NO178261B - Substituted diaminophthalimides and analogs, pharmaceutical preparations containing them and their use in drugs - Google Patents
Substituted diaminophthalimides and analogs, pharmaceutical preparations containing them and their use in drugs Download PDFInfo
- Publication number
- NO178261B NO178261B NO922133A NO922133A NO178261B NO 178261 B NO178261 B NO 178261B NO 922133 A NO922133 A NO 922133A NO 922133 A NO922133 A NO 922133A NO 178261 B NO178261 B NO 178261B
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- Prior art keywords
- bis
- formula
- evaporated
- mmol
- ethyl acetate
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- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
- 239000003814 drug Substances 0.000 title claims description 3
- 229940079593 drug Drugs 0.000 title description 2
- YTJWBAMDRDWGEG-UHFFFAOYSA-N 4,5-diaminoisoindole-1,3-dione Chemical class NC1=CC=C2C(=O)NC(=O)C2=C1N YTJWBAMDRDWGEG-UHFFFAOYSA-N 0.000 title 1
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- 230000005764 inhibitory process Effects 0.000 claims abstract description 9
- -1 cyano, nitro, amino Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
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- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- AAALVYBICLMAMA-UHFFFAOYSA-N 4,5-dianilinophthalimide Chemical group C=1C=CC=CC=1NC=1C=C2C(=O)NC(=O)C2=CC=1NC1=CC=CC=C1 AAALVYBICLMAMA-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- NOUUUQMKVOUUNR-UHFFFAOYSA-N n,n'-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1NCCNC1=CC=CC=C1 NOUUUQMKVOUUNR-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical class C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940113046 sorine Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 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
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910001428 transition metal ion Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- BEIXTGGJVNHLEO-UHFFFAOYSA-N trimethyl(3-trimethylsilyloxybuta-1,3-dien-2-yloxy)silane Chemical compound C[Si](C)(C)OC(=C)C(=C)O[Si](C)(C)C BEIXTGGJVNHLEO-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Luminescent Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
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Abstract
Description
Foreliggende oppfinnelse angår forbindelser med formel I The present invention relates to compounds of formula I
hvor Aj og A2 uavhengig av hverandre står for hydrogen, laverealkyl, laverealkenyl eller laverealkanoyl; eller hvor Ai og A2 sammen står for -( CE2) 2~ eHer "(^2)3-; Ar^ og Ar2 står uavhengig av hverandre for fenyl, som er ikke-substituert eller substituert med en eller flere substituenter fra gruppen bestående av halogen, fenyl, fenyllaverealkoksy, laverealkoksy, dilaverealkylamino, cyano, nitro, amino og trifluormetyl; eller står for C3~Cg-cykloalkyl; gruppen -C(=X) står for -C(=0) eller -C(=S); og R står for hydrogen eller laverealkyl, eller et salt derav, såfremt det foreligger saltdannende grupper, for fremstilling av farmasøytis-ke preparater. where A 1 and A 2 independently represent hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; or where Ai and A2 together stand for -( CE2) 2~ eHer "(^2)3-; Ar^ and Ar2 stand independently of each other for phenyl, which is unsubstituted or substituted with one or more substituents from the group consisting of halogen, phenyl, phenyl lower alkyl, lower alkoxy, di lower alkylamino, cyano, nitro, amino and trifluoromethyl; or represents C3~Cg cycloalkyl; the group -C(=X) represents -C(=0) or -C(=S); and R stands for hydrogen or lower alkyl, or a salt thereof, if salt-forming groups are present, for the production of pharmaceutical preparations.
De ovenfor og nedenfor anvendte begreper har i denne søknaden følgende betydning: Prefikset "lavere" betegner en rest med til og med 7, fortrinnsvis opp til og med 4 og i det minste en eller to karbonatomer. The terms used above and below have the following meaning in this application: The prefix "lower" denotes a residue with up to and including 7, preferably up to and including 4 and at least one or two carbon atoms.
Laverealkyl er fortrinnsvis n-propyl, isopropyl, n-butyl, isobutyl, sek.-butyl, tert.-butyl, n-pentyl, neopentyl, n-heksyl eller n-heptyl, fortrinnsvis etyl og helst metyl. Lower alkyl is preferably n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and preferably methyl.
Laverealkenyl har 2 til 7, fortrinnsvis 2 til 4 karbonatomer og er for eksempel allyl eller krotyl. Lower alkenyl has 2 to 7, preferably 2 to 4 carbon atoms and is, for example, allyl or crotyl.
Laverealkanoyl er fortrinnsvis formyl, acetyl, propionyl, n-butyryl, pivaloyl eller valeroyl, i særdeleshet acetyl. Aryllaverealkyl er fortrinnsvis fenyllaverealkyl og i særdeleshet benzyl. Lower realkanoyl is preferably formyl, acetyl, propionyl, n-butyryl, pivaloyl or valeroyl, in particular acetyl. Aryl lower alkyl is preferably phenyl lower alkyl and in particular benzyl.
C3-Cg-cykloalkyl er spesielt Cs-Cy-cykloalkyl, som skal bety at den inneholder 3 til 8 og fortrinnsvis 5 til 7 karbon-ringatomer. C3-C8 cycloalkyl is particularly Cs-Cy cycloalkyl, which should mean that it contains 3 to 8 and preferably 5 to 7 carbon ring atoms.
Halogen står i særdeleshet for fluor, klor og brom, men kan også være lod. Halogen stands for fluorine, chlorine and bromine in particular, but can also be lead.
Salter av oppfinnelsens forbindelser med saltbindende grupper er i første rekke farmasøytisk anvendbare, ikke-toksiske salter. Eksempelvis kan forbindelser med formel I med basiske grupper danne syreaddisjonssalter, for eksempel med uor-ganiske syrer som saltsyre, svovelsyre og salpetersyre eller med egnede organiske karboksyl- eller sulfonsyrer, for eksempel eddiksyre, fumarsyre eller metansulfonsyre eller med aminosyrer, som arginin eller lysin. Salts of the compounds of the invention with salt-binding groups are primarily pharmaceutically usable, non-toxic salts. For example, compounds of formula I with basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid or with suitable organic carboxylic or sulphonic acids, for example acetic acid, fumaric acid or methanesulphonic acid or with amino acids, such as arginine or lysine.
Komplekser av forbindelser med formelen I (Ai,Å2 = hydrogen) med overgangsmetal1 ioner, for eksempel kobber, kobolt eller mangan faller også innenfor salter av oppfinnelsens forbindelser . Complexes of compounds with the formula I (Ai,Å2 = hydrogen) with transition metal ions, for example copper, cobalt or manganese also fall within salts of the compounds of the invention.
Farmasøytisk uegnede salter, for eksempel pirkrater og perklorater, kan også finne anvendelse for isolering og rensing. Kun de farmasøytisk anvendbare, ikke-toksiske saltene er derfor foretrukket for farmasøytisk bruk. Pharmaceutically unsuitable salts, for example pyrrates and perchlorates, can also be used for isolation and purification. Only the pharmaceutically usable, non-toxic salts are therefore preferred for pharmaceutical use.
Oppfinnelsens forbindelser fremviser verdifulle, spesielt farmasøytisk anvendbare egenskaper. Spesielt viser de spesifikk hemming som er av farmakologisk interesse. I første rekke virker de som proteintyrosinkinasehemmere og viser for eksempel en kraftig hemming av tyrosinkinaseaktiviteten til reseptorene for den epidermale vekstfaktoren (EGF) og c-erbB2-kinasen. Denne reseptorspesifikke enzymaktiviteten spiller en nøkkelrolle i signaloverføringen i mange pattedyrceller inkludert humane celler, i særdeleshet for epitel-celler, celler i immunsystemet og celler i det sentrale og perifere nervesystem. Den EGF-induserte aktiveringen av proteintyrokinasen (RGF-R-PTK) som er bundet til reseptorer er hos forskjellige celletyper en forutsetning for celledelingen og dermed for formeringen i en cellepopulasjon. Ved tilsetning av EGF-reseptorspesifikk tyrosinkinasehemmer ble derved formeringen av disse cellene hemmet. The compounds of the invention exhibit valuable, particularly pharmaceutically usable, properties. In particular, they show specific inhibition that is of pharmacological interest. Primarily, they act as protein tyrosine kinase inhibitors and show, for example, a strong inhibition of the tyrosine kinase activity of the receptors for the epidermal growth factor (EGF) and the c-erbB2 kinase. This receptor-specific enzyme activity plays a key role in signal transmission in many mammalian cells including human cells, in particular for epithelial cells, cells of the immune system and cells of the central and peripheral nervous system. The EGF-induced activation of the protein thyrokinase (RGF-R-PTK) which is bound to receptors is, in various cell types, a prerequisite for cell division and thus for reproduction in a cell population. By adding an EGF receptor-specific tyrosine kinase inhibitor, the proliferation of these cells was thereby inhibited.
Hemmingen av EGF-reseptor spesifikk proteintyrokinase (EGF-R-PTK) kan for eksempel bli vist emd metoden fra C. House et al., Europ. J. Biochem. 140, 363-367 (1984). Oppfinnelsens forbindelser hemmer enzymaktiviteten med 50# (IC50) i konsentrasjoner <1 pM. De viser dessuten i mikromolare mengder for eksempel en hemming av celleveksten i en EGF-avhengig cellelinje, som den epidermale mus-keratinocyt-cellelinjen. For å måle denne hemmingen av celleveksten, blir den EGF stimulerte celledelingen av epidermale Balb/MK-keratinocyter anvendt (beskrivelse av fremgangsmåten i meyer, T. , et al, Int. J. Cancer 43, 851 (19S9). Disse cellene er samtidig avhengige av EGF for formering (Weissmann, B. E. , Aaronson, S. A, Cell 32,599 (1983). For gjennomføring av testen blir Balb/MK-cellene (10000/hull) tatt opp i 96-hulls-mikrotiterplater og inkubert over natten. Teststoffene (løst i DJJSO) ble tilsatt i forskjellige konsentrasjoner (i fortynningsrekker), slik at sluttkonsentrasjonen i DMSO ikke er større enn 1%. Etter tilsetningen blir platene inkubert i tre dager, i løpet av hvilken tid kontrollkulturene uten teststoff har kunnet gjennomløpe minst 3 celledelings-sykluser. Veksten av MK-cellene ble målt ved hjelp av metylenblåfarging. IC5g-verdier ble definert som konsentra-sjonen på hvert av teststoffene som første til en 505É reduksjon i forhold til kontrollkulturene uten hemmer. The inhibition of EGF receptor specific protein thyrokinase (EGF-R-PTK) can for example be shown by the method of C. House et al., Europ. J. Biochem. 140, 363-367 (1984). The compounds of the invention inhibit the enzyme activity by 50# (IC50) at concentrations <1 pM. They also show, in micromolar amounts, for example, an inhibition of cell growth in an EGF-dependent cell line, such as the mouse epidermal keratinocyte cell line. To measure this inhibition of cell growth, the EGF-stimulated cell division of epidermal Balb/MK keratinocytes is used (description of the method in meyer, T. , et al, Int. J. Cancer 43, 851 (19S9). These cells are simultaneously dependent on EGF for proliferation (Weissmann, B.E., Aaronson, S.A, Cell 32,599 (1983). To perform the assay, the Balb/MK cells (10,000/well) are plated in 96-well microtiter plates and incubated overnight. The test substances (dissolved in DJJSO) were added in different concentrations (in dilution series) so that the final concentration in DMSO is not greater than 1%. After the addition, the plates are incubated for three days, during which time the control cultures without test substance have been able to pass through at least 3 cell division cycles. The growth of the MK cells was measured by means of methylene blue staining. IC5g values were defined as the concentration of each of the test substances first to a 505É reduction compared to the control cultures without inhibitor.
Oppfinnelsens forbindelser hemmer foruten EGF-R-PTK også andre tyrosinkinaser, som er involvert i formidlingen av signaler gjennom den tropiske faktoren, for eksempel abl-kinasen, kinaser fra familien src-kinaser og c-erbB2-kinasen (HER-2), så vel som serin/threonin-kinaser, for eksempel proteinkinase C, ' som alle spiller en rolle for vekst-regulering og transformasjon for pattedyrceller omfattende humanceller. In addition to EGF-R-PTK, the compounds of the invention also inhibit other tyrosine kinases, which are involved in the transmission of signals through the tropic factor, for example the abl kinase, kinases from the src kinase family and the c-erbB2 kinase (HER-2), so as well as serine/threonine kinases, such as protein kinase C, all of which play a role in growth regulation and transformation for mammalian cells including human cells.
Hemmingen av c-erbB2-tyrokinase (HER-2), kan bli vist for eksempel analogt med metoden anvendt for EGF-R-PTK ifølge C. House et al., Europ. J. Biochem. 140, 363-367 (1984). c-erbB2-kinasen kan bli isolert etter en kjent fremgangsmåte og dets aktivitet kan bli bestemt, for eksempel etter T. Akiyama et al., Science 232, 1644 (1986). The inhibition of c-erbB2-tyrokinase (HER-2) can be shown, for example, analogously to the method used for EGF-R-PTK according to C. House et al., Europ. J. Biochem. 140, 363-367 (1984). The c-erbB2 kinase can be isolated according to a known method and its activity can be determined, for example according to T. Akiyama et al., Science 232, 1644 (1986).
Følgelig er oppfinnelsens forbindelser også egnede for hemming av visse og beslektede tyrokinase formidlede prosesser. Accordingly, the compounds of the invention are also suitable for the inhibition of certain and related thyrokinase mediated processes.
Oppfinnelsen forbindelser er derfor nyttige for eksempel til behandling av beninge eller maligne tumorer. De er i stand til å bevirke tumorregressjon og å forhindre tumormetastase-dannelse og veksten av mikrometastaser. De er særdeles anvendbare ved epidermalhyperprolifiering (psoriasis), ved behandlingen av neoplasma med epidermal karakter, for eksempel mammakarzinomer og leukemi. Dessuten kan de benyttes i forbindelse med behandling av sykdommer i immunsystemet og av inflammasjon, i den grad proteinkinaser er involvert i disse sykdommene. Også ved behandling av sykdommer i det sentrale eller perifale nervesystemet er forbindelsene nyttbare, dersom signaloverføring ved proteinkinaser er involvert. The compounds of the invention are therefore useful, for example, in the treatment of bony or malignant tumors. They are able to effect tumor regression and to prevent tumor metastasis formation and the growth of micrometastases. They are particularly useful in epidermal hyperproliferation (psoriasis), in the treatment of epidermal neoplasms, for example mammary carcinomas and leukaemia. Furthermore, they can be used in connection with the treatment of diseases of the immune system and of inflammation, to the extent that protein kinases are involved in these diseases. The compounds are also useful in the treatment of diseases of the central or peripheral nervous system, if signal transmission by protein kinases is involved.
Oppfinnelsens forbindelser kan bli benyttet så vel alene som i kombinasjon med andre farmakologisk virksomme stoffer, for eksempel sammen med (a) inhibitorer for enzymer i polyamin-syntesen, (b) inhibitorer for proteinkinase C, (c) inhibitorer fro andre tyrosinkina.ser, (d) Cytokiner, (e) negative vekstregulatorer, for eksempel TGF-p<-> eller IFN-e, (f) aromatasehemmere, (g) antiøstrogener eller (h) cyto-statika. The compounds of the invention can be used either alone or in combination with other pharmacologically active substances, for example together with (a) inhibitors for enzymes in polyamine synthesis, (b) inhibitors for protein kinase C, (c) inhibitors from other tyrosine kinases, (d) Cytokines, (e) negative growth regulators, for example TGF-β<-> or IFN-ε, (f) aromatase inhibitors, (g) antiestrogens or (h) cytostatics.
Spesielt foretrukket er de forbindelsene med formel I som ble omtalt i forrige avsnitt, hvor A± og A2 uavhengig av hverandre står for hydrogen eller laverealkyl, gruppen-C(=X)- står for -C(=0)-. -C(=S)- eller -C(=CH2)- og R står for hydrogen eller laverealkyl og salter av disse. Particularly preferred are the compounds of formula I which were discussed in the previous section, where A± and A2 independently of each other stand for hydrogen or lower alkyl, the group -C(=X)- stands for -C(=0)-. -C(=S)- or -C(=CH2)- and R stands for hydrogen or lower alkyl and salts thereof.
Enda mer foretrukket er forbindelser med formel I hvor A^ og A2 uavhengig av hverandre står for hydrogen, laverealkyl, laverealkenyl eller laverealkanoyl; eller hvor A^ og A2 sammen betyr C1-C4 laverealkylen; hvor Ar^ og Ar2 uavhengig av hverandre står for fenyl eller naftyl som enten er ikke-substituert eller substituert med en eller flere substituenter av gruppen bestående av laverealkyl, laverealkylen (bundet til to nabo C-atomer), hydroksy, fenyoloksy, halogen, nitro, amino, laverealkylamino, dilaverealkylamino, lavereal-kanoylamino, karboksy, laverealkoksykarbonyl, karbamoyl, N-laverealkylkarbamoyl, N,N-dilaverealkylkarboamoyl, og cyano; pyridyl; pyrimidinyl; eller C3-Cg-cykloalkyl; gruppen -C(=X)-står for -C(=0)- eller -C(=S)- og R står for hydrogen, laverealkyl, fenyllaverealkyl, amino eller hydroksy og salter av disse såfremt det foreligger saltdannende grupper. Even more preferred are compounds of formula I where A 1 and A 2 independently of each other stand for hydrogen, lower alkyl, lower alkenyl or lower alkanoyl; or where A 1 and A 2 together mean C 1 -C 4 lower alkylene; where Ar^ and Ar2 independently stand for phenyl or naphthyl which is either unsubstituted or substituted with one or more substituents from the group consisting of lower alkyl, lower alkylene (bonded to two neighboring C atoms), hydroxy, phenyloxy, halogen, nitro , amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, and cyano; pyridyl; pyrimidinyl; or C 3 -C 8 cycloalkyl; the group -C(=X)-stands for -C(=0)- or -C(=S)- and R stands for hydrogen, lower alkyl, phenyl lower alkyl, amino or hydroxy and salts thereof if salt-forming groups are present.
I første rekke angår oppfinnelsen forbindelser med formel I, hvor Ai og A2 uavhnegig av hverandre står for hydrogen eller metyl; eller hvor A^ og A2 sammen står for -(CH2)2- eller -(0112)3-; ^rl°S ^r2 uavhengig av hverandre står for fenyl, som er ikke-substituert eller substituert med en eller flere substituenter av gruppen bestående av laverealkoksy, fenyllaverealkoksy, nitro, amino, dilaverealkylamino, halogen, trifluormetyl, cyano; eller for cyklopentyl eller cykloheksyl; gruppen -C(=X)- står for -C(=0)- eller -C(=S)-og R står for hydrogen eller laverealkyl, og deres faramsøyt-isk anvendbare salter. In the first place, the invention relates to compounds of formula I, where Ai and A2 independently of each other stand for hydrogen or methyl; or where A^ and A2 together stand for -(CH2)2- or -(0112)3-; ^rl°S ^r2 independently of each other represents phenyl, which is unsubstituted or substituted with one or more substituents from the group consisting of lower alkoxy, phenyl lower alkyl, nitro, amino, dilower alkylamino, halogen, trifluoromethyl, cyano; or for cyclopentyl or cyclohexyl; the group -C(=X)- stands for -C(=O)- or -C(=S)- and R stands for hydrogen or lower alkyl, and their pharmaceutically usable salts.
Først og fremst angår oppfinnelsen forbindelser med formel I, hvor Ai og A2 står for hydrogen; Ar^ og Ar2 uavhengig av hverandre fenyl om er ikke-substituert eller substituert med trifluormetyl, fenyl, laverealkoksy, benzyloksy, amino, dilaverealkylamino, halogen eller cyano; eller cykloheksyl; gruppen -C(=X)- står for -C(=0)- eller -C(=S)- og R står for hydrogen og deres farmasøytisk anvendbare salter. First and foremost, the invention relates to compounds of formula I, where Ai and A2 stand for hydrogen; Ar 1 and Ar 2 are independently phenyl if unsubstituted or substituted with trifluoromethyl, phenyl, lower alkoxy, benzyloxy, amino, dilower alkylamino, halogen or cyano; or cyclohexyl; the group -C(=X)- stands for -C(=O)- or -C(=S)- and R stands for hydrogen and their pharmaceutically usable salts.
Oppfinnelsen angår fremfor alt de spesifikt beskrevne forbindelsene og farmasøytiske anvendbare salter av disse som er beskrevet i eksemplene, spesielt 4,5-bis(anilin)ftalimid eller 4,5-bis(4-fluoranilin)ftalimid. The invention relates above all to the specifically described compounds and pharmaceutically usable salts thereof which are described in the examples, in particular 4,5-bis(aniline)phthalimide or 4,5-bis(4-fluoroaniline)phthalimide.
Forbindelsene med formel I kan bli fremstilt på kjent måte ved at man for eksempel The compounds of formula I can be prepared in a known manner by, for example
(a) omsetter en forbindelse med formel II (a) reacts a compound of formula II
hvor Ar^, Ar2. A^ og A2 har betydningen angitt under formel I og R3 og R4 uavhengig av hverandre står for aryl eller laverealkyl, med en forbindelse med formel III hvor R har betydningen som angitt under formel I, eller (b) omsetter en forbindelse med formel IV hvor Ar og A har den betydningen som er angitt under formel I, med en forbindelse med formel III where Ar^, Ar2. A^ and A2 have the meaning given under formula I and R3 and R4 independently of each other stand for aryl or lower alkyl, with a compound of formula III where R has the meaning given under formula I, or (b) reacts a compound of formula IV where Ar and A are as defined under formula I, with a compound of formula III
hvor R har betydningen som angitt under formel I; where R has the meaning given under formula I;
og/eller omdanner en oppnådd forbindelse med formel I til en annen forbindelse med formel I, og/eller omdanner et oppnådd salt til den frie forbindelsen eller til et annet salt, og/eller omdanner en oppnådd fir forbindelse I til et salt og/eller renser de enkelte isomerene fra den oppnådde blandingen av isomere forbindelser med formel I. and/or converts an obtained compound of formula I into another compound of formula I, and/or converts an obtained salt into the free compound or into another salt, and/or converts an obtained four compound I into a salt and/or purifies the individual isomers from the resulting mixture of isomeric compounds of formula I.
I den følgende beskrivelsen av fremgangsmåten har symbolene Ar^, Ar2 , A^, A2 1 X, R, R3 og R4 den betydningen som er angitt under formel I og II, så fremt ikke annet er angitt. In the following description of the method, the symbols Ar 1 , Ar 2 , A 2 , A 2 1 X, R, R 3 and R 4 have the meanings given under formulas I and II, unless otherwise stated.
Fremgangsmåte (a): Omsetningen ble utført ifølge fremgangsmåten (a) ved en kjent aminolyse av ftalsyredisterne med ammoniak eller primært amin. Omsetningen foregår med aktiverte ftalsyrediestere, for eksempel di(p-nitrofenyl )-esterene, normalt ved romtemperatur, med dilaverealkylesterene derimot for det meste ved høyere temperaturer. Fortrinnsvis blir dimetylesterene anvendt. Omsetningen av dilaverealkylesterene blir fortrinnsvis utført i et oppløs-ningsmiddel, helst i en alkohol med høyt kokepunkt, for eksempel en diol , som etylenglykol, ved temperaturer fra 100 til 150"C, for eksempel ca 120°C, eller omsetningen av laverealkylesterene med ammoniak eller det aktuelle amin med formel III ved den samme temperaturen i nærvær av et oppløsningsmiddel, for eksempel en alkohol, som en lavereal-kohol, for eksempel metanol eller etanol, eller i fravær av et oppløsningsmiddel i en autoklavere ved et forhøyet trykk. Method (a): The reaction was carried out according to method (a) by a known aminolysis of the phthalic acid esters with ammonia or primary amine. The reaction takes place with activated phthalic acid diesters, for example the di(p-nitrophenyl) esters, normally at room temperature, with the dilover alkyl esters, on the other hand, mostly at higher temperatures. Preferably, the dimethyl esters are used. The reaction of the lower alkyl esters is preferably carried out in a solvent, preferably in an alcohol with a high boiling point, for example a diol, such as ethylene glycol, at temperatures from 100 to 150 °C, for example about 120 °C, or the reaction of the lower alkyl esters with ammonia or the relevant amine of formula III at the same temperature in the presence of a solvent, for example an alcohol, such as a lower alcohol, for example methanol or ethanol, or in the absence of a solvent in an autoclave at an elevated pressure.
Utgangsforbindelsen med formel II blir for eksempel fremstilt ved at man omsetter et cykloheksadien med formel V The starting compound with formula II is prepared, for example, by reacting a cyclohexadiene with formula V
hvor Me står for metyl, med et anilin med formel VI where Me stands for methyl, with an aniline of formula VI
hvor A fortrinnsvis står for hydrogen eller laverealkyl, under syrekatalyse [s. Matlin, Stephen A. og Barron, kenneth, J. Chem. res. Synop. 8, 246-247 (1990)]. where A preferably stands for hydrogen or lower alkyl, under acid catalysis [p. Matlin, Stephen A. and Barron, Kenneth, J. Chem. res. Synopsis. 8, 246-247 (1990)].
Fremstillingen av forbindelsen med formel V følger for eksempel via en Diels-Alder-reaksjon og er eventuelt beskrevet i den angitte litteraturen. The preparation of the compound of formula V follows, for example, via a Diels-Alder reaction and is possibly described in the indicated literature.
For fremstilling av usymmetriske forbindelser med formel II, hvor Ai og A2 og/eller Ar^ og Ar2 er forskjellige, kan for eksempel forbindelser med formel V omsatt med to forskjellige forbindelser med formel VI, for eksempel trinnvis, og den ønskede forbindelsen med formel II blir isolert ved hjelp av kromatografisk rensing. For the preparation of unsymmetrical compounds of formula II, where Ai and A2 and/or Ar^ and Ar2 are different, for example compounds of formula V can be reacted with two different compounds of formula VI, for example stepwise, and the desired compound of formula II is isolated by means of chromatographic purification.
Dessuten kan for eksempel forbindelser med formel II med Ai=A2=H bli omsatt i forhold 1:1 med et laverealkylerings-middel for eksempel metyleniodid, hvorved man oppnår usymmetriske forbindelser med formel II med A^ = laverealkyl og A2 = H. Tilsetter man laverealkyleringsmiddelet i overskudd, for eksempel 10:1, oppnår man symmetriske forbindelser med formel II med A^ = A<* = laverealkyl. Furthermore, for example, compounds of formula II with Ai=A2=H can be reacted in a 1:1 ratio with a lower alkylating agent, for example methylene iodide, whereby unsymmetrical compounds of formula II with A^ = lower alkyl and A2 = H are obtained. the lower alkylating agent in excess, for example 10:1, symmetrical compounds of formula II with A^ = A<* = lower alkyl are obtained.
Fremgangsmåte (b): Omsetningen etter fremgangsmåten (b) følger den kjente aminolysen av ftalsyreanhydrider, for eksempel med ammoniak eller primære aminer, ved forhøyede temperaturer eller med heksametyldisilazan og metanol ved romtemepratur [Davis, Peter D. og Bit, Eino A., Tetrahedron Lett. 31, 5201-5204 (1990)]. Method (b): The reaction according to method (b) follows the known aminolysis of phthalic anhydrides, for example with ammonia or primary amines, at elevated temperatures or with hexamethyldisilazane and methanol at room temperature [Davis, Peter D. and Bit, Eino A., Tetrahedron Easy. 31, 5201-5204 (1990)].
Startforbindelsen med formel IV blir for eksempel fremstilt ved at man omsetter en forbindelse med formel VII The starting compound of formula IV is prepared, for example, by reacting a compound of formula VII
med et syreanhydrid med formel VIII, (R5C0)(R5* CO)0, hvor R5 og R5' uavhengig av hverandre står for hydrogen eller laverealkyl, men ikke begge for hydrogen. with an acid anhydride of formula VIII, (R5C0)(R5* CO)0, where R5 and R5' independently of each other stand for hydrogen or lower alkyl, but not both for hydrogen.
Forbindelsene med formel VII er for eksempel tilgjengelige ved hydrolyse, for eksempel i surt eller alkalisk medium, av en oppnådd forbindelse med formel II. The compounds of formula VII are available, for example, by hydrolysis, for example in acidic or alkaline medium, of an obtained compound of formula II.
Forbindelsen med formel I kan på kjent måte bli omdannet til andre forbindelser med formel I. The compound of formula I can be converted into other compounds of formula I in a known manner.
For eksempel kan en forbindelse med formel I, hvor gruppen-C(=X)- står for -C(=0)- bli omsatt med et egnet reagens slik at en annen forbindelse med formel I, hvor gruppen -C(=X.)-står for -C(=S)-, blir oppnådd. Et egnet reagens for overføringen av -C(=0=- i -C(=S)- er for eksempel Lawesson-reagenset (=2,4-bis-(4-metoksyfenyl)-2,4-ditiokso-l,3,2,4-dithiafosfetan), hvor reaksjonen eksempelvis blir utført i et halogenert hydrokarbon, som diklormetan, ved temperaturer fra 30° C til tilbakeløpskjølingstemperatur, fortrinnsvis ved tilbakeløpskjølingstemperatur. For omdanningen av -C(=0)- i-CH2- er eksempelvis systemet LiAlB^/tetrahydrofuran eller zinkamalgam/HCl/etanol egnet. For example, a compound of formula I, where the group -C(=X)- stands for -C(=0)- can be reacted with a suitable reagent so that another compound of formula I, where the group -C(=X. )-stands for -C(=S)-, is obtained. A suitable reagent for the transfer of -C(=0=- into -C(=S)- is, for example, the Lawesson reagent (=2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3 ,2,4-dithiaphosphetane), where the reaction is carried out, for example, in a halogenated hydrocarbon, such as dichloromethane, at temperatures from 30° C to reflux temperature, preferably at reflux temperature. For the conversion of -C(=0)- into -CH2- is, for example the system LiAlB^/tetrahydrofuran or zinc amalgam/HCl/ethanol suitable.
Dessuten kan for eksempel forbindelser med formel I, hvor R står for hydrogen, bli overført via alkylering, for eksempel med laverealkylhalogenider etter behandling med egnede baser, eventuelt natriumhydrid eller kalium-tert.-butoksyd, til andre forbindelser med formel I hvor R står for laverealkyl. Moreover, for example compounds of formula I, where R stands for hydrogen, can be transferred via alkylation, for example with lower alkyl halides after treatment with suitable bases, possibly sodium hydride or potassium tert-butoxide, to other compounds of formula I where R stands for lower alkyl.
Videre kan for eksempel forbindelser med formel I, hvor A^ og/eller A2 står for hydrogen, bli overført via omdannelse med egende reagenser til andre forbindelser med formel I, hvor A^ og/eller A2 står for laverealkyl, aryl, acyl, laverealkylsulfonyl eller arylsulfonyl. Furthermore, for example, compounds of formula I, where A^ and/or A2 stand for hydrogen, can be transferred via conversion with appropriate reagents to other compounds of formula I, where A^ and/or A2 stand for lower alkyl, aryl, acyl, lower alkylsulfonyl or arylsulfonyl.
For innføring av A^ og/eller A2 = laverealkyl er for eksempel behandlingen med basen LDA og påfølgende omsetning med en dilaverealkyleter eller en laverealkylhalogenid aktuell. Under denne behandligen blir eventuelt en tilstedeværende-N(-R)- = -NH- som er til stede i molekylet kun alkyelert litt eller ikke i det hele tatt. For the introduction of A^ and/or A2 = lower alkyl, treatment with the base LDA and subsequent reaction with a dilower alkyl ether or a lower alkyl halide is relevant, for example. During this treatment, a possibly present -N(-R)- = -NH- which is present in the molecule is alkylated only slightly or not at all.
For innføring av A^ og/eller A2 = laverealkylsulfonyl, kan utgangsforbindelsen for eksempel først bli omsatt med LDA og deretter med et acyleingsmiddel, for eksempel acetylklorid. For the introduction of A 1 and/or A 2 = lower alkylsulfonyl, the starting compound can, for example, first be reacted with LDA and then with an acylating agent, for example acetyl chloride.
Forbindelser med formel I, hvor Ar^ og Ar2 står for fenyl substituert med halogen, fortrinnsvis brom, kan bli omdannet til de tilsvarende derivater, hvor et eller alle de til-stedeværende halogenatomene i fenylets Ar^ og/eller Ar2 bli erstattet med cyano, eksempelvis ved omsetning med et overgangsmetallcyanidsalt, i særdeleshet CuCN, ved temperaturer mellom 50 og 150°C, fortrinnsvis mellom 60 og 140°C, i et inert polart oppløsningsmiddel, som et N,N-dilaverealkyl-laverealkankarbonsyreamid, for eksempel dimetylformamid, uten eller med tilsetning av en katalysator, for eksempel et overgangsmetallhalogenid, som jern(III)klorid, i vandig oppløsning (se også Rosenmund et al., Ber. 52, 1749 (1916); fra Braun et al., Ann. 488, 111 (1931). Compounds of formula I, where Ar^ and Ar2 stand for phenyl substituted with halogen, preferably bromine, can be converted into the corresponding derivatives, where one or all of the halogen atoms present in the phenyl's Ar^ and/or Ar2 are replaced with cyano, for example by reaction with a transition metal cyanide salt, in particular CuCN, at temperatures between 50 and 150°C, preferably between 60 and 140°C, in an inert polar solvent, such as an N,N-dilower alkyl-lower alkane carboxylic acid amide, for example dimethylformamide, without or with the addition of a catalyst, for example a transition metal halide, such as ferric chloride, in aqueous solution (see also Rosenmund et al., Ber. 52, 1749 (1916); from Braun et al., Ann. 488, 111 ( 1931).
I forbindelser med formel I, kan med restene Ar^ og/eller Ar2, som står for ikke-substituert fenyl, uavhengig av hverandre bli nitrert ved innføring av en eller flere nitrogrupper, eksempelvis under vanlige betingelser for innføring av en nitrogruppe i aromater, for eksempel med konsentrert eller 100% salpetersyre med temperaturer mellom 0 og 100°C, fortrinnsvis mellom 10 og 40°C, i et inert oppløsningsmiddel, for eksempel et organisk syreanhydrid, som acetanhydrid. Derved oppstår flere forskjellige produkter med forskjellige posisjoner og antall nitrogrupper, som kan bli renset ved vanlige fremgangsmåter, eksempelvis kolonne-kromatografi. In compounds of formula I, with the residues Ar^ and/or Ar2, which stand for unsubstituted phenyl, can be independently nitrated by introducing one or more nitro groups, for example under normal conditions for introducing a nitro group in aromatics, for for example with concentrated or 100% nitric acid with temperatures between 0 and 100°C, preferably between 10 and 40°C, in an inert solvent, for example an organic acid anhydride, such as acetic anhydride. This results in several different products with different positions and numbers of nitro groups, which can be purified by conventional methods, for example column chromatography.
Nitrosubstituentene i restene Ar^ og/eller Ar2 kan bli redusert til aminogrupper, eksempelvis ved hydrering under vanlige betingelser, for eksempel ved hydrering i nærvær av egnede katalysatorer for selektiv reduksjon av nitrogruppene, som Raney-Nickel, i et inert oppløsningsmiddel, for eksempel en cyklisk eller ikke-cyklisk eter, som tetrahydrofuran, under normal trykk eller ved et forhøyet trykk opp til 5 bar. The nitro substituents in the residues Ar^ and/or Ar2 can be reduced to amino groups, for example by hydrogenation under normal conditions, for example by hydrogenation in the presence of suitable catalysts for the selective reduction of the nitro groups, such as Raney-Nickel, in an inert solvent, for example a cyclic or non-cyclic ether, such as tetrahydrofuran, under normal pressure or at an elevated pressure up to 5 bar.
Forbindelser med formel I med foredrede hydroksygrupper, eksempelvis med laverealkoksyrester som substituenter på Ar^ og/eller A2, kan ved eterspalting bli overført til de tilsvarende hydroksysubstituerte forbindelsene med formel I. Eterspaltingen skjer under kjente betingelser, eksempelvis i nærvær av halogenhydrogensyrer, som hydrogenbromid eller hydrogeniodid, i nærvær eller fravær av oppløsningsmidler, som karbonsyre, for eksempel laverealkankarbonsyre, som eddiksyre, ved temperaturer mellom 20°C og tilbakeløps-kjlingstemperaturen for reaksjonsblåndingen, eller fortrinnsvis under gående betingelser med borhalogenider, spesielt bortribromid, i et inert oppløsningsmiddel, som et klorert hydrokarbon, for eksempel metylenklorid eller kloroform, med temperaturer mellom -80 og 0°C, fortrinnsvis mellom -50 og-20<*>C. Compounds of formula I with preferred hydroxy groups, for example with lower carboxylic acid residues as substituents on Ar^ and/or A2, can by ether cleavage be transferred to the corresponding hydroxy-substituted compounds of formula I. The ether cleavage takes place under known conditions, for example in the presence of hydrohalic acids, such as hydrogen bromide or hydrogen iodide, in the presence or absence of solvents, such as carboxylic acid, for example lower alkanecarboxylic acid, such as acetic acid, at temperatures between 20°C and the reflux cooling temperature of the reaction mixture, or preferably under running conditions with boron halides, especially boron tribromide, in an inert solvent, such as a chlorinated hydrocarbon, for example methylene chloride or chloroform, with temperatures between -80 and 0°C, preferably between -50 and -20<*>C.
Frie forbindelser med formel I med saltdannede egenskaper, som er dannet under fremgangsmåte, kan på kjent måte bli overført til sine salter. Free compounds of formula I with salt-forming properties, which are formed during the process, can be transferred to their salts in a known manner.
De ifølge oppfinnelsen oppnådde blandingene av isomere kan bli renset til de enkelte isomere på kjent måte, racemater kan for eksempel bli renset ved å danne salter med optisk rene saltoppbyggende reagenser og rense den Oppnådde diastomerblandingen for eksempel ved hjelp av fraksjonert krystall isering. The mixtures of isomers obtained according to the invention can be purified into the individual isomers in a known manner, racemates can for example be purified by forming salts with optically pure salt-forming reagents and purifying the obtained diastomer mixture for example by means of fractional crystallization.
De ovenfor nevnte reaksjoner kan bli gjennomført under kjente reaksjonsbetingelser, fravær eller vanligvis nærvær av oppløsnings- eller fortynningsmiddel, fortrinnsvis slike som er inerte overfor de anvendte reagenser og oppløser disse, i fravær eller nærvær av katalysator, kondensasjonsmiddel eller nøytraliserende reagenser, alt etter typen reaksjon og/eller utføres reaksjonen ved lavere, normal eller forhøyet temperatur, for eksempel i temperaturområdet fra ca -80°C til ca 200°C, fortrinnsvis fra ca -20°C til ca 150°C, for eksempel ved det anvendte oppløsningsmiddelet kokepunkt, under atmosfærisk trykk eller et lukket kar, eventuelt under trykk og/eller i en inert atmosfære, for eksempel under nitrogenatmosfære. The above-mentioned reactions can be carried out under known reaction conditions, absence or usually the presence of a solvent or diluent, preferably those that are inert to the reagents used and dissolve these, in the absence or presence of a catalyst, condensing agent or neutralizing reagents, depending on the type of reaction and/or the reaction is carried out at a lower, normal or elevated temperature, for example in the temperature range from about -80°C to about 200°C, preferably from about -20°C to about 150°C, for example at the boiling point of the solvent used, under atmospheric pressure or a closed vessel, optionally under pressure and/or in an inert atmosphere, for example under a nitrogen atmosphere.
På grunn av den nære sammenhengen mellom forbindelser med formel I i fri form og i form av salter skal det med frie forbindelser henholdsvis deres salter i denne beskrivelsen i praksis forstås også i tilsvarende salter henholdsvis frie forbindelser, så fremt forbindelsene inneholder saltdannende grupper, for eksempel basiske grupper som amino- og imino-grupper, også slike som Ikke inneholder mer enn et umettet karbonatom, som gruppene -NA^Ar^ og/eller -NA2Ar2 som rest på C-atomet i den sentrale fenylringen, hvor Ar^ og Ar2 og/eller Ar2 og A2 ikke er bundet til et umettet karbonatom. Due to the close relationship between compounds of formula I in free form and in the form of salts, free compounds or their salts in this description shall in practice also be understood as corresponding salts or free compounds, as long as the compounds contain salt-forming groups, for example basic groups such as amino and imino groups, also those which do not contain more than one unsaturated carbon atom, such as the groups -NA^Ar^ and/or -NA2Ar2 as residues on the C atom in the central phenyl ring, where Ar^ and Ar2 and /or Ar2 and A2 are not bound to an unsaturated carbon atom.
Forbindelsene, inkludert deres salter, kan også bli oppnådd i form av hydrater, eller deres krystaller kan innebefatte for eksempel oppløsningsmiddelet som ble anvendt til krystalli-ser ing. The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may contain, for example, the solvent used for crystallisation.
Ved fremgangsmåten ifølge oppfinnelsen ble det fortrinnsvis brukt utgangsstoffer som fører til dannelse av de spesielt verdifulle beskrevne forbindelsene. In the method according to the invention, starting materials were preferably used which lead to the formation of the particularly valuable described compounds.
Oppfinnelsen angår også de utføringsformene av fremgangsmåten hvor man går ut fra et ønsket fremgangsmåte tr inn fra anskaffede forbindelser som mellomprodukter og gjennomfører de manglende fremgangsmåtetrinnene, eller de hvor det blir anvendt et utgangsstoff som blir dannet under reaksjons-betingelsene eller i form av et derivat, for eksempel et salt. The invention also relates to those embodiments of the method where one starts from a desired method steps in from acquired compounds as intermediates and carries out the missing method steps, or those where a starting material is used which is formed under the reaction conditions or in the form of a derivative, for example a salt.
Oppfinnelsen angår dessuten farmasøytiske preparater, som inneholder en av forbindelsene med formel I som virksomt stoff. Spesielt foretrukket er preparater for enteral, spesielt oralt, som for parental levering. Preparatene inneholder det virksomme stoffet alene eller eventuelt sammen med et farmasøytisk anvendbart bærermateriale. Doseringen av virkestoffet henger sammen med sykdommen som skal behandles, så vel som art, alder, vekt og individuell tilstand, så vel som av leveringsmåten. The invention also relates to pharmaceutical preparations, which contain one of the compounds of formula I as active substance. Particularly preferred are preparations for enteral, especially oral, as for parental delivery. The preparations contain the active substance alone or possibly together with a pharmaceutically usable carrier material. The dosage of the active substance is related to the disease to be treated, as well as the species, age, weight and individual condition, as well as the method of delivery.
Foretrukket er en farmasøytisk sammensetning som er egnet for levering til en varmblodig, spesielt menneske, som lider av en sykdom som blir påvirket av hemming av en proteinkinase, eksempelvis psoriasis eller en tumor, omfattende en mengde av en forbindelse med formel I eller et salt av denne, dersom det finnes saltdannende grupper, som er virksomme for hemming av proteinkinasen, sammen med minst et farmasøytisk aksep-tabelt bærermateriale. Preferred is a pharmaceutical composition suitable for delivery to a warm-blooded, especially human, suffering from a disease affected by inhibition of a protein kinase, for example psoriasis or a tumor, comprising an amount of a compound of formula I or a salt of this, if there are salt-forming groups, which are effective for inhibiting the protein kinase, together with at least one pharmaceutically acceptable carrier material.
Det faramsøytiske preparatet inneholder fra ca 5 til ca 95% av det virksomme stoffet, hvor enkelt doserte applikasjonsformer inneholder fortrinnsvis fra 20 til ca 90% og ikke enkelt doserte applikasjonsformer inneholder fortrinnsvis fra ca 5 til ca 2056 virksomt stoff. Doseringsenhetsf ormer, som drageer, tabletter eller kapsler inneholder fra ca 0,05g til ca lg av det virksomme stoffet. The pharmaceutical preparation contains from about 5 to about 95% of the active substance, where single dosed application forms preferably contain from 20 to about 90% and non-simply dosed application forms preferably contain from about 5 to about 2056 active substance. Dosage unit forms, such as dragees, tablets or capsules contain from about 0.05g to about 1g of the active substance.
De farmasøytiske preparatene ifølge oppfinnelsen ble fremstilt på kjent måte, for eksempel ved hjelp av konven-sjonelle blande, granulerings, dragerings, oppløsnings eller lyofiliseringsfremgangsmåter. Således kan man oppnå farma-søytiske sammensetninger for oral anvending ved at man blander virksomme stoffer med et eller flere faste bærestoffer, eventuelt granulerer den oppnådde blandingen og bearbeider blandingen henholdsvis granulatet hvis ønsket, eventuelt ved tilsetning av egnede hjelpestoffer, til The pharmaceutical preparations according to the invention were prepared in a known manner, for example by means of conventional mixing, granulation, coating, dissolving or lyophilization methods. Thus, pharmaceutical compositions for oral use can be obtained by mixing active substances with one or more solid carriers, possibly granulating the obtained mixture and processing the mixture or the granulate if desired, possibly by adding suitable excipients, to
tabletter eller dragekjerner. tablets or dragon cores.
Egnede bærestoffer er i særdeleshet fyllstoffer, som sukker, for eksempel lactose, saccharose, mannit eller sorbit, cellulosepreparat og/eller kalsiumfosfat, for eksempel trikalsiumfosfat eller kalsiumhydrogenfosfat, for uten bindemiddel som stivelse, for eksempel mais-, hvete-, ris-eller potetstivelse, metylcellulose, hydroksymetylpropyl-metylcellulose, natriumkarboksymetylcellulose og/eller polyvinylpyrrolidin, og/eller hvis ønsket, sprengmiddel som de over nevnte stivelsene, dessuten karboksymetylstivelse, tverrbundet polyvinylpyrrolidon, alginsyre eller et salt av dette, som natriumalginat. Ytterligere hjelpemidler er i første rekke flytregulerende og smørende midler, for eksempel kiselsyre, talk, stearinsyre eller salter av dette, som magnesium- eller kalsiumstearat, og/eller polyetylenglykol eller derivater av disse. Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparation and/or calcium phosphate, for example tricalcium phosphate or calcium hydrogen phosphate, for without a binder such as starch, for example corn, wheat, rice or potato starch . Further auxiliaries are primarily flow regulating and lubricating agents, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol or derivatives thereof.
Dragekjernene kan bli utstyrt med egnede magesaftresistente overtrekk, hvor man anvender blant annet konsentrerte sukkeroppløsninger som inneholder eventuelt gummiarabikum, talk, polyvinylpyrrolidon, polyetylenglykol og/eller titandioksyd, lakkoppløsninger i egnede organiske opp-løsningsmidler eller oppløsningsmiddelblandinger eller, for fremstilling av magesaftresistente overtrekk, oppløsninger av egnede cellulosepreparater som acetylcelluloseftalat eller hydroksypropylmetylcelluloseftalat. Tablettene eller drageovertrekkene kan bli tilført fargestoffer eller pigmenter, for eksempel for identifisering eller kjenne-tegning av forskjellige doser av virksomt stoff. The kite cores can be equipped with suitable gastric juice-resistant coatings, where one uses, among other things, concentrated sugar solutions containing possibly gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragon coatings can be added with dyes or pigments, for example for identification or identification of different doses of active substance.
Oralt anvendbare farmasøytiske sammensetninger er også stikk-kapsler av gelatin, som myke, lukkede kapsler av gelatin og en mykner som glycerin eller sorbit. Stikk-kapslene kan inneholde det virksomme stoffet i form av et granulat, for eksempel i blanding med fyllstoffer, som maisstivelse, bindemidler og/eller glidemidler, som talk eller magnesium-stearat og eventuelt med stabilisatorer. I myke kapsler er det virksomme stoffet fortrinnsvis oppløst eller suspendert i egnede flytende hjelpestoffer, som fettoljer, parafinolje eller flytende polyetylenglycol, hvor eventuelt stabilistorer kan være tilsatt. Orally usable pharmaceutical compositions are also injectable capsules of gelatin, such as soft, closed capsules of gelatin and a plasticizer such as glycerin or sorbitol. The stick capsules can contain the active substance in the form of a granule, for example in a mixture with fillers, such as corn starch, binders and/or lubricants, such as talc or magnesium stearate and possibly with stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycol, where stabilizers may be added.
Ytterligere orale applikasjonsformer er for eksempel på vanlig måte siruper som inneholder virkestoffet for eksempel i suspendert form og i en konsentrasjon på fra 5% til 20%, fortrinnsvis ca 10% eller en annen egnet konsentrasjon, som for eksempel ved mål på 5 eller 10 ml gir en egnet enkelt-dose. Dessuten kommer for eksempel også pulverformige eller flytende konsentrater for fremstilling av "Shakes", for eksempel 1 melk, 1 betrakting. Slike konsentrater kan også være inntatt i mengder for enkeltdoser. Further oral forms of application are, for example, in the usual way syrups containing the active ingredient, for example in suspended form and in a concentration of from 5% to 20%, preferably about 10% or another suitable concentration, such as for example in measures of 5 or 10 ml provides a suitable single dose. In addition, for example, powdery or liquid concentrates for the production of "Shakes", for example 1 milk, 1 consideration, also come. Such concentrates can also be taken in amounts for single doses.
Som rektalt anvendbare farmasøytiske preparater kommer for eksempel stikkpiller i betraktning, som består av en blanding av det virksomme stoffet i en stikkpillegrunnmasse. Som stikkpillegrunnmasse egner for eksempel naturlig eller syntetisk triglycerider, parafinhydrokarboner, polyetylenglykol eller høyere alkanoler seg. As rectally applicable pharmaceutical preparations, for example, suppositories come into consideration, which consist of a mixture of the active substance in a suppository base. Natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycol or higher alkanols are suitable as suppository base material.
For parental levering egner først og fremst vandige opp-løsninger av et virksomt stoff i vannoppløselig form seg, for eksempel et vannoppløselig salt eller vandige injeksjons-suspensjoner, som inneholder viskositetsøkende stoffer, for eksempel natriumkarboksymetylcellulose, sorbit og/eller dekstran og eventuelle stabilisatorer. Der kan det virksomme stoffet foreligge eventuelt sammen med hjelpestoffer, også i form av et lyofilisett og bli bragt i oppløsning for parental levering ved tilsetning av egnede oppløsningsmidler. For parental delivery, primarily aqueous solutions of an active substance in water-soluble form are suitable, for example a water-soluble salt or aqueous injection suspensions, which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and any stabilizers. There, the active substance can optionally be present together with excipients, also in the form of a lyophilisate kit and be brought into solution for parental delivery by adding suitable solvents.
Oppløsninger som blir anvendt for eksempel for parental levering, kan også bli anvendt som infusjonsoppløsninger. Solutions that are used, for example, for parental delivery, can also be used as infusion solutions.
Oppfinnelsen angår dessuten anvendelsen av en forbindelse med formel I eller et salt derav, for fremstilling av et medikament mot sykdommer som påvirkes av hemming av protein-tyrosinkinaser eller serin/treoninkinaser. Forbindelsene med formel I kan bli gitt profylaktisk eller terapeutisk, fortrinnsvis mot de nevnte sykdommer, i en mengde som er virksom mot de nevnte sykdommene hos varmblodige, for eksempel mennesker, som behøver en slik behandling, hvor man fortrinnsvis anvender dette i form av farmasøytiske preparater. Da blir det med en kroppsvekt på ca 70 kg benyttet en daglig dose på ca 0,1 g til ca 5 g, fortrinnsvis ca 0,05 g til ca 2 g av en forbindelse ifølge oppfinnelsen. The invention also relates to the use of a compound of formula I or a salt thereof, for the production of a drug against diseases affected by inhibition of protein tyrosine kinases or serine/threonine kinases. The compounds of formula I can be given prophylactically or therapeutically, preferably against the mentioned diseases, in an amount which is effective against the mentioned diseases in warm-blooded, for example humans, who need such treatment, where this is preferably used in the form of pharmaceutical preparations . Then, with a body weight of about 70 kg, a daily dose of about 0.1 g to about 5 g, preferably about 0.05 g to about 2 g, of a compound according to the invention is used.
De etterfølgende eksemplene illustrerer oppfinnelsen; temperaturen er angitt i grader Celsius. Følgende for-kortelser blir brukt: eter tilsvarer dietyleter; etylacetat tilsvarer eddiksyreetylester; THF = tetrahydrofuran; DMF = N,N-dimetylformamid; RT tilsvarer romtemperatur; MS tilsvarer massespektrum; FAB tilsvarer "Fast Atom Monbardment". The following examples illustrate the invention; the temperature is given in degrees Celsius. The following abbreviations are used: ether corresponds to diethyl ether; ethyl acetate corresponds to acetic acid ethyl ester; THF = tetrahydrofuran; DMF = N,N-dimethylformamide; RT corresponds to room temperature; MS corresponds to mass spectrum; FAB is equivalent to "Fast Atom Montbardment".
Eksempel 1: 4. 5- bis( anllino ) ftalimld Example 1: 4. 5-bis(anllino) phthalimld
En suspensjon av 230 mg (0,7 mmol) 4,5-bis(anilino)ftalsyredimetylester i 23 ml etylenglykol ble oppvarmet til 120°C; ammoniakgass bnle ledet gjennom under omrøring i 24 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble deretter vasket to ganger med vann og en gang med mettet koksaltoppløsning, tørket over natriumsulfat og inndampet. Inndampingsresten ble kromatografert med diklormetan/metanol 40:1 på kiselgel, produktfraksjonen slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, smeltepunkt 215-217°C, FAB-MS: 330[M<+>+E]. A suspension of 230 mg (0.7 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 23 ml of ethylene glycol was heated to 120°C; ammonia gas was passed through with stirring for 24 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was then washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The evaporation residue was chromatographed with dichloromethane/methanol 40:1 on silica gel, the product fraction was combined and evaporated. The title compound was obtained as yellow crystals, mp 215-217°C, FAB-MS: 330[M<+>+E].
aj 4 . 5- bis( trimetvlsilvloksv) cykloheksa- l . 4- dien- l . 2-dlkarbons<y>redimet<y>lester ouch 4 . 5-bis(trimethylsilvlox) cyclohexa-l. 4-diene-l. 2-dlcarbon<y>redimeth<y>lester
En oppløsning av 7,1 g (50 mmol) acetylendikarbonsyredimetyl-ester i 30 ml toluen ble under argonatmosfære dryppet til 12,5 g (50 mmol) 2,3-bis(trimetylsilyloksy)-l,3-butadien (95$) og deretter kokt i 19 timer ved tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet inndampet og resten destillert i høyvakuum (0,1 mbar, 124-127°C). Forbindelsen i tittelen ble oppnådd som en høyviskøs olje, <1>H-NMR (CDC13):S - 0,18 (s, 18E), 3,09 (s, 4H), 3,78 (s, 6H). A solution of 7.1 g (50 mmol) of acetylene dicarboxylic acid dimethyl ester in 30 ml of toluene was added dropwise under an argon atmosphere to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (95$) and then boiled for 19 hours at reflux. The reaction mixture was cooled, the solvent evaporated and the residue distilled in high vacuum (0.1 mbar, 124-127°C). The title compound was obtained as a highly viscous oil, <1>H-NMR (CDCl 3 ): S - 0.18 (s, 18E), 3.09 (s, 4H), 3.78 (s, 6H).
b) 4 . 5- bis( anllino) ftalsyredlinetvlester b) 4 . 5- bis(anllino) phthalic acid dlinet ester
En oppløsning av 5,6 g (15 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyredimetylester og 5,5 ml (60 mmol) anilin i 60 ml iseddik ble kokt i 4 timer med tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket etter hverandre i 20 ml IN HC1, 50 ml mettet NaHC03 og to ganger i 20 ml vann, tørket over natriumsulfat og inndampet. Råproduktet ble omkrystallisert fra etanol. Forbindelsen i tittelen ble oppnådd som gule krystaller, smeltepunkt 17S'C, FAB-MS: 377 [M<+>+H]. A solution of 5.6 g (15 mmol) 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester and 5.5 ml (60 mmol) aniline in 60 ml glacial acetic acid was boiled in 4 hours with reflux cooling. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed successively in 20 ml 1N HCl, 50 ml saturated NaHCO 3 and twice in 20 ml water, dried over sodium sulfate and evaporated. The crude product was recrystallized from ethanol. The title compound was obtained as yellow crystals, mp 17S'C, FAB-MS: 377 [M<+>+H].
Eksempel 2j 5 . 8- difenvl- 5 . 8- diaza- 5 . 6. 7 . 8- tetrahvdro-naftalin- 2. 3- dikarbonsyrelmid Example 2j 5 . 8- difenvl- 5 . 8- diaza- 5 . 6. 7 . 8- tetrahydro-naphthalene- 2. 3- dicarboxylic acid imide
Analogt med eksempel 1 ble 40 mg (0,1 mmol) 5,8-difenyl-5,8-diaza-5,6,7,8-tetrahydronaftalin-2,3-dikarbonsyredimetylester i 4ml etylenglykol oppvarmet til 120°C, hvor det ble ledet gjennom ammoniakgass under omrøring i 24 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket to ganger med vann og en gang med mettet koksaltoppløsning, tørket over natriumsulfat og inndampet. Resten ble kromatografert med diklormetan/metanol 20:1 på kiselgel, produktfraksjonene ble slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd som gule krystaller, FAB-MS: 356[M<+>+E]. Analogous to example 1, 40 mg (0.1 mmol) of 5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylic acid dimethyl ester in 4 ml of ethylene glycol was heated to 120°C, where it was passed through ammonia gas with stirring for 24 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 20:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as yellow crystals, FAB-MS: 356[M<+>+E].
aj 5 , 8- difenyl- 5. 8- diaza- 5. 6. 7. 8- tetrahydro- naftalin- 2. 3-dikarbonsvredlmet<y>lester aj 5 , 8- diphenyl- 5. 8- diaza- 5. 6. 7. 8- tetrahydro- naphthalene- 2. 3- dicarbosvredlmet<y>ester
En oppløsning av 2,24 g (6 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyremetylester (eksempel la) og 5,1 g (24 mmol) N,N'-difenyletylendiamin i 24 ml iseddik ble kokt i to timer under tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket med 20 ml IN HC1, 50 ml mettet NaHC03 og to ganger med 20 ml vann, tørket over natrlumsulfat og Inndampet. Råproduktet ble kromatografert med heksan/etylacetat 3:1 på kiselgel, produktfraksjonen inndampet og resten omkrystallisert fra etanol. Forbindelsen i tittelen ble oppnådd som orange krystaller, FAB-MS: 402[M<+>], 403[M<+>+H], A solution of 2.24 g (6 mmol) 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) and 5.1 g (24 mmol) N,N' -diphenylethylenediamine in 24 ml of glacial acetic acid was boiled for two hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed with 20 ml of 1N HCl, 50 ml of saturated NaHCO 3 and twice with 20 ml of water, dried over sodium sulfate and evaporated. The crude product was chromatographed with hexane/ethyl acetate 3:1 on silica gel, the product fraction evaporated and the residue recrystallized from ethanol. The title compound was obtained as orange crystals, FAB-MS: 402[M<+>], 403[M<+>+H],
Eksempel 3: 4. 5- bis( 4- fluoranllino) ftalimld Example 3: 4. 5-bis(4-fluoroanllino) phthalimld
Analogt med eksempel 1 ble 290 mg (0,7 mmol) 4,5-bis(4-f luoranllino)ftalsyredimetylester i 22 ml etylenglykol oppvarmet til 120"C og ammoniakgass ble ledet gjennom under omrøring I 18 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med heksan/etylacetat 1:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd som orange krystaller, smeltepunkt større enn 220°C, FAB-MS: 366 [M<+>+H]. Analogously to example 1, 290 mg (0.7 mmol) of 4,5-bis(4-fluoroanllino)phthalic acid dimethyl ester in 22 ml of ethylene glycol was heated to 120°C and ammonia gas was passed through with stirring for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fractions combined and evaporated. The title compound was obtained as orange crystals , melting point greater than 220°C, FAB-MS: 366 [M<+>+H].
a) 4. 5- bis( 4- fluoranilino) ftalsyredimetylester a) 4. 5-bis(4-fluoroanilino) phthalic acid dimethyl ester
En oppløsning av 2,4 g (6 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyremetylester (eksempel la) og 2,3 ml (24 mmol) 4-fluoranilin i 60 ml iseddik ble kokt i 2 timer med tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket henholdsvis med 20 ml IN HC1, 50 ml mettet NaHC03 og to ganger 20 ml vann, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med etylacetat/heksan 2:1 på kiselgel, produktfraksjonene inndampet og omkrystallisert fra etylacetat/heksan. Forbindelsene i tittelen ble oppnådd som gule krystaller, <1>H-NMR (CDC13):5 = 7,40 (S, 2E), 7,10-6,80 (m, 8H), 5,70 (br s, 2H), 3,83 (s, 6H). A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 20 ml 1N HCl, 50 ml saturated NaHCO 3 and twice 20 ml water, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 2:1 on silica gel, the product fractions evaporated and recrystallized from ethyl acetate/hexane. The title compounds were obtained as yellow crystals, <1>H-NMR (CDCl 3 ): δ = 7.40 (S, 2E), 7.10-6.80 (m, 8H), 5.70 (br s, 2H), 3.83 (s, 6H).
Eksempel 4: 4. 5- bis( 4- benzyloksy- anilino) ftalimid Example 4: 4. 5-bis(4-benzyloxy-anilino) phthalimide
Analogt med eksempel 1 ble 294,4 mg (0,5 mmol) 4,5-bis(4-benzyloksy-anillno )ftalsyredimetylester i 22 ml etylenglykol oppvarmet til 120°C, og ammoniakgass ble ledet gjennom under omrøring i 16 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med diklormetan/metanol 50:1 på kislegel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd som røde krystaller, smeltepunkt 187 til 189°C, FAB-MS: 542[M<+>+H]. Analogous to example 1, 294.4 mg (0.5 mmol) of 4,5-bis(4-benzyloxy-anillno)phthalic acid dimethyl ester in 22 ml of ethylene glycol was heated to 120°C, and ammonia gas was passed through with stirring for 16 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 50:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as red crystals, mp 187 to 189°C, FAB-MS: 542[M<+>+H].
a) 4 t5- bis( 4- benzyloksy- anilino) ftalsyredimetylester a) 4 t5-bis(4-benzyloxy-anilino) phthalic acid dimethyl ester
En oppløsning av 2,4 g (6 mmol) 4,5-bis(trimétylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyredimetylester (eksempel la) og 4,8 g (24 mmol) 4-benzyloksyanilin i 24 ml iseddik ble kokt i 2 timer ved tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket i henholdsvis 20 ml IN HC1, 50 ml mettet NaHC03 og to ganger 20 ml avnn, tørket over natriumsulfat og inndampet. Resten ble oppløst i varm etylacetat og filtrert, så lot man den krystallisere ved 0°C. Den krystallinske resten ble kromatografert med etylacetat/heksan 3:2 på kiselgel, produktfraksjonene inndampet og omkrystallisert fra etylacetat/heksan. Forbindelsen i tittelen ble oppnådd som beige krystaller, FAB-MS: 589[M<+>+H]. A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid was boiled for 2 hours at reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed in respectively 20 ml of 1N HCl, 50 ml of saturated NaHCO 3 and twice 20 ml of aqn, dried over sodium sulfate and evaporated. The residue was dissolved in hot ethyl acetate and filtered, then allowed to crystallize at 0°C. The crystalline residue was chromatographed with ethyl acetate/hexane 3:2 on silica gel, the product fractions evaporated and recrystallized from ethyl acetate/hexane. The title compound was obtained as beige crystals, FAB-MS: 589[M<+>+H].
Eksempel 5: 4, 5- bisr4-( N. N- dietvlamino)- anilino] ftalimid-bish<y>droklorid Example 5: 4,5-bis[4-(N,N-diethylamino)-anilino]phthalimide bis<y>hydrochloride
Analogt med eksempel 1 ble 294,4 mg (0,5 mmol) 4,5-bis[4-(N,N-dietylamino)-anilino]ftalsyredimetylester i 22 ml etylenglykol oppvarmet til 120°C hvoretter ammoniakgass ble ledet gjennom under omrøring i 22 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksalt oppløsning, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med diklormetan/metanol 30:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Den røde krystallinske resten ble oppløst I diklormetan og gjort til 4,1 N HC1 (g) i eter. Den krystallinske utfellingen ble filtrert fra og tørket. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, smeltepunkt 228 til 230°C, FAB-MS: 472 [M<+>+H]. Analogous to example 1, 294.4 mg (0.5 mmol) of 4,5-bis[4-(N,N-diethylamino)-anilino]phthalic acid dimethyl ester in 22 ml of ethylene glycol was heated to 120°C after which ammonia gas was passed through with stirring for 22 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 30:1 on silica gel, the product fractions were combined and evaporated. The red crystalline residue was dissolved in dichloromethane and made into 4.1 N HCl (g) in ether. The crystalline precipitate was filtered off and dried. The title compound was obtained as yellow crystals, mp 228 to 230°C, FAB-MS: 472 [M<+>+H].
a) 4. 5- bisr4- N. N- dietvlamino )- anllinolftalsyredimetylester a) 4.5-bisr4-N.N-diethylamino)-anllinolphthalic acid dimethyl ester
En oppløsning av 2,4 g (6 mmol) 4 ,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyremetylester (eksempel la) og 3,94g (24 mmol) 4-(N,N-dietylamino)-anilin i 24 ml iseddik ble kokt i 2 timer med tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket med henholdsvis 50 ml mettet NaHC03 og to ganger 20 ml vann, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med diklormetan/metanol 400:15 på kiselgel, produktfraksjonene inndampet og på nytt kromatografert med etylacetat/heksan 1:1 på kiselgel. Produktfraksjonene ble inndampet. Forbindelsene i tittelen ble oppnådd som grønne krystaller, FAB-MS: 518[M<+>], 519 [M<+>+H]. A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) and 3.94 g (24 mmol) of 4-(N, N-diethylamino)-aniline in 24 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 50 ml of saturated NaHCO 3 and twice with 20 ml of water, dried over sodium sulfate and evaporated. The residue was chromatographed with dichloromethane/methanol 400:15 on silica gel, the product fractions evaporated and again chromatographed with ethyl acetate/hexane 1:1 on silica gel. The product fractions were evaporated. The title compounds were obtained as green crystals, FAB-MS: 518[M<+>], 519 [M<+>+H].
Eksempel 6: 4. 5- bis( cykloheksylamino) ftalimid Example 6: 4. 5-bis(cyclohexylamino) phthalimide
Analogt med eksempel 1 ble 194 mg (0,5 mmol) 4,5-bis-(cykloheksylamino)ftalsyredimetylester i 15 ml etylenglykol oppvarmet til 120°C, deretter ble ammoniakgass ledet gjennom under omrøring i løpet av 12 timer. Reaksjonsblandingen ble avkjølt, ekstrahert med mettet natriumklorid og med etylacetat. Atylacetat fasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksalt oppløsning, tørket over natriumsulfat og inndampet. Resten ble kromatografert med heksan/etylacetat 3:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd som orange krystaller, smeltepunkt 170 til 175°C, FAB-MS: 342[M<+>+H]. Analogously to example 1, 194 mg (0.5 mmol) of 4,5-bis-(cyclohexylamino)phthalic acid dimethyl ester in 15 ml of ethylene glycol was heated to 120°C, then ammonia gas was passed through with stirring during 12 hours. The reaction mixture was cooled, extracted with saturated sodium chloride and with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue was chromatographed with hexane/ethyl acetate 3:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as orange crystals, mp 170 to 175°C, FAB-MS: 342[M<+>+H].
a) 4. 5- bis( cykloheksylamino) ftalsyredimetylester a) 4. 5- bis (cyclohexylamino) phthalic acid dimethyl ester
En oppløsning av 2,4 g (6 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyremetylester (eksempel la) i 21,5 ml (188 mmol) cykloheksylamin og 4,5 iseddik ble kokt i 3,5 time ved tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket henholdsvis med 100 ml 2N HC1, 50 ml mettet NaHC03 og to ganger med 20 ml vann, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med etylacetat/heksan 5:12 på kiselgel, produktfraksjonene inndampet og igjen kromatografert med etylacetat/heksan 1:4. Forbindelsen i tittelen ble oppnådd som gul olje, FAB-MS: 388 [M<+>]. A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid methyl ester (Example 1a) in 21.5 ml (188 mmol) of cyclohexylamine and 4, 5 glacial acetic acid was boiled for 3.5 hours at reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 100 ml of 2N HCl, 50 ml of saturated NaHCO 3 and twice with 20 ml of water, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 5:12 on silica gel, the product fractions evaporated and again chromatographed with ethyl acetate/hexane 1:4. The title compound was obtained as a yellow oil, FAB-MS: 388 [M<+>].
Som biprodukt ble det oppnådd 4-cykloheksylamino-ftalsyredimetylester, som ble omdannet analogt med eksempel 6 i 4-cykloheksylamino-ftalimid. På denne måten ble det oppnådd et fargeløst pulver: FAB-MS: 245 [M<+>], smeltepunkt 217-219<0>C. As a by-product, 4-cyclohexylamino-phthalic acid dimethyl ester was obtained, which was converted analogously to example 6 into 4-cyclohexylamino-phthalimide. In this way a colorless powder was obtained: FAB-MS: 245 [M<+>], melting point 217-219<0>C.
Eksempel 7: 4. 5- bis( 4- metoksyanilino) ftalimid Example 7: 4. 5-bis(4-methoxyanilino) phthalimide
Analogt med eksempel 1 ble 393 mg (0,9 mmol) 4,5-bis(4-metoksyanilino)ftalsyredimetylester i 25 ml etylenglykol oppvarmet til 120"C, og deretter ble ammoniakgass ledet gjennom omrøring i løpet av 18 timer. Reaksjonsblandingen ble avkjølt, mettet med natriumklorid og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natriumsulfat og inndampet. Resten ble kromatograftert med etylaceta/heksan 1:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, smeltepunkt 191 til 193"C, FAB-MS: 390 [M<+>+H]. Analogous to example 1, 393 mg (0.9 mmol) of 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol was heated to 120°C, and then ammonia gas was passed through stirring during 18 hours. The reaction mixture was cooled , saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:1 on silica gel, the product fractions were combined and evaporated. The compound in the title was obtained as yellow crystals, mp 191 to 193°C, FAB-MS: 390 [M<+>+H].
a) 4. 5- bis( 4- metoksyanilino) ftalsyredimetylester a) 4. 5- bis(4-methoxyanilino) phthalic acid dimethyl ester
En oppløsning av 2,4 g (6 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyredimetylester (eksempel la) og 3,0 g (24 mmol) 4-anisidin i 24 ml iseddik ble kokt i 2 timer med tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket henholdsvis med 20 ml IN HC1, 50 ml mettet NaHC03 og 2 ganger 20 ml vann, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med etylacetat/heksan 1:1 på kiselgel og produktfraksjonene inndampet. Forbindelsen i tittelen ble oppnådd som gult skum, FAB-MS: 437 [M<+>+H]. A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.0 g (24 mmol) of 4-anisidine in 24 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 20 ml 1N HCl, 50 ml saturated NaHCO 3 and 2 times 20 ml water, dried over sodium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:1 on silica gel and the product fractions evaporated. The title compound was obtained as a yellow foam, FAB-MS: 437 [M<+>+H].
Eksempel 8: 4. 5- bis( 2- iodanilino) ftalimid Example 8: 4. 5-bis(2-iodanilino) phthalimide
Analogt med eksempel 1 ble 1,48 g (2,36 mmol) 4,5-bis(2-iodanilino)ftalsyredimetylester i 25 ml etylenglykol oppvarmet til 120°C og det ble ført gjennom ammoniakgass under omrøring i 19 timer. Reaksjonsblandingen ble avkjølt, fortynnet med saltlake og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natriumsulfat og inndampet. Den oppnådde resten etter inndamping ble filtrert med diklormetan gjennom kiselgel og produktfraksjonene ble slått sammen og inndampet. Den oppnådde resten etter inndamping ble krystallisert fra kokende diklormetan. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, smeltepunkt 108-110°C, FAB-MS: 582 [M<+>+H]. Analogous to example 1, 1.48 g (2.36 mmol) of 4,5-bis(2-iodanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol was heated to 120°C and it was passed through ammonia gas with stirring for 19 hours. The reaction mixture was cooled, diluted with brine and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue obtained after evaporation was filtered with dichloromethane through silica gel and the product fractions were combined and evaporated. The residue obtained after evaporation was crystallized from boiling dichloromethane. The title compound was obtained as yellow crystals, mp 108-110°C, FAB-MS: 582 [M<+>+H].
a) 4. 5- bis( 2- iodanilino) ftalsyredimetylester a) 4. 5-bis(2-iodanilino) phthalic acid dimethyl ester
En oppløsning av 2,4 g (6 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-dien-l,2-dikarbonsyredimetylester (eksempel la) og 5,3 g (24 mmol) 2-iodanilin i 24 ml iseddik ble kokt i 2 timer med tilbakeløpskjøling. Reaksjonsblandingen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i diklormetan og oppløsningen vasket henholdsvis med 20 ml IN BC1, 50 ml mettet NaHC03 og to ganger 20 ml vann, tørket over natrlumsulfat og inndampet. Den oppnådde resten etter inndamping ble kromatografert med etylacetat/heksan 2:1 på kiselgel og produktfraksjonene inndampet. Forbindelsen i tittelen ble oppnådd i form av et gult skum: ^H-NMR (DMSO-d6):S - 7,91 (dxd, <J>1<=>8, J2=l, 2H), 7,39(dxdxd, J1=10, J2=8, J3=l, 2H), 7,32 (br s, 2H), 7,22-7,05(m,2H), 7,01 (s, 2E), 6,88 (txd, Jt=8, Jd=l,2H), 3,73 (s, 6E). A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 5.3 g (24 mmol) of 2-iodaniline in 24 ml of glacial acetic acid was boiled for 2 hours under reflux. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in dichloromethane and the solution washed respectively with 20 ml 1N BCl, 50 ml saturated NaHCO 3 and twice 20 ml water, dried over sodium sulfate and evaporated. The residue obtained after evaporation was chromatographed with ethyl acetate/hexane 2:1 on silica gel and the product fractions evaporated. The title compound was obtained as a yellow foam: 1H-NMR (DMSO-d6):S - 7.91 (dxd, <J>1<=>8, J2=1, 2H), 7.39( dxdxd, J1=10, J2=8, J3=l, 2H), 7.32 (br s, 2H), 7.22-7.05(m, 2H), 7.01 (s, 2E), 6 .88 (txd, Jt=8, Jd=1.2H), 3.73 (s, 6E).
Eksempel 9: 4. 5- bis( 2- cyananilino) ftalimid Example 9: 4. 5-bis(2-cyananilino) phthalimide
En oppløsning av 581 mg (1 mmol) 4,5-bis(2-iodanilino)-ftalimid og 197 mg (2,2 mmol) kobber(I)cyanid i DMF omrørt i 6 timer ved 130-140°C, hvorved den mørkebrune oppløsningen går over til en mørkegul suspensjon. Reaksjonsblandingen ble avkjølt til 80°C og fortynnet med 8 ml eddikester. Etter ytterligere avkjøling til 60 til 70°C ble en oppløsning av 467 mg (2,88 mmol) jern( III )klorid i 1,6 ml vann og 300 pl konsentrert saltsyre dryppet til og omrørt i 30 minutter. Reaksjonsblandingen ble tilsatt 2 ml vann og Hyflo Super Cel® A solution of 581 mg (1 mmol) 4,5-bis(2-iodanilino)-phthalimide and 197 mg (2.2 mmol) copper (I) cyanide in DMF stirred for 6 hours at 130-140°C, whereby the the dark brown solution changes to a dark yellow suspension. The reaction mixture was cooled to 80°C and diluted with 8 ml of acetic acid. After further cooling to 60 to 70°C, a solution of 467 mg (2.88 mmol) of iron (III) chloride in 1.6 ml of water and 300 µl of concentrated hydrochloric acid was added dropwise and stirred for 30 minutes. To the reaction mixture was added 2 ml of water and Hyflo Super Cel®
(kiselgur fra firmaet Fluka, Buchs, Sveits) og filtrert gjennom supergel og fasene ble skilt. Den vandige fasen ble ekstrahert en gang med eddikester, de sammenslåtte organiske fasene ble vasket to ganger med vann, en gang med mettet natriumbikarbonatoppløsning og igjen to ganger med vann, tørkte over magneslumsulfat og inndampet. Den resulterende oljeaktige brune krystallblandingen ble kromatografert med etylacetat/heksan 2:3 på kiselgel. Produktfraksjonene ble inndampet og krystallisert fra kokende diklormetan. For- (diatomaceous earth from the company Fluka, Buchs, Switzerland) and filtered through supergel and the phases were separated. The aqueous phase was extracted once with ethyl acetate, the combined organic phases were washed twice with water, once with saturated sodium bicarbonate solution and again twice with water, dried over magnesium sulfate and evaporated. The resulting oily brown crystal mixture was chromatographed with ethyl acetate/hexane 2:3 on silica gel. The product fractions were evaporated and crystallized from boiling dichloromethane. For-
bindelsen i tittelen ble oppnådd som blekgule krystaller: FAB-MS: 330 (M<+>+E), smeltepunkt 279-280°C. the title compound was obtained as pale yellow crystals: FAB-MS: 330 (M<+>+E), mp 279-280°C.
Som biprodukt ble det oppnådd 5-anilino-4-(2-cyananilino)-ftalimid i form av gule krystaller: FAB-MS: 355 (M<+>+E), smeltepunkt 115-117°C. 5-anilino-4-(2-cyananilino)-phthalimide was obtained as a by-product in the form of yellow crystals: FAB-MS: 355 (M<+>+E), melting point 115-117°C.
Eksempel 10: 4. 5- bis( 2- nitroanilino) ftalamid. 4-( 4- nitro-anillno- 5-( 2. 4- dinltroanlllno ) ftalimid og 4. 5- bls( 4- nitro-anillno) ftallmid Example 10: 4. 5-bis(2-nitroanilino) phthalamide. 4-( 4- nitro-anillno- 5-( 2. 4- dinitroanillno ) phthalimide and 4. 5- bls( 4- nitro-anillno) phthalimide
Til en blanding av 12 mmol acetanhydrid og 24 mmol iseddik og 7,5 mmol salpetersyre ( 10056) ble det ved temperaturer under 20'C tilsatt 990 mg (3 mmol) 4,5-bis(anilino)ftalimid. Etter 20 minutters omrøring ble reaksjonsblandingen slått på is og ekstrahert med iseddik. Den organiske fasen ble vasket en gang med mettet NaHCC^-oppløsning og en gang med vann, tørket over natrlumsulfat og filtrert. Ved to gangers kromatografering på kiselgel med en gradient av diklormetan/eddikester 1:1 til 3:1 ble de følgende amorfe forbindelsene oppnådd: 4,5-bis(2-nitroanilino)ftalimid i form av et raedt-svart pulver: smeltepunkt 87 til 90° C; 4-(4-nitroanilino-5-(2,4-dinitroanilino)ftalimid i form av et rød-svart pulver: smeltepunkt 176 til 178° C, 1-E-NMR (DMS0-d6): 9,25 (br s, 2H), 8,85 (d, J=2,5, 1H), 8,16 (dxd, J1=8, J2=2,5, 1E) , 8,13 (d, j=9, 2H), 7,88 (s, 1E), 7,75 (s, 1H), 7,17 (d, J=9, 2H), 6,96 (d, J=9,5, 1H); 4,5-bis(4-nitroanilino )ftalimid i form av et rødt glinsende pulver: smeltepunkt >250°C, zers. fra ca 105° C, -*-E-NMR (DMS0-d6): 9,22 (br s, 2E), 8,12 (d, J=9,l, 4E), 7,71 (s, 2E), 7,13 (d, J=9,l, 4E); <13>C-NMR (DMSO-d6): 168,9 s, 149,8 s, 139,6 s, 138,2 s, 128,2 s, 125,9 d, 116,2 d, 115,6 d. To a mixture of 12 mmol of acetic anhydride and 24 mmol of glacial acetic acid and 7.5 mmol of nitric acid (10056), 990 mg (3 mmol) of 4,5-bis(anilino)phthalimide was added at temperatures below 20°C. After stirring for 20 minutes, the reaction mixture was put on ice and extracted with glacial acetic acid. The organic phase was washed once with saturated NaHCO3 solution and once with water, dried over sodium sulfate and filtered. Chromatography twice on silica gel with a gradient of dichloromethane/acetic ester 1:1 to 3:1 gave the following amorphous compounds: 4,5-bis(2-nitroanilino)phthalimide in the form of a red-black powder: melting point 87 to 90°C; 4-(4-nitroanilino-5-(2,4-dinitroanilino)phthalimide in the form of a red-black powder: melting point 176 to 178° C, 1-E-NMR (DMS0-d6): 9.25 (br s , 2H), 8.85 (d, J=2.5, 1H), 8.16 (dxd, J1=8, J2=2.5, 1E) , 8.13 (d, j=9, 2H) , 7.88 (s, 1E), 7.75 (s, 1H), 7.17 (d, J=9, 2H), 6.96 (d, J=9.5, 1H); 4.5 -bis(4-nitroanilino )phthalimide in the form of a red glistening powder: melting point >250°C, zers from about 105°C, -*-E-NMR (DMS0-d6): 9.22 (br s, 2E ), 8.12 (d, J=9,1, 4E), 7.71 (s, 2E), 7.13 (d, J=9,1, 4E); <13>C-NMR (DMSO- d6): 168.9s, 149.8s, 139.6s, 138.2s, 128.2s, 125.9d, 116.2d, 115.6d.
Eksempel 11: 4. 5- bis( 4- aminoani1ino) ftalimid Example 11: 4. 5-bis(4-aminoaniline) phthalimide
Oppløsning av 38 mg (0,009 mmol) 4,5-bis(4-nitroanilino)-ftalimid i 15 ml THF ble hydrert med 1056 Raney-Nickel som katalystor i løpet av 3 timer ved normal trykk og RT. Katalysatoren ble filtrert fra reaksjonsblandingen som ble inndampet. Forbindelsen i tittelen ble oppnådd som et svakt, gulaktig pulver: smeltepunkt 154 til 157°C, FAB-MS: 360 Solution of 38 mg (0.009 mmol) of 4,5-bis(4-nitroanilino)-phthalimide in 15 ml of THF was hydrogenated with 1056 Raney-Nickel as catalyst during 3 hours at normal pressure and RT. The catalyst was filtered from the reaction mixture which was evaporated. The title compound was obtained as a faint yellowish powder: mp 154 to 157°C, FAB-MS: 360
(M<+>+H). (M<+>+H).
Eksempel 12: Analogt til eksemplene angitt i parentes ble det fremstilt: (a) 4,5-bis(4-iodanilino)ftalimid, FAB-MS: 582 (M<+>+H), smeltepunkt: 246-147°C (analogt med eksempel 8). (b) 4,5-bis(3-iodanilino)ftalimid, FAB-MS: 582 (M<+>+H), smeltepunkt: 244-245°C (analogt med eksempel 8). (c) 4,5-bis(2,6-dibromanilino)ftalimid, FAB-MS: 642 (M<+>+H), smeltepunkt: 235-237°C (analogt med eksempel 8). (d) 4,5-bis(3-metoksyanilino)ftalimid, FAB-MS: 390 (M<+>+H), smeltepunkt: 169 til 171°C (analogt med eksempel 7). (e) 4,5-bis(2-metoksyanilino)ftalimid, FAB-MS: 390 (M<+>+H), smeltepunkt: 227 - 228°C (analogt med eksempel 97). (f) 4,5-bis(4-trifluormetylanilino)ftalimid, FAB-MS: 512 (M<+>+H), <i>H-NMR (CD30D): 7,7 (s, 2E), 7,5 (d, 4H), 7,2 (d, 4H) (analogt med eksempel 1), som biprodukt. (g) 4-cyanilino-5-trifluormetylanilino-ftalimid, FAB-MS: 423 (M<+>+H), <i>H-NMR (CDCl3):7,7(d,2H), 7,6(d,4H),7,1(d,2H),7,0-(d,2H),6,2(s,lH),6,1(S,1H) (analogt med ceksempel 1). (h) 4,5-bis(4-bifenylamino)ftalimid, FAB-MS: 482 (M<+>+H), smeltepunkt: 230-231°C (analogt med eksempel 1). (i) 4,5-bis(4-cyanilino)ftalimid, FAB-MS: 380 (M<+>+H), smeltepunkt: >250°C, <1>H-NMR(DMS0-d6): 7,1 (d, 4H), 7,6 (d,4H), 7,7 (s, 2H) (analogt med eksempel 9). Example 12: Analogously to the examples indicated in parentheses, the following was prepared: (a) 4,5-bis(4-iodanilino)phthalimide, FAB-MS: 582 (M<+>+H), melting point: 246-147°C ( analogous to example 8). (b) 4,5-bis(3-iodanilino)phthalimide, FAB-MS: 582 (M<+>+H), melting point: 244-245°C (analogous to Example 8). (c) 4,5-bis(2,6-dibromanilino)phthalimide, FAB-MS: 642 (M<+>+H), melting point: 235-237°C (analogous to Example 8). (d) 4,5-bis(3-methoxyanilinino)phthalimide, FAB-MS: 390 (M<+>+H), mp: 169 to 171°C (analogous to Example 7). (e) 4,5-bis(2-methoxyanilino)phthalimide, FAB-MS: 390 (M<+>+H), melting point: 227-228°C (analogous to Example 97). (f) 4,5-bis(4-trifluoromethylanilino)phthalimide, FAB-MS: 512 (M<+>+H), <i>H-NMR (CD30D): 7.7 (s, 2E), 7, 5 (d, 4H), 7.2 (d, 4H) (analogous to example 1), as by-product. (g) 4-cyanilino-5-trifluoromethylanilino-phthalimide, FAB-MS: 423 (M<+>+H), <i>H-NMR (CDCl 3 ): 7.7(d,2H), 7.6( d,4H),7,1(d,2H),7,0-(d,2H),6,2(s,1H),6,1(S,1H) (analogous to check example 1). (h) 4,5-bis(4-biphenylamino)phthalimide, FAB-MS: 482 (M<+>+H), melting point: 230-231°C (analogous to example 1). (i) 4,5-bis(4-cyanilino)phthalimide, FAB-MS: 380 (M<+>+H), melting point: >250°C, <1>H-NMR(DMS0-d6): 7, 1 (d, 4H), 7.6 (d, 4H), 7.7 (s, 2H) (analogous to Example 9).
(j) 4,5-bis(3-cyanilino)ftalimid, FAB-MS: 380 (M<+>+H), smeltepunkt: 225-227°C (analogt med eksempel 9). (j) 4,5-bis(3-cyanilino)phthalimide, FAB-MS: 380 (M<+>+H), melting point: 225-227°C (analogous to Example 9).
Eksempel 13: 4. 5- bis( N- metvl- N- fenylamino) ftalimid Example 13: 4. 5-bis(N-methyl-N-phenylamino) phthalimide
Analogt med eksempel 1 ble 66 mg (0,16 mmol) 4,5-bis(N-metyl-N-fenylamino)-ftalsyredimetylester (eksempel 14A) oppvarmet i 5 ml etylenglykol til 120°C og gjennomledet ammoniakgass under omrøring i 18 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med heksan/etylacetat 1:1 på kiselgel, produktfraksjonen renset og inndampet. Forbindelsen i tittelen ble oppnådd i form av svakt gule krystaller, FAB-MS: 358 [M++H] , <1->H-NMR (CDC13): 3,05 (s, 6H). Analogously to Example 1, 66 mg (0.16 mmol) of 4,5-bis(N-methyl-N-phenylamino)-phthalic acid dimethyl ester (Example 14A) was heated in 5 ml of ethylene glycol to 120°C and passed through ammonia gas with stirring for 18 hours . The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fraction purified and evaporated. The title compound was obtained as pale yellow crystals, FAB-MS: 358 [M++H] , <1->H-NMR (CDCl 3 ): 3.05 (s, 6H).
Eksempel 14: 4-( N- metyl- N- fenyIamino)- 5- anilino- ftalimid Example 14: 4-(N-methyl-N-phenylamino)-5-anilinophthalimide
Analogt med eksempel 1 ble 160 mg (0,41 mmol) 4-(N-metyl-N-fenylamino)-5-anilinftalsyredimetylester i 12 ml etylenglykol oppvarmet til 120<*>C og gjennomledet ammoniakgass under omrøring i 18 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med heksan/etylacetat 1:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd i form av svakt gule krystaller, FAB-MS: 344[M<+>+H], ^H-NMR (CDCI3): 3,28 (s, 3H). Analogous to example 1, 160 mg (0.41 mmol) of 4-(N-methyl-N-phenylamino)-5-aniline phthalic acid dimethyl ester in 12 ml of ethylene glycol was heated to 120<*>C and ammonia gas was passed through with stirring for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as pale yellow crystals, FAB-MS: 344 [M<+>+H], 1 H-NMR (CDCl 3 ): 3.28 (s, 3H).
a .) 4, 5- bis( N- metyl- N- fenylamino ) ftalsyredimetylester ( A) og 4-( N- metyl- N- fenylamino)- 5- anllino- ftalsyredimetylester ( B) a .) 4, 5-bis(N-methyl-N-phenylamino)phthalic acid dimethyl ester (A) and 4-(N-methyl-N-phenylamino)-5-anllino- phthalic acid dimethyl ester (B)
En oppløsning av 564 mg (1,5 mmol) 4,5-bis(anilino)ftalsyredimetylester (eksempel lb) i 5 ml acetonitril ble oppvarmet med 0,93 ml (15 mmol) metyliodid og 442 mg (3,2 mmol) vannfri kaliumkarbonat i bomberør i 16 timer ved 80°C. Reaksjonsblandingen ble inndampet til tørrhet, resten oppløst to ganger i diklormetan, filtrert og filtratet inndampet. Flere gangers kromatografi med heksan/etylacetat på kiselgel ga forbindelsen i tittelen som et svakt gulaktig pulver. (A): FAB-MS: 405[M<+>+E]; (B): FAB-MS: 391 [M<+>+E]. A solution of 564 mg (1.5 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1b) in 5 ml of acetonitrile was heated with 0.93 ml (15 mmol) of methyl iodide and 442 mg (3.2 mmol) of anhydrous potassium carbonate in a bomb tube for 16 hours at 80°C. The reaction mixture was evaporated to dryness, the residue dissolved twice in dichloromethane, filtered and the filtrate evaporated. Multiple chromatography with hexane/ethyl acetate on silica gel afforded the title compound as a faint yellowish powder. (A): FAB-MS: 405[M<+>+E]; (B): FAB-MS: 391 [M<+>+E].
Eksempel 15: 4. 5- bis( anillno)- N- metvl- ftalimid Example 15: 4. 5-bis(anillno)-N-methylphthalimide
Analogt med eksempel 1 ble 376 mg (1 mmol) 4 ,5—bis(ani 1 ino)-ftalsyredimetylester i 33 ml etylenglykol oppvarmet til 120°C og metylamin ble ledet gjennom under omrøring i 18 timer. Reaksjonsblandingen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket henholdsvis tre ganger med vann og en gang med mettet koksaltoppløsning, tørket over natrlumsulfat og inndampet. Resten ble kromatografert med heksan/- etylacetat 1:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd i form av svakt gule krystaller FAB-MS: 344[M<+>+H], smeltepunkt 195-196°C. Analogously to Example 1, 376 mg (1 mmol) of 4,5-bis(ani1ino)-phthalic acid dimethyl ester in 33 ml of ethylene glycol was heated to 120°C and methylamine was passed through with stirring for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed respectively three times with water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was chromatographed with hexane/ethyl acetate 1:1 on silica gel, the product fractions were combined and evaporated. The title compound was obtained as pale yellow crystals FAB-MS: 344[M<+>+H], mp 195-196°C.
Eksempel 16: 4. 5- bis( anilino)- tioftalimid f=5. 6- bis-( anilino )- isoindol- l- on- 3- tion~ l Example 16: 4. 5-bis(anilino)-thiophthalimide f=5. 6- bis-( anilino )- isoindol- l- on- 3- thione~ l
En oppløsning av 100 mg (0,3 mmol) 4,5-bis(anilino)ftalimid (eksempel 1) i 15 ml diklormetan ble tilsatt 138 mg (0,36 mmol) Lawesson-reagens [=2,4-bis-(4-metoksyfenyl)-2,4-ditiokso-1,3,2,4-dithiafosfet] og kokt med tilbakeløps-kjøling i 4 timer. Reaksjonsblandingen ble inndampet og direkte kromatografert med heksan/etylacetat 2:1 på kiselgel. Produktfraksjonene ble inndampet. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, FAB-MS: 346 [M<+>+H]. To a solution of 100 mg (0.3 mmol) of 4,5-bis(anilino)phthalimide (Example 1) in 15 ml of dichloromethane was added 138 mg (0.36 mmol) of Lawesson's reagent [=2,4-bis-( 4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphate] and refluxed for 4 hours. The reaction mixture was evaporated and directly chromatographed with hexane/ethyl acetate 2:1 on silica gel. The product fractions were evaporated. The title compound was obtained as yellow crystals, FAB-MS: 346 [M<+>+H].
Eksempel 17: 4. 5- bis( anilino)- N^ >N5— propan- 1, 3- divl- ftalimid Example 17: 4. 5- bis(anilino)- N^ >N5— propane- 1, 3- divlphthalimide
I en autoklavere ble 457 mg (1 mmol) 4,5-bis(anilino)-N<4>,N<5->propan-1,3-diyl-ftalsyredimetylester i 5 ml metanol oppløst og 15 ml ammoniak tilsatt for amiddannelse. Denne lukkede autoklavereen ble oppvarmet til 120"C i 24 timer, deretter avkjølt, åpnet og ammoniaken med nitrogen ble tatt av. Resten ble spylt med eddikester, filtrert og filtratet kromatografert på kiselgel med heksan/eddiksester 3:1. Produktfraksjonene ble inndampet og krystallisert fra heksan/- eddikester. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, FAB-MS: 370 [M<+>+E]. In an autoclave, 457 mg (1 mmol) of 4,5-bis(anilino)-N<4>,N<5->propane-1,3-diyl-phthalic acid dimethyl ester in 5 ml of methanol were dissolved and 15 ml of ammonia was added for amide formation . This closed autoclave was heated to 120°C for 24 hours, then cooled, opened and the ammonia with nitrogen stripped off. The residue was flushed with ethyl acetate, filtered and the filtrate chromatographed on silica gel with hexane/ethyl acetate 3:1. The product fractions were evaporated and crystallized from hexane/-acetic ester The title compound was obtained as yellow crystals, FAB-MS: 370 [M<+>+E].
a) 4 . 5- bis( anillnol- N^-. N^— propandivl- ftalsyredimetylester og 4. 5- bis( N- allylanllino) ftalsyredimetylester a) 4. 5- bis(anillnol- N^-. N^— propanedivl- phthalic acid dimethyl ester and 4. 5- bis( N- allylanllino) phthalic acid dimethyl ester
En oppløsning av 3,76 g (10 mmol) 4,5-bis(anilino)ftalsyredimetylester (eksempel lb) i 15 ml HMPT (heksametylfosfor-syretriamid) eller DMPU ble ved romtemperatur under argon tilsatt 0,6 g (15,4 mmol) natriumamid og oppvarmet til 60°C i 30 minutter. Den dyprøde oppløsningen ble avkjølt til romtemperatur og evakuert i 5 minutter (1 torr). Deretter ble en oppløsning av 1,5 ml (15,2 mmol) l-brom-3-klorpropan i 2 ml TEF dryppet til og reaksjonsblandlngen ble omrørt i 18 timer ved romtemperatur. Reaksjonsblandlngen ble helt på isvann, ekstrahert med iseddik, de organiske fasene slått sammen og grundig vasket med vann, tørket over natriumsulfat og inndampet. Resten ble kromatografert på kiselgel med heksan/eddikester 5:1. Forbindelsene i tittelen ble på denne måten oppnådd: 4,5-bis(anilino)-N<4>,N<5->propandiylftalsyre-dimetylester i form av fargeløse krystaller, FAB-MS; 457[M<+>+E]. A solution of 3.76 g (10 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1b) in 15 ml of HMPT (hexamethylphosphoric acid triamide) or DMPU was added at room temperature under argon to 0.6 g (15.4 mmol ) sodium amide and heated to 60°C for 30 minutes. The deep red solution was cooled to room temperature and evacuated for 5 minutes (1 torr). Then a solution of 1.5 ml (15.2 mmol) 1-bromo-3-chloropropane in 2 ml TEF was added dropwise and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto ice water, extracted with glacial acetic acid, the organic phases combined and thoroughly washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel with hexane/acetic ester 5:1. The compounds of the title were thus obtained: 4,5-bis(anilino)-N<4>,N<5->propanediylphthalic acid dimethyl ester in the form of colorless crystals, FAB-MS; 457[M<+>+E].
Eksempel 18: Analogt med eksemplene 13 til 17 ble det fremstilt: (a) 4-(N-acetyl-N-fényl)amino-5-anilino-ftalimid, FAB-MS: 372[M<+>+E], ifl-NMR (DMS0-d6): 2,05 (s, 3E) analogt med eksempel 14). (b) 4,5-bis(N-allylanilino)ftalimid, FAB-MS: 410 (analogt med eksempel 17). Example 18: Analogous to examples 13 to 17, the following was prepared: (a) 4-(N-acetyl-N-phenyl)amino-5-anilino-phthalimide, FAB-MS: 372[M<+>+E], ifl -NMR (DMS0-d6): 2.05 (s, 3E) analogous to example 14). (b) 4,5-bis(N-allylanilino)phthalimide, FAB-MS: 410 (analogous to Example 17).
Eksempel 19: Det ble fremstilt 5000 kapsler, som hver inneholdt 0,25 g virksomt stoff, for eksempel en av de forbindelsene som ble fremstilt i eksemplene 1 til 16: Fremgan<g>småte: De pulverformige stoffene ble siktet gjennom en sikt med en maskevidde på 0,6 mm og blandet. Porsjoner hver på 0,33 g av blandingen ved hjelp av en kapselfyllings-maskin fylt i gelatinkapsler. Example 19: 5000 capsules were prepared, each containing 0.25 g of active substance, for example one of the compounds that were prepared in examples 1 to 16: Procedure: The powdered substances were sieved through a sieve with a mesh size of 0.6 mm and mixed. Portions each of 0.33 g of the mixture using a capsule filling machine filled into gelatin capsules.
Eksempel 20: 4- anilino- 5-( 4- hvdroksv- anllino) ftalimid Example 20: 4-anilino-5-(4-hydroxyvanillino)phthalimide
Til en oppløsning av 359,4 mg (1 mmol) 4-anilino-5-(4-metoksy-anilno )f talimid i 5 ml kloroform ble det ved -40° C til -30° C dryppet til en oppløsning av 186pl (2 mmol) bortribromid i 5 ml kloroform. Reaksjonsblandlngen bl omrørt i 5 timer ved -30°C og deretter stanset av 5 ml vann ved-30°C. Reaksjonsblandlngen ble oppvarmet til romtemperatur og fasene ble adskilt. Den organiske fasen ble vasket to ganger med vann, tørket over magnesiumsulfat og inndampet. Resten ble kromatografert med etylcetat/heksan 1:1 på en kiselgel-kolonne som var avkjølt med isvann, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, FAB-MS: 346[M<+>+H]. To a solution of 359.4 mg (1 mmol) of 4-anilino-5-(4-methoxy-anilino)phthalimide in 5 ml of chloroform was added dropwise at -40° C. to -30° C. to a solution of 186 µl ( 2 mmol) boron tribromide in 5 ml chloroform. The reaction mixture was stirred for 5 hours at -30°C and then quenched with 5 ml of water at -30°C. The reaction mixture was warmed to room temperature and the phases were separated. The organic phase was washed twice with water, dried over magnesium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:1 on a silica gel column cooled with ice water, the product fractions combined and evaporated. The title compound was obtained as yellow crystals, FAB-MS: 346[M<+>+H].
a) 4- anilino- 5-( 4- metoksy- anilino) ftalimid a) 4-anilino-5-(4-methoxy-anilino) phthalimide
0,7 g (1,7 mmol) 4-anilino-5-(4-metoksy-anilino)ftalsyredimetylester i 20 ml etylenglykol ble analogt med eksempel 1 oppvarmet til 120'C, hvoretter ammoniakgass ble ledet gjennom i løpet av 18 timer under omrøring. Reaksjonsblandlngen ble avkjølt og ekstrahert med etylacetat. Etylacetatfasen ble vasket to ganger med vann og en gang med mettet koksalt-oppløsning, tørket over magnesiumsulfat og inndampet. Resten 0.7 g (1.7 mmol) of 4-anilino-5-(4-methoxy-anilino)phthalic acid dimethyl ester in 20 ml of ethylene glycol was analogously to example 1 heated to 120°C, after which ammonia gas was passed through during 18 hours under stirring. The reaction mixture was cooled and extracted with ethyl acetate. The ethyl acetate phase was washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The rest
ble kromatografert med etylacetat/heksan 1:1 på kiselgel, produktfraksjonene slått sammen og inndampet. Forbindelsen i tittelen ble oppnådd i form av gule krystaller, smeltepunkt 266 til 267°C, FAB-MS: 360[M<+>+H]. was chromatographed with ethyl acetate/hexane 1:1 on silica gel, the product fractions combined and evaporated. The title compound was obtained as yellow crystals, mp 266 to 267°C, FAB-MS: 360[M<+>+H].
b) 4- anillno- 5-( 4- metoksv- anllino) ftalsyredimetylester og 4. 5- bis( 4- metoksyoksy- anilino) ftalsyredimetylester b) 4- anilno- 5-( 4- methoxy- anilino) phthalic acid dimethyl ester and 4. 5- bis ( 4- methoxyoxy-anilino) phthalic acid dimethyl ester
En oppløsning av 4,8 g (12 mmol) 4,5-bis(trimetylsilyloksy)-cykloheksa-1,4-din-l,2-dikarbonsyremetylester (eksempel la), 2,6 g (24 mmol) p-anisidin og 2,2 ml (24 mmol) anilin i 48 ml iseddik ble kokt med tilbakeløpskjøling i 2 timer. Reaksjonsblandlngen ble avkjølt, oppløsningsmiddelet avdampet, den mørkebrune resten oppløst i etylacetat og oppløsningen vasket henholdsvis med 40 ml IN HC1, 100 ml mettet NaHC03 og to ganger 100 ml vann, tørket over magnesiumsulfat og inndampet. Resten ble kromatografert med etylacetat/heksan 1:3 på kiselgel og produktfraksjonen inndampet. Fra den første produktreaksjonen ble på denne måten 4,5-bis(4-metoksyanilino)ftalsyredimetylester oppnådd i form av et gult skum: FAB-MS: 437[M<+>+H]. Resten i den etterfølgende produktfraksjonen ble omkrystallisert fra etylacetat/heksan og 4-anilino-5(4-metoksy-anilino)ftalsyredimetylester ble oppnådd som gule krystaller, smeltepunkt 122 til 124°C, FAB-MS: 407[M<+>+H]. A solution of 4.8 g (12 mmol) 4,5-bis(trimethylsilyloxy)-cyclohexa-1,4-dyne-1,2-dicarboxylic acid methyl ester (Example 1a), 2.6 g (24 mmol) p-anisidine and 2.2 ml (24 mmol) of aniline in 48 ml of glacial acetic acid was refluxed for 2 hours. The reaction mixture was cooled, the solvent evaporated, the dark brown residue dissolved in ethyl acetate and the solution washed respectively with 40 ml 1N HCl, 100 ml saturated NaHCO 3 and twice 100 ml water, dried over magnesium sulfate and evaporated. The residue was chromatographed with ethyl acetate/hexane 1:3 on silica gel and the product fraction evaporated. From the first product reaction, 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester was thus obtained in the form of a yellow foam: FAB-MS: 437[M<+>+H]. The residue in the subsequent product fraction was recrystallized from ethyl acetate/hexane and 4-anilino-5(4-methoxy-anilino)phthalic acid dimethyl ester was obtained as yellow crystals, mp 122 to 124°C, FAB-MS: 407[M<+>+H ].
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US5491144A (en) * | 1991-05-30 | 1996-02-13 | Ciba-Geigy Corporation | Substituted diaminophthalimides and analogues |
EP0600830A1 (en) * | 1992-11-27 | 1994-06-08 | Ciba-Geigy Ag | Substituted derivatives of diaminophthalimide as protein-tyrosine kinase inhibitors |
EP0600831A1 (en) * | 1992-11-27 | 1994-06-08 | Ciba-Geigy Ag | Phtalazinon derivatives |
AU691815B2 (en) * | 1993-06-25 | 1998-05-28 | Main Camp Marketing Pty. Ltd. | Therapeutic agent |
CA2165794A1 (en) * | 1993-06-25 | 1995-01-05 | Brian Daunter | Therapeutic agent |
GB9314893D0 (en) * | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
GB9325217D0 (en) * | 1993-12-09 | 1994-02-09 | Zeneca Ltd | Pyrimidine derivatives |
WO1995024190A2 (en) | 1994-03-07 | 1995-09-14 | Sugen, Inc. | Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof |
GB9600545D0 (en) | 1996-01-11 | 1996-03-13 | Ciba Geigy Ag | Compositions |
EP1661566A3 (en) * | 1996-08-05 | 2008-04-16 | Myriad Genetics, Inc. | Use of beta-sheet mimetics as protease and kinase inhibitors and as inhibitors of transcription factors |
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DE60233675D1 (en) * | 2001-11-30 | 2009-10-22 | Panasonic Corp | BISIMIDINE COMPOUND, ACID GENERATOR AND PROTECTION LACQUER COMPOSITION, WHICH INCLUDE THESE COMPOUNDS, AND METHOD FOR THE FORMATION OF PATTERNS FROM THE COMPOSITION |
US20050182061A1 (en) * | 2003-10-02 | 2005-08-18 | Jeremy Green | Phthalimide compounds useful as protein kinase inhibitors |
US20060142591A1 (en) * | 2004-10-25 | 2006-06-29 | Susan Lindquist | DAPH analogs and inhibition of protein aggregation |
US7745641B2 (en) | 2005-04-19 | 2010-06-29 | Kyowa Hakko Kirin Co., Ltd. | Nitrogen-containing heterocyclic compound |
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JP5934559B2 (en) * | 2012-04-05 | 2016-06-15 | 国立大学法人京都工芸繊維大学 | Luminescent material and organic EL device |
CN105434432B (en) * | 2015-12-04 | 2018-11-13 | 中国科学院昆明植物研究所 | N-Hydroxyphthalimide class compound application in preparation of anti-tumor drugs |
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