GB2260134A - Derivatives of poly-5-amino-3-carboxy-1-methyl compounds - Google Patents
Derivatives of poly-5-amino-3-carboxy-1-methyl compounds Download PDFInfo
- Publication number
- GB2260134A GB2260134A GB9121205A GB9121205A GB2260134A GB 2260134 A GB2260134 A GB 2260134A GB 9121205 A GB9121205 A GB 9121205A GB 9121205 A GB9121205 A GB 9121205A GB 2260134 A GB2260134 A GB 2260134A
- Authority
- GB
- United Kingdom
- Prior art keywords
- methyl
- bis
- imino
- pyrrole
- carbonylimino
- 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- Withdrawn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 122
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 239000002253 acid Substances 0.000 claims abstract description 33
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 13
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 6
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 235000000346 sugar Nutrition 0.000 claims abstract description 4
- 125000002541 furyl group Chemical group 0.000 claims abstract description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 29
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 28
- -1 carbonylimino Chemical group 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- FKORGLNGEASTQE-UHFFFAOYSA-N naphthalene-1,3-disulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC(S(O)(=O)=O)=C21 FKORGLNGEASTQE-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- INMHJULHWVWVFN-UHFFFAOYSA-N naphthalene-1,3,5-trisulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC(S(O)(=O)=O)=C21 INMHJULHWVWVFN-UHFFFAOYSA-N 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- HYFMZOAPNQAXHU-UHFFFAOYSA-N naphthalene-1,7-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC=C21 HYFMZOAPNQAXHU-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 4
- 229940121369 angiogenesis inhibitor Drugs 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 4
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 4
- VILFVXYKHXVYAB-UHFFFAOYSA-N naphthalene-2,7-disulfonic acid Chemical compound C1=CC(S(O)(=O)=O)=CC2=CC(S(=O)(=O)O)=CC=C21 VILFVXYKHXVYAB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 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 3
- MBPFNOMGYSRGQZ-PBXRRBTRSA-N 2-deoxy-D-glucose 6-phosphate Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@H](O)CC=O MBPFNOMGYSRGQZ-PBXRRBTRSA-N 0.000 claims description 3
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000011319 anticancer therapy Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 230000033115 angiogenesis Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 238000011275 oncology therapy Methods 0.000 abstract description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 2
- 125000004434 sulfur atom Chemical group 0.000 abstract 2
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- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- XZNVRCJXZWONQE-UHFFFAOYSA-K trisodium;naphthalene-1,3,5-trisulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(S(=O)(=O)[O-])=CC(S([O-])(=O)=O)=C21 XZNVRCJXZWONQE-UHFFFAOYSA-K 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 241000124008 Mammalia Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229940093499 ethyl acetate Drugs 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
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- 230000012010 growth Effects 0.000 description 3
- 150000007529 inorganic bases Chemical class 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
- ZPBSAMLXSQCSOX-UHFFFAOYSA-N naphthalene-1,3,6-trisulfonic acid Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=CC2=CC(S(=O)(=O)O)=CC=C21 ZPBSAMLXSQCSOX-UHFFFAOYSA-N 0.000 description 3
- HEWDOWUUTBCVJP-UHFFFAOYSA-N naphthalene-1,6-disulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 HEWDOWUUTBCVJP-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
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- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
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- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- 229960000583 acetic acid Drugs 0.000 description 2
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- 125000002947 alkylene group Chemical group 0.000 description 2
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- 238000007796 conventional method Methods 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
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- FEWNRIKJXAQRJJ-UHFFFAOYSA-N naphthalene-1,3,7-trisulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=CC(S(=O)(=O)O)=CC=C21 FEWNRIKJXAQRJJ-UHFFFAOYSA-N 0.000 description 2
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- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- SAIKULLUBZKPDA-UHFFFAOYSA-N Bis(2-ethylhexyl) amine Chemical compound CCCCC(CC)CNCC(CC)CCCC SAIKULLUBZKPDA-UHFFFAOYSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
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Classifications
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- 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
-
- 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
- C07D207/42—Nitro radicals
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Abstract
Compounds of the formula (I> <IMAGE> wherein W is =O, =S or =N-H, m and n are 1 to 4. B and B1 are a) -(CH2)p-NR1R2 wherein p is 2 to 4 and R1 and R2 @are H or C1-C6 alkyl; b) wherein q is 1 to 4, R3 is H and R4 and R5 @are H or C1-C6 alkyl; @or R3 and R4 taken together form -CH=CH-, CH2CH2- or -CH2CH2CH2- and R5 is H or C1-C6 alkyl; c) a saturated or unsaturated carbocyclic or condensed carbocyclic ring substituted by one to three basic groups; d) a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing 1 to 3 O, N or S atoms and substituted by 1 to 3 @basic groups; e) a saturated or unsaturated carbocyclic or condensed carbocyclic ring containing 1 to 3 acid groups; f) a saturated or unsaturated heteromonocyclic or heterobicyclic ring containing 1 to 3 O, N or S atoms and substituted by 1 or @more acid groups; g) a pyranyl of furanyl sugar residue substituted by 1 too 3 acid groups; or h) -CH2(CHA)rCH2A wherein each A is an acid group and r is 0 to 2, and the pharmaceutically acceptable @salts thereof have activity as antiogenesis inhibitors and are useful in particular in cancer therapy, administered either alone or together with an antitumour agent. Precursors of the above compounds have the formula:- <IMAGE> or are acid addition salts thereof.r
Description
DERIVATIVES OF POLY-5-AMINO-3-CARBOXY-1-METHYL COMPOUNDS
The present invention relates to new derivatives of substituted carboxy pyrroles, to a process for their preparation and to a pharmacological composition containing them.
