-bis(2-chloroethyl)amino]benzoylchloride are added to the reaction ~0 94/20463 1S7187 PCT/EP94/00557 mixture, which is maintained under stirring at 40 C.
After 2 hours, the mixture is acidified with lN HCl and extracted with CH2C12; the organic extracts are coll ected and extracted on their turn with an aqueous solution of NaHC03, and the basic phase, 5 after acidification with lN HCl i~ extracted with CH2Cl2 thus obt~;nine after evaporation of the organic phase, 1.32 g of III (A
= p-phenylene, m = O, R1 = R2 = 2-chloroethyl. B = -CONHCH(R3)-, R3 = H), (yield 52 ,X) lH-NMR (DMSO-d6), d: 3.78 (m, 8H), 3.88 (d. 2H), 6.78 10 (d, 2H). 7.72 (d. 2H), 8.46 (t. lH).
BAI~LE 4 3-[1-Methyl-4-~1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycylamino]pyrrol-2-ca~l~o~y 'do]pyrrol-2-carl~o~y ~o]pyrrol-2-cE~ G~y do]propion~ 13in~ hydrochlorate 15 (I, X = -CONH-, A ~ p-phenylene, B z -CO~;n(R3)-, R3 = H, m = O, n 1, R1 = R2 = 2-chloroethyl).
308 mg (0.58 mmoles) N-deformyldystamicine, 136 mg (1 mmole) N-hydroxybenzotriazole (HOBT), 182 mg (0.85) mmoles 1,8-bis-(dimethylamino)-naphthalene and 191 mg (0.11 mmoles) [1-(3-20 dimethylaminopropyl)-3-ethylcarbodiimide ( EDC ) are added to a solution of 270 mg, (0.85 mmoles) III (A = p-phenylene, m = O, R1 =
R2 = 2-chloroethyl, B = -CONHCH(R3) -, R3 = H ), prepared as described in example 3 and dissolved in anhydrous dimethylformamide (45 ml).
25 The reaction mixture is maintained under stirring at room WO 94/20463 PCT~EP94/00557 temperature for one hour, then ethylacetate is added up to precipitation o~ the raw product, which after chromatography on silica gel (eluent CH2Cl2/anhydrous EtOH/H2O 65/35/2) gives 275 mg of I (X - -CONH-, A = p-phenylene, B ~ -CONHCH(R3)-, R3 ~ H, m - O.
n = 1. Rl = R2 = 2-chloroethyl) (yleld 60 %) H-NMR (DMSO-d6), d : 2.64 (t, 2H), 3.50 (m, 2H), 3.78 (s, 8H), 3.82 (s, 3H), 3.84 (s, 6H), 3.97 (d, 2H), 6.78 (d, 2H), 6.91 (s. 2H), 7.O4 (d. lH), 7.14 (d, lH), 7.18 (d. lH), 7.21 (d, lH), 7.78 (d, 2H), 8.21 (t, lH), 8.52 (t, lH), 8.78 (bs, 2H), 9.O4 (bs, 2H), 9.89 (s, 2H), 9.95 (8, lH).
Claims (15)
1 1. Compounds of general formula (I) (I) and their pharmaceutically acceptable salts wherein :
n is 0 or an integer ranging from 1 to 4 m is 0 or an integer ranging from 1 to 4 A is selected from a group consisting of cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole;
B is selected from the group consisting of : simple chemical bond, -CO-NH-CH(R3)-, -NH-CO-CH(R3)- wherein R3 is H or the side chain of a natural alpha-aminocarboxylic acid X is selected from the group consisting of : -NHCO-, -CONH- and wherein :
i) R1 and R2 are equal and are selected from the group consisting of: oxiranomethyl, 1-aziridinomethyl, C2-4 alkyl optionally substituted in position 2 with a -OH, C2-4 alkoxy, halogen or -OSO2R4 group wherein R4 is selected from the group consisting of C1-4 alkyl or phenyl or ii) R1 = H and R2 is as above described provided that :
when B = chemical bond, n is different from 1 when X = -CONH-, B = simple chemical bond, m is different from O
when B = -CO-NH-CH(R3)- X is different from -NHCO-when B = -NH-CO-CH(R3)- X is different from -CONH-
n is 0 or an integer ranging from 1 to 4 m is 0 or an integer ranging from 1 to 4 A is selected from a group consisting of cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole;
B is selected from the group consisting of : simple chemical bond, -CO-NH-CH(R3)-, -NH-CO-CH(R3)- wherein R3 is H or the side chain of a natural alpha-aminocarboxylic acid X is selected from the group consisting of : -NHCO-, -CONH- and wherein :
i) R1 and R2 are equal and are selected from the group consisting of: oxiranomethyl, 1-aziridinomethyl, C2-4 alkyl optionally substituted in position 2 with a -OH, C2-4 alkoxy, halogen or -OSO2R4 group wherein R4 is selected from the group consisting of C1-4 alkyl or phenyl or ii) R1 = H and R2 is as above described provided that :
when B = chemical bond, n is different from 1 when X = -CONH-, B = simple chemical bond, m is different from O
when B = -CO-NH-CH(R3)- X is different from -NHCO-when B = -NH-CO-CH(R3)- X is different from -CONH-
2. The compounds as claimed in claim 1 wherein:
n is as above defined m is zero or an integer comprised between 1 and 3 A is as above identified B is a simple chemical bond, or when it is a -CO-NH-CH(R3)- group or a -NH-CO-CH(R3)- group, R3 is preferably methyl, isobuthyl, sec-buthyl, hydroxymethyl, mercaptomethyl, carbamoylmethyl, benzyl, 4-hydroxybenzyl, 5-imidazolylmethyl, 2-carbamoylethyl, 2-methylthioethyl, 1-hydroxyethyl, 3-guanidinopropyl, 4-aminobutyl R1 and R2 represent preferably an ethyl group, 2-hydroxyethyl, 2-chloroethyl, methansulfonylethyl.
n is as above defined m is zero or an integer comprised between 1 and 3 A is as above identified B is a simple chemical bond, or when it is a -CO-NH-CH(R3)- group or a -NH-CO-CH(R3)- group, R3 is preferably methyl, isobuthyl, sec-buthyl, hydroxymethyl, mercaptomethyl, carbamoylmethyl, benzyl, 4-hydroxybenzyl, 5-imidazolylmethyl, 2-carbamoylethyl, 2-methylthioethyl, 1-hydroxyethyl, 3-guanidinopropyl, 4-aminobutyl R1 and R2 represent preferably an ethyl group, 2-hydroxyethyl, 2-chloroethyl, methansulfonylethyl.
3. The compounds of formula (I) as claimed in claim 2. selected from the group consisting of:
3-[1-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene-aminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl) amino]benzeneaminocarbonyl]-pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]
propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzeneaminocarbonyl]pyrrol-2 carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2 carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene butanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)-amino]benzenebutanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propio-namidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,N-bis(2-chloroethyl)amino]benzenebutanamido]pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4[N,N-bis(2-chloroethyl)amino]benzyl-amino carbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propio-namidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2 chloroethylamino)benzylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino) phenyl] ethanaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxya-mido] propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis (2-chloroethyl) amino]phenyl]ethanaminocarbonyl]pyrrol-2-carboxya-mido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]propylaminocarbonyl]pyrrol-2-carboxypyrrol-2-carboxya-mido] propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate;
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzyl carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propio-namidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzylcarboxyamido]pyrrol-2-carboxyamodo]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]
propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxy-amido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis (2-chloroethyl)amino]phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloro-ethyl)amino]benzoyl]glycylamino]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycylamino]-pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene-aminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl) amino]benzeneaminocarbonyl]-pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]
propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzeneaminocarbonyl]pyrrol-2 carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2 carboxyamido] pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzene butanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)-amino]benzenebutanamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propio-namidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,N-bis(2-chloroethyl)amino]benzenebutanamido]pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] pyrrol-2-carboxyamido]
pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4[N,N-bis(2-chloroethyl)amino]benzyl-amino carbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propio-namidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2 chloroethylamino)benzylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propiona-midine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino) phenyl] ethanaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxya-mido] propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis (2-chloroethyl) amino]phenyl]ethanaminocarbonyl]pyrrol-2-carboxya-mido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]propylaminocarbonyl]pyrrol-2-carboxypyrrol-2-carboxya-mido] propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido] propionamidine hydrochlorate;
3-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-[4-[N,N-bis(2-chloroethyl)amino]phenyl]propylaminocarbonyl]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzyl carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propio-namidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-[N,N-bis(2-chloroethyl)amino]benzylcarboxyamido]pyrrol-2-carboxyamodo]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]
propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[2-[4-[N,N-bis(2-chloroethyl)amino]
phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxy-amido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-[4-[N,N-bis (2-chloroethyl)amino]phenyl]ethylcarboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloro-ethyl)amino]benzoyl]glycylamino]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
3-[1-Methyl-4-[1-methyl-4-[1-methyl-4-[1-methyl-4-[N,a-[4-[N,N-bis(2-chloroethyl)amino]benzoyl]glycylamino]-pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]pyrrol-2-carboxyamido]propionamidine hydrochlorate;
4. Compounds of formula (VI) (VI) wherein p is an integer comprised between 3 and 6.
5. Compounds of formuls (IX) wherein A, m, R1, R2, R3 and R5 are as claimed in claims 1) and 2).
6. Compounds of formula (XII) wherein A, m, R1, R2, R3 and R6 are as claimed in claims 1) and 2).
7. A process for the prepsration of compounds of formula (I) (I) wherein:
n is 0 or an integer ranging from 1 to 4 m is 0 or an integer ranging from 1 to 4 A is selected from the group consisting of cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole;
B is selected from the group consisting of : simple chemical bond, -CO-NH-CH(R3)-, -NH-CO-CH(R3)- wherein R3 is H or the side chain of a natural alpha-aminocarboxylic acid X is selected from the group consisting of : -NHCO-, -CONH- and wherein :
i) R1 and R2 are equal and are selected from the group consisting of: oxiranomethyl, 1-aziridinomethyl, C2-4 alkyl optionally substituted in position 2 with a OH, C2-4 alkoxy, halogen or -OSO2R4 group wherein R4 is selected from the group consisting of C1-4 alkyl or phenyl or ii) R1 = H and R2 is as above described provided that :
when B = chemical bond, n is different from 1 when X = -CONH-, B = simple chemical bond, m is different from 0 when B = -CO-NH-CH(R3)- X is different from -NHCO-when B = -NH-CO-CH(R3)- X is different from -CONH-comprising reacting the compound of formula (III), wherein A, m, B, R1 and R2 are as above defined, with a compound of formula (IV) (IV) wherein p is an integer comprised between 2 and 6.
n is 0 or an integer ranging from 1 to 4 m is 0 or an integer ranging from 1 to 4 A is selected from the group consisting of cyclohexyl, p-phenylene, 1-methylpyrrole, thiophene, thiazole, imidazole, furan, isoxazole, oxazole, triazole, pyridine, pyrrole;
B is selected from the group consisting of : simple chemical bond, -CO-NH-CH(R3)-, -NH-CO-CH(R3)- wherein R3 is H or the side chain of a natural alpha-aminocarboxylic acid X is selected from the group consisting of : -NHCO-, -CONH- and wherein :
i) R1 and R2 are equal and are selected from the group consisting of: oxiranomethyl, 1-aziridinomethyl, C2-4 alkyl optionally substituted in position 2 with a OH, C2-4 alkoxy, halogen or -OSO2R4 group wherein R4 is selected from the group consisting of C1-4 alkyl or phenyl or ii) R1 = H and R2 is as above described provided that :
when B = chemical bond, n is different from 1 when X = -CONH-, B = simple chemical bond, m is different from 0 when B = -CO-NH-CH(R3)- X is different from -NHCO-when B = -NH-CO-CH(R3)- X is different from -CONH-comprising reacting the compound of formula (III), wherein A, m, B, R1 and R2 are as above defined, with a compound of formula (IV) (IV) wherein p is an integer comprised between 2 and 6.
8. A process for the preparation of compounds of formula (I) (I) wherein:
B is a simple chemical bond or a -NH-CO-CH(R3)- group, X is the -NHCO- group and m, n, R1, R2 and R3 are as claimed in claim 7), provided that, if B is a chemical bond n is different from 1;
comprising reacting the compound of formula (V) (V) wherein A, B, m, R1 and R2 are as above defined, with a compound of formula (VI) (VI) wherein p is an integer comprised between 2 and 6.
B is a simple chemical bond or a -NH-CO-CH(R3)- group, X is the -NHCO- group and m, n, R1, R2 and R3 are as claimed in claim 7), provided that, if B is a chemical bond n is different from 1;
comprising reacting the compound of formula (V) (V) wherein A, B, m, R1 and R2 are as above defined, with a compound of formula (VI) (VI) wherein p is an integer comprised between 2 and 6.
9. A process for the preparation of the compounds of formula (I) (I) wherein:
B is a simple chemical bond X represent the -NHCO- group or the -CONH- group and m, n, A, R1 and R2 are defined in claim 7), provided that:
if B is a chemical bond, n is different from 1;
if X is -CONH- and contemporaneously B is a chemical bond and m is equal to zero, n is different from zero;
comprising reacting the compound of formula (VII) (VII) wherein A, X, m, R1 and R2 are as above defined, with a compound of formula (IV) (IV) wherein p is an integer comprised between 1 and 5.
B is a simple chemical bond X represent the -NHCO- group or the -CONH- group and m, n, A, R1 and R2 are defined in claim 7), provided that:
if B is a chemical bond, n is different from 1;
if X is -CONH- and contemporaneously B is a chemical bond and m is equal to zero, n is different from zero;
comprising reacting the compound of formula (VII) (VII) wherein A, X, m, R1 and R2 are as above defined, with a compound of formula (IV) (IV) wherein p is an integer comprised between 1 and 5.
10. Use of compounds as claimed in claims 1-3 for the preparation of pharmaceutical compositions.
11. Pharmaceutical compositions containing as active principle a compound as claimed in claim 1 in combination with a pharmaceutically acceptable vehicle or diluent.
12. The pharmaceutical compositions as claimed in claim 11 as antitumoral agents.
13. The pharmaceutical compositions as claimed in claim 11 as antiviral agents.
14. A therapeutic method for the treatment of tumoral affections comprising administering to patients, from 1 to 4 times a day, pharmaceutical compositions containing as active ingredient a compound as claimed in claim 1, in an amount ranging from 0.1 to 100 mg per unitary dose in a pharmaceutically acceptable diluent or vehicle.
15. A therapeutic method for the treatment of viral affections comprising administering to patients, from 1 to 4 times a day, pharmaceutical compositions containing as active ingredient a compound as claimed in claim 1, in an amount ranging from 0.1 to 100 mg per unitary dose in a pharmaceutically acceptable diluent or vehicle.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITFI930030A IT1271456B (en) | 1993-03-01 | 1993-03-01 | PYROL-AMIDINE COMPOUNDS, AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS, PREPARATION PROCESSES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| ITFI93A000030 | 1993-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2157187A1 true CA2157187A1 (en) | 1994-09-15 |
Family
ID=11350335
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002157187A Abandoned CA2157187A1 (en) | 1993-03-01 | 1994-02-25 | Novel distamycin analogues |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0690840A1 (en) |
| JP (1) | JPH08508720A (en) |
| KR (1) | KR960701007A (en) |
| AU (1) | AU6206894A (en) |
| CA (1) | CA2157187A1 (en) |
| IT (1) | IT1271456B (en) |
| WO (1) | WO1994020463A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9416005D0 (en) * | 1994-08-08 | 1994-09-28 | Erba Carlo Spa | Peptidic compounds analogous to distamycin a and process for their preparation |
| US6635417B1 (en) | 1996-07-31 | 2003-10-21 | California Institute Of Technology | Complex formation between DSDNA and oligomer of cyclic heterocycles |
| WO1998037066A1 (en) | 1996-02-26 | 1998-08-27 | California Institute Of Technology | Improved polyamides for binding in the minor groove of double stranded dna |
| US6143901A (en) * | 1996-07-31 | 2000-11-07 | Genesoft, Inc. | Complex formation between dsDNA and pyrrole imidazole polyamides |
| AU6757698A (en) | 1996-02-26 | 1998-10-30 | California Institute Of Technology | Stereochemical control of the dna binding affinity, sequence specificity, and orientation-preference of chiral hairpin polyamides in the minor groove |
| US6090947A (en) * | 1996-02-26 | 2000-07-18 | California Institute Of Technology | Method for the synthesis of pyrrole and imidazole carboxamides on a solid support |
| US6506906B1 (en) | 1996-02-26 | 2003-01-14 | California Institute Of Technology | Preparation and use of bifunctional molecules having DNA sequence binding specificity |
| US6555692B1 (en) | 1996-02-26 | 2003-04-29 | California Institute Of Technology | Preparation and use of bifunctional molecules having DNA sequence binding specificity |
| US5998140A (en) | 1996-07-31 | 1999-12-07 | The Scripps Research Institute | Complex formation between dsDNA and oligomer of cyclic heterocycles |
| GB9623522D0 (en) * | 1996-11-11 | 1997-01-08 | Pharmacia & Upjohn Spa | Benzoheterocycle distamycin derivatives process for preparing them and their use as antitumour and antiviral agents |
| GB9806692D0 (en) * | 1998-03-27 | 1998-05-27 | Pharmacia & Upjohn Spa | Benzoheterocyclic distamycin derivatives, process for preparing them and their use as antitumour agents |
| GB9816652D0 (en) * | 1998-07-30 | 1998-09-30 | Pharmacia & Upjohn Spa | Sulfurated distamycin derivatives process for preparing them and their use as antitumor agents |
| US6559125B1 (en) | 2000-01-28 | 2003-05-06 | California Institute Of Technology | Polyamide-alkylator conjugates and related products and method |
| US7078536B2 (en) | 2001-03-14 | 2006-07-18 | Genesoft Pharmaceuticals, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
| KR20030043785A (en) | 2000-03-16 | 2003-06-02 | 젠소프트, 인크. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
| WO2002088119A1 (en) | 2001-04-26 | 2002-11-07 | Genesoft Pharmaceuticals, Inc | Halogen-substituted thienyl compounds |
| US20030236198A1 (en) | 2001-06-13 | 2003-12-25 | Genesoft, Inc. | Antipathogenic benzamide compounds |
| WO2004012736A1 (en) | 2002-08-02 | 2004-02-12 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
| WO2004039318A2 (en) | 2002-10-25 | 2004-05-13 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
| AU2003297822A1 (en) | 2002-12-10 | 2004-06-30 | Oscient Pharmaceuticals Corporation | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8612218D0 (en) * | 1986-05-20 | 1986-06-25 | Erba Farmitalia | Site specific alkylating agents |
| GB8906709D0 (en) * | 1989-03-23 | 1989-05-10 | Creighton Andrew M | Acryloyl substituted pyrrole derivatives |
| IT1262921B (en) * | 1992-01-10 | 1996-07-22 | Federico Arcamone | ANALOGUE AGENTS ANALOGUES OF PYROL-AMIDINE OLIGOPEPTIDES BACK TO PREPARATION PROCESSES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM |
-
1993
- 1993-03-01 IT ITFI930030A patent/IT1271456B/en active IP Right Grant
-
1994
- 1994-02-25 WO PCT/EP1994/000557 patent/WO1994020463A1/en not_active Application Discontinuation
- 1994-02-25 EP EP94909068A patent/EP0690840A1/en not_active Withdrawn
- 1994-02-25 AU AU62068/94A patent/AU6206894A/en not_active Abandoned
- 1994-02-25 KR KR1019950703699A patent/KR960701007A/en not_active Application Discontinuation
- 1994-02-25 CA CA002157187A patent/CA2157187A1/en not_active Abandoned
- 1994-02-25 JP JP6519534A patent/JPH08508720A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994020463A1 (en) | 1994-09-15 |
| IT1271456B (en) | 1997-05-28 |
| ITFI930030A1 (en) | 1994-09-01 |
| AU6206894A (en) | 1994-09-26 |
| ITFI930030A0 (en) | 1993-03-01 |
| JPH08508720A (en) | 1996-09-17 |
| KR960701007A (en) | 1996-02-24 |
| EP0690840A1 (en) | 1996-01-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2157187A1 (en) | Novel distamycin analogues | |
| EP0941218B1 (en) | Antithrombotic organic nitrates | |
| CA2125080A1 (en) | Peptidic phosphinyloxymethyl ketones as interleukin-1beta-converting enzyme inhibitors | |
| WO2009141240A1 (en) | Novel dual targeting antitumoural conjugates | |
| US5300671A (en) | Gem-diphosphonic acids, and pharmaceutical compositions containing them | |
| US5886046A (en) | Dicarbonyl-containing compounds | |
| JPS61100564A (en) | Heterocyclic immunoaccelerator substituted with peptide | |
| EP1100778B1 (en) | Oxidised sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents | |
| EP0500989B1 (en) | N-(alpha-substituted-pyridinyl) carbonyl dipeptide antihypertensive agents | |
| US20040208822A1 (en) | New quaternary ammonium compounds | |
| JP2004535459A (en) | Compound having prolyl oligopeptidase inhibitory activity, production method thereof and use thereof | |
| US5281717A (en) | Epoxysuccinamic acid derivatives | |
| SU1272982A3 (en) | Method of producing proline derivatives or pharmaceutically acceptable salts thereof | |
| AU2004246821A1 (en) | Enalapril-nitroxyderivatives derivatives and related compounds as ace inhibitors for the treatment of cardiovascular diseases | |
| EP0195433B1 (en) | Amide derivatives processes for preparing them and use thereof | |
| EP0587767A1 (en) | Hydroxyazido derivatives and related compounds as renin inhibitors | |
| JPH0699457B2 (en) | Heterocyclic bisphosphonic acid derivative and its medicine | |
| IE68060B1 (en) | Nitratoalkanecarboxylic acid derivatives a process for their preparation use thereof and medicaments containing them | |
| GB2212158A (en) | Trialkylsilymethyl-substituted peptides; renin inhibitors | |
| JPH10502048A (en) | Novel pharmaceutically active compounds which can be formed from 1,3,4,6,7,8-hexahydro-2H-pyrimido- (1,2-a) -pyrimidine | |
| SK112197A3 (en) | Arginine analogues having nitric oxide synthase inhibitor activity | |
| FI68622C (en) | FOERFARANDE FOER FRAMSTAELLNING AV INDOLAETTIKSYRADERIVAT | |
| JPS63502432A (en) | Acylated cyanamide composition | |
| GB2102412A (en) | Proline derivatives and process for producing the same | |
| JPS59141544A (en) | Lactam peptide, manufacture and medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |