WO2007133112A1 - Dérivés de noscapine (et variantes), bibliothèques combinatoire et focalisée, composition pharmaceutique et procédés de fabrication (variantes) et d'utilisation - Google Patents
Dérivés de noscapine (et variantes), bibliothèques combinatoire et focalisée, composition pharmaceutique et procédés de fabrication (variantes) et d'utilisation Download PDFInfo
- Publication number
- WO2007133112A1 WO2007133112A1 PCT/RU2007/000138 RU2007000138W WO2007133112A1 WO 2007133112 A1 WO2007133112 A1 WO 2007133112A1 RU 2007000138 W RU2007000138 W RU 2007000138W WO 2007133112 A1 WO2007133112 A1 WO 2007133112A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- tetrahydro
- methoxy
- dimethoxy
- dioxolo
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 32
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical class CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 title claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 61
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 46
- 125000001424 substituent group Chemical group 0.000 claims abstract description 40
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 17
- 125000003277 amino group Chemical group 0.000 claims abstract description 15
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 13
- 150000004677 hydrates Chemical class 0.000 claims abstract description 9
- 230000003287 optical effect Effects 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001301 oxygen Chemical group 0.000 claims abstract description 6
- 238000002347 injection Methods 0.000 claims abstract description 5
- 239000007924 injection Substances 0.000 claims abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003826 tablet Substances 0.000 claims abstract description 5
- 239000002775 capsule Substances 0.000 claims abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 4
- -1 3-chlorophenylaminocarbonyl Chemical group 0.000 claims description 117
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 claims description 16
- 229960004708 noscapine Drugs 0.000 claims description 16
- 230000009471 action Effects 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 6
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 3
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 2
- 230000003217 anti-cancerogenic effect Effects 0.000 claims description 2
- 230000004663 cell proliferation Effects 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 150000002611 lead compounds Chemical class 0.000 claims 1
- 238000004806 packaging method and process Methods 0.000 claims 1
- 230000002829 reductive effect Effects 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 239000005864 Sulphur Chemical group 0.000 abstract 1
- QURQFFHJRCPURU-UHFFFAOYSA-N [1,3]dioxolo[4,5-g]isoquinoline-2-carbaldehyde Chemical compound O1C(OC=2C1=CC=1C=CN=CC1C2)C=O QURQFFHJRCPURU-UHFFFAOYSA-N 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 description 43
- 125000000753 cycloalkyl group Chemical group 0.000 description 24
- 125000003710 aryl alkyl group Chemical group 0.000 description 22
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 125000004434 sulfur atom Chemical group 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- 229940024606 amino acid Drugs 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- 150000001204 N-oxides Chemical class 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 10
- 125000003367 polycyclic group Chemical group 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000004430 oxygen atom Chemical group O* 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 125000003435 aroyl group Chemical group 0.000 description 7
- 125000004104 aryloxy group Chemical group 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000001766 physiological effect Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 125000004475 heteroaralkyl group Chemical group 0.000 description 6
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 125000003302 alkenyloxy group Chemical group 0.000 description 5
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 5
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
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- 201000010099 disease Diseases 0.000 description 5
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- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000007429 general method Methods 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
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- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 description 1
- 229940019931 silver phosphate Drugs 0.000 description 1
- 229910000161 silver phosphate Inorganic materials 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- OGNAOIGAPPSUMG-UHFFFAOYSA-N spiro[2.2]pentane Chemical compound C1CC11CC1 OGNAOIGAPPSUMG-UHFFFAOYSA-N 0.000 description 1
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- 230000000707 stereoselective effect Effects 0.000 description 1
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- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Noscapine derivatives (options), combinatorial and focused libraries, pharmaceutical composition, methods for their preparation (options) and applications
- This invention relates to new derivatives of the natural alkaloid of noscapine or (S, R) -6,7-dimethoxy-3- (5,6,7,8-tetrahydro-4-methoxy-6-methyl-l, 3-dioxol [4 , 5-g] isoxinolin-5-yl) -l (3H) -isobenzofyranone having physiological activity.
- the present invention relates to the specific physiological activity of these compounds, allowing them to be used as “molecular tools)) or active drug substances that block interprotein interactions (roteip-prototype ip) or cause programmed cell death (apoptosis), as well as to a method the synthesis of such derivatives, to focused libraries containing these substances, to pharmaceutical compositions containing these compounds in the form of active substances, and also to a method for treating cancer.
- Noskapin is an opium alkaloid, its content in the poppy Parave somniferum L. Paraveraceae reaches 11%, but noscapine is completely non-narcotic. Noskapin is approved for use as an antitussive, included in the United States Pharmacoreia (USP) (on the market since 1963), and is included as an active substance in the following drugs: Sarval, Loubekh, Narcotussip, Tussarip.
- noscapine Ye K., Ke Y., Kesha N., Shanks J., Carr J., T. R., Retros J., Joshi H. Orium alkoid pozsarip is aptitumor agate that arrests metarhas ap ipodus arorthosis ip dividipell slls. Roc. Natl. Acad. Sretei. USA 1998, 95: 1601-1606]. Due to the unusual mechanism of interaction of noscapine with tubulin (a protein that forms the cytoskeleton) [Zhou J, et.al.
- noscapine The low toxicity of noscapine is also very attractive, especially when compared with other antitumor substances [R. Lapg, et.al. The same alkoid posssarip is a louw tohisit agept with sigpifissapt aptumor effest ip melapoma. 62pd Appy Meat Sos Ipest Dertatol (Mau 9-12, Washington DC DC) 2001, Abst 568].
- the unique properties of noscapine including its specific effect on microtubular dynamics, cell cycle arrest [Update JT, Type AE, Bozer S., Group J. KR, Crumrine C, J. J., T.
- noscapine derivatives have been described, but with rare exceptions they are degradation products of one or two heterocyclic rings (for example, [Jasob A. l- (3-Phenylpropyl) -2-methyl-6,7-methylene-dioxy -8-methoxy-l, 2,3,4-tetrahoudroisoquipolip, and Rhartasolisillo active natrix derivatives. J Med Chet. 1965: 697-698]).
