GB2261661A - Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles - Google Patents
Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles Download PDFInfo
- Publication number
- GB2261661A GB2261661A GB9124733A GB9124733A GB2261661A GB 2261661 A GB2261661 A GB 2261661A GB 9124733 A GB9124733 A GB 9124733A GB 9124733 A GB9124733 A GB 9124733A GB 2261661 A GB2261661 A GB 2261661A
- Authority
- GB
- United Kingdom
- Prior art keywords
- methyl
- bis
- pyrrolecarbonylimino
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 112
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 37
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 10
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 10
- 239000004037 angiogenesis inhibitor Substances 0.000 claims abstract description 9
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000005864 Sulphur Substances 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical class OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 29
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- -1 carbonylimino Chemical group 0.000 claims description 7
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- QHHHLHCCVDMOJI-UHFFFAOYSA-N 1,3-thiazol-4-amine Chemical compound NC1=CSC=N1 QHHHLHCCVDMOJI-UHFFFAOYSA-N 0.000 claims description 5
- YFOOEYJGMMJJLS-UHFFFAOYSA-N 1,8-diaminonaphthalene Chemical compound C1=CC(N)=C2C(N)=CC=CC2=C1 YFOOEYJGMMJJLS-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims 2
- 241001024304 Mino Species 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- 238000001356 surgical procedure Methods 0.000 claims 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 229910001868 water Inorganic materials 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 108010042747 stallimycin Proteins 0.000 description 4
- 229950009902 stallimycin Drugs 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- AJUXDFHPVZQOGF-UHFFFAOYSA-N n,n-dimethyl-1-naphthylamine Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1 AJUXDFHPVZQOGF-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 241001458120 Orophe Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A derivative of a substituted carboxypyrrole having the following formula (I> <IMAGE> wherein W is = 0, = S or = N-H each of m and n is 1 to 4; each of B and B1 is: a) a -(CH2)p-NR1R2 group, wherein p is 2 to 4 and each of R1 and R2 is hydrogen or C1-C6 alkyl; b) <IMAGE> group, wherein q is 1 to 4; R3 is hydrogen and each of R4 and R5 is hydrogen or C1-C6 alkyl; or R3 and R4, taken together, form a-CH=CH-, -CH2-CH2- or -CH2CH2-CH2- chain, and R5 is hydrogen or C1-C6 alkyl; c) a saturated or unsaturated, carbocyclic or condensed carbocyclic ring substituted by one to three basic groups; or d) a saturated or unsaturated, heteromonocyclic or heterobicyclic ring, containing one to three heteroatom chosen from nitrogen, oxygen and sulphur, substituted by one to three basic groups; and the pharmaceutically acceptable salts thereof, (including known compounds in which W is 0, m and n are 2, B and B1 are the same and as defined above under b), q is 2 and R3, R4 and R5 are hydrogen) are active as angiogenesis inhibitors.
Description
DERIVATIVES OF POLY-4-AMINO
-2-CARBOXY-1-METHYL COMPOUNDS"
The present invention relates to new derivatives of substituted pyrroles, to a process for their preparation and to a pharmacological composition containing them.
The pyrrole derivatives of the invention may be regarded as derivatives of Distamycin A which is a known compound having the following formula
Literature referring to Distamycin A includes, for example
NATURE 203, 1064 (1964).
The present invention provides new derivatives of substituted carboxypyrroles having the following general formula (I)
wherein
W is =0, =S or =N-H each of m and n, being the same or different, is an integer of 1 to 4; each of B and B1, which may be the same or different, is: a) a -(CH2)p-NR1R2 group, wherein p is an integer of 2 to 4
and each of R1 and R2, independently, is hydrogen or
C1-C6 alkyl;
group, wherein is an integer of 1
to 4;
R3 is hydrogen and each of R4 and R5, independently, is
hydrogen or C1-C6 alkyl; or R3 and R4, taken together,
form a -CH=CH- -CH2-CH2- or -CH2-CH2-CH2- chain, CH2 R5 is hydrogen or C1-C6 alkyl; c) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to three basic groups; or d) a saturated or unsaturated, heteromonocyclic or hetero
bicyclic ring, containing one to three heteroatoms
chosen from nitrogen, oxygen and sulphur, substituted by
one to three basic groups ; and the pharmaceutically
acceptable salts thereof, and wherein, when, at the same
time, W is =0, m and n being the same are 2, B and B1 are same and as defined above under b), q is 2, then at
least one of R4 and R5 is other then hydrogen.
An alkyl group may be a branched or straight alkyl group.
A C1-C6 alkyl group is preferably a C1-C4 alkyl group.
A C1-C4 alkyl group is preferably methyl, ethyl, propyl or isopropyl.
When two or three basic groups are present on the same B or
B1 substituent, they may be the same or different.
Examples of basic groups,according to the definitions of B and B1, given above under c) and d), for instance may be those chosen from -(CH2)r-NR6R7, in whichr is zero or an integer of 1 to 4 and each of R6 and R7, independently, is hydrogen or C1-C6 alkyl;
in which r is as defined above, R8 is hydrogen and each of Rg and R10, independently, is hydrogen or C1-C6 alkyl, or R8 and R9, taken together, form a -CH=CH-, -CH2-CH 2 or -CH2-CH2-CH2- chain and R10 is hydrogen or C1-C6 alkyl and
wherein R8, R9 and R10 are as defined above.
a.
When n a -(CH2)p - or - (CH2)r - group p and/or r is higher than 1, the alkylene chain,thus provided, may be a branched or straight alkylene chain.
When B or B1 is a ring as defined above under c), it is for example phenyl or naphthyl, in particular naphthyl.
When B or B1 is a ring as defined above under d), it is for example thiazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydropyran or tetrahydrofuran ; in particular thiazole, pyrimidine or tetrahydropyran.
As already said, the invention includes within its scope also the pharmaceutically acceptable salts of the compounds of formula (I).
The pharmaceutically acceptable salts of the compounds of formula (I) include those formed with an inorganicacide.g. nitric acid, hydrochloric acid or sulphuric acid, or with an organic acid, e.g; citric, malic, maleic, mandelic, tartaric, fumaric or methanesulphonic acid.
The present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
Preferred compounds according to the present invention are the compounds of formula (I), wherein each of m and n, being the same, is 2 or 3; W is as defined above, each of B and B1, which are the same or different, is a' -(CH2)p-NR1R2 wherein p is 2 or 3 and each of R1 and R2 independently is hydrogen or C1-C4 alkyl;
wherein q is 2 or 3; R3, BA and R5 are each hydrogen or R3 and R4, together, form a -CH2-CH2-, -CH=CHor -CH2-CH2-CH2- chain and R5 is hydrogen ; c') a phenyl or naphthyl group substituted by one, two or
three basic groups chosen independently from
(CH2)rNR6R7 and
in which r is as defined above and each of R6and R7,
independently, is hydrogen or C1-Cfl alkyl, or d) a thiazole, pyrimidine or tet.rahydropyranyl ring
substituted by one, two or three basic groups, as defined above under c'); and the pharmaceutical3y acceptable salts thereof, and wherein when, at the
same time, W is =0, m and n are 2, B and B1 are the
same and as defined above under b'), R3, R4 and R5 are
hydrogen, then q is 3.
specific examples of preferred compounds of the invention, are the following : 4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl)imino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl -4,2-pyrrolecarbonylmino(3-proptonamidine)) ; 4,4t-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl -d,2-lryrrolecarbonyZimino(3-propyldimethylam.ine)); 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl -4, 2-pyrrolecarbonylimino(3-propionamidine)); 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4.2-pyrrole)carbonylimino))-bis(N-methyl 4,2-pyrrolecarbonylimino(3-propyldimenthylamine));; 4,4'-(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl4,2-pyrrolecarbonylimino(3-propionamidine)) ; 4,4'-(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonyl imino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl- -4,2-pyrrolecarbonylimino(3-propyldimethylamine)); 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl) ; 8,8'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(i-naphthaleneamine -N,N-dimethyl); 5,5'-(carbonyl-bis(imino-N-methyl4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl);
As 5,5'-(thiocarbonyl-bis(imino-N-methl-4,2-pyrrolecarbonylino (N-methyl-4,2-pyrrole)carbonylimino))-bis(l-naphthaleneamine -N,N-dimethyl); 4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenediamine -N,N,N',N',-tetramethyl) ; 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenediamine -N,N,N',N+ -tetramethyl) ; 3,3'-(carbonyl-bis(imino-N-methl-4,2-pyrrolecarbonylimino (N'-methyl-4,2-pyrrole)carbonylimino))-bis(l-phenyleneamine - N,Ndimethyl); 3,3'-(thiocArbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (Ns-methyl-4,2-pyrrole)carbonylimino))-bis(1-pheneyleneamine - N,Ndimethyl); 2,2'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino ( methyl-4,Z-pyrrole)carbonylimino))-bis(4-thiazoleamine -N,N-dimethy ; 2,2'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (NSmethyl-4,2-pyrrcle)carbonylimino))-bis(4-thia2oleamine -N,Ndimethyl); and the pharmaceutically acceptable salts threof, in particular the salts with hydrochloric acid and hydrobromic acid.
The above proviso in formula (I) excludes from its scope a known compound, which has been disclosed by J. Med. Chem.
1989, 32, 2368-2375. In that paper the synthesis of a group of oligopeptides and their antiviral and tumour cell cytotoxic properties have been reported. However, no invention is made of their use as angiogenesis inhibitors. Now we have found that this known compound, in common with the new compounds of formula (1), according to the present invention, has angiogenesis inhibition activity.Accordingly a further object of the present invention is the use of a compound of formula (I)
wnereln
W is = O, =S or =N-H each of m and n, being the same or different, is an integer of 1 to 4; each of B and B1, which may be the same or different, is: a) a -(CH2)p-NRlR2 group, wherein p is an integer of 2 to 4
and each of R1 and R2, independently, is hydrogen or
C1-C6 alkyl;
group, wherein q is an integer of 1
to 4; R3 is hydrogen and each of R4 and B, independently, is hydrogen or C1-C6 alkyl; or R3 and R4, taken together, form a -Ct=CH, -CH2-CHz- or -CH 2-CH2-CH2 - chain, and
R5 is hydrogen or C1-C6 alkyl; c) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to three basic groups; or d) a saturated or unsaturated, heteromonocyclic or
heterobicyclic ring, containing one to three heteroatoms
chosen from nitrogen, oxygen and sulphur, substituted by
one to three basic groups; or a pharmaceutically
acceptable salt thereof, in the preparation of a
pharmaceutical composition for the use as an angiogenesis
inhibitor in mammals.
Preferred compounds of formula (I) to be used as active agents in the preparation of a pharmaceutical composition for use as angiogenesis inhibitor are the followings: 4,4'-(carbonyl-bis(Imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl -4,2-yrrolecarbonylmino(3-propionamidine)) ;
4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl
imino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl
-4,2-pyrrolecarbonylimino(3-propyldimethylamine)) ; a 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(Nmethyl-4,2-pyrrole)carbonylimino))-bis(N-methyl -4,2-pyrrolecarbonylimino(3-propionamidine)) ; 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl4,2-pyrrolecarbonylimino(3-propyldimenthylamine)) ; 4,4'-(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl4,2-pyrrolecrbonylimino(3-propionamidine)) ; 4,4'-(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl -4,2-pyrrolecarbonylimino(3-propyldimethylamine)) ; 4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino)-bis-(N-methyl-4,-2-pyrrolecarbonylimino(3 -propionamidine)) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(i-naphthaleneamine -N,N-dimethyl) ; 8,8'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl) ; 5,5'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl) ; 5,5'-(thiocarbonyl-bis(imino-N-methyl-4,2-yrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine - N,Ndimethyl) 4,4'-(earbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenediamine -N,N,N,N' ,-tetramothyl); 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenediamine -N,N,N,N'-tetramethyl) ; 3,3'-(carbonyl-bin(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-phenyleneamine -NfN-dimethyl ); 3,3'-(thiocarbonyl-bistimino-N-met;hyl-4,2-pyrrolecarbonyliminn (N-methyl-4,2-pyrrole)carbonylimino)-bis(1-phenyleneamine -N,N-dimethyl): 2,2'-(carbonyl-tis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(4-thiazoleamine -N,N-dimethyl ; 2,2'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (Nmethyl-4,2-pyrrole)carbonylimino))-bis(4-thiazoleamine -N,N-dimethyl) : and the pharmaceutically acceptable salts thereof.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof will be defined hereafter as the "compounds of the invention" or as the "active ingredients" of the pharmaceutical composition according to the present invention. The compounds of formula (I), and the salts thereof, can be prepared by a process comprising: a) reacting a compound of formula (II)
wherein n and B1 are as defined above, or a salt thereof, with a compound of formula (III)
wherein W' is =O or =S, and each of the X groups, which may be the same or different, is a leaving group, so as to obtain a compound of formula (I), in which W is =O or =S, m and n are the same and B and B1 are the same; or b) reacting a compound of formula (IV), or a salt thereof,
wherein B, X, W' and m are as defined above, with a compound of formula (II), as defined above, so as to obtain a compound of formula (I) wherein W is =O or =S; or c) reacting a compound of formula (V), or a salt thereof,
wiierei n 8 and m are as defined above, with a compound of formula (II), as defined above. so as to obtain a compound of formula (I), wherein W is =NH; and if desired, salifying a compound of formula (1) thus obtained; and/or if desired, obtaining a free compound of formula (I) from a salt thereof.
A salt of a compound of formula (II),(IV) and (V) may be A salt with organic or inorganic acids, for example those mentioned above, as to the pharmaceutically acceptable salts of the invention, the hydrochloride and hydrobromide salts being the preferred.
Preferred examples of good leaving groups, according to the meaning of X, are halogen atoms, in particular chlorine, or other easily displaceable groups such as, imidazolyl. triazolyl, p-nitrophenoxy or trich)orophe.noxy.
The reaction of a compound of formula (II), or a salt thereof with a compound of formula (III) is an analogy process and can be carried out according to well known methods; for example according to the conditions described in organic chemistry for this kind of reaction, i.e. for synthesis of urea derivatives. Preferably when in a compound of formula (III) X is an halogen atom, e.g. chlorine, the reaction may be carried out at a molar ratio of compound (it), or a salt thereof: compound (III) from about 1:1 to about 1:4.
The reaction is preferably performed in organic solvents such as dimethylsulphoxide, hexamethylphosphotriamide, dimethylacetamide or, preferably, dimethylformamide ,or their aqueous mixtures, or in water/dioxane or water/toluene mixtures, in the presence of either an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as sodium bicarbonate or sodium acetate.
The reaction temperature may vary from about 100 C. to about 500C. and the reaction time about I to about 12 hours.
The reaction of a compound of formula (IV), or a salt thereof, with a compound of formula (II), and the reaction of a compound of formula (V), or a salt thereof, with a compound of formula (II), respectively, can be performed by following the same procedure described above as to the reaction of a compound of formula (II), or a salt thereof, and a compound of formula (III). In particular the reaction temperature may range from room temperature to about 900 C.
The compounds of formula (I) prepared according to the above described procedures may be purified by conventional methods such as by silica gel or alumina column chromatography, and/or by recrystallization from organic solvents such as lower aliphatic alcohols or dimethylformamide.
Analogously salification of a compound of formula (I) can be carried out by known methods in the art.
The compounds of formula (II) may be obtained according to known procedures.
For instance, a compound of formula (II) may be obtained by reduction of a compound of formula (VI)
wherein n and B1 are as defined above by methods well known in the art. The compounds of formula (VI) may be obtained by reacting an amine of formula B1-NH2, where By is defined as above, with a compound of formula (VII) A
wherein n and X are as defined above.
Also the reaction of an amine of formula B1-NH2 with a compound of formula (VII) is a well known process.
Alternatively a compound of formula (VI) whereinnis 2 or 3 may be obtained by å multi-step-process comprising reacting a compound of formula (VIII)
wherein
X is as defined above, with an amine of formula B1-NH2, in which B1 is as defined above. The reaction, which may be carried out according to known methods, -provides compounds of formula (IX)
wherein
B1 is as defined above.
A compound of formula (IX) is reduced according to known methods to provide a compound of formula (X)
wherein
B1 is as defined above, which in its turn is reacted with a compound of formula (VIII), as defined above, thus obtaining a compound of formula (VI), as defined above, wherein n is 2. If a compound of formula (VI), wherein n is 3 is desired, a further reduction and acylation step is required. The compounds of formula (VII) are known compounds and may be obtained for example according to Heterocycles, vol 27, No. 8, 1988, p. 1945-52.
The compounds of formula (VIII) and the amine of formula
B-NH2 are known products or may be easily obtained according to known methods.
The compounds of formula (IV) may be obtained by reaction of a compound of formula (XI)
wherein m and B are as defined above, with an excess of the compounds of formula (III), the compounds of formula (XI) may be prepared analogously to the compound of formula (11).
The compounds of formula (III) are commercially available products. The compounds of formula (V) may be obtained by reaction of a compound of formula (XI), as defined above with a compound of formula (XII),
X-C=N (XII) wherein
X is as defined above, in particular chlorine or bromine.
Also compounds (XII) are commercially available products.
When in the intermediate products, herein described, groups are present which may interfere with the reaction, such groups are protected in a conventional way before the reaction takes place and then are deprotected at the end of the reaction, according to well known methods, typical protecting groups may be those used in the chemistry of peptides.
PHARMACOLOGY
The compounds of the invention have been found to be active as angiogenesis inhibitors.
By angiogenesis inhibitor is meant an agent capable of suppressing -the growth of new blood vessels. Therefore the compounds of the present invention are useful in treating several pathological conditions in mammals, including humans, where the growth of new blood vessels is detrimental, for example in chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis and tumour growth. In particular, in cancer therapy the compounds of the invention can be administered alone or in a combined method of treatment with antitumor agents such as doxorubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastin or mitomycin.The term "combined" method of treatment is meant to include both separate and substantially contemporaneous administration of a pharmaceutical composition containing a therapeutically effective amount of a compound according to the invention and a pharmaceutical composition containing a therapeutically effective amount of a different pharmaceutically active agent. The angiogenesis inhibitor activity of the compounds of the present invention is shown e.g. by the fact that they have been found to be active in the chorioallantoic membrane test, according to the
Folkman's method Nature, 279, 307 (1982). The compounds of the invention can be administered by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcut: eously, topically or orally.The dosage depends on the age, weight and condition of the patient and on the administration route.
For example, a suitable dosage for administration to adult humans may range from about 0.5 to about 100 mg dry dose 1-4 times a day.
The pharmaceutical compositions of the invention may contain a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active substance, in association with one or more pharmaceutically acceptable excipients and/or carriers.
The pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
For instance, solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably, they may be in the form of sterile aqueous isotonic saline solutions.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
In formulations for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
The solid oral forr-, e.g. tablets and capsules, may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene gly ols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates: and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.Said pharmaceutical preparations may be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coatig, or film-coating processes.
Furthemore, according to the invention there is provided a method of treating pathological conditions where the growth of neu blood vessels is detrimental, for example chronic inflaration, diabetic retinopathy, psosiaris, rheumatoid and arthritis and tumors, in mammals in need thereof, including humans, comprising administering to the said normals a composition of the invention.
The following examples illustrate but do not limit the invention.
Example 1 4,4t-(Carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imine (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2 -pyrrolecarbonylimino(3-propianamidine)). dihydrochloride.
To a solution of N-deformyl Distamycin A dihydrochloride (576 mg, j mmol) in water (20 ml) and dioxane (10 ml), sodium bicarbonate (420 me, 5.mmols) is added under stirring.
The whele is cooled to 5 C wl with nice bath, then a solution of phosgene in toluene (1 ml#4 eg.) is added dropwise.
The mixture is stirred 3 hr at 50C.
The solvents is evaporated under vacuum and the residue is taken up with methanol and filtered. The filtrate is evaporated and the residue is chromatographed on a silica gel column with methylene chloride: methanol water 350:150:15 as eluent; affording 296 mg of the title compound.
N.M.R. (DMSO-d6) : 6 2,60(2H,t) ; 3.50 (2H, m) ; 3.79 (3H,s);
3.82 (3H,s) ; 3.83(3H, s) ; 6.80-7.25(6H,m);
8.22(1H,t) ; 8.58 (1H,bs) ; 8.60 (2H,bs) ; 8.95(2H,bs);
9.84 (1H,bs); 9,91 (1H, bs).
F.A.B.-M.S. : m/z 933, M4+1 ; 454,M-478.
U.V. (H2O)nm: # m@x (E1cm1%) 310(495); 242(435).
By analogous procedure the following compounds can be obtained: 4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl-imino (N-methyl-4,2-pyrrole)carbonylimino)-bis(N-methyl-4,2 -pyrrolecarbonylimino(3-propyldimethylamine); and 4,4'-(carbonyl-bis.imino-N-methyl-4,2-pyrrolecarbonyl-imino)bis-(N-methyl-4,-2-pyrrolecarbonylimino(3-propianamidine)).
Example 2 4,4'-Thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2 -pyrrolecaronylimino(3-propianamidine)),dihydrochloride.
To a solution of N-deformyl Distamycin A dihydrochloride (1052 mg, 2 mmoles) in DMF (10 ml), 1,1'-thiocarbonyldiimidazole (178 mg, 1 mmol) is added under stirring. The mixture was stirred 2 hr at room temperature, and then 1 hr at 850C.
The solvent is evaporated under vacuum at 500C, the residue dissolved in methanol, acidified at pH 3 with 1N HCl, and evaporated to dryness.
The residue is chromatographed on a silica gel column with methylene chloride: methanol: water 350:150:15 as eluent, affording 650 mg of the.title compound
N.M.R. (DMSO-d6): 6 2.61(2H,t); 3.51(2H,m); 3.80(3H,s); 3,83(3H,s); 3,85(3H,s); 6,8-7,35(6H,m); 8,22(1H,t);
8.63(2H,bs) ; 8,98(2H, bs); 9,65(1H,bs); 9,91(1H,bs); 9.92(1H,bs).
F.A.B.- M.S.: m/z 949, M++1; 879, M±70; 483;454.
UV(H2O)nm: # max (E1cm1%) 304(578) ; 244(469) I.R.(KBr)cm ; 3400b, 1690, 1635, 1580.
By analogous procedure the following compound can be obtained: 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2 -pyrrolecarbonylimino(3-propyldimethylamine)).
Example 3 4,4'-(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonyl-imino (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2 -pyrrolecarbonylimino ( 3-propianamidine).
To a solution of or N-deformyl Distamycin A dihydrochloride (526 mg, 1 mmol) in water (15 ml) and dioxane (5 ml), sodium acetate (328 mg, 4 mmols) is added under stirring.
The whole is cooled to 50C with anice bath, then a solution of cyanogen bromide(212 mg, 2 mmols) in dioxane (10 ml) is added dropwise. The mixture is stirred 2 hrs at room temperature. The solvents are evaporated under vacuum and the residue chromatographed on a silica gel column with methylene chloride methanol: water, 350:150:15 as eluent, affording 248 mg of the title compound.
N.M.R. (DMSO-d6): 6 2,65(2H,t); 3,5(2H,m); 3,78(3H,s); .
.-.,79(3jH,s); 3,81(3H,s); 6,92-7,29(6H,M); 8,25(1H,t); 8,86(2H,bs); 9,12(2H,bs); 9,90(1H,bs); 10,01(1H,bs); F.A.B.-M.S.: m/z 932,M++1;; 861,M-70; 844,M-70-17
By analogous procedure the following compound can be obtained: 4,4(guanidine-bis-(N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2 -pyrrolecarbonylimino(3-propyldimethylamine)).
Example 4 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthalene- amine-N,N-dimethyl).
To a solution of 8-(amino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino)(1-dimethylaminonaphtha- lene)-hydrochloride(570 mg, 1.13 mmols) in N,N-dimethyl formamide (50 ml), trietylamine (0,3 ml, 2,26 mmols) is added under stirring. A solution of 1,1'-carbonyldiimidazole (100 mg, 0.06 mmols) in N,N'-dimethylformamide (15 ml) is added dropwise, in half an hour, at room temperature. The solution is stirred for 1 hr, then is evaporate under vacuum to dryness. The residue is taken up with methanol (30 ml), stirred for I hr and filtered.
The methanolic solution is evaporated and the residue is chromatographed on a silica gel column with ethyl acetate: methanol 20 : 10 as eluent, affording 200 mg of the title compound.
N.M.R. (DMS0): 6 2.90(6H,s); 3,80(3H,s); 3,96(3H,s); 6,80(1H,d); 6,92(1H,d); 7,00(1H,d); 7.25(1H,d); 7.40 + 7.80(5H,m);
8.78 + 8,88(1H,dd); 9.30(1h,bs);
1O.O0(lH,bs); 14.28(lh,bs).
By analogous procedure the following compounds can be obtained: 8,8'-Thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine N,N-dimethyl); 5,5'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrolecarbonylimino))-bis(l-naphthaleneamine
N,N-dimethyl); 5,5'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl); 4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenediamine-N,N,N',N'-tetramethyl); 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl imino(N-methyl-4,2-pyrrole@ carbonylimino))-bis(1,8-naphthalene- -diamine- N,N,N',N'-tetramethyl) ; 3,3'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-phenyleneamine -N,N-dimethyl); 3,3-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino) )-bis(1-phenyleneamine N,N-dimethyl); 2,2'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(4-thiazoleamine -N,N-dimethyl)); and 2,2'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(A-thiazoleamine-N,N- -dimethyl).
Example 5 8-(Amino-N-methyl-4,2-pyrrolecarbonylimino(N-met.hyl-4,2- -pyrrole)carbonylimino)(1-dimethylaminonaphthalene) dihydrochloride.
The compound 8-(nitro-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino)(l-dimethylaminonaphtha- -lene)!(520 mg = 1.13 mmoles) is dissolved into a mixture of water (50 ml), dioxane (260 ml) and 2N HC1 (2 ml) and reduced over a Pd catalist (5% on carbon; mg 200) under H2 pressure (40 p.s.i.) for 4 hours.
The catalyst is filtered and the resulting solution is concentrated in vacuum to dryness, affording 500 mg of the title compound.
N.M.R. (DMSO-d6): # 2.90(6H,s); 3,88(3H,s); 3.90(3H,s); 7.03(1H,d) ; 7.09(1H,d) ; 7.25 - 7.80
(7H,m); 8.70-8.80(1H,dd); 10.15(4H,bs);
10.25(1H,bs); 14.20(1H,bs).
Example 6 8-(nitro-N-methyl-4,2-pyrrolecarbonyl-imino(N-methyl-4,2pyrrole)carbonylimino)-l-dimethylaminonaphthalene
To a solution of 8-(amino-(N-methyl-4,2pyrrole)carbonylimino) (1-dimethylaminonaphthalene)dihydrochloride (725 mg, 1. 9 mmols) in dioxane (50 ml), water (20 ml) and triethylamine (0.8 ml, 5.7 mmols) is added dropwise under stirring at room temperature, a solution of (4-nitro-N-methyl-2-pyrrole) carbonyl chloride (360 mg, 1.9 mmols) in dioxane (15 ml).
The mixture is stirred 1 hr at room temperature and then evaporated under vacuum to dryness.
The residue is treated with methanol (30 ml), stirred for half an hour and filtred, to obtain the title compound (650mg).
N.M.R. (DM50-d6) : # 2,88(6H, s); 3.90(3H,s); 4.00(3H,s); 7,00(1H,d); 7,30(1H,d); 7,40-7,80;
(6H,m) ; 8,15(1H,d); 8,75-8,85;
(lH,dd) ; 10,30(1H,bs); 14,25(1H,bs); Example 7 8-(amino(N-methyl-4,2-pyrrole)carbonylimno)(1-dimethyl= aminonaphthalene ) dihydrochloride.
To a solution of 8-(nitro(N-methyl-4,2-pyrrole)carbonylimino) -1-dimethylaminonaphtalene (650 mg, 1.9 mmols) in dioxane (90 ml), water (lOml) and 2N HCL (3ml) is reduced over a Pd catalyst (5% on carbon, 400mg) under H2 pressure (40 p.s.i.) for 2 hr.
The catalyst is filtered and the resulting solution is concentrated in vacuum to dryness, affording 710 mg of the title compound.
N.M.R. (DMSO-d6): # 2.85(6H,s); 3.90(3H,s) ; 6,78(1H,d); 7,18(1H,d); 7.30-7.80(5H,m); 8.70-8.80(1H,dd);
10,28(4H,bs); 14,40(1H,bs); Example 8 8-(nitro(N-methyl-4,2-pyrrole)carbonylimino)-1-dimethyl= aminonaphthalene.
To a solution of 8-(nitro(N-methyl-4,2-pyrrole)carbonylimino) l-aminonaphthalene (620 mg, 2 mmols) in acetonitrile (10 ml), a 40% solution of formaldehyde in water (1.5 ml, 20 mmols) and sodium cyanobrorohydride (380 mg,6 mmols) are added under stirring at room temperature. Glacial acetic acid (0.3 ml), diluited with acetonitrile (5 ml), is added over 10 minute, and the reaction mixture is stirred at room temperature for 2 hrs.An additional 0.3 ml of glacial acetic acid is added, and stirring is continued for 30 minutes more.
The reaction mixture is poured into ethyl acetate (100 ml) and then washed with three 20-ml portions of 1N NaOH.
The organic solution id drie (Na2SO4) and evaporated in vacuum to dryness. Crystalization from 95% ethanol afforded the title compound (400 mg).
N.M.R. (DMSO-d6): # 2.80(6H,s); 4.00(3H,s); 7,25(1H,d);
7.35 7.85(5H,m) ; 8.23(1H,d); 8,63- 6.73(1H,dd); 14.60(1H,bs); Example 9 8-(nitro(N-methyl-4,2-pyrrole)carbonylimino)-1-aminonaphthalene.
To a solution of 1.8-diaminonaphthalene (1.58 g, 10 mmols), indioxane (100 ml), triethylamine (1.4 ml, 10 mmols) is added under stirring. A solution of (4-nitro-N-methyl-2pyrrole) carbonyl chloride (1.88 g, 10 mmols) indioxene (50 ml) is added dropwise, in 1 hr, at room temperature.
The mixture was stirred 2 hrs,then the reaction mixture is evaporated under vacuum to dryness. The residue is treated with water (200 ml) stirred for half an hour and filtred to obtain the title compound (2.45 g).
N.M.R. (DMSO-d6): # 4.05 (3H,s): 6.40-6.70(2H,m); 6.95-7.30(6H,m); 7.50(1H,d);
8.18(1H,d); 10.40(1H,bs).
I.R.(KBr) cm : 3440(b), 3350, 3120, 1630, 1615,
1600, 1480, 1330.
E.I.-M.S.: m/z: 310(M+ ), 292(M -H20).
Example 10
Intravenous injection 20mg/ml.
Ainjectable pharmaceutical preparation can be manufactured by dissolving 20 g of 4,4'-(carbonyl-bis(imino-n-methyl-4,2-pyrrolecarbonylimino (n-methyl-4,2-pyrrole)carbonylimino))-bis(n-methyl-4,2pyrrolecarbonylimino(3-propionamidine)), dihydrochloride in water for injection (1000 ml) and sealing ampoules of 1-10 m.l.
Claims (11)
1. A derivative of a substituted carboxypyrrole having the following formula (I)
where in
W is =0, =S or =N-H each of m and n, being the same or different, is an integer of 1 to 4; each of B and B1, which may te the same-or different, is: a) a -(CH2)p-NR1R2 group, wherein p is an integer of 2 to 4
and each of %C1-C6 alkyl;R1 and R2, independently, is hydrogen or
C1-C6 alkyl;
group, wherein g is an integer of 1 to 4;
R3 is hydrogen and each of R4 and R5, independently, is hydrogen cr C1-Có alkyl; or R3 and =4, taken together, form a -CH=CH-, -CH2-CH2- or -CH2CH2-CH2- chain, and
R5 is is hydrogen or C1-C6 alkyl; c) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to three basic groups;
or d) a saturated or unsaturated, heteromonocyclic or hetero
bicyclic ring, containing one to three heteroatom
chosen from nitrogen, oxygen and sulphur, substituted by
one to three basic groups; and the pharmaceutically
acceptable salts thereof, and wherein, when at the same
time, W is =0, m and n being the same are 2, B and B1
are the same and as defined above under b), q is 2, then
at least one of R4 and R5 is other then hydrogen.
2. A compound of formula (I), according to claim 1, wherein each of m and n,being the same, is 2 or 3; W is as defined in claim 1, each of B and B1, which are the same or different, is a') (CH2)pNR1R2 wherein p is 2 or 3 and each of R1 and R2 independently is hydrogen or C1-C4 alkyl;
wherein q is 2 or 3;R3, R4 and R5 are
each hydrogen or R3 and R4, together, form a -CH2-CH2 -CH=CH- or -CH2-CH2-CH2- chain and R5 is hydrogen; c') a phenyl. or naphthyl group substituted by one, two or
three basic groups chosen independently from
(CH2)rNR6R7 and
in which r is zero or an integer of 1 to 4 and each of
R6 and R7, independently, is hydrogen or C1-C4 alkyl; or lA d') a thiazole, pyrimidine or tetrahydropyranyl ring
substituted by one, two or three basic groups, as
defined above under c'); and the pharmaceutically
acceptable salts thereof, and wherein when, at the same
time, W is =0, m and n are 2, B and B1 are the same and
as defined above under b'),R3,R4and R5 are hydrogen, then
q is 3.
3. A compound selected from 4,4 '-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2- pyrrolecarbonylimino(3-propionamidine)); 4,1'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2- pyrrolecarbonylimino(3-propionamidine)); 4,4 '-(thiocarbonyl-bis-(imino-N-methyl-4,2-pyrrolecarbonyli- mino(N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2pyrrole carbonylimino(3-propionamidine)); 4,4'-(thiocarbonyl-bis(imino-N-mehtyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(N-methyl-4,2 pyrrolecarbonylimino(3-propyldimenthylamine)); 4,4'-(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole) carbonylimino))-bis(N-methyl-4,2 pyrrolecarbonylirrino(3-propionamidine)); 4,4'(1,3-guanidine-bis-(N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(IN-methyl-4,2- pyrrolecarbonylïmino(3-propyldimethylamine)); 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-A, 2-pyrrole)carbonylimino) )-bis(l-naphthaleneamine- -N,N-dimethyl); 8,8'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(l-naphthaleneamine -N,N-dimethyl); 5,5'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl); 5,5'-(thiocarbonyl-bis(imeno-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl); 4,4'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-mesthyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenedia- mine-N,N,N',N' ,-tetramethyl); 4,4'-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1,8-naphthalenediamine -N,N,N',N'-tetramethyl); 3,3'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(1-phenyleneamine -N,N-dimethyl); 3,3'-tthiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino) )-bis(1-pheneyleamine -N,N-dimethyl); 2,2'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(A-thiazoleamine -N,N-dimethyl); 2,2-(thiocarbonyl-bis(imino-N-methyl-4,2-pyrrolecarbOnylimino (N-methyl-4,2-pyrrole)carbonylimino))-bis(4-thiazoleamine -N,N-dimethyl); and the pharmaceutically acceptable salts thereof.
4. A compound according to claim 3, which is a salt with hydrochloric or hydrobromic acid.
5. The use of a compound of formula (I)
wherein W is =0, =S or =N-H each of m and n, being the same or different, is an integer of 1 to 4; each of B and B1, which may be the same or cifferent, is: a) a -(CH2)p-NR2 group, wherein p is an integer of 2 to 4
and each of R1 and R2, independently, is hydrogen or
C1-C6 alkyl;
group, wherein q is an-integer of 1
to 4;
R3 is hydrogen and each of R4 and R5, independently, is hydrogen or C1-C6 alkyl; or R3 and R4, taken together, foa a -CH=CH, -CH2-CH2- or -CH2-CH2-CH2- chain, and R5 is hydrogen or C1-C6 alkyl; c) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to three basic groups;
or d) a saturated or unsaturated, heteromonocyclic or heterobi
cyclic ring, containing one to three heteroatome chosen
from nitrogen, oxygen, and sulphur, substituted by one to
three basic groups; our a pharmaceutically acceptable salt
thereof, in the preparation of a pharmaceutical for use
as an angiogenesis inhibitor in mammals.
6. A process for the preparation of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, said process comprising a) reacting a compound of formula (II)
wherein n and B1 are as refined in claim 1, or a salt thereof, with a compound of formula (III)
wherein W' is =O or =S, and each of the X groups, which may be the same or different, is a leaving group, so as to obtain a compound of formula (I), in which W is =O or -S, m and n are the same and B and B1 are the same; or b) reacting a compound of formula (IV), or a salt thereof,
wherein
B and m are defined in claim 1 and X and W are as defined above, with a compound formula (II), as defined above, so as to obtain a compound of formula (I) wherein W is =O or =S; or c) reacting a compound of formula (V), or a salt thereof,
where in
B and m are as defined in claim 1, with a compound of formula (II), as defined above, so as to obtain a compound of formula (I), wherein W is =NH; and if desired, obtaining a free compound of formula (I) from a salt thereof.
7. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an active agent, and a pharmaceutically acceptable diluent and/or carrier.
8. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body.
9. A compound or salt according to claim 8 for use as an angiogenesis inhibitor.
10. A process for the preparation of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 9.
11. A pharmaceutical composition according to claim 7 and substantially as hereinbefore described in Example 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9124733A GB2261661A (en) | 1991-11-21 | 1991-11-21 | Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9124733A GB2261661A (en) | 1991-11-21 | 1991-11-21 | Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9124733D0 GB9124733D0 (en) | 1992-01-15 |
| GB2261661A true GB2261661A (en) | 1993-05-26 |
Family
ID=10704989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9124733A Withdrawn GB2261661A (en) | 1991-11-21 | 1991-11-21 | Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2261661A (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0583161A2 (en) * | 1992-08-11 | 1994-02-16 | PHARMACIA S.p.A. | 4-Aminopyrrole-2-carboxamide derivatives as antiviral agents |
| WO1999000364A1 (en) * | 1997-06-27 | 1999-01-07 | Pharmacia & Upjohn S.P.A. | Poly-branched polycarboxamido compounds |
| US5998140A (en) * | 1996-07-31 | 1999-12-07 | The Scripps Research Institute | Complex formation between dsDNA and oligomer of cyclic heterocycles |
| 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 |
| US6143901A (en) * | 1996-07-31 | 2000-11-07 | Genesoft, Inc. | Complex formation between dsDNA and pyrrole imidazole polyamides |
| US6472537B1 (en) | 1996-02-26 | 2002-10-29 | California Institute Of Technology | Polyamides for binding in the minor groove of double stranded DNA |
| 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 |
| US6635417B1 (en) | 1996-07-31 | 2003-10-21 | California Institute Of Technology | Complex formation between DSDNA and oligomer of cyclic heterocycles |
| US7049061B1 (en) | 1996-02-26 | 2006-05-23 | California Institute Of Technology | Stereochemical control of the DNA binding affinity, sequence specificity, and orientation-preference of chiral hairpin polyamides in the minor groove |
| EP3381897A1 (en) | 2017-03-27 | 2018-10-03 | Leadiant Biosciences SA | Derivatives of the disodium 2,2'-{carbonylbis[imino-3,1-phenylenecarbonylimino(1-methyl-1h-pyrrole-4,2-diyl)carbonylimino]}dinaphthalene-1,5-disulfonate salt and related compounds as heparanase inhibitors for the treatment of cancer |
| EP3381898A1 (en) * | 2017-03-27 | 2018-10-03 | Leadiant Biosciences SA | Symmetrical tris-aryl-amide derivatives and their use as anti-heparanase |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4912199A (en) * | 1987-07-06 | 1990-03-27 | The Governors Of The University Of Alberta | Oligopeptide anticancer and antiviral agents |
| WO1991010649A1 (en) * | 1990-01-11 | 1991-07-25 | Farmitalia Carlo Erba S.R.L. | New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds |
-
1991
- 1991-11-21 GB GB9124733A patent/GB2261661A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4912199A (en) * | 1987-07-06 | 1990-03-27 | The Governors Of The University Of Alberta | Oligopeptide anticancer and antiviral agents |
| WO1991010649A1 (en) * | 1990-01-11 | 1991-07-25 | Farmitalia Carlo Erba S.R.L. | New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds |
Non-Patent Citations (4)
| Title |
|---|
| Actual. Chim. Ther., 18 (Rencontres Int. Chim Ther,26. 1990)(1991) pages 21 to 42. * |
| Biochim. Biophys. Acta. 1090 (1) 52 -60 (1991) * |
| J. Med. Chem 32 (10)2368 -75 (1989) * |
| J. Med. Chem. 35 (15) 2890 -7 (1992) * |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0583161A3 (en) * | 1992-08-11 | 1994-07-20 | Erba Carlo Spa | 4-aminopyrrole-2-carboxamide derivatives as antiviral agents |
| US5596105A (en) * | 1992-08-11 | 1997-01-21 | Farmitalia Carlo Erba S.R.L. | Therapeutically active naphthalenesulfonic pyrrolecarboxamido derivatives |
| EP0583161A2 (en) * | 1992-08-11 | 1994-02-16 | PHARMACIA S.p.A. | 4-Aminopyrrole-2-carboxamide derivatives as antiviral agents |
| US6545162B1 (en) | 1996-02-26 | 2003-04-08 | California Institute Of Technology | Method for the synthesis of pyrrole and imidazole carboxamides on a solid support |
| US7049061B1 (en) | 1996-02-26 | 2006-05-23 | 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 |
| US6683189B1 (en) | 1996-02-26 | 2004-01-27 | California Institute Of Technology | Method for the synthesis of pyrrole and imidazole carboxamides on a solid support |
| US6555692B1 (en) | 1996-02-26 | 2003-04-29 | California Institute Of Technology | Preparation and use of bifunctional molecules having DNA sequence binding specificity |
| US6472537B1 (en) | 1996-02-26 | 2002-10-29 | California Institute Of Technology | Polyamides for binding in the minor groove of double stranded DNA |
| US6506906B1 (en) | 1996-02-26 | 2003-01-14 | 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 |
| US6303312B1 (en) | 1996-07-31 | 2001-10-16 | California Institute Of Technology | Complex formation between dsDNA and oligomer of cyclic heterocycles |
| US6635417B1 (en) | 1996-07-31 | 2003-10-21 | California Institute Of Technology | Complex formation between DSDNA and oligomer of cyclic heterocycles |
| US6143901A (en) * | 1996-07-31 | 2000-11-07 | Genesoft, Inc. | Complex formation between dsDNA and pyrrole imidazole polyamides |
| WO1999000364A1 (en) * | 1997-06-27 | 1999-01-07 | Pharmacia & Upjohn S.P.A. | Poly-branched polycarboxamido compounds |
| EP3381897A1 (en) | 2017-03-27 | 2018-10-03 | Leadiant Biosciences SA | Derivatives of the disodium 2,2'-{carbonylbis[imino-3,1-phenylenecarbonylimino(1-methyl-1h-pyrrole-4,2-diyl)carbonylimino]}dinaphthalene-1,5-disulfonate salt and related compounds as heparanase inhibitors for the treatment of cancer |
| EP3381898A1 (en) * | 2017-03-27 | 2018-10-03 | Leadiant Biosciences SA | Symmetrical tris-aryl-amide derivatives and their use as anti-heparanase |
| WO2018177861A1 (en) * | 2017-03-27 | 2018-10-04 | Leadiant Biosciences Sa In Liquidazione | Symmetrical tris-aryl-amide derivatives and their use as anti-heparanase |
| WO2018177863A1 (en) | 2017-03-27 | 2018-10-04 | Leadiant Biosciences Sa In Liquidazione | Derivatives of the disodium 2,2'-{carbonylbis[imino-3,1-phenylenecarbonylimino(1-methyl-1h-pyrrole-4,2-diyl) carbonylimino]}dinaphthalene-1,5-disulfonate salt and related compounds as heparanase inhibitors for the treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9124733D0 (en) | 1992-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5260329A (en) | Ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds | |
| US5753629A (en) | Distamycin A analogues as antitumour or antiviral agents | |
| US6153642A (en) | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
| US5175182A (en) | Acryloyl substituted pyrrole derivatives | |
| EP1064281B1 (en) | Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor agents | |
| US6165980A (en) | Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
| GB2261661A (en) | Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles | |
| KR100408538B1 (en) | Acryloyl substituted distamycin derivatives, and process for preparing them | |
| US6753316B1 (en) | Acryloyl derivatives analogous to distamycin, process for preparing them, and their use as antitumor agents | |
| EP1100777B1 (en) | Sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents | |
| EP1100778A1 (en) | Oxidised sulfurated distamycin derivatives, process for preparing them, and their use as antitumor agents | |
| WO1999064413A1 (en) | Cinnamoyl distamycin analogous derivatives, process for their preparation, and their use as antitumor agents | |
| GB2289274A (en) | Angiogenesis inhibiting sialic acid derivatives and process for their preparation | |
| GB2260134A (en) | Derivatives of poly-5-amino-3-carboxy-1-methyl compounds | |
| US5332738A (en) | Imidazolidine antipsychotic agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |