WO2010133672A1 - Derivatives of quinoline-3-carboxylic acid and their medical use - Google Patents
Derivatives of quinoline-3-carboxylic acid and their medical use Download PDFInfo
- Publication number
- WO2010133672A1 WO2010133672A1 PCT/EP2010/056971 EP2010056971W WO2010133672A1 WO 2010133672 A1 WO2010133672 A1 WO 2010133672A1 EP 2010056971 W EP2010056971 W EP 2010056971W WO 2010133672 A1 WO2010133672 A1 WO 2010133672A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- carboxylic acid
- quinoline
- compound according
- methylcarbamoyl
- Prior art date
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- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical class C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 106
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 206010012689 Diabetic retinopathy Diseases 0.000 claims abstract description 14
- 206010061218 Inflammation Diseases 0.000 claims abstract description 14
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 14
- 206010064930 age-related macular degeneration Diseases 0.000 claims abstract description 14
- 230000004054 inflammatory process Effects 0.000 claims abstract description 14
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 14
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 13
- 208000001344 Macular Edema Diseases 0.000 claims abstract description 13
- 206010025415 Macular oedema Diseases 0.000 claims abstract description 13
- 208000006011 Stroke Diseases 0.000 claims abstract description 13
- 230000000302 ischemic effect Effects 0.000 claims abstract description 13
- 201000010230 macular retinal edema Diseases 0.000 claims abstract description 13
- 210000004165 myocardium Anatomy 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000002950 monocyclic group Chemical group 0.000 claims description 24
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000002619 bicyclic group Chemical group 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000005108 alkenylthio group Chemical group 0.000 claims description 6
- 125000005109 alkynylthio group Chemical group 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 5
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- UJAXDSTVHMDTJH-UHFFFAOYSA-N 4-(2-fluoroanilino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=CC=C1F UJAXDSTVHMDTJH-UHFFFAOYSA-N 0.000 claims description 4
- KRKKTVSKCIRYRW-UHFFFAOYSA-N 4-(4-fluoroanilino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=C(F)C=C1 KRKKTVSKCIRYRW-UHFFFAOYSA-N 0.000 claims description 4
- ZYBZPMOSMIALQK-UHFFFAOYSA-N 6-(methylcarbamoyl)-4-(4-propan-2-ylanilino)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=C(C(C)C)C=C1 ZYBZPMOSMIALQK-UHFFFAOYSA-N 0.000 claims description 4
- GAQGCIDHXZCPHM-UHFFFAOYSA-N 4-(2,6-dimethylanilino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=C(C)C=CC=C1C GAQGCIDHXZCPHM-UHFFFAOYSA-N 0.000 claims description 3
- NFIFDLZGOYWVAT-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=C(Cl)C=C1 NFIFDLZGOYWVAT-UHFFFAOYSA-N 0.000 claims description 3
- ZMVOCZVEXVIPOB-UHFFFAOYSA-N 4-[4-(difluoromethoxy)anilino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=C(OC(F)F)C=C1 ZMVOCZVEXVIPOB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004951 trihalomethoxy group Chemical group 0.000 claims description 3
- ZTQVTVJNXZZCSI-UHFFFAOYSA-N 4-(3-methoxyanilino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=CC(OC)=C1 ZTQVTVJNXZZCSI-UHFFFAOYSA-N 0.000 claims description 2
- NQLMNIMBKDBLOQ-UHFFFAOYSA-N 4-(benzylamino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NCC1=CC=CC=C1 NQLMNIMBKDBLOQ-UHFFFAOYSA-N 0.000 claims description 2
- LFTFOZRYIYRYMT-UHFFFAOYSA-N 4-anilino-6-(methylcarbamoyl)quinoline-3-carboxylic acid Chemical compound C12=CC(C(=O)NC)=CC=C2N=CC(C(O)=O)=C1NC1=CC=CC=C1 LFTFOZRYIYRYMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- -1 halo aniline derivative Chemical class 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 108010044426 integrins Proteins 0.000 description 20
- 102000006495 integrins Human genes 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 15
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 14
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 238000001727 in vivo Methods 0.000 description 12
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- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 210000002889 endothelial cell Anatomy 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 230000033115 angiogenesis Effects 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- ZUVOVKKMXVBSBT-UHFFFAOYSA-N ethyl 4-chloro-6-(methylcarbamoyl)quinoline-3-carboxylate Chemical compound C1=CC(C(=O)NC)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 ZUVOVKKMXVBSBT-UHFFFAOYSA-N 0.000 description 7
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 7
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- 108010067306 Fibronectins Proteins 0.000 description 6
- 102000016359 Fibronectins Human genes 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- 125000004122 cyclic group Chemical group 0.000 description 6
- YGMLKBFPHVLHGT-UHFFFAOYSA-N ethyl 6-bromo-4-chloroquinoline-3-carboxylate Chemical compound C1=CC(Br)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 YGMLKBFPHVLHGT-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
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- 239000002904 solvent Substances 0.000 description 5
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- AQTSNKXEMWZOGA-UHFFFAOYSA-L (2-methanidylphenyl)-bis(2-methylphenyl)phosphane;palladium(2+);diacetate Chemical compound [Pd+2].[Pd+2].CC([O-])=O.CC([O-])=O.CC1=CC=CC=C1P(C=1C(=CC=CC=1)[CH2-])C1=CC=CC=C1C.CC1=CC=CC=C1P(C=1C(=CC=CC=1)[CH2-])C1=CC=CC=C1C AQTSNKXEMWZOGA-UHFFFAOYSA-L 0.000 description 4
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000002491 angiogenic effect Effects 0.000 description 4
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- 238000003556 assay Methods 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 0 C*OC(c(cnc(c1c2)ccc2Br)c1Cl)=O Chemical compound C*OC(c(cnc(c1c2)ccc2Br)c1Cl)=O 0.000 description 3
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to quinoline-3-carboxylic acid derivatives and to the use 5 thereof in therapy. Particularly, the present invention relates to their use for the treatment of cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
- Angiogenesis the outgrowth of new capillaries from pre-existing vessels, is essential for embryonic development, organ formation, tissue regeneration, and remodeling [Folkman, J. & 5 Shing, Y. (1992) J. Biol. Chem. 267, 10931-10934]. It also contributes to the development and progression of a variety of pathological conditions, including tumor growth and metastasis, cardiovascular diseases, diabetic retinopathy, rheumatoid arthritis, psoriasis [Folkman, J. Nat.
- Angiogenesis and vasculogenesis are complex multistep processes that include proliferation, migration and differentiation of endothelial cells, degradation of the extracellular matrix, tube formation, and sprouting of new capillary branches [Hanahan, D.; Folkman, J. Cell
- vascular endothelial growth factor (VEGF)/ 0 vascular permeability factor is one of the best-characterized positive regulators with its distinct specificity for vascular endothelial cells [Senger, D. R.; Galli, S. J.; Dvorak, A. M.; Perruzzi, C.
- VEGF vascular endothelial growth factor
- the biological actions of VEGF include stimulation of endothelial cell proliferation, migration, differentiation, tube formation, increase of vascular permeability, and maintenance of vascular integrity [Mustonen, T.; Alitalo, K. J Cell Biol. 1995, 129, 895-898; Ferrara, N.; Davis-Smyth, T. Endocr. Rev. 1997, 18, 4-25; Thomas, K. J Biol. Chem. 1996, 271, 603-606; Risau, W. Nature (London) 1997, 386, 671-674; Breier, G.; Risau, W. Trends Cell Biol. 1997, 6, 454-456].
- tyrosine kinase receptors which are expressed primarily on vascular cells of the endothelial lineage [Mustonen, T.; Alitalo, K. J Cell Biol. 1995, 129, 895-898; De Vries, C; Escobedo, J. A.; Ueno, H.; Huck, K.; Ferrara, N.; Williams, L. T. Science 1992, 255, 989-99; Terman, B. L; Dougher-Vermazen, M.; Carrion, M. E.; Dimitrov, D.; Armellino, D. C; Gospodorawicz, D.; Bohlen, P. Biochem. Biophys. Res. Commun. 1992, 187, 1579-1586].
- ECM endothelial cell membrane
- VEGFRs vascular endothelial growth factor
- ⁇ l ⁇ l ⁇ 2 ⁇ l, ⁇ 3 ⁇ l, ⁇ 5 ⁇ l, ⁇ 6 ⁇ l, ⁇ 6 ⁇ 4, ⁇ v ⁇ 3, and ⁇ v ⁇ 5 are known to be present in endothelial cells [Rupp, P. A.; Little, C. D. Circ. Res., 2001, 566-572; Stupack, D. G.; Cheresh, D. A. Sci.
- the ligands for the extracellular domain of many integrins are the proteins of the extracellular matrix and the intracellular domain of the integrins are either directly or indirectly connected to intracellular components such as kinases and the cytoskeleton. Integrins serve as bidirectional signalling receptors, whereby protein activities and gene expression are changed by integrins in response to ligand binding to the extracellular domain thereof, which is also referred to as outside-in-signalling. On the other hand, the affinity of the integrins is modulated in response to intracellular changes such as binding of proteins to the extracellular domain of the integrin, which is referred to as inside-out signalling [Humphries, M. J. Biochem. Soc. Trans.
- vitronectin receptors ⁇ v ⁇ 3, ⁇ v ⁇ 5 and the fibronectin receptor ⁇ 5 ⁇ l play a critical role in angiogenesis. Integrin ⁇ 5 ⁇ l expression
- Integrin ⁇ 5 ⁇ l is poorly expressed on quiescent endothelium but its expression is significantly upregulated on endothelium during tumor angiogenesis in both mice and humans, which makes ⁇ 5 ⁇ l a viable target for anti-angiogenic therapy [Kim, S.; Bell, K.; Mousa, S. A.;
- the present invention relates to a compound of formula (I)
- LO n is 0 (zero) or 1;
- R and R are independently selected from hydrogen; branched or unbranched Cj-C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl; monocyclic or bicyclic, saturated or unsaturated C 3 -C 8 carbocyclyl; and monocyclic or bicyclic, saturated or unsaturated C 1 -C 7 heterocyclyl wherein the heteroatoms are independently selected from N, O and S;
- R 3 is selected from monocyclic or bicyclic C 6 -C 10 aryl; and monocyclic or bicyclic C 1 -C 9 heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups R ; >0 Y is selected from -C(O)-; -S(O)-; and -S(O) 2 -;
- X is selected from -NR C -; -0-; and -S-; each R is independently selected from halogen; hydroxy; carbonyl; methoxy; halomethoxy; dihalomethoxy; and trihalomethoxy; each R is independently selected from halogen, branched or unbranched C 1 -C 4 alkyl, C 2 - .5 C 4 alkenyl or C 2 -C 4 alkynyl; branched or unbranched C 1 -C 4 alkyloxy, C 2 - C 4 alkenyloxy or C 2 - C 4 alkynyloxy; branched or unbranched C 1 -C 4 alkylthio, C 2 -C 4 alkenylthio or C 2 -C 4 alkynylthio; wherein any alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy alkynyloxy, alkylthio, alkenylthio or alky
- Another aspect of the invention relates to a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, for use in therapy.
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient.
- said pharmaceutical composition comprises at least one further, pharmaceutically active compound.
- Said further pharmaceutically active compound may have anti-tumor activity.
- Another aspect of the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
- diseases or disorders such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
- Another aspect of the invention provides the use of the compounds of formula (I) or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of disorders such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
- Another aspect of the invention provides a method of treating a mammal suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said mammal in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- said mammal is a human.
- Another aspect of the invention provides a method of treating a mammal suffering from a disease or disorder related to VEGFR tyrosine kinase or integrin activity, comprising administering to said mammal in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- said mammal is a human.
- Another aspect of the invention provides a method of treating a mammal suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent that inhibits VEGF, VEGFR tyrosine kinase or integrin.
- said second therapeutic agent is a therapeutic antibody.
- said second therapeutic agent is a therapeutic antibody.
- 5 therapeutic agent is selected from an alkylating agent; a folic acid antagonist; an antimetabolite of nucleic acid metabolism; a pyrimidine analog; 5-fluorouracil; and a purine nucleoside.
- said mammal is a human.
- said second therapeutic agent is administered in combination or sequentially with the first therapeutic agent.
- Another aspect of the invention provides a method of treating a patient suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula (I) in combination with radiological treatment, including irradiation and/or administration of a
- Another aspect of the invention provides a method of treating a patient suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula (I) or a
- Such a method can involve the combination a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with any antiangiogenic agent, radiological treatment and/or chemotherapy.
- the present invention relates to substituted quinoline derivatives, which can be utilized to treat diseases and conditions such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema,
- a quinoline-3-carboxylic acid ester of the invention may be formed in a six step procedure wherein, first, a suitable halo aniline derivative is reacted with a suitable mono- or diethylester, the formed intermediate cyclized to give a 4-halo-quinoline-3- carboxylic acid ester, which is then coupled with a suitable amine, H(R c )N-(CH 2 )n-R 3 to form a substituted secondary or tertiary 4-amino quinoline-3 -carboxylic acid ester.
- the halogen can then be carbonylated, to yield the corresponding amide, -C(O)-NR 1 R 2 .
- a substituted sulphonamide, -S(O) 2 -NR R can be prepared via reaction of the halogen with sulfite ion, followed by further manipulation to yield the corresponding sulphonamide or corresponding sulfoxide.
- the quinoline-3 -carboxylic acid ester can then be hydrolysed to give the corresponding inventive compounds.
- the entire synthesis is illustrated by Reaction Scheme 1. With regard to the below reaction sequence, it should be well within the capability of the person skilled in the art to select suitable reaction components as well as reaction conditions.
- alkyl as employed herein, alone or as part of another group, refers to an acyclic
- alkyl also includes a straight or branched chain radical, unless otherwise specified containing 1, 2, 3, 4, 5, 6, 7 or 8 carbons in the normal chain, which includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.
- branched chain radicals not excluding any of the possible isomers not mentioned, are iso-propyl, sec-butyl, iso-pentyl, 3-methylpentyl, 2,3-dimethylhexyl, 3-ethylhexyl, and the like.
- alkyl also includes a straight or
- the alkyl portions can be attached at any variable point of attachment to the carbocyclyl, including the same ring carbon, as exemplified below:
- the total number of carbon atoms of the alkyl chain and the carbocyclyl is at most 8. hi other words, in the above given example, the sum of z and w is at most 5.
- substituted alkyl when substituted alkyl is present, this refers to a straight or branched alkyl group as defined above, substituted with 1, 2 or 3 groups of R a .
- the alkyl group preferably contains 1, 2, 3
- R a 1, 2 or 3 groups of R a , which groups may be the same or different at any available point, as defined with respect to each variable.
- the preferred substitution is halogen such as in -CH 2 Cl, -CF 3 , -CH 2 I, -CHF 2 , -CH 2 Br, -CH 2 F, -CHFCH 2 F, -CHFCH 2 Cl, - CHFCHClCH 3 , -CHClCHBrCH 2 CF 3 , -CHClCBrICH 2 CF 3 , -CH 2 CH 2 CH 2 CH 2 I, and the like.
- alkenyl refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7 or 8 carbons, which contains at least one carbon to carbon double bond. Preferably only one carbon to carbon double bond is present, such as in the normal chain vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, and the like.
- the alkenyl group preferably contains 2, 3 or 4 carbons in the normal chain.
- the straight or branched portion of the alkenyl group may be optionally substituted when a substituted alkenyl group is provided.
- the chain may be interrupted or terminated by a carbocyclyl group, in which case the total number of carbon atoms of the chain and the carbocyclyl is at most 8.
- alkynyl refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7 or 8 carbons, which contains at least one carbon to carbon triple bond.
- only one carbon to carbon triple bond is present, such as in the normal chain 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3- pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, and the like.
- the alkynyl group preferably contains 1, 2, 3 or 4 carbons in the normal chain.
- the straight or branched portion of the alkynyl group may be optionally substituted when a substituted alkynyl group is provided.
- the chain may be interrupted or terminated by a carbocyclyl group, in which case the total number of carbon atoms of the chain and the carbocyclyl is at most 8.
- any alkyl, alkenyl, or alkynyl group having a number of p (p being an integer of 4 to 8) carbon atoms, optionally and independently from any other alkyl, alkenyl or alkynyl group present in the compound includes a carbocyclic portion of a number of q (q being an integer of 3 to 7 and q being less than p) carbon atoms, which carbocyclic portion may be located so as to interrupt or terminate the straight or branched chain of the alkyl, alkenyl, or alkynyl group, whereby the number of carbon atoms in the straight or branched chain of the alkyl, alkenyl or alkynyl group equals p-q.
- any alkyl, alkenyl, or alkynyl group having p carbon atoms has all p carbon atoms in the straight or branched chain portion, i.e. does not include any terminating or interrupting carbocyclic portion.
- carbocyclyl as employed herein alone or as part of another group includes saturated cyclic hydrocarbyl groups or unsaturated (at least 1 double bond) cyclic hydrocarbyl groups, containing at least one ring of in total of 3, 4, 5, 6, 7 or 8 ring carbons, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and the like.
- the cyclic hydrocarbyl may be monocyclic or bicyclic (i.e. containing two rings of 3 to 8 ring carbons each).
- the carbocyclyl may be monocyclic and 3- to 6-membered.
- the carbocyclyl group may be optionally substituted by 1, 2 or 3 halogens, which may be the same or different.
- heterocyclyl mean a non- aromatic cyclic group that optionally might be unsaturated, containing one or more heteroatom(s) preferably selected from N, O and S, such as a 4 to 10-membered ring system containing at least one heteroatom, e.g. 1-4 heteroatoms.
- a suitable heterocyclyl may be a non-aromatic cyclic group that optionally might be unsaturated, containing one or more heteroatom(s) preferably selected from N, O and S, such as a 5 to 6-membered monocyclic ring system containing at least one heteroatom, e.g.
- a heterocyclyl e.g. may be, but is not limited to, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl, imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, pyrrolidinyl, pyrrolidinonyl, piperidyl, piperazinyl, piperidinyl, pyrazolidinyl, quinuclidinyl, sulfalonyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, thietanyl, thiiranyl,
- saturated when referring to a bicyclic system, is meant a ring system comprising at least one double or triple bond in at least one ring. Thus, it is contemplated that both rings may be unsaturated or only one ring may be unsaturated, and the other one being saturated.
- unsaturated bicyclic also is intended to refer to a non- aromatic bicyclic system comprising a ring that is either unsaturated or saturated fused to a ring that by itself would be aromatic, such as in indane or 4,5-dihydro-l -indole.
- halogen refers to fluorine, chlorine, bromine and iodine, where the preferred halogen radicals are fluorine and chlorine.
- aryl means an aromatic group, monocyclic or bicyclic such as phenyl or naphthyl, and the like.
- the aryl group is preferably a monocyclic C 6 aryl (i.e. phenyl).
- heteroaryl means a mono- or bicyclic heteroaromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as, but not limited to, pyridyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, isoquinolinyl, naphthyridinyl, imidazolyl, phenazinyl, phenothiazinyl, phthalazinyl, indolyl, pyridazinyl, quinazolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, pyrazinyl, indazolyl, indolinyl
- n denotes the number of -CH 2 - linking X to R , and is either 0 or 1. In one 5 embodiment n is 1 ; however, more preferably n is 0.
- the groups R and R 2 are independently selected from hydrogen; branched or unbranched C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl; monocyclic or bicyclic, saturated or unsaturated C 3 -C 8 carbocyclyl; and monocyclic or bicyclic, saturated or unsaturated C 1 -C 7 heterocyclyl wherein the heteroatoms are independently selected from N, O and S; and wherein said alkyl, 10 alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally are substituted with 1, 2, or 3 groups R .
- R 1 and R 2 are independently selected from hydrogen and branched or unbranched C 1 -C 8 alkyl, C 2 -C 8 alkenyl and C 2 -C 8 alkynyl, wherein said alkyl, alkenyl, or alkynyl are substituted with 1, 2, or 3 groups R a .
- R 1 and R 2 may be independently selected from hydrogen and branched or unbranched C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl, said ⁇ 5 alkyl, alkenyl, or alkynyl optionally being substituted with 1, 2, or 3 groups R .
- R 1 and R 2 are independently selected from hydrogen and branched or unbranched C 1 -C 8 alkyl, said alkyl optionally being substituted with 1, 2, or 3 groups R a .
- R and R 2 may be independently selected from hydrogen and branched or unbranched C J -C 4 alkyl, e.g. methyl, said alkyl, alkenyl, or alkynyl optionally being substituted with 1, 2, or !0 3 groups R , e.g. 1 or 2 groups R , or 1 group R , or no group R .
- R is hydrogen, and R is as defined herein above.
- R is hydrogen, and R 2 is as defined herein above, but is not hydrogen.
- R 1 is hydrogen, and R 2 is methyl.
- R 3 is selected from monocyclic or bicyclic C 6 -C 10 aryl; and '5 monocyclic or bicyclic Ci -Cg heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups R b .
- R 3 is selected from monocyclic C 6 (i.e. phenyl); and monocyclic C 1 -C 5 heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups R .
- R is selected from monocyclic or bicyclic C 6 -Ci O aryl; said aryl 5 optionally being substituted with 1, 2, 3, 4 or 5 groups R .
- R may be phenyl; optionally substituted with 1, 2, 3, 4 or 5 groups R .
- R 3 is selected from (unsubstituted) phenyl, fluorophenyl, chlorophenyl, isopropylphenyl, difluoromethoxyphenyl, dimethylphenyl and methoxyphenyl.
- R may be selected from phenyl, 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- 10 isopropylphenyl, 4-(difluoromethoxy)phenyl, 2,6-dimethylphenyl, and 3 -methoxyphenyl.
- the moiety Y is - is selected from -C(O)-; -S(O)-; and -S(O) 2 -, but preferably is -C(O)-.
- the moiety X is selected from -NR 0 -; -O-; and -S-; but preferably is -NR C -.
- any alkyl, alkenyl, or alkynyl in either of R and R optionally 15 may be substituted with 1, 2, or 3 groups R a .
- the number of substituents R e.g. may be 1 or 2, or 1, and each R is independently selected from halogen; hydroxy; carbonyl; methoxy; halomethoxy; dihalomethoxy; and trihalomethoxy; e.g. from halogen.
- R a is absent.
- any aryl or heteroaryl optionally is substituted with 1, 2, 3, 4 or 5 groups R .
- the number of groups R present on any given ring in a monocyclic or bicyclic moiety may be 1-4, or 1-3, e.g.l or 2.
- Each R is independently selected from halogen, branched or unbranched C 1 -C 4 alkyl, C 2 - C 4 alkenyl or C 2 -C 4 alkynyl; branched or unbranched C 1 -C 4 alkyloxy, C 2 -C 4 alkenyloxy or C 2 -C 4 alkynyloxy; branched or unbranched C 1 -C 4 alkylthio, C 2 -C 4 alkenylthio or C 2 -C 4 alkynylthio; '.5 wherein any alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy alkynyloxy, alkylthio, alkenylthio or alkynylthio group optionally is substituted with 1, 2 or 3 halogens.
- each R is independently selected from halogen, branched or unbranched Ci-C 4 alkyl; branched or unbranched C 1 -C 4 alkyloxy; and branched or unbranched C 1 -C 4 alkylthio; wherein any alkyl, alkyloxy or alkylthio group optionally is substituted with 1, 2 0 or 3 halogens.
- each R may be independently selected from halogen, branched or unbranched C 1 -C 4 alkyl; and branched or unbranched C 1 -C 4 alkyloxy; wherein any alkyl or alkyloxy group optionally is substituted with 1, 2 or 3 halogens.
- each R is independently selected from halogen, branched or unbranched C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl; and branched or unbranched C 1 -C 4 alkyloxy, C 2 -C 4 alkenyloxy or C 2 -C 4 alkynyloxy; wherein any alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, or alkynyloxy group optionally is substituted with 1, 2 or 3 halogens.
- any C 1 -C 4 alkyl moiety present in R is selected from C 1 - C 3 alkyl.
- any C 2 -C 4 alkenyl moiety in R may be selected from C 2 -C 3 alkenyl.
- Any C 2 -C 4 alkynyl moiety in R may be selected from C 2 -C 3 alkynyl.
- each R is selected from halogen, e.g. fluoro, chloro and bromo, in particular fluoro and chloro.
- halogen e.g. fluoro, chloro and bromo, in particular fluoro and chloro.
- each R is independently selected from halomethyl; dihalomethyl and trihalomethyl.
- each R is selected from fluoro, chloro; methyl, isopropyl, and methoxy, the methyl, isopropyl and methoxy groups optionally being substituted by 1, 2 or 3 hhaallooggeennss.
- R may be selected from fluoro, chloro, methyl, isopropyl, methoxy, and difluoromethoxy.
- R c is selected from hydrogen and branched or unbranched C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl. In one embodiment, R is selected from hydrogen and branched or unbranched C 1 -C 4 alkyl, e.g. hydrogen and methyl. In one embodiment, R is hydrogen.
- R 1 and R 2 are independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 - C 4 alkynyl; R a is halogen; X is -NR C - and n is 0 (zero).
- n is 0 (zero); R and R are independently selected from hydrogen and C 1 -C 8 alkyl; R is a monocyclic C 6 aryl; substituted with 1, 2, 3, 4 or 5 groups each independently selected from '5 R ; Y is -C(O)-; X is -NR 0 -; and R is independently selected from halogen; halomethyl; dihalomethyl; and trihalomethyl.
- compounds of formula (I) wherein R represents hydrogen; R represents C 1 -C 4 alkyl; X represents NR ; R represents hydrogen; R 3 represents a monocyclic C 6 aryl (phenyl), substituted with R ; R represents halomethyl; dihalomethyl or trihalomethyl; and n represents 0 (zero).
- any C p alkyl, alkynyl or alkenyl group has a number p > 4 of carbon atoms
- said alkyl, alkenyl or alkynyl group optionally includes a C q carbocyclic portion of q of carbon atoms, whereby 3 ⁇ q ⁇ p.
- the compounds of the invention can be present as salts, which are also within the scope of this invention.
- Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred.
- the inventive compounds can form acid addition salts, e.g. at the amino function.
- These may be formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid; strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (Ci-C 4 ) alkyl or arylsulfonic acids which are un
- the compounds of formula I having at least one acid group can also form salts with bases.
- Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine.
- Corresponding internal salts may furthermore be formed. Salts that are unsuitable for pharmaceutical uses but which can be employed, for example, for the
- the present invention also includes prodrugs.
- the esters of formula I display improved uptake in vivo and are hydrolyzed to their corresponding carboxylic acids in vivo.
- prodrug is intended to represent a compound bonded to a carrier, which prodrug is
- Prodrugs of compounds of the invention include compounds wherein a hydroxyl, amino, carboxylic, or a similar group is modified.
- Examples of prodrugs include, but are not limited to, esters (e.g. acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl of hydroxyl or amino functional
- amides e.g., trifluoroacetylamino, acetylamino, and the like, and the like.
- the compounds of the invention may be administered as is or as an alternative prodrug, for example in the form of an in vivo hydrolysable ester or in vivo hydrolysable amide.
- An in vivo hydrolysable ester of a compound of the invention containing carboxy or hydroxyl group is, for
- a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
- suitable pharmaceutically acceptable esters for carboxy include Q-Cealkyloxymethyl esters (e.g., methoxymethyl) d-C ⁇ alkanoyloxymethyl esters (e.g., pivaloyloxymethyl), phthalidyl esters, Ca-Cscycloalkyloxycarbonyloxy-Ci-C ⁇ alkyl esters (e.g. 1- cyclohexylcarbonyloxyethyl), l,3-dioxolen-2-onylmethyl esters (e.g., 5 -methyl- 1,3 -dioxolen-2-
- Cj-Cealkyloxycarbonyloxyethyl esters e.g., 1-methoxycarbonyloxyethyl
- An in vivo hydrolysable ester of a compound of the invention containing a hydroxyl group includes inorganic esters such as phosphate esters and acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent
- acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
- a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and 7V-(N,iV-dialkylamino- ethyl)-7V-alkylcarbamoyl (to give carbamates), A ⁇ N-dialkylaminoacetyl and carboxyacetyl.
- substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.
- a suitable value for an in vivo hydrolysable amide of a compound of the invention containing a carboxy group is, for example, an N-Ci-C 6 alkyl or 7V,7V-diCj-C 6 alkyl amide such as iV-methyl, iV-ethyl, JV-propyl, ⁇ yV-dimethyl, iV-ethyl-iV-methyl or N ⁇ /V-diethyl amide.
- an administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention.
- therapeutically effective amount refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein.
- the precise effective amount for a subject will depend upon the subject's size and general condition, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to exactly specify an exact effective amount in advance.
- the dosage might, however, vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I) or the corresponding amount of a pharmaceutically acceptable salt thereof.
- composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
- routes of administration e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal.
- the precise nature of the carrier or other material will depend on the route of administration.
- parenteral administration a parenterally acceptable aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability.
- a parenterally acceptable aqueous solution which is pyrogen free and has requisite pH, isotonicity and stability.
- the pharmaceutically acceptable excipients described herein for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public.
- the pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Examples of pharmaceutical formulations can be found in Remington: The Science and Practice of Pharmacy. A. R. Gennaro, Editor. Lippincott, Williams and Wilkins, 20th edition (2000). All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
- the compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diasteromeric forms or in
- another agent that is effective for those purposes such as, but not limited to, another antiangiogenic compounds inhibiting VEGF, VEGFR tyrosine kinase, integrin inhibitors, phototherapies, antibodies against VEGF, or one or more conventional therapeutic agents such as, alkylating agents, folic acid antagonists, anti-metabolites of nucleic acid metabolism, pyrimidine analogs, 5-fluorouracil, purine
- nucleosides Such other agents may be present in the composition being administered or may be administered separately.
- the compounds of the invention are suitably administered serially or in combination with radiological treatments, whether involving irradiation or administration of radioactive substances.
- antiangiogenic as used herein by itself or as a part of another definition refers to a
- antiangiogenic agents may include, but not limited to, compounds that inhibit cell proliferation, inhibit cell migration of endothelial cells, activate immune system, downregulate angiogenesis stimulators, stimulate angiogenesis
- inhibitor formation inhibits binding of angiogenesis stimulators, inhibit basement membrane degradation, induce apoptosis of endothelial cells, inhibit survival of endothelial cells, inhibit cell adhesion and inhibit survival of endothelial cells.
- the number of compounds or monoclonal antibodies that are antiangiogenic may include, but is not limited to, Avastin® (bevacizumab) carboxyamidotriazole (5-Amino-l-((3,5-dichloro-)
- CM-IOl a bacterial polysaccharide exotoxin produced by group B Streptococcus (GBS), also referred to as GBS toxin
- Germanin® also known as suramin, CAS number 145-63-1
- SU5416 semaxinib, (3Z)-3-[(3,5-dimethyl-lH-pyrrol-2- yl)methylidene]-l,3-dihydro-2H-indol-2-one
- TSP thrombospondins, a group of secreted proteins with antiangiogenic abilities
- VEGF vascular endothelial growth factor
- platelet-derived growth factor family of cystine-knot growth factors are important signaling proteins involved in angiogenesis, as well as vasculogenesis (de 10 novo formation of the embryonic circulatory system).
- VEGFR tyrosine kinase refers to the tyrosine kinase receptors that the members of the VEGF family bind to.
- integrin as used herein by itself or as a part of another definition refers to a family of transmembrane glycoproteins consisting of noncovalent heterodimers.
- the integrins consist of .5 at least three identified families where each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including oncogenic transformation.
- the compounds according to formula (I) will be useful for treating various diseases such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic !0 myocardium, atherosclerosis, macular edema and psoriasis.
- the treatment may be preventive, palliative or curative.
- the compounds of the invention provides a method of treating a mammal suffering from a disease or disorder related to VEGFR tyrosine kinase or integrin activity, comprising administering to said mammal in need thereof, a therapeutically effective amount of a compound 15 of formula (I).
- the said mammal can be a human.
- the compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of hyperproliferative diseases, e.g. antiangiogenic agents, including both compounds and monoclonal antibodies, and a cytostatic agent.
- additional drugs useful in the treatment of hyperproliferative diseases e.g. antiangiogenic agents, including both compounds and monoclonal antibodies, and a cytostatic agent.
- the components may be in the same formulation or in separate formulations for 0 administration simultaneously or sequentially.
- the compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
- cytotstatic agents for use as indicated herein above are DNA alkylating compounds, topoisomerase I inhibitors, topoisomerase II inhibitors, compounds interfering with RNA and DNA synthesis, compounds polymerising the cytoskeleton, and compounds depolymerising the cytoskeleton.
- reaction mixture was irradiated at 130°C for 5 minutes in a microwave reactor.
- the reaction mixture was concentrated and then purified on column (silica gel, dichloromethane/methanol 98:2) to give 0.39 g of ethyl 4-(4-fluorophenylamino)-6- (methylcarbamoylt ⁇ uinoline-S-carboxylate as a solid.
- Example 2 4-(4-chlorophenylamino)-6-(methylcarbamoyl)quinoIine-3-carboxylic acid.
- reaction mixture was irradiated at 130°C for 5 minutes in a microwave reactor.
- the reaction mixture was concentrated and then purified on column (silica gel, dichloromethane/methanol 98:2) to give 0.25 g of ethyl 4-(4-chlorophenylamino)-6-(methyl- carbamoyl)quinoline-3-carboxylate.
- reaction mixture was irradiated at 130 °C for 5 minutes in a microwave reactor.
- the reaction mixture was concentrated and the crude product was purified on column (flash chromatography, silica gel, dichloromethane/methanol 98:2). This gave 0.33 g (79% yield) of ethyl 6-bromo-4- [(4-isopropylphenyl)amino]quinoline-3-carboxylate.
- Example 4 4-[[4-(Difluoromethoxy)phenyl]amino]-6-(methylcarbamoyl)quinoline-3- carboxylic acid.
- 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (0.30 g, 0.95 mmol) and 4- difluoromethoxyaniline (0.23 g, 1.43 mmol) was mixed in dioxane (4 mL) and heated under microwave conditions at 150°Cfor 20 minutes. The reaction mixture was cooled, concentrated in vacuo and suspended in dichloromethane. The reaction mixture was filtered, the residue evaporated and triturated with diethyl ether.
- a 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (150 mg, 0.514 mmol), benzylamine (0.082 g, 0.765 mmol), triethylamine (0.011 mL, 0.077 mmol) and dry A ⁇ iV-dimethylamine (10 mL).
- the vial was capped and the mixture irradiated with microwaves for 30 minutes at 160°C.
- the reaction mixture was cooled to room temperature and diluted with dichloromethane.
- the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo.
- Example 6 4-(2,6-Dimethyl-phenylamino)-6-methylcarbamoyl-quinoline-3-carboxyIic acid.
- a 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (400 mg, 1.370 mmol), 2,6-dimethylaniline (0.25 g, 2.066 mmol), triethylamine (0.028 mL, 2.06 mmol) and dry N,N-dimethylformamide (10 mL).
- the vial was capped and the mixture was irradiated with microwaves for 30 minutes at 160 °C.
- the reaction mixture was cooled to room temperature and diluted with dichloromethane.
- the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo.
- Example 7 4-(3-Methoxy-phenylamino)-6-methyIcarbamoyl-quinoIine-3-carboxylic acid.
- a 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (150 mg, 0.514 mmol), w-anisidine (0.095 g, 0.771 mmol), triethylamine (0.010 mL, 0,51 mmol) and dry iV,JV-dimethylformamide (10 mL).
- the vial was capped and the mixture was irradiated with microwaves for 30 minutes at 160°C.
- the reaction mixture was cooled to room temperature and diluted with dichloromethane.
- the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo.
- Example 8 4-(2-Fluoro-phenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid.
- a 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (360 mg, 1.233 mmol), 2-fluoroaniline (0.206 g, 1.853 mmol), triethylamine (0.025 mL, 1.85 mmol) and dry N ⁇ V-dimethylformamide (10 mL).
- the vial was capped and the mixture was irradiated with microwaves for 30 minutes at 160 °C.
- the reaction mixture was cooled to room temperature and diluted with dichloromethane.
- the organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo.
- Example 9 6-Methylcarbamoyl-4-phenylamino-quinoline-3-carboxyIic acid.
- the Boyden Chamber assay is based on a chamber of two medium-filled compartments separated by a microporous membrane. Cells are placed in the upper compartment and are allowed to migrate through the pores of the membrane into the lower compartment, in which chemotactic agents are present. After an appropriate incubation time, the membrane between the two compartments is fixed and stained, and the number of cells that have migrated to the lower side of the membrane is determined.
- the Boyden chamber-based cell migration assay has also been called chemotaxis assay.
- the compounds were tested for their capacity of influencing chemotaxis, using porcine aorta endothelial (PAE) cells expressing VEGFR2 and VEGFR3 (PAE/VEGFR-2 and PAE/VEGFR- 3) with VEGF-A and VEGF-C, respectively, as chemotactic agent.
- the method used a modified Boyden chamber assay.
- the migration of the PAE cells expressing VEGFR2 and VEGFR3 receptors toward VEGF-A and VEGF-C respectively used as chemo-attractant was studied though micropore polycarbonate filter and was scored in the absence of serum.
- the assay was performed in the presence of compounds at 10 ⁇ M concentrations and the quantified measure of the inhibiton activity of compounds is expressed in %.
- the cell adhesion assay is a measure of the ability of a compound to inhibit adhesion to fibronectin. Therefore a high % inhibition value indicates that the compounds inhibit adhesion to flbronectine and are therefore integrin antagonists for ⁇ 5 ⁇ 1.
- Day 1 Flat-bottomed microwell plates (Maxisorb, Nunc) are coated with 20 ⁇ g/ml of fibronectin (FN) and incubated over night at room temperature in a humified box.
- FN fibronectin
- the plates are washed 5 times in pre-warmed EMEM medium and the cells that had adhered to fibronectin is fixated in 4 % paraformaldehyde for 30 minutes in the humified box.
- To the fixated cells 0.5 % toluidine blue is added and the plates are incubated over night in the humified chamber.
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Abstract
A compound of formula (I) as well as pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising a therapeutically effective amount of the compounds. The compounds are useful in treatment of cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis.
Description
DERIVATIVES OF QUINOLINE-3-CARBOXYLIC ACID AND THEIR MEDICAL USE
FIELD OF THE INVENTION
The present invention relates to quinoline-3-carboxylic acid derivatives and to the use 5 thereof in therapy. Particularly, the present invention relates to their use for the treatment of cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
BACKGROUND OF THE INVENTION 0 The following review of the state of art is only provided to aid the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.
Angiogenesis, the outgrowth of new capillaries from pre-existing vessels, is essential for embryonic development, organ formation, tissue regeneration, and remodeling [Folkman, J. & 5 Shing, Y. (1992) J. Biol. Chem. 267, 10931-10934]. It also contributes to the development and progression of a variety of pathological conditions, including tumor growth and metastasis, cardiovascular diseases, diabetic retinopathy, rheumatoid arthritis, psoriasis [Folkman, J. Nat.
Med. 1995, 1, 27-30] and age-related macular degeneration [Barakat, M. R.; Kaiser, P. K. Expert
Opin. Investig. Drugs 2009, 18, 637-46; Chappelow, A. V.; Kaiser, P. K. Drugs 2008, 68, 1029- :0 1036].
Angiogenesis and vasculogenesis are complex multistep processes that include proliferation, migration and differentiation of endothelial cells, degradation of the extracellular matrix, tube formation, and sprouting of new capillary branches [Hanahan, D.; Folkman, J. Cell
1996, 86, 353-364; Risau, W. Nature (London) 1997, 386, 671-674]. The complexity of the ,5 angiogenic processes suggests the existence of multiple controls of the system, which can be transiently switched on and off. A switch of the angiogenic phenotype in tissues is thought to depend on a local change of the balance between angiogenic stimulators and inhibitors
[Folkman, J. N Engl. J. Med. 1995, 333, 1757-1763].
Among many described angiogenic factors, vascular endothelial growth factor (VEGF)/ 0 vascular permeability factor is one of the best-characterized positive regulators with its distinct specificity for vascular endothelial cells [Senger, D. R.; Galli, S. J.; Dvorak, A. M.; Perruzzi, C.
A.; Harvey, V. S.; Dvorak, H. F. Science 1983, 219, 983-985; Ferrara, N.; Henzel, W. J.
Biochem. Biophys. Res. Commun. 1989, 161, 851-858; Gospodarowicz, D.; Abraham, J. A.;
Schilling, J. Proc. Natl. Acad. ScL USA 1989, 86, 7311-7315]. The biological actions of VEGF
include stimulation of endothelial cell proliferation, migration, differentiation, tube formation, increase of vascular permeability, and maintenance of vascular integrity [Mustonen, T.; Alitalo, K. J Cell Biol. 1995, 129, 895-898; Ferrara, N.; Davis-Smyth, T. Endocr. Rev. 1997, 18, 4-25; Thomas, K. J Biol. Chem. 1996, 271, 603-606; Risau, W. Nature (London) 1997, 386, 671-674; Breier, G.; Risau, W. Trends Cell Biol. 1997, 6, 454-456]. The angiogenic responses induced by VEGF are mediated by tyrosine kinase receptors, which are expressed primarily on vascular cells of the endothelial lineage [Mustonen, T.; Alitalo, K. J Cell Biol. 1995, 129, 895-898; De Vries, C; Escobedo, J. A.; Ueno, H.; Huck, K.; Ferrara, N.; Williams, L. T. Science 1992, 255, 989-99; Terman, B. L; Dougher-Vermazen, M.; Carrion, M. E.; Dimitrov, D.; Armellino, D. C; Gospodorawicz, D.; Bohlen, P. Biochem. Biophys. Res. Commun. 1992, 187, 1579-1586].
Inhibition of cell adhesion to the endothelial cell membrane (ECM), the fundamental step for activation, survival, targeting and migration of activated endothelial cells, might be one of the most promising target mechanisms for anti-angiogenesis. Not only VEGF is involved in these mechanisms but many of these interactions are also mediated by integrins, a family of multifunction cell adhesion receptors [Stupack, D. G. Oncology (Williston Park) 2007, 21 (9 Suppl 3), 6-12; Avraamides, C. J.; Garmy-Susini, B.; Varner, J. A. Nat. Rev. Cancer 2008, 8, 604-17.]. Members of the integrin family are non-covalent alpha/beta heterodimers that mediate cell-cell, cell-extracellular matrix and cell-pathogen interactions. They are also are believed to modulate the effect of receptors for vascular endothelial growth factor (VEGFRs) [Napione, L.; Cascone, L; Mitola, S.; Serini, G.; Bussolino, F. Autoimmun. Rev. 2007, 7, 18-22].
Until now, 19 different integrin alpha subunits and 8 different beta subunits are known that combine to form at least 24 different alpha/beta heterodimers with different ligand specificity [Silva, R.; D'Amico, G.; Hodivala-Dilke, K. M.; Reynolds, L. E. Arterioscler Thromb Vase Biol, 2008, 28, 1701-1713]. Of the presently approximately 24 known integrins, 16 have been reported to have involvement in some aspects of vascular biology. Of these αlβl, α2βl, α3βl, α5βl, α6βl, α6β4, αvβ3, and αvβ5 are known to be present in endothelial cells [Rupp, P. A.; Little, C. D. Circ. Res., 2001, 566-572; Stupack, D. G.; Cheresh, D. A. Sci. STKE, 2002, PE7], while vascular smooth muscle cells have been reported to have αlβl, α2βl, α3βl, α4βl, α5βl, α6βl, α7βl, α8βl,α9βl, αvβl, αvβ3, αvβ5, and α6β4 [Moiseeva, E. P. Cardivasc. Res., 2001, 372- 386].
The ligands for the extracellular domain of many integrins are the proteins of the extracellular matrix and the intracellular domain of the integrins are either directly or indirectly connected to intracellular components such as kinases and the cytoskeleton. Integrins serve as bidirectional signalling receptors, whereby protein activities and gene expression are changed by
integrins in response to ligand binding to the extracellular domain thereof, which is also referred to as outside-in-signalling. On the other hand, the affinity of the integrins is modulated in response to intracellular changes such as binding of proteins to the extracellular domain of the integrin, which is referred to as inside-out signalling [Humphries, M. J. Biochem. Soc. Trans.
5 2000, 28, 311-339; Hynes, R. O. Cell, 2002, 110, 673-687].
Several studies on the integrin pattern on activated endothelial cells, mice gene knockouts and inhibition studies in angiogenic animal models with antibodies, peptides and small molecules have provided information about integrins and ECM proteins involved in critical steps of angiogenesis [Brooks, P. C; Clark, R. A.; Cheresh, D. A. Science, 1994, 264, 569-571;
0 Brooks, P. C. Eur. J. Cancer, 1996, 32A, 2423-2429; Mousa, S. A. Curr Opin Chem Biol, 2002, 6, 534-541; Hynes, R. O. Nature Medicine 2002, 8, 918-21; Kim, S.; Bell, K.; Mousa, S. A.; Varner, J. A.; Am. J. Pathol. 2000, 156, 1345-1362].
From studies referred to herein above it appeared that the vitronectin receptors αvβ3, αvβ5 and the fibronectin receptor α5βl play a critical role in angiogenesis. Integrin α5βl expression
5 is significantly upregulated in blood vessels in human tumors and after stimulation with growth factors and, once expressed, α5βl regulates the survival and migration of endothelial cells in vitro and in vivo. Integrin α5βl is poorly expressed on quiescent endothelium but its expression is significantly upregulated on endothelium during tumor angiogenesis in both mice and humans, which makes α5βl a viable target for anti-angiogenic therapy [Kim, S.; Bell, K.; Mousa, S. A.;
!0 Varner, J. A.; Am. J. Pathol. 2000, 156, 1345-1362; Bhaskar, V.; Zhang, D.; Fox, M.; Seto, P.; Wong, M. H.; Wales, P. E.; Powers, D.; Chao, D. T; Dubridge, R. B.; Ramakrishnan, V. J. Transl. Med. 2007, 27, 61]. Expression of this integrin is also upregulated during corneal angiogenesis [Muether, P. S.; Dell, S.; Kociok, N.; Zahn, G.; Stragies, R.; Vossmeyer, D.; Joussen, A. M.; Exp. Eye. Res. 2007, 85, 356-365].
'5 Combination of anti-angiogenetic therapy and other therapeutic approaches, such as chemotherapy, radiotherapy and gene therapy has also been applied and suggested for cancer treatment. Mounting evidence suggests that there is potentially synergistic effect of combined therapeutic approaches over single modality alone [Huveneers, S.; Truong, H.; Danen, H. J. Int. J. Radial Biol. 2007, 83, 743-751; Huber, P. E.; Bischof, M.; Jenne, J.; Heiland, S.; Peschke, P.;
0 Saffrich, R.; Grδne, H. J.; Debus, J.; Lipson, K. E.; Abdollahi, A. Cancer Res. 2005, 65, 3643- 3655].
SUMMARY OF THE INVENTION
The present inventors now have found that novel quinoline derivatives with certain side- chain patterns, compared to similar analogs in the field have improved in vitro or in vivo properties when used in therapy.
Consequently, according to one aspect, the present invention relates to a compound of formula (I)
(I) wherein:
LO n is 0 (zero) or 1;
R and R are independently selected from hydrogen; branched or unbranched Cj-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; monocyclic or bicyclic, saturated or unsaturated C3-C8 carbocyclyl; and monocyclic or bicyclic, saturated or unsaturated C1-C7 heterocyclyl wherein the heteroatoms are independently selected from N, O and S;
[5 said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally being substituted with 1,
2, or 3 groups Ra;
R3 is selected from monocyclic or bicyclic C6-C10 aryl; and monocyclic or bicyclic C1-C9 heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups R ; >0 Y is selected from -C(O)-; -S(O)-; and -S(O)2-;
X is selected from -NRC-; -0-; and -S-; each R is independently selected from halogen; hydroxy; carbonyl; methoxy; halomethoxy; dihalomethoxy; and trihalomethoxy; each R is independently selected from halogen, branched or unbranched C1-C4 alkyl, C2- .5 C4 alkenyl or C2-C4 alkynyl; branched or unbranched C1-C4 alkyloxy, C2- C4 alkenyloxy or C2- C4 alkynyloxy; branched or unbranched C1-C4 alkylthio, C2-C4 alkenylthio or C2-C4 alkynylthio; wherein any alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy alkynyloxy, alkylthio, alkenylthio or alkynylthio group optionally is substituted with 1, 2 or 3 halogens;
R is selected from hydrogen and branched or unbranched Cj-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; or a pharmaceutically acceptable salt thereof.
Another aspect of the invention relates to a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, for use in therapy.
Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient. hi one embodiment of this aspect said pharmaceutical composition comprises at least one further, pharmaceutically active compound. Said further pharmaceutically active compound may have anti-tumor activity.
Another aspect of the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
Another aspect of the invention provides the use of the compounds of formula (I) or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of disorders such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis. Another aspect of the invention provides a method of treating a mammal suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said mammal in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, said mammal is a human.
Another aspect of the invention provides a method of treating a mammal suffering from a disease or disorder related to VEGFR tyrosine kinase or integrin activity, comprising administering to said mammal in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, said mammal is a human.
Another aspect of the invention provides a method of treating a mammal suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said
patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent that inhibits VEGF, VEGFR tyrosine kinase or integrin. In another embodiment of this aspect, said second therapeutic agent is a therapeutic antibody. In one embodiment of this aspect, said second
5 therapeutic agent is selected from an alkylating agent; a folic acid antagonist; an antimetabolite of nucleic acid metabolism; a pyrimidine analog; 5-fluorouracil; and a purine nucleoside. In another embodiment of this aspect, said mammal is a human. In another embodiment of this aspect, said second therapeutic agent is administered in combination or sequentially with the first therapeutic agent.
10 Another aspect of the invention provides a method of treating a patient suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula (I) in combination with radiological treatment, including irradiation and/or administration of a
5 radioactive substance.
Another aspect of the invention provides a method of treating a patient suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of formula (I) or a
!0 pharmaceutically acceptable salt thereof in combination with at least two of the treatment mentioned above. Such a method can involve the combination a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with any antiangiogenic agent, radiological treatment and/or chemotherapy.
Further aspects and embodiments of the invention are as defined in the claims.
'.5
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to substituted quinoline derivatives, which can be utilized to treat diseases and conditions such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema,
0 psoriasis, and the like in mammals.
The preparation of the compounds of the invention lies well within the capability of the person skilled in the art. As an example, a quinoline-3-carboxylic acid ester of the invention may be formed in a six step procedure wherein, first, a suitable halo aniline derivative is reacted with a suitable mono- or diethylester, the formed intermediate cyclized to give a 4-halo-quinoline-3-
carboxylic acid ester, which is then coupled with a suitable amine, H(Rc)N-(CH2)n-R3 to form a substituted secondary or tertiary 4-amino quinoline-3 -carboxylic acid ester. The halogen can then be carbonylated, to yield the corresponding amide, -C(O)-NR1R2. It this context, it should be obvious for the one skilled in the art that a substituted sulphonamide, -S(O)2-NR R , can be prepared via reaction of the halogen with sulfite ion, followed by further manipulation to yield the corresponding sulphonamide or corresponding sulfoxide. The quinoline-3 -carboxylic acid ester can then be hydrolysed to give the corresponding inventive compounds. The entire synthesis is illustrated by Reaction Scheme 1. With regard to the below reaction sequence, it should be well within the capability of the person skilled in the art to select suitable reaction components as well as reaction conditions.
Reaction Scheme 1
Preparation of a compound of formula (I) wherein X is -NRC-
(I, X is -NR0-)
Another synthetic method useful for preparing the inventive compounds is illustrated in Reaction Scheme 2. In this case the synthesis is started from a suitable 6-aniline derivative, -Y-
NR . l Rr.2 , and the amine group, -(R )N(CH2)nR , is introduced in a later step. The entire synthesis is illustrated by Reaction Scheme 2.
Reaction Scheme 2
Preparation of a compound of formula (I) wherein X is -NR -
(I; X is -NRC-)
Numerous methods exist in the literature for the synthesis of ethers and sulfides from aryl halides, which should be contemplated when X is O (oxygen) or S. A summary of this work can be found in, for example, Jerry March in Advanced Organic Chemistry, 4* Ed, John Wiley & Sons Inc, New York, 1992, p654-656. An example of a modern synthetic procedure that directly leads to compounds as biaryl ethers can be found in: Evans, D. A.; et al., Tetrahedron Lett. 1998, 39, 2937-2940.
1 9 "-Ϊ C
In summary, there are several ways in which order to introduce the groups R , R , R , R , Y and X, all well known for the one skilled in the art, in order to arrive at the compounds of the invention, and the synthetic routes mentioned herein are not limiting for the invention.
The term "alkyl" as employed herein, alone or as part of another group, refers to an acyclic
5 straight or branched chain radical, unless otherwise specified containing 1, 2, 3, 4, 5, 6, 7 or 8 carbons in the normal chain, which includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. Examples of branched chain radicals, not excluding any of the possible isomers not mentioned, are iso-propyl, sec-butyl, iso-pentyl, 3-methylpentyl, 2,3-dimethylhexyl, 3-ethylhexyl, and the like. Unless otherwise specified, the term alkyl also includes a straight or
10 branched alkyl group that contains or is interrupted by a carbocyclyl, exemplified by cyclopropane, as exemplified below:
In case the alkyl is interrupted or terminated by a carbocyclyl, the alkyl portions can be attached at any variable point of attachment to the carbocyclyl, including the same ring carbon, as exemplified below:
5 When the alkyl chain is interrupted or terminated by a carbocyclyl, the total number of carbon atoms of the alkyl chain and the carbocyclyl is at most 8. hi other words, in the above given example, the sum of z and w is at most 5.
When substituted alkyl is present, this refers to a straight or branched alkyl