- noscapine for example, (thio) carbamoyl analogues of N- demethylated noscapine [Aggarwal S., et al. A Compliance Supth Canalsis THERf Arul-Substitut N- ⁇ arbamoul / N-Thiosarbamoul N réelletocipe apd Relatome ⁇ omroshids. HeIv ⁇ h ⁇ issuedht, 85: 2002; et.al. US 6,376,516 Bl 04.23.2002; US 6,673,814 B2 06/01/2004]).
- noscapine A derivatives containing a substituent in the 5-position of the isoquinoline ring are known (Table 1).
- “Aheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a cycle.
- An azaheterocycle may have one or more “cyclic substitutes”) systems.
- "Aliphatic" radical means a radical obtained by removing a hydrogen atom from a non-aromatic C-H bond.
- An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section.
- aliphatic radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, heteroaralkenyl, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated arylheterocyclyl, annelated heteroarylheterocytes clyl, annelated arylheterocyclenyl
- Alkenyl means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including a carbon-carbon double bond. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
- Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine.
- Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylbutenyl.
- Alkenyloxy means an alkenyl-O— group in which alkenyl is defined in this section. Allyloxy and 3-butenyloxy are preferred alkenyloxy groups.
- Alkenyloxyalkyl means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.
- Alkyl means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl” substituents.
- Alkyl may have one or more, same or different substituents (“alkyl substituents))), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkyl , heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylhetero
- Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl methoxycarbonylmethyl and piridilmetiloksikarbonilmetil .
- Alkyloxyalkyl means an alkyl-O-alkyl group in which the alkyl groups are independent of each other and are defined in this section. Preferred alkyloxyalkyl groups are methoxyethyl, ethoxymethyl, n-butoxymethyl, methoxypropyl and isopropyloxyethyl.
- Preferred alkyl hydroxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl tert-butyloxycarbonyl., Iso-propyloxycarbonyl, benzylcarbonyl and phenethylcarbonyl.
- Alkylthio means an alkyl-S group in which an alkyl group is defined in this section.
- Alkoxy means an alkyl-O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
- Preferred alkoxycarbonylalkyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl and methoxycarbonylethyl and ethoxycarbonylethyl.
- Amino group means R ⁇ R k + ⁇ N is a group substituted or unsubstituted by “a substituent of the amino group”, Rk a and Rk + D are defined in this section, for example, amino (H 2 N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamino or phenethylamino.
- Amino acid means a natural amino acid or a non-natural amino acid, the meaning of which is defined in this section. Preferred amino acids are amino acids containing an ⁇ or ⁇ amino group.
- Examples of natural amino acids are ⁇ -amino acids, they can be alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, series, threonine and cysteine.
- Annelated cycle (condensed cycle) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycyclic with which it is “annealed” have at least two common atoms.
- Annelated apylheterocycloalkenyl means annelated aryl and heterocycloalkenyl, the meaning of which is defined in this section. Annelated arylheterocycloalkenyl can bind through any possible atom of the ring system.
- the prefix "aza”, “okca” or “tia” before “heterocycloalkenyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Annelated arylheterocycloalkenyl may have one or more “substituent ring systems)), which may be the same or different.
- the nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
- Representatives of annelated arylheterocycloalkenyls are indolinyl, ⁇ -2-oxoquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroxinolinyl, and the like.
- Annelated apylheterocycloalkyl means annelated aryl and heterocycloalkyl, the meaning of which is defined in this section. Annelated arylheterocycloalkyl can bind through any possible atom of the cyclic system.
- the prefix "aza”, “okca” or “tia” before “heterocycloalkyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Annelated arylheterocycloalkyl may have one or more “substituent ring systems)), which may be the same or different.
- the nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
- Representatives of annelated arylheterocycloalkyls are indolyl, 1,2,3,4-tetrahydroisoxinoline, 1,3-benzodiocol, and the like.
- “Annelated apylcycloalkenyl” means annelated aryl and cycloalkenyl, the meanings of which are defined in this section. Annelated arylcycloalkenyl can bind through any possible cyclic atom system.
- Annelated arylcycloalkenyl may have one or more “cyclic system substitutes,” which may be the same or different.
- Representatives of annelated arylcycloalkenyls are 1,2-dihydro-naphthalene, indene, etc.
- Annelated apylcycloalkyl means annelated aryl and cycloalkyl, the meanings of which are defined in this section. Annelated arylcycloalkyl can bind through any possible atom of the cyclic system. Annelated arylcycloalkyl may have one or more “cyclic system substitutes,” which may be the same or different. Representatives of annelated arylcycloalkyls are indanine, 1,2,3., 4-tetrahydronaphthalene, 5,6,7,8-tetrahydronaphth-l-yl, etc.
- Annelated heteroapylcycloalkenyl means annelated heteroaryl and cycloalkenyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkenyl can bind through any possible atom of the cyclic system.
- the prefix “aza”, “okca” or “tia” before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Annelated heteroarylcycloalkenyl may have one or more “ring system substituents)), which may be the same or different.
- the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
- annelated heteroarylcycloalkenyls are 5,6-dihydroquinolinyl, 5,6-dihydroisoxinolinyl, 4,5-dihydro-lH-benimidazolyl, and the like.
- “Annelated heteroapylcycloalkyl” means annelated heteroaryl and cycloalkyl, the meanings of which are defined in this section. Annelated heteroarylcycloalkyl can bind through any possible atom of the cyclic system.
- the prefix "aza", “okca” or “tia" before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Annelated heteroarylcycloalkyl may have one or more “ring system substituents)), which may be the same or different.
- the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
- Representatives of annelated heteroarylcycloalkyls are 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoxinolinyl, 4,5,6,7-tetrahydro-IH-benzimidazolyl, and the like.
- Annelated heteroapylheterocycle means annelated heteroaryl and heterocyclenyl, the meanings of which are defined in this section. Annelated heteroaryl heterocyclenyl may bind through any possible atom of the cyclic system.
- the prefix “aza”, “okca” or “tia” before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Annelated heteroarylheterocyclenyl may have one or more “cyclic system substitutes” that may be the same or different.
- the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
- the nitrogen and sulfur atoms in the heterocyclenyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
- Representatives of annelated heteroarylheterocyclenyls are l, 2-dihydro [2,7] naphthyridinyl, 7,8-dihydro [l, 7] naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, etc.
- “Annelated heteroapylheterocyclyl” means annelated heteroaryl and heterocyclyl, the meanings of which are defined in this section.
- Annelated heteroaryl heterocyclyl can bind through any possible atom of the ring system.
- the prefix “aza”, “okca” or “tia” before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Annelated heteroarylheterocyclyl may have one or more “cyclic system substitutes,” which may be the same or different.
- the nitrogen atom in the heteroaryl moiety can be oxidized to N-oxide.
- the nitrogen and sulfur atoms in the heterocyclyl moiety can be oxidized to N-oxide, S-oxide or S-dioxide.
- annelated heteroaryl heterocyclyls are 2,3-dihydro-III-pyrpolo [3,4-b] quinolin-2-yl, 2,3-dihydro-III-pyrpolo [3,4-b] indol-2-yl, l, 2,3,4-tetrahydro [l, 5] naphthyridinyl and the like.
- “Aralkenyl” means an aryl-alkenyl group in which the meanings of aryl and alkenyl are defined in this section. For example, 2-phenethyl is an aralkenyl group.
- Alkyl means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are benzyl, 2,2-diphenylethyl or phenethyl. “Aralkylamino” means an aryl-alkyl-NH— group in which the meanings of aryl and alkyl are defined in this section.
- Alkylcylfinyl means an aralkyl-SO— group in which the meaning of aralkyl is defined in this section.
- “Aralkylcylphonyl” means aralkyl-SO 2 —the group in which the meaning of aralkyl is defined in this section.
- “Aralkylthio” means an aralkyl-S- group in which the meaning of aralkyl is defined in this section.
- Alkoxy means an aralkyl-O— group in which the meaning of aralkyl is defined in this section. For example, benzyloxy or 1- or 2-naphthylenmethoxy are aralkyl groups.
- Alkoxyalkyl means an aralkyl-O-alkyl group in which the meanings of aralkyl and alkyl are defined in this section.
- An example of an aralkyl-O-alkyl group is benzyloxyethyl.
- An example of an aralkoxycarbonyl group is benzyloxycarbonyl.
- An example of an aralkoxycarbonylalkyl group is benzyloxycarbonylmethyl or benzyloxycarbonylethyl.
- Aryl means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
- Aryl may contain one or more “substituents of the cyclic system)), which may be the same or different.
- Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl.
- Aryl can be annelated with a non-aromatic ring system or heterocycle.
- Aminyl means an aryl-SO— group in which the meaning of aryl is defined in this section.
- Amylcylphone means apyl-SO 2 —the group in which the meaning of aryl is defined in this section.
- Apilthio means an aryl-S- group in which the meaning of aryl is defined in this section. Representative arylthio groups are phenylthio and 2-naphthylthio. “Apoylamino” means an aroyl-NH group in which the meaning of aroyl is defined in this section.
- “Aromatic” radical means a radical obtained by removing a hydrogen atom from an aromatic C — H bond.
- the “aromatic” radical includes the aryl and heteroaryl rings defined in this section. Aryl and heteroaryl rings may additionally contain substituents — aliphatic or aromatic radicals defined in this section.
- Aromatic radicals include aryl, annelated cycloalkenylaryl, annelated cycloalkylaryl, annelated heterocyclylaryl, annelated heterocyclylaryl, heteroaryl, annelated cycloalkylheteroaryl, annelated cycloalkenylheteroaryl heteroeryl heteroaryl.
- “Aromatic cycle” means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system including, according to the Hückel rule, (4n + 2) ⁇ -electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like.
- hetero matric cycles In the case of “hetero matric cycles”, ⁇ electrons and p electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like.
- the aromatic cycle may have one or more “substitutes for the cyclic)) system and can be annelated with a non-aromatic cycle, heteroaromatic or heterocyclic system.
- acylamino means an acyl-NH— group in which the meaning of acyl is defined in this section.
- Bifunctional reagent means a chemical compound having two reaction centers participating simultaneously or sequentially in the reactions.
- bifunctional reagents are reagents containing a carboxyl group and an aldehyde or ketone group, for example, 2- formylbenzoic acid, 2- (2-oxo-ethylcarbamoyl) -benzoic acid, 2- (3-formylthiophen-2-yl) -benzoic acid or 2- (2-formylphenyl) -thiophene-3-boan.
- 1,2-vinyl vinyl radical means a —CH ⁇ CH— group which contains one or more identical or different alkyl substituents, the meaning of which is defined in this section.
- Halogen means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred.
- Hetero-linked loop means that a loop that attaches (annelates or condenses) to another loop or polycycle contains at least one heteroatom.
- Heteroapalkenyl means a heteroaryl alkenyl group in which heteroaryl and alkenyl are defined in this section.
- heteroarylalkenyl includes a lower alkenyl group.
- Representatives of heteroarylalkenyls are A-pyridylvinyl, thienylethenyl, imidazolylethenyl, pyrazinylethenyl and the like.
- Heteroapalkyl means a heteroaryl-alkyl group in which heteroaryl and alkyl are defined in this section.
- heteroarylalkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.
- “Heteroapalkyloxy” means a heteroarylalkyl-O— group in which heteroarylalkyl is defined in this section.
- Preferred heteroarylalkyloxy groups are 4-pyridylmethyloxy, 2-thienylmethyloxy and the like.
- Representative heteroaroyls are nicotinoyl, thienoyl, pyrazoloyl, etc.
- Heteroapyl means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are substituted with heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen.
- the prefix “aza”, “okca” or “tia” before “heteroapyl” means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- the nitrogen atom in the heteroaryl may be oxidized to N-oxide.
- a vegetarian can have one or more “cyclic system substitutes,” which can be the same or different.
- heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridoxyninyl phthalazinyl, imidazo [l, 2-a] pyridinyl, imidazo [2, lb] thiazolyl, benzofurazanil, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridinopyridinyl, 2,4-thiazinyl, thienopyrrolyl, furopyrrolyl, etc. “Heteroapylcylphonyl
- Heterocycle means a non-aromatic monocyclic or polycyclic system comprising from 3 to 13 carbon atoms, preferably from 5 to 13 carbon atoms, in which one or more carbon atoms are replaced by a hetero atom such as nitrogen, oxygen, sulfur and which contains at least , one carbon-carbon double bond or carbon-nitrogen double bond.
- aza, "okca” or “thia” before heterocyclenyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Heterocyclenyl may have one or more “cyclic system substitutes,” which may be the same or different.
- heterocyclenyl can be oxidized to N-oxide, S-oxide or S-dioxide.
- Representative heterocyclenyls are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2-pyrpolinyl, 3-pyrpolinyl, 2-imidazolyl, 2-pyrazolinyl, dihydrofuranyl, dihydrothiophenyl and the like.
- Heterocyclyl means a non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur.
- a heteroatom such as nitrogen, oxygen, sulfur.
- the prefix "aza”, “okca” or “thia” before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively.
- Heterocyclyl may have one or more “cyclic system substitutes,” which may be the same or different.
- the nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide.
- heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.
- Heterocyclyloxy means a heterocyclyl-O— group in which heterocyclyl is defined in this section.
- “Hydrate” means a solvate in which water is a molecule or molecules of a solvent.
- Hydroalkyl means a HO-alkyl group in which alkyl is defined in this section.
- Substituent means a chemical radical that attaches to the scaffold
- Alkyl substituent means a substituent attached to alkyl, alkenyl, the meaning of which is defined in this section.
- Alkyl substituent is hydrogen, alkyl, halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkilsulfonilgeteroaralkiloksi, annelated heteroarylcycloalkenyl , annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annel
- Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentil, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl and methoxycarbonylmethyl piridilmetiloksikarbonilmetil .
- the meaning of the alkyl substituents is defined in this section.
- Amino group substituent "means a substituent attached to an amino group.
- the amino substituent is hydrogen, alkyl, cycloalkyl, aryl, geheroaril, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated aryl
- Carbamoyl substituent means a substituent attached to a carbamoyl group, the meaning of which is defined in this section.
- the meaning of “carbamoyl substitutes” is defined in this section.
- Nucleophilic substituent means a chemical radical that is attached to scaffold by reaction with a nucleophilic reagent, for example, selected from the group of primary or secondary amines, alcohols, phenols, mercaptans and thiophenols.
- “Substituent cyclic system)) means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, geterotsiklilalkiloksialkil, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfinyl, arylsulfinyl, geterotsiklilsulfinil, al
- Electrophilic substituent means a chemical radical that attaches to scaffold as a result of reaction with an electrophilic reagent, for example, selected from the group of organic acids or their derivatives (anhydrides, imidazolides, halides), ethers of organic sulfonic acids or organic sulfonyl chlorides, organic halides, organic isocyanides organic isothiocyanates.
- Amino amino group means an R k a R k + 1 a N group in which R k a and R k + i a are amino substituents as defined in this section.
- Substituted carboxyl means a C (O) OR group.
- the substituted carboxyl has a substituent R, including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
- Substituted mercapto group means an SR, S (O) R or S (02) R group in which the substituent R is alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meanings of which are defined in this section.
- “Protection group” means a chemical radical that attaches to a scaffold or intermediate to synthesize the amino group in multifunctional compounds, including but not limited to: amide a substituent such as formyl, optionally substituted acetyl (for example trichloroacetyl, trifluoroacetyl, 3-phenylpropionyl, etc.), optionally substituted benzoyl, etc .; a carbamate substituent, such as optionally substituted C 1 -C 7 alkyloxycarbonyl, for example, methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), etc .; optionally substituted C 1 -C 7 alkyl substituent, for example, tert-butyl, benzyl, 2,4-dimethixibenzyl, 9-phenylphyloinyl and others; sulf
- Protective groups are described in the book: Protective groups and organic supervisor, Third Edite Grepe, TW ap Wuts, PGM 1999, p. 494-653. Publishing house Johan Willeu & Sops, Ips, New York, Shikhester, Wehim, Vrisbape, Toropto, S ⁇ pgarore.
- Protected primary or secondary amine “means a group of the formula Rk a Rk + i a N-, in which R k a represents a protective group PG and R k + i a represents hydrogen," a substituent of the amino group ", the meaning of which is defined in this section e.g.
- “Inert substituent (or” not interfering, “Nopperfer substitupt”) means a low or non-reactive radical, including but not limited to C 1 - C 7 alkyl, C 2 - C 7 alkenyl, C 2 - C 7 alkynyl, C 1 - C 7 alkoxy, C 7 - C 12 aralkyl substituted with inert substituents of aralkyl, C 7 - C 12 heterocyclylalkyl, substituted with inert substituents of heterocyclylalkyl, C 7 - C 12 alkaryl, C 3 - C 10 cycloalkyl, C 3 - C 10 cycloalkenyl, phenyl, substituted phenyl, toluyl, xylene, biphenyl, C 2 - C 12 alkoxyalkyl, C 2 - C 10 alkylsulfinyl, C 2 - C 10 alkylsulfonyl, (CH 2
- Carbamoyl may have one or more identical or different "carbamoyl substituents" R k a and R réelle + ⁇ including hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
- Carbamoylheterocycle means an azaheterocycle containing as
- Kembocycle means a mono- or polycyclic system consisting only of carbon atoms. Carbocycles can be either aromatic or alicyclic.
- Alicyclic polycycles may have one or more common atoms.
- spiro-carbocycles are formed (for example, spiro [2.2] pentane), in the case of two
- “Combinative library” means a collection of compounds obtained by parallel synthesis designed to search for a hit or leader compound, as well as to optimize the physiological activity of a hit or leader, each library compound corresponding to a common scaffold, and the library is a collection of related homologues or analogues.
- “Methylene radical” means —CH 2 — a group that contains one or two identical or different “alkyl substituents”, the meanings of which are defined in this section.
- a non-aromatic cycle may have one or more “substituent cyclic)) systems and may be annelated with aromatic, heteroaromatic or heterocyclic systems. Examples of non-aromatic rings are cyclohexane or piperidine, examples of a partially saturated ring are cyclohexene or piperidine.
- Non-natural amino acid means an amino acid of a non-nucleic nature.
- unnatural amino acids are the D-isomers of natural ⁇ -amino acids, aminobutyric acid, 2-aminobutyric acid, ⁇ -aminobutyric acid, N- ⁇ -alkylated amino acids, 2,2-dialkyl- ⁇ -amino acids, 1-amino-cycloalkyl carboxylic acids, ⁇ -alanine, 2-alkyl- ⁇ -alanines, 2-cycloalkyl- ⁇ -alanines, 2-apyl- ⁇ -alanines, 2-heteroapyl- ⁇ -alanines, 2-heterocyclyl- ⁇ -alanines and (1-amino-cycloalkyl ) -cyclic acids in which the meanings of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are defined in this section.
- Optional aromatic cycle means a cycle that can be either an aromatic cycle or a non-aromatic cycle, the meanings of which are defined in this section.
- Optionally substituted radical means a radical without substituents or containing one or more substituents.
- Optionally annelated (condensed) cycle means a condensed, non-condensed cycle, the meanings of which are defined in this section.
- “Lower alkyl” means a linear or branched alkyl with 1-4 carbon atoms.
- Parallel synthesis means a method for conducting chemical synthesis of a combinatorial library of individual compounds.
- 1,3-Propylene radical means —CH 2 —CH 2 —CH 2 — a group that contains one or more identical or different “alkyl substituents”, the meanings of which are defined in this section.
- Leader means a compound with outstanding (maximum) physiological activity associated with a specific biological target related to a specific (or several) pathology or disease.
- Compound-hit (“hit”) means a compound that exhibits the desired physiological activity during the initial screening process.
- “Sweet group” means R k a R k + i a NSO 2 is a group substituted or unsubstituted by “a substituent of the amino group” R k a and R k + i a , the meanings of which are defined in this section.
- Cylfonyl means R-SO 2 - a group in which R is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, annelated heteroarylcycloalkenyl, annelated heteroaryl heterocyclylalkenyl, annelated heteroaryl heterocyclylalkylalkyl the meaning of which is defined in this section.
- Tempolate means the general structural formula of a group of compounds or compounds included in the “combinational library)).
- Thiocarbamoyl may have one or more identical or different “amino group substitutes” R k a and R k + i a , the meaning of which is defined in this section, for example, including alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the meaning of which is defined in this section.
- Cycloalkyl means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “substituents of the cyclic system)), which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Cycloalkyl can be annelated with an aromatic ring or heterocycle. Preferred “substituents of the cyclic system)) are alkyl, aralkoxy, hydroxy or R k a R k + i a N, the meaning of which is defined in this section.
- Representatives of cycloalkylcarbonyl groups are cyclopropylcarbonyl or cyclohexylcarbonyl.
- “Cycloalkoxy” means a cycloalkyl-O— group in which the meaning of cycloalkyl is defined in this section.
- “Pharmaceutical Composition” means a composition comprising a compound of formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceptive means, means deliveries such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents you, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.
- suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like.
- the composition may also include isotonic agents, for example, sugars, sodium chloride and the like.
- the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin.
- suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
- excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
- grinders and distributors are starch, alginic acid and its salts, silicates.
- lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
- the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers.
- Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.
- “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention.
- salts can be prepared in situ during the synthesis, isolation or purification of compounds or prepared specially.
- base salts can be prepared specifically based on the purified free base of the claimed compound and a suitable organic or inorganic acid.
- salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like.
- Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized.
- Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
- Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
- amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
- amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
- tetraalkylammonium hydroxides for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation.
- amino acids the main amino acids can be used - lysine, ornithine and arginine.
- “Focussed library” means a combinatorial library or a collection of several combinatorial libraries, or a collection of libraries and substances specially organized in order to increase the likelihood of finding hits and leaders or to increase the efficiency of their optimization.
- the design of focused libraries is associated with a directed search for effectors (inhibitors, activators, agonists, antagonists, etc.) of specific biological targets (enzymes, receptors, ion channels, etc.).
- “Fragment” means the structural formula of a part of a molecule characteristic of a group of compounds, or the molecular framework characteristic of a group of compounds or compounds included in a “combinational library)).
- 1,2-Ethyl radical means —CH 2 —CH 2 — a group that contains one or more of the same or different “alkyl substituents”, the meanings of which are defined in this section.
- the aim of the present invention are new azaheterocycles, a method for their preparation and use.
- R is an amino substituent selected from alkyl
- R is an amino substituent selected from alkyl
- R represents a cyclic system substituent selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted and optionally fused heteroaryl
- Ar represents aryl or heteroaryl.
- more preferred compounds are also derivatives of (R, S) -nocapine of the general formula 1.2:
- R 3 and R 4 independently from one another are the same or different substituents of the amino group selected from hydrogen, alkyl, aryl, or R 3 and R 4 together with the nitrogen atom to which they are bonded, are shorted through R 3 and R 4 azaheterocycle.
- more preferred compounds are also derivatives of (R, S) -nocapine of the general formula 1.3:
- R 3 and R 4 have the meanings indicated for compounds of General formula 1.2.
- the most preferred compounds of general formula 1 are: 3- (9-iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo- [4,5-g] isoxinolin-5- il) -6,7-dimethoxy-3H-isobenzofuran-1-one 1 (1), 3 ⁇ (4-methoxy-6-methyl-9-chloromethyl-5,6,7,8-tetrahydro [l, 3] -dio-colo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one 1 (2), 5- (4,5-dimethoxy-3-oxo-l, 3 -dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-
- the most preferred compounds of general formula 1.1 are: 3- (9-phenyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxolo- [4,5-g] isoxinoline-5- il) -b, 7-dimethoxy-3H-isobenzofyran-1-one 1.1 (1), 3- (9-p-tolyl-4-methoxy-6-methyl-5,6,7,8- tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one 1.1 (2), 3- [9- (4-methoxyphenyl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol- [4,5-g] isoxinolin-5-yl] -6,7-dimethoxy-3H-isobenzofyran- l-OH
- the most preferred compounds of general formula 1.2 are: 3- (9-benzylaminomethyl-4-methoxy-6-methyl-5,6,7,8-tetra-hydro [l, 3] dioxol [4,5-g] isoxinolin-5 -yl) -6,7-dimethoxy-3H-isobenzofyran-l-one 1.2 (1), 3- (9-diethylaminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one 1.2 (2), 3- (9-N-pyrpolidinomethyl-4-methoxy- 6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-l-one
- the most preferred compounds of general formula 1.3 are: 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8- tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-9-sulfonylamide 1.3 (1), 6,7-dimethoxy-3- [4-methoxy-6-methyl-9- (pyrpolidin-l-cylfo -nyl) -5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-5-yl] -ZH-isobenzofyran-l-one 1.3 (2), 6.7- dimethoxy-3- [4-methoxy-6-methyl-9- (piperidin-l-sulfonyl) -5,6,7,8-tetrahydro- [l, 3] dioxol [4,5
- the aim of this invention is a method for producing compounds of General formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates. According to the present invention, methods have been developed for the preparation of derivatives of (R, S) -nocapine, which allow preserving the optical activity inherent in the starting alkaloid.
- a method for producing 3- (9-iodine-4-methoxy-b-methyl-5,6 5 7,8-tetrahydro [l, 3] dio-colo- [4,5-g] isoxinolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (1), consisting in the action of ICl on (R, S) -scapine NSC in acetic acid according to the following scheme:
- a method for producing 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -dioxol [4,5-g] isoxinolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (2), which consists in the action of thionyl chloride on 3- (9-hydroxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [ l, 3] -dio-colo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one A-04 according to the following scheme:
- a method for producing 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxynolin-9-carbaldehyde 1 (3), which consists in the action of hexamethylenetetramine 2 on 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8- tetrahydro [l, 3] - dioxol [4,5-g] isoxinolin-5-yl) -b, 7-dimethoxy-3H-isobenzofyran-l-one 1 (2) in an organic solvent medium according to the following scheme:
- a method for producing 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxinolin-9-carbonitrile 1 (4), which consists in the action of copper (I) cyanide on 3- (9-bromo-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-l-one A-Ol or 9-iodine-4-methoxy-6-methyl- 5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one 1
- a method for producing 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5, b, 7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxynolin-9-carboxylic acid 1 (5) by hydrolysis of 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy 6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxole [4,5-g] isoxinolin-9-carbonitride 1 (4) according to the following scheme:
- a method for producing 3- (9-methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -dio-colo [4,5-g] isoxynolin-5-yl) is developed -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (6) by the interaction of 3- (9-chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -di -oxo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one 1 (2) with methanol in the presence of a base according to the following scheme:
- a method for producing 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] [4,5-g] isoxynolin-9-sulfonyl chloride 1 (7), consisting in the action of chlorosulfonic acid on (R, S) -scapine NSC according to the following scheme:
- a method for producing derivatives of (R 3 S) - noscapine of general formula 1.1 which consists in the interaction of 3- (9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-one A-Ol or its iodide analog 1 (1) in the presence of a palladium catalyst with an aryl- or heteroaryl boron derivatives of the general formula 3 according to the following scheme:
- Cross-coupling is carried out in a polar aprotic solvent (dimethylformamide, N-methylpyrrolidone, dimethoxyethane or the like), in the presence of 1-5 equivalents of an inorganic base (carbonates, fluorides, bicarbonates or fully substituted alkali and alkaline earth metal phosphates, for example, cesium carbonate, potassium fluoride as well as silver phosphate) and 5-25 mol% of the catalyst, which is used as palladium chloride or acetate, as well as their complexes with organophosphorus ligands, such as triphenylphosphine.
- the reaction is carried out by heating at a temperature of 100-170 0 C, in the conditions of microwave irradiation or without it.
- a stereospecific method for the synthesis of noscapine derivatives of the general formula 1.1 characterized in that the cross-combination of A-01 and (get) acylboric acids is carried out in polar aprotic solvents (for example, dimethoxyethane) in the presence of 3-4 equivalents of cesium carbonate and 10-20 mol. % complex of palladium chloride with triphenylphosphine at 130-150 0 C under the influence of microwave irradiation.
- polar aprotic solvents for example, dimethoxyethane
- the developed method for the preparation of (R, S) -nocapine derivatives of the general formula 1.2 consists in reductive amination of 5- (4,5-dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6 -methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-9-carbaldehyde 1 (3) amines of general formula 4 in an organic solvent medium according to the following scheme:
- the developed method for producing derivatives of (R, S) -nocapine of the general formula 1.3 consists in the interaction of 5- (4,5-dimethoxy-3-oxo-1, 3-dihydroisobenzofyran-1-yl) -4-methoxy-6- methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-9-sulfonyl chloride 1 (7) with amines of the general formula 4 according to the following scheme:
- the compounds of general formula 1 of the present invention can form hydrates or pharmaceutically acceptable salts.
- Inorganic acids and organic acids for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzene sulfonic acid, can be used. , paratoluenesulfonic acid.
- the compounds of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates can be used as an active ingredient for the treatment and prevention of influenza and acute viral respiratory diseases, in addition, this invention also provides a method for the treatment and prevention of these diseases, including the introduction of sick or susceptible to these diseases patients chemical compounds of the present invention in effective therapist ble doses.
- the aim of the present invention is a new combinatorial library for determining leader compounds.
- the aim of the present invention is a new focused library for determining leader compounds.
- the aim of the present invention is a new pharmaceutical composition having anticarcinogenic activity.
- compositions containing, as an active ingredient, the compounds of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates, as well as pharmaceutically acceptable excipients.
- pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field.
- the compounds of general formula 1 of the present invention can be used in combination with other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.
- compositions of the present invention can be mixed for the manufacture of various forms, and they may include traditional pharmaceutical carriers, for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions) ; injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).
- traditional pharmaceutical carriers for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions) ; injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).
- the carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, are used in oral forms colorless agents, flavoring agents; antiseptic agents, solubilizers, stabilizers are used in injection forms. In local forms, bases, diluents, lubricants, antiseptic agents are used. Pharmaceutical preparations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically). If any medicinal substance is not stable under the conditions of the stomach, it can be used to make tablets coated with a film of a substance soluble in the stomach or intestines.
- the clinical dosage of the compounds of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates in patients may be adjusted depending on the therapeutic the effectiveness and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, as well as depending on the age, gender and stage of the patient’s disease.
- the daily dose in adults is usually 10 ⁇ 500 mg, preferably 50 ⁇ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention as dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 10 ⁇ 500 mg of the compound of general formula 1, preferably 50 ⁇ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).
- the aim of the present invention is a method of treating and preventing the development of various diseases of warm-blooded animals and people associated with tumor growth, in particular various types of human cancers.
- This goal is achieved by administering to a warm-blooded animal or human a pharmaceutical composition containing, as an active ingredient, compounds of the general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and / or hydrates, as well as pharmaceutically acceptable excipients.
- the aim of the present invention are antimitotic compounds and substances for experimental (ip vivo, ip vitro) studies of processes that stop cell division, used as “pharmaceutical tools)).
- Example 1 3- (9-Bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one A-Ol.
- NSC N-(2-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one A-Ol.
- reaction mixture was poured onto 60 ml of a saturated ammonia solution cooled to 0 ° C.
- the colorless precipitate formed is filtered off, washed thoroughly with water, dried, and 63% A-Ol is obtained.
- Example 2 3- (9-Iodo-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] Dioxol- [4,5-g] isoxinolin-5-yl) -6, 7-dimethoxy-3H-isobenzofyran-l-one 1 (1).
- a solution of 206 mg (0.5 mmol) of NSC in 4 ml of AcOH was mixed with 100 mg (0.6 mmol) of ICl and stirred for 3 hours at 50 ° C (reaction control using LC-MS). The reaction mass is neutralized with ammonia while cooling with ice. The precipitate is filtered off, washed with water and dried. 246 mg (71%) 1 (1) is obtained.
- Example 3 3- (9-Chloromethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -Di-oxo [4,5-g] isoxinolin-5-yl) - 6,7-dimethoxy-3H-isobenzofyran-l-one hydrochloride 1 (2).
- a solution of 0.45 g (0.27 ml, 3.75 mmol) of SOCl 2 in 3 ml of dichloromethane was added dropwise to a solution of 1.11 g (2.5 mmol) of 5-HOCH 2 -NSC A-04 in 10 ml of dichloromethane, maintaining the temperature of the reaction mixture in the range of 0-3 C.
- Example 4 5- (4,5-Dimethoxy-3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxol [4,5-g] isoxinolin-9-carbaldehyde 1 (3).
- a solution of 200 mg (0.4 mmol) of hydrochloride 1 (2) in 2 ml of water is mixed with 0.6 ml of IN NaOH.
- the resulting emulsion was extracted with chloroform, the extract was dried with anhydrous Na 2 SO 4 , concentrated to 2 ml and boiled with 70 mg (0.5 mmol) of hexamethylenetetramine.
- Example 5 The General method of obtaining 5- (4,5-dimethoxy ⁇ 3-oxo-l, 3-dihydroisobenzofyran-l-yl) -4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l , 3] dioxol [4,5-g] isoxinolin-9-carbonitrile 1 (4).
- reaction mass is cooled to 4 ° C and 15 ml of ammonia and 15 ml are added with stirring. chloroform.
- the organic layer was separated, washed with water, dried over Na 2 SO 4 , filtered, the resulting solution was stirred for 15 minutes with activated carbon, filtered and concentrated. The precipitate was filtered off and recrystallized from isopropanol.
- Example 6 3- (9-Methoxymethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] -Di-oxo [4,5-g] isoxinolin-5-yl) - 6,7-dimethoxy-3H-isobenzofyran-l-one 1 (5).
- 0.5 ml of diisopropylethylamine is added to a suspension of 100 mg (0.2 mmol) 1 (2) in 3 ml of MeOH, the mixture is boiled until the initial hydrochloride is completely dissolved, cooled, treated with water, the precipitated oil is extracted with EtOAc, the organic layer is dried over Na 2 SO 4 , and the solvent is evaporated.
- Example 7 General method for producing 3- (9-apyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro [l, 3] dioxol- [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzofyran-1-ones of the general formula 1.1.
- Activated carbon is added to the combined aqueous solution, brought to a boil, filtered hot through celite, the filtrate is cooled and treated with an excess of aqueous solution NH 3 .
- the precipitate after keeping the mixture in the refrigerator for 2-3 hours, is filtered off, washed with plenty of water, and 160 mg of a colorless product 1.1 are obtained.
- Example 7 General method for producing 3- (9-aminomethyl-4-methoxy-6-methyl-5,6,7,8-tetrahydro- [l, 3] dioxolo [4,5-g] isoxinolin-5-yl) -6,7-dimethoxy-3H-isobenzo-fyran-1-ones 1.2.
- Example 8 General method for producing 6,7-Dimethoxy-3- [4-methoxy-6-methyl-9- (sylphamoyl) -5,6,7,8-tetrahydro- [l, 3] dioxol [4,5- g] isoxinolin-5-yl] -CH - isobenzofyran-1-ones 1.3.
- Example 9 Testing the anticancer activity of compounds of the general formula 1.
- a focused library of noscapines of the general formula 1 was tested for their ability to suppress cell growth in four tumor lines: DLD-I - colorectal adenocarcinoma; DU-145 - metastatic prostate cancer; T-47D - metastatic breast cancer and Jurkat - T leukemia.
- cell cultures were maintained in a standard nutrient medium containing specified concentrations of the studied compounds. The substances were introduced into the medium in the form of solutions in DMSO.
- Profile proliferation of tumor cells was measured using Alamar Blue dye, which allows the number of living cells to be determined photometrically.
- the invention can be used in medicine, veterinary medicine, biochemistry.
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Abstract
L'invention se rapporte à de nouveaux dérivés substitués de noscapine de formule générale (1) ou à leurs racémates ou isomères optiques ou à leurs sels pharmaceutiquement acceptables et / ou leurs hydrates présentant une activité antitumorale, à la composition pharmaceutique sous la forme de comprimés, de capsules ou d'injections, conditionnés dans un emballage pharmaceutiquement acceptable, ainsi qu'à des procédés de fabrication et à un procédé de suppression de la prolifération qui les mettent en oeuvre. Dans la formule générale (1), R1 est un substitutif de groupe aminé sélectionné parmi un alkyl éventuellement substitué, les substitutifs étant sélectionnés dans un groupe aminé éventuellement substitué, ou un azahétérocycle contenant éventuellement en tant qu'hétéroatome supplémentaire O, S ou N et relié par un atome d'azote au groupe alkylé, éventuellement un aryle substitué, un hétéroaryle ééventuellement substitué et éventuellement condensé contenant un hétéroatome sélectionné parmi l'azote, le soufre et l'oxygène, et d'un sulfamoyle éventuellement substitué. En plus, l'invention concerne 3-(9-iodo-4-métoxy-6-méthyl-5,6,7,8-tétrahydro[1,3]dioxolo-[4,5-g]isoquinoline-5-il)-6,7-dimétoxy-3H- isobenzofuran-1, 3-(9-chlorométhyl-4-métoxy-6-méthyl-5,6,7,8-tétrahydro [1,3]dioxolo-[4,5-g] isoquinoline-5-il)-6,7-dimétoxy-3H-isobenzofuran-1, 5-(4,5-dimétoxy-3-oxo- 1,3-dihydroisonenzofuran-1-il) -4-métoxy-6-méthyl-5,6,7,8-tétrahydro [1,3]dioxolo-[4,5-g] isoquinoline-carbaldéhyde (ou -9-carbonitril, ou -9-sulphonylchlorure, ou acide -9-carboxylique et 3-(9-métoxyméthyl-métoxy-6-méthyl-5,6,7,8-tétrahydro[1,3]dioxolo-[4,5-g]isoquinoline-5-il)-6,7-dimétoxy-3H- isobenzofuran-1 et leurs procédés de fabrication. L'invention porte aussi sur des bibliothèques combinatoire et focalisée.
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RU2006116302 | 2006-05-12 | ||
RU2006116302/04A RU2304584C1 (ru) | 2006-05-12 | 2006-05-12 | Производные носкапина (варианты), комбинаторная и фокусированная библиотеки, фармацевтическая композиция, способы их получения (варианты) и применения |
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WO2007133112A1 true WO2007133112A1 (fr) | 2007-11-22 |
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PCT/RU2007/000138 WO2007133112A1 (fr) | 2006-05-12 | 2007-03-21 | Dérivés de noscapine (et variantes), bibliothèques combinatoire et focalisée, composition pharmaceutique et procédés de fabrication (variantes) et d'utilisation |
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WO (1) | WO2007133112A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010028259A2 (fr) * | 2008-09-05 | 2010-03-11 | Emory University | 9-aminonoscapine et son utilisation dans le traitement des cancers, y compris les cancers résistant aux médicaments |
EP2328578A2 (fr) * | 2008-09-11 | 2011-06-08 | Emory University | Noscapine et analogues de la noscapine et leur utilisation dans le traitement de maladies infectieuses par inhibition par liaison à la tubuline |
CN115433195A (zh) * | 2021-06-01 | 2022-12-06 | 华东理工大学 | 烷基取代那可丁衍生物及其制备方法与应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3056791A (en) * | 1959-10-27 | 1962-10-02 | Sandoz Ag | Isoquinoline derivatives |
US4970212A (en) * | 1982-05-18 | 1990-11-13 | Nowicky Wassili | Method of treating human illnesses which compromise the ability to mount an effective immunological response |
US20020137762A1 (en) * | 1997-08-19 | 2002-09-26 | Joshi Harish C. | Delivery systems and methods for noscapine and noscapine derivatives, useful as anticancer agents |
-
2006
- 2006-05-12 RU RU2006116302/04A patent/RU2304584C1/ru not_active IP Right Cessation
-
2007
- 2007-03-21 WO PCT/RU2007/000138 patent/WO2007133112A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3056791A (en) * | 1959-10-27 | 1962-10-02 | Sandoz Ag | Isoquinoline derivatives |
US4970212A (en) * | 1982-05-18 | 1990-11-13 | Nowicky Wassili | Method of treating human illnesses which compromise the ability to mount an effective immunological response |
US20020137762A1 (en) * | 1997-08-19 | 2002-09-26 | Joshi Harish C. | Delivery systems and methods for noscapine and noscapine derivatives, useful as anticancer agents |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010028259A2 (fr) * | 2008-09-05 | 2010-03-11 | Emory University | 9-aminonoscapine et son utilisation dans le traitement des cancers, y compris les cancers résistant aux médicaments |
WO2010028259A3 (fr) * | 2008-09-05 | 2010-07-22 | Emory University | 9-aminonoscapine et son utilisation dans le traitement des cancers, y compris les cancers résistant aux médicaments |
US8394957B2 (en) | 2008-09-05 | 2013-03-12 | Emory University | 9-aminonoscapine and its use in treating cancers, including drug-resistant cancers |
US8815835B2 (en) | 2008-09-05 | 2014-08-26 | Emory University | 9-aminonoscapine and its use in treating cancers, including drug-resistant cancers |
EP2328578A2 (fr) * | 2008-09-11 | 2011-06-08 | Emory University | Noscapine et analogues de la noscapine et leur utilisation dans le traitement de maladies infectieuses par inhibition par liaison à la tubuline |
EP2328578A4 (fr) * | 2008-09-11 | 2012-04-25 | Univ Emory | Noscapine et analogues de la noscapine et leur utilisation dans le traitement de maladies infectieuses par inhibition par liaison à la tubuline |
CN115433195A (zh) * | 2021-06-01 | 2022-12-06 | 华东理工大学 | 烷基取代那可丁衍生物及其制备方法与应用 |
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RU2304584C1 (ru) | 2007-08-20 |
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