The present invention provides new compounds 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 either a group chosen from: a) a -(CH2) -NE1R2 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 4, taken together, form 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; 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;
or a group chosen finn: e) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to tree acid groups;
f) a saturated or unsaturated, heteromonocyclic or hetero
bicyclic ring, containing one to three heteroatoms chosen
from nitrogen, oxygen and sulphur, substituted by one or
more acid groups;
g) a pyranyl or furanyl sugar residue substituted by one to
three acid groups; or
h) a -CH2(CEA)CH2A group, wherein each A group, being the
same or different, is an acid group and r is 0, 1 or 2;
and the pharmaceutically acceptable salts thereof.
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 or acid groups are present on the same B
Gr B1 substituent, whey may be the same or different.
When in a -(CH2)p-, (CH2)@ or -(CH2)r-group p and/or q 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) and e), it is for example phenyl or naphthyl, in particular naphthyl.
When B or B1 is a ring as defined above under d) and f), it is for example thiazole, pyridine,pyrimidine, pyrazine, pyridazine, tetrahydropyran or tetrahydrofuran; in particular thiazole, pyrimidine or tetrahydropyran. When B and B1 are a sugar residue as defined above under g) they are for example a residue deriving from glucose or ribose.
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)s-NR6R7, in whichs is zero or an integer of I to 4 and each of R6 and R7, independently, is hydrogen or C1-C6 alkyl;
in which s is as defined above, R8 is hydrogen and each of Rg and R10, independently, is hydrogen or C1-C6 alkyl, or R8 and Rg, taken together, form a -CH=CH-, -CH2-CH2- or -CH2-CH2-CH2 - chain and R10 is hydrogen or C1-C6 alkyl;and
wherein R8, R9 and R10 are as defined above.
Examples of acid groups according to the definition of B and B1 groups given above under e), f), g) and h) for instance may be those chosen from the group including sulfonic, sulfuric, sulfamic, sulfinic, phosphoric, phosphonic, phosphamic or carboxylic acid groups, i.e. S03 H, S04 H, S03 NH2, SO2 H,
P04 H2, P03 H2, P03 NH3 and C02 H.
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 flrmula (I) include both 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, and those with inorganic bases, sucn as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, N-methyl-glucamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-die thylaminoethylamine, N-ethylmorpholine, ss-phene- thylamine, N-benzyl-ss-phenethylamine, N-benzyl-N,N-dimethyl
amine and the other acceptable organic amines.
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 ccnverted 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 either a group chosen from wherein R2 wherein p is 2 or 3 and each of R1 and b;2 independently is hydrogen or C1-C 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 ptienyl or naphthyl group substituted by one. two or
three basic groups chosen independently from
in wllicit s is as defined above and each of R6and R7, independen@ly. is hydrogen or C1-C4 alkyl, or
d') a thiazole, pyrimidine or tetrahydropyranyl ring
substituted by one, two or Lhree basic groups, as defined above under c');
or a group chosen from : e') an unsaturated carbocyclic or condensed carbocyclic ring substituted by 1 to 3 acid groups; f) a tetrahydropyranyl or tetrahydrofuranyl rin & BR< substituted by 1 to 3 acid groups; or g' ) a glucoseruranosyl
residue substituted by 1 to 3 acid groups; and the pharma
ceutically acceptable salts thereof.
Specific examples of preferred compounds of the invention,
are the followings:
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl
imino(N-methyl-5,3-nyrrole)carbonylimino))-bis(N-methyl
-5,3-pyrrolecarbonylmino(3-propionamidine));
4,4'-(1,3-guanidine-bis-(N-methyl-5,3-pyrrolecarbonyl
imino(N-methyl-5,3-pyrrole)carbonylimino))-bis(N-methyl
5,3-pyrrolecarbonylimino(3-propionamidine)); 8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3 -pyrrole)carbonylimino) )-bis( 1-naphthaleneamine -N,N-dimethyl); 4,4'- ( carbonyl-bis ( irnino-N-methyl- 3 -pyrrolecarbonyl - imino(N-methyl-5,3 -pyrrole)carbonylimino) )bis( 1naphthalen- sulfonic acid); 8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino(N-methyl-5,3-pyrrole)carboyliminb))bis(1-naphthalensulfonic acid); 8,8'-(carbonyl-bis(imino-N-methyl- 5,3-pyrrolecarbonyl-imino (N-methyl- 5,3-pyrrole)carbonylimino) )bis( 1,3-naphthalendisulfonic acid);
4,4'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3'-pyrrole)carbonylimino))bis(1,7-naphthalendisulfonic acid);
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3 spyrrole)carbonylimino))bis( 1,5-naphthalendisulfonic acid): 8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)arboylimino))bis(1,3,5-naphthalentrisulfonic acid)::
8,8'-(carbonl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3,6-naphthalentrisulfonic acid); 7,7' -(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3-naphthalendisulfonic acid);
6,6'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3-naphthalendisulfonic acid);
3,3'-(carbonyl-bis(imino-N-methyl- s,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,7 naphthalendi
sulfonic acid);
3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3 -pyrrole)carbony2imino) )bis(2,7 -naphthalendi
sulfonic acid);;
7,7' (carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonlimino))bis(1,3,5-naphthalentri
sulfonic acid); 7,7'-thiocarbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bisk1,3 - naphthalendi
sulfonic acid); 2,2'-(carbonyl-bis(imino-N-methyl- 5,3 pyrrolecarbonyl-imino (N-methyl-5,3-pirrole)carbonylimino))bis(2-deoxy-D-glucose6-sulphate); and 2,2' (carbonyl-bis(imino-N-methyl 5,3 -pyrrolec arbonyl- imino (N-methyl- 5,3 pyrrole)carbonylimino))bis(2-deoxy-D-glucose
6-phosphate);
and the pharmaceutically acceptable salts thereof.
It has to be noticed that the compounds of the present invention
according to IUPAC should be termed as "N-methyl-2,4-pyrrolecar- bonyl-imino" compounds, however for convenience's reasons they
are herein termed as "N-methyl-5,3-pyrrolecarbonyl-imino"
compounds.
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 Lo 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 fl. 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 (r) wherein W is =O or =S; or c) reacting a compound of formula (V), or a salt thereof,
wherein
ss 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 =Nfl; and if desired, salifying a compound
of formula (I) 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 either a salt with organic or inorganic acid or a salt with inorganic bases, for example those mentioned above as to the pharmaceutically acceptable salts of the invention, the hydrochloride and hydrobromide salts or the sodium and the potassium 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, trichlorophenoxy or trichloromethyloxy.
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 (II), 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 -100C. to about 500C. and the reaction time about 1 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 B( is defined as
above, with a compound of formula (VII)
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 a 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 above1 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 (VIII) may be obtained from a product of formula (XI)
according to well known methods of carboxylic acid activation.
The compound of formula (XI) is a new compound and it may be obtained from a product of formula (XII) prepared as in
Tetrahedron Vol.27 pp 245-353,1971, K.J.Morgan, D.P.Morrey
through the conventional N-alkylation methods of heterocyclic compounds, bearing an acidic hydrogen atom attached to nitrogen, and the following hydrolysis of methyl ester.
The compounds of formula (?CI ) 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
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 (II).
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-I)as defined above with a compound of formula (on'), X-C-N (XIV) wherein
X is as defined above, in particular chlorine or bromine.
Also compounds (XIV) 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 a A further object of the present invention is a combined method of treatment of cancer in mammals, including humans, in need of such treatment, said method comprising administering 1) a compound of formula (I ),cra pharmaceutically acceptable salt thereof, and 2) an antitumor agent, in amounts and close enough together in time sufficient to effect a therapeutically useful interaction.
Object of the present invention is also to provide products containing a compound of formula (I ), or a pharmaceutically acceptable salt, and an antitumor agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.
The term "ant tumor agent" is meant te comprise both a single antitumor drug and cocktails" i.e. a mixture of such drugs, according to the clinical practice.
Antitumor agents that can be formulated with a compound of the invention or alternatively, can be administered in a combined method of treatment are e.g. doxorubicin, daunomycin, epirubicin, idarubicin, etoposide, fluorouracyl, mephalan, cyclophosphamide, bleomycin, vinblastin and mitomycin or a mixture of two or more thereof.
The compounds of the invention can therefore be used in particular
with an antitumor agent, for example an anthra-cycline glycoside
such as doxorubicin, daunorubicin, epirubicin or idarubicin as mentioned above, in a treatment to ameliorate or improve the
conditions of a patient suffering from cancer.
A compound of the invention and an anti tumor agent such as an anthracycline glycoside can be for instance administered to improve the conditions of a patient having a leukaemia such as myeloblastic leukaemia, linphoma, sarcoma, Wilm's tumor, malignant neoplasm of
the bladder, breast, lung or thyroid.
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 Folkmans 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, subcutaneously, 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 pro dose
1-4 times a day.
Object of the present invention are also pharaceutical compositions nG h compound of formula (I) or a pharmaceutically
acceptable salt thereof as the active substance, in
association with one or nore 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 hydro
chloride.
In formulations for topical application, e.g. creams lotions or pastes for use in dermatological treatment, the
active ingredient may be Mixed with conventional olcaginous or emulsifying excipients.
The solid oral forms, 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; disaggrega
ting agents, e.g. a starch, alginic acid, alginates, sodium
starch glycolate; effervescing mixtures; dyestuffs; sweeteners;
wetting agents, for instance, lecithin, polysorbates, lauryl
sulphates: 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-coating, or film-coating processes.
Furthermore,according to the invention there is provided a
method of treating pathological conditions where the growth of
new blood vessels is detrimental, for example chronic in'1a.-.r.ation, diabetic retinopathy, psosiaris, rheumatoid
arthritis and tumors, in mammals in need thereof including
humans, comprising administering to the said mammals a
composition of the invention.
The following examples illustrate but do not limit the invention.
Example 1 B,B'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3-pyrrole)carbonylimino))-bis(l-naphthaleneamine-N,N-dimethyl).
To a solution of ss-(amino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl- 5,3-pyrrole)carbonylimino) (l-dimethylaminonaphtha lene)-hydrochloride( 750 mg, 1,48 :nmols) in N,N-dimethylformamide (50 ml), trietylamine (0,39 ml, 2,96 mmols) is added under stirring. A solution of 1,1'-carbonyldiimidazole (1,23 mg, 0,74 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 1 hr and filtered.
The methanolic solution is evaporated and the residue is chromatographed o a silica gel column with ethyl acetate: methanol 20 : 10 as eluent, affording 260 mg of the title compound, The title compound was characterised as follows:
N.M.R. (DMSO): 6 ppm 2.90 (6H,s); 3.82 (3H,s); 3.98 (3H,s); 6.80 t 7.30 (4H, 4d); 7.45 + 7.82 (5H,m); 8.20 (lH, bs); 8.80 (lH, dd); 10.08 (1H, bs); 11.28 (1H, bs).
F.A.B. - M.S.: M/g 887 [M+H]+; 702 [M-185]+; 430.
By analogous procedure the following compounds can be obtained: 8,8'-Thiocarbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3-prrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl); 5,5'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3-pyrrole)carbonylimino))-bis(1-naphthaleneamine-N,N -dimethyl); 5,5'-(thiocarbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl); 4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-53 -pyrrole)carbonylimino) )-bis(1,8-naphthalene- diamine-N,N,N',N'-tetramethyl); 4,4'-(thiocarbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonylimino(N-methyl-5,3-pyrrole)carbonylimino))-bis(1,8-naphthalene -diamine- N,N,N' 1N'-tetramethyl); 3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-s,3-pyrrole)carbonylimino))-bis(1-phenyleneamine- -N,N-dimethyl);
3,3-(thiocarbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino
(N-methyl- 5,3-pyrrole)carbonylimino))-bis(l-phenyleneamine- N,N-dimethyl);
2,2'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3-pyrrole)carbonylimino))-bis(4-thiazoleamine-
-N,N-dimethyl));; 2,2'-(thiocarbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-s,3-pyrrole)carbonylimino))-bis(4-thiazoleamine-N,N- -dimethyl); 4.4'-(carbonyl-bis(imino-N-methyl- 5, 3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))-bis(N-methyl-5,3- pyrrolecarbonylmino(3-propionamidine)); and 4,4'(1,3guanidine-bis-(N-methyl-5,3-pyrrolecarbonyl-imino(N-methyl 5,3-pyrrole)carbonylimino))-bis(N-methyl-5,3- pyrrolecarbonylimino(3-propionamidine)).
Example 2 8-(Amino-N-methyl-5,3-pyrrolecarbonylimino(N-methyl-5,3- pyrrole)carbonylimino)(l dimethylaminonaphthalene) dihydrochloride.
The compound 8-(nitro-N-methyl-5,3-pyrrolecarbonylimino (N-methyl-5,3-pyrrole)carbonylimino)(l dimethylaminonaphtha-lene):(650mg = 1.41 mmoles) is dissolved into a mixture of water (50 ml), dioxane (200 ml) and 2N HC1 (2,5 ml) and reduced over a Pd catalyst (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 600 mg of the title compound.
Example 3 8-(nitro-N-methyl-5,3-pyrrolecarbonyl-imino(N-methyl-5t3 pyrrole)carbonylimino)-l-dimethylaminonaphthalene.
To a solution of 8-(amino-(N-methyl-5,3 pyrrole) carbonylimino) (1- dimethylaminonaphthalene)dihydrochloride (820 mg, 2.15 mmols) in dioxane (50 ml), water (20 ml) and triethylamine (0,9 ml, 6,4 mmols) is added dropwise under stirring at room temperature, a solution of (5-nitro-N-methyl-3,pyrrole) carbonyl chloride (407 mg, 2,15 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 filtered, to obtain the title compound (730 mg).
The title compound was characterised as follows:
N.M.R. (DMSO): 6 ppm 3.82 (6H,s); 6.80 . 7.40 (4H,4d); 7.90 (1H, d); 8.80 (1H, d); 8.05 (1H, bs); 8.60 (1H, d); 9.33 (lH,d); 9.90 (1H, bs); 12.30 (lH, bs).
F.A.B. - M.S.: M/Z 1411 [M-H]-; 1389 [M-Na]'; Example 4 8-(amino(N-methyl-5,3-pyrrole)carbonylimino)(l-dimethyl= aminonaphthalene)dihydrochoride.
To a solution of 8-(nitro(N-methyl-5,3 pyrrole) carbonylimino) -l-dimethylaminonaphtalene (900 mg, 2.63 mmols) in dioxane (90 ml), water (10 ml) and 2N HCl (4,15 ml) is reduced over a Pd catalyst (5% on carbon, 400 mg) 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 810 mg of the title compound.
Example 5 8- (nitro (N-methyl-S, 3-pyrrole) carbonylimino) -l-dimethyl= aminonaphthalene.
To a solution of 8-(nitro(N-methyl-5,3 pyrrole) carbonylimino) -l-aminonaphthalene (760 mg, 2,45 mmols) in acetonitrile (10 ml), a 40% solution of formaldehyde in water (1.84 ml, 24,5 mmols) and sodium cyanoborohydride (465 mg, 735 mmols) are added under stirring at room temperature. Glacial acetic acid (0,37 ml), diluted with acetonitrile (5 ml), is added over 10 minute, and the reaction mixture is stirred at room temperature for 2 hrs.
An additional 0.37 ml of glacial acetic acid is added, and stirring is continued for 30 minutes more. The reaction mixture is poured into ethyl acetate (120 ml) and then washed with three 20-ml portions of 1N NaOH.
The organic solution is dried (Na2S04) and evaporated in vacuum to dryness. Crystallization from 95% ethanol afforded the title compound (490 mg).
Example 6 8-Nitro(N-methyl-5,3-pyrrole)carbonylimino)-1-aminonaphthalene To a solution of 1,8-diaminonaphthalene(2,35 g, 14,87 mmols), in dioxane (150 ml), triethylamine (2,35 ml, 14,87 mmols) is added under stirring. A solution of !5-nitro-N-methyl-3-pyrrole) carbonyl chloride (2,8 g, 14,87 mmols) in dioxene (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 (300 ml) stirred for half an hour and filtred to obtain the title compound (3,64 g).
Example 7 5-nitro-N-methyl-3-pyrrole methyl carboxylate.
To a solution of 18-crown-6-(0,8 g, 3 mmols) in diethyl ether (50 ml), potassium tert. butoxide (3,9 g, 35 mmols) is added under stirring. After 30 minutes 5-nitro-3-pyrrole methyl carboxylate (4,68 g, 30 mmols) is introduced in a single portion, and stirring is continued for 15 minutes.
A solution of methyl iodide (4,97 g, 35 mmols) in diethyl ether (20 m1) is added dropwise in 30 minutes, at room temperature to the reaction mixture. The solution is stirred for 2 hrs, then water (20 ml) is added, the layers are separated, and the acqueous layer is extracted with ether (40 ml). The combined organic phases are dried over anhydrous sodium sulphate. The solvent is removed under vacuum, and the residue afforded after recrystallization the title compound (3,56 g).
Example 8 5-nitro-N-methyl-3-pyrrole carboxylic acid.
To a suspension of 5-nitro-N-methyl-3-pyrrole methyl carboxylate (1 g) in ethanol (40 ml), a solution of sodium hydroxyde (800 mg) in water (40 ml) was added and the mixture was boiled under reflux until a clear solution was obtained.
The solution was cooled, filtered and the filtrate was acidified with 6N HCl; a white precipitate was formed, which was filtered off to obtain the title compound (920 mg).
Example 9
8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino(N
methyl-5,3-pyrrole)carbonylimino))bis(1,3,5-naphthalentrisulfonic
acid) hexasodium salt.
To a solution of 8-(amino-N-methyl-5,3 -pyrrolecarbonyl-imino(Nmethyl-5,3-pyrrole)carbonylimino))(1,3,5-naphthalentrisulfonic acid trisodium salt) hydrochloride (2. 55 g, 3,5mmols) in water (60 ml) and dioxane (15 ml), sodium acetate (l.15 g, 14 mmols) was added under stirring. The whole was cooled to SOC with an ice bath, then a ~ solution of bis(trichloromethyl)cartonate (692 mg 2,33 mmols) in dioxane (10 ml) was added dropwise in 1 hr.
The mixture was stirred 2 hrs at # 8 C.
The solvents were evaporated under vacuum and the residue was taken up with methanol.
After filtration of the salts, the filtrate was evaporated and the residue was cromotographed on a silica gel column with methylene chloride: methanol: water 60:40:4 as eluent, affording g 0. 92 of the title compound.
By analogous procedure the following compounds can be obtained: 8-8'-(carbonyl-bis(imino-N-methyl-s,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,4,6-naphthalentrisulonic acid) hexasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(2,4,6-naphthalentrisulfonic acid) hexasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3,6-naphthalentrisulfonic acid) hexasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(2,3,5-naphthalentrisulfonic acid) hexasodium salt 8,8'-(carbonyl-ois (imino-N-mehyl-5,3-pyrrole-ca@@@@@@@@@@ (N-methyl- 5,3-pyrrole)carbonylimino) )bis( 3-naphthalensulfonic- acid)dlsodium salt;
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino(N
methyl-5,3-pyrrole)carbonylimino))bis(2,7-naphthalendisulfonic
acid) tetrasodium salt.
8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-S,3 -pyrrole)carbonylimino) )bis(l-naphthalensulfonic acid) disodium salt; 4,4' -(carbonyl-bis(imino-N-methyl- 5,3 pyrrolecarbonyl-imino
(N-methyl- 5,3pyrrole)carbonylimino) )bis( l-naphthalensulfonic
acid) disodium salt; 8,8|-(carbonyl-bis(imino-N-methyl--s,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3-naphthalendisulfonic acid) tetrasodium salt;
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino(Nmethyl-5,3-pyrrole)carbonylimino))bis(1,7-naphthalendisulfonic acid) tetrasodium salt; 4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino(Nmethyl-5,3-pyrrole)carbonylimino))bis(1,6-naphthalendisulfonic acid) tetrasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino(Nmethyl-5,3-pyrrole)carbonylimino))bis(2,4-naphthalendisulfonic acid) tetrasodium salt; 4,4' -(arbonyl-bis(imino-N-methyl- s,3-pyrrolecarbonyl-imino(N- methyl-5,3 -pyrrole)carbonylimino) )bis(2,5 naphthalendisulfonic acid) tetrasodium salt; and
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino(Nmethyl-5,3 pyrrole)carbonylimino))bis(2,6-naphthalendisulfonic acid) tetrasodium salt.
Example 10 8-(Amino-N-methyl-5,3 pyrrolecarbonyl-imino(N-methyl-5,3-pyrrole) carbonylimino))(1,3,5-naphthalentrisulfonic acid trisodium salt) hydrochloride.
The compound 8-(nitro-N-methyl-5,3-pyrrolecarbonyl-imino(N-methyl5,3-pyrrole)carbonylimino))(1,3,5-naphthalentrisulfonic acid trisodium salt) (2.17 g = 3 mmols) was dissolved into a mixture of water (120 ml) and 1N HCl (3 ml) and reduced over a Pd catalyst (10% on carbon; mg 900) under H2 pressure (50 p.s.i.) ,,.
for 3 hours.
The catalyst was filtered and the resulting solution was concentrated in vacuum to dryness, affording 2,1 g of the title compound.
Example 11 8(Nitro-N-methyl-5,3-pyrrolecarbonyl-imino(N-methyl-5,3-pyrrole) carbonylimino))(1,3,5-naphthalenetrisulfonic acic trisodium salt)
To a solution of 8-(amino(N-methyl- 5,3 pyrrole)carbonylimino)
(1,3,5-naphthalentrisulfonic acid trisodium salt)hydrochloride (.2,43 g, 4mmols) in water ( 50 ml) and 1N NaOH(1,34 ml), sodium acetate (0,656. g, 8 mmols) was added under stirring.
The solution was cooled at 50C with an ice bath, then a solution
of (-5-nitro-N methyl-3.pyrroie) carbonyl chloride (0,754 g,
4 mmols) in dioxane (30 ml) was added dropwise in 1 hr. The
mixture was stirred 1 hr at 50C, acidified at pH 4 with 1N HCl
and evaporated under vacuum to dryness. The residue was treated
with ethyl acetate (400 ml), stirred for 1 hour and filtered,
to obtain the title compound (2,81) Example 12
8-(amino(N-methyl-5,3 -pyrrole)carbonylimino)(1,3,5-naphthalen .trisulfonic acid trisodium salt), hydrochloride.
The splution of 8-(nitro(N methyl-5,3-pyrrole)carbonylimino)
(1,3,5-naphthalentrisulfonic acid trisodium salt)(l.B03 g
3 mmols) in water (120 ml) and lNHCl (3 ml) was reduced over
a Pd catalyst (1OX on carbon g 800) under H2 pressure (50 p.s.i.)
for 4 h.
The catalyst was filtered and the resulting solution was concen
trated in vacuum to dryness, affording 1.8 g of the title
compound.
Example 13
8-(nitro(N-methyl-5,3-pyrrole) carbonylimino)(1,3,5-naphthalentrisolfonic acid trisodium salt).
To a sclution of 8-amino, 1,3,5-naphthalentrisulfonic acid trisodium salt (1,347 g 9 3 mmols) in water (45 ml), sodium.
acetate (0.492 g = 6 mM) was added under stirring. The solution was cooled at 5'C with an ice bath, then a solution of (5 nitro-
N-methyl-3-pyrrole)carbonyl chloride (0.943 = 5 mmols) in dioxane (45 r.l) was added dropwise in 1 h. The mixture was stirred 3 h at 5 C, acidified and pH 4 with iN HCl and evaporated under vacuum to dryness.
The residue was treated with ethylacetate (300 ml), stirred for 1 hour and filtered, to obtain g 1.7 of the title compound.
Example 14 7,7'-(carbcnyl-bis(imino-N-methyl--5,3-pyrrolecarbonyl~imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3-naphthalendisulfonic acid) tetrapotassium salt.
To a sclution of 7-(amino-N-methyl-5,3 -pyrrolecarbonylimino(N methyl-5.3-pyrrole)carbonylim.ino))(1,3-naphthalendlSulfonic acid dipotassium salt) hydrochloride (200 mg, 0.3 mmols) in water (23 ml) and dioxane (15 ml), potassium acetate (118 mg, 1,2 mmols) was added under stirring. A , solution of bis (trichloromethyl)carbonate (44.5 mg, 0.15 mmols) in dioxane (5 ml), was added dropwise in half hr at room temperature.
The mixture was stirred 1 hr. at room temperature.
The solvents were evaporated under vacuum, the residue was cromatographed on a silica gel column with methylene chloride:methanol:water 40:60:6 as eluent, affording 115 mg of the title compound.
The title compound was characterised as follows:
N.M.R. (DMSO): 6 p.p.m. 3.85 (3H, s); 3.88 (3H, s); 6.80 + 7.30 (4H, 4d); 7.88 (2H, m); 8.02 (1H, d); 8.20 (lH, d); 8.60 (lH, bs); 8.95 (1H, bs); 9.85 (1H, bs); 10.22 (1H, bs).
F.A.B. - M.S. M/Z 1273 [M+H]+; 1311 [M+K]+ By analogous procedure the following compounds can be obtained: 7,7'-carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino(Nmethyl-5,3 pyrrole)carbonylimino))bis(l-naphthalensulfonic acid)disodium salt; 7,7'-(carbonyl-bis (imino-N-methyl-S, 3-pyrrolecarbonyl-imino (N-methyl-5,3 pyrrole) carbonylimino) ) bis (2-naphthalensulfonic acid) disodium salt; 6,6'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3- pyrrole)carbonylimino))bis(2-naphthalensulfonic acid) disodium salt; 6,6'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1-naphthalen- sulfonic acid) disodium salt; 6,6'-(Carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(2,3-naphthalendisulfonic acid) tetrasodium salt; 6,6'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3-naphthalen- disulfonic acid) tetrasodium salt; 3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(1,5-naphthalendisulfonic acid) tetrasodium salt;
3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(1,6-naphthalen
disulfonic acid) tetrasodium salt;
3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(1,7 -naphthalen
disulfonic salt;
3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3 -pyrrole)carbonylimino) )bis(2,S -naphthalen
disulfonic acid) tetrasodium salt; 3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(2,6-naphthalendisulfonic acid) tetrasodium salt; 3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl- 5,3-pyrrole ) carbonyl imino ) )bis(2,7-naphthalen- disulfonic acid) tetrasodium salt; 7-7'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3,5-naphthalen- trisulfonic acid) hexasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,4,6-naphthalen trisifonic acid) hexasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3 -pyrrole)carbonylimino))bis(1,3,6-naphthalen- trisulfonic acid) bexasodium salt; 7,7-(carbonyl-bis(imino-N-methyl-5,3-pyrrole-carbonyl-imino (N-methyl- 5,3-pyrrole)carbonylimino))bis(2,4,6-naphthalen- trisulfonic acid) hexasodium salt;
7,7'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(2,3,5-naphthalen
trisulfonic acid) hexasodium salt; 2,2'-(carbonyl-bis(imino-N-methyl- 5,3-pyrrolecarbonyl-imino (N-methyl- 5,3-pyrrole )carbonylimino) )bis( 2-deoxy-D-glucose
6-sulfate) disodium salt;
2,2'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(2-deOxy-D-glucose- 6-phosphate) disodium salt;;
5,5'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolcarbonyl-imino (N-methyl-S,3-pyrrole)carbonylimino) )bis(8-quinolinesulfonic acid) disodium salt;
5,5'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl- 5,3-pyrrole)carbonylimino) )bis(6-quinolinesulfonic
acid) disodium salt;
8,8'-(carbonyl-bis(imino-N-methyl- 5,3-pyrrolcarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(5,7-quinoline
disulfonic acid) tetrasodium salt;
5,5'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl- S,3-pyrrole)carbonylimino) )bis(6,8-quinoline disulfonic acid) tetrasodium salt; 4,44-(carbonyl-bis(imino-N-methyl- S,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,5-naphthalendisulfonic acid); and 7,7'-thiocarbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imin@
(N-methyl-5,3-pyrrole)carbonylimino))bis;1,3 1,3 -naphthalendi- sulfonic acid),
Example 15 8,8'-crbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3,5-naphthanentrisulfonic acid).
A solution of 8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrole carbonyl-imino(rI-mehyl-5,3 .pyrrole)carbonylimino) )bis (1,1,5-naphthalentrisulfonic acid)hexasodium salt (400 mg) in water (10 ml), is chromatographed on an Amberlite 1R-120(H) column (20 ml), with water as eluent.
The solution is evaporated to dryness in vacuum, affording 0,3 g of the title compound.
Example 16
Intramuscular injection 40 mq/ml.
A injectable pharmaceutical preparation can be manufactured by dissolving 40 g of 8,8'-(carbonyl-bis(imino-N-methyl-5,3 pyrrole-carbonyl-imino(N-methyl-5,3-pyrrole)carbonylimino)) bis(1 ,3,5-naphthalentrisulfonic acid)hexasodium salt in water for injection (1000 ml) and sealing ampoules of 1-10 ml.
Claims (9)
1. 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 different, is either a group chosen from: 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 is is hydrogen or C1-C6 alkyl;
c) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to three basic graphs; 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;
or a group chosen from e) a saturated or unsaturated, carbocyclic or condensed
carbocyclic ring substituted by one to three acid groups;;
f) a saturated or unsaturated, heteromonocyclic or hetero
bicyclic ring, containing one Lc three heteroatoms chosen
from nitrogen, oxygen and sulphur, substituted by one or
more acid groups;
g) a pyranyl or furanyl sugar residue substituted by one to
three acid groups; or
h) a -CH2(CHA)@CH2A group, wherein each A group, being the
same or different, is an acid group and r is 0, l or 2;
and the pharmaceutically acceptable salts thereof.
2. A compound of formula (.), 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 either a group chosen from
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, R4 and R5 are each hydrogen or R3 and R4, together, form a -CH2-CH2-, -CH=CH or -c;I , -CH2-CH2- chain and R5 is hydrogen; c') a phenyl or naphthyl group substituted by one, two or
three basic groups chosen Independently from
in wliich s is 0,1,2,3, or 4 and each of R6and R7, independently, is hydrogen or C1-C4 alkyl, or
d') a thiazole, pyrimidine or tetrahydropyranyl ring
substituted hy one, two or three basic groups, as cefined above under c');
or a group chosen from : e') an unsaturated
carbocyclic or condensed carbocyclic ring substituted by 1 to 3 acid groups; f) a tetrahydropyranyl or tetrahydrofuranyl ring
substituted by l to 3 acid groups; or g' ) a glucosefuranosyl
residue substituted by 1 to 3 acid groups; and the pharma
ceutically acceptable salts thereof.
3. A compound selected from the group consisting of
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolearbonyl
imino(N-methyl-5,3-pyrrole)carbonylimino))-bis(N-methyl
-5,3-pyrrolecarbonylimio(3-propionamidine)) ;
4,4'-(1,3-guanidine-bis-(N-methyl-5,3-pyrrolecarbonyl imino(N-methyl-5;n-pyrrole)carbonylimino))-bisw -methyl- 5,3-pyrrolecarbonylimino(3-propionamidine)) ;
8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino
(N-methyl-5,3-pyrrole)carbonylimino))-bis(1-naphthaleneamine -N,N-dimethyl);
4,4'-(carbonyl-bis(imino-N-methyl-53-pyrrolecarbonyl
imino(N-methyl-5,3-pyrrole)carbonylimino))bis(1 naphthalen sulfonic acid);
8,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonylimino(N-methyl-5,3-pyrrole)carbonylimino))bis(1-naphthalensulfonic acid);; e,8'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl- 5,3-pyrrole)carbonylimino) )bis( 1,3-naphthalendisulfonic acid);
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3'-pyrrole)carbonylimino) )bis( 1,7-naphthalendi- sulfonic acid);
4,4'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,5-naphthalendisulfonic acid):
8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)caronylimino))bis(1,3,5-naphthalentrisulfonic acid)::
8,8'-(carbonyl-bis(imino-N-methyl-5,3 -pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3,6 -naphthalentisulfonic acid); 7,7' -(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl- 5,3 pyrrole)carbonylimino))bis(1,3naphthalendi- sulfonic acid);
6,6'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pyrrole)carbonylimino))bis(1,3-naphthalendisulfonic acid); 3,3'-(carbonyl-bis( imino-N-methyl- 5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(1,7 naphthalendi
sulfonic acid);
3,3'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(2,7 -naphthalendi
sulfonic acid);
7,7' (carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(1,3,5 -naphthalentri
sulfonic acid);;
7,7'-thiocarbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino
(N-methyl-5,3-pyrrole)carbonylimino))bis(1,3 -naphthalendi
sulfonic acid); 2,2'-(carbonyl-bis(imino-N-methyl-5,3-pyrrolecarbonyl-imino (N-methyl-5,3-pirrole)carbonylimino))bis(2-deoxy-D-glucose6-sulphate); and 2,2'(carbonyl-bis(imino-N-methyl- 5,3-pyrrolecarbonyl-imino
(N-methyl- 5,3 pyrrole) carbonylimino))bis(2-deoxy-D-glucose6-phosphate);
and the pharmaceutically acceptable salts thereof.
4. A process for the preparation of a compound of formula (I), or
a pharmaceutically acceptable salt thereof, according to clain 1,
the process comprising:
a) reacting a compound of formula (II)
wherein n and B are as definedir.claimlor 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,
wtierel n
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,
wherein
Band m are as defined in claml with a compound of formula (II),
as defined above. so as to obtain a compound of formula (1), wherein W is =NIl; and if desired, salifying a compound of formula (I) thus obtained; and/or if desired, obtaining
a free compound of formula (I) from a salt thereof.
5. A pharmaceutical composition containing a pharmaceutically
acceptable carrier and/or diluent and, as an active principle,
a compound of formula (I) according to claim 1 or apharrnaceuticaL- ly acceptable salt thereof.
6 . A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use as an angiogenesis inhibitor.
7. Use of a compound of formula (I) according to
claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the treatment of ang iogenesis.
8 . Products containing a compound of formula (I), according to claim 1, or a pharmaceutically acceptable salt thereof, and an antitumor agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.
9. A compound of formula: (XI):
or an acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9121205A GB2260134A (en) | 1991-10-04 | 1991-10-04 | Derivatives of poly-5-amino-3-carboxy-1-methyl compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9121205A GB2260134A (en) | 1991-10-04 | 1991-10-04 | Derivatives of poly-5-amino-3-carboxy-1-methyl compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9121205D0 GB9121205D0 (en) | 1991-11-20 |
| GB2260134A true GB2260134A (en) | 1993-04-07 |
Family
ID=10702499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9121205A Withdrawn GB2260134A (en) | 1991-10-04 | 1991-10-04 | Derivatives of poly-5-amino-3-carboxy-1-methyl compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2260134A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2310207A (en) * | 1996-02-15 | 1997-08-20 | Pharmacia Spa | Antiviral ureido derivatives of substituted heterocyclic compounds |
| WO1998003573A1 (en) * | 1996-07-17 | 1998-01-29 | Biomolecular Research Institute Ltd. | Angiogenic inhibitory 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1061639A (en) * | 1963-07-26 | 1967-03-15 | Farmaceutici Italia | Pyrrole derivatives |
| GB2178036A (en) * | 1985-07-16 | 1987-02-04 | Erba Farmitalia | Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation |
-
1991
- 1991-10-04 GB GB9121205A patent/GB2260134A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1061639A (en) * | 1963-07-26 | 1967-03-15 | Farmaceutici Italia | Pyrrole derivatives |
| GB2178036A (en) * | 1985-07-16 | 1987-02-04 | Erba Farmitalia | Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2310207A (en) * | 1996-02-15 | 1997-08-20 | Pharmacia Spa | Antiviral ureido derivatives of substituted heterocyclic compounds |
| WO1998003573A1 (en) * | 1996-07-17 | 1998-01-29 | Biomolecular Research Institute Ltd. | Angiogenic inhibitory compounds |
| US6426067B1 (en) | 1996-07-17 | 2002-07-30 | Biomolecular Research Institute, Ltd. | Angiogenic inhibitory 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 |
| 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 |
|---|---|
| GB9121205D0 (en) | 1991-11-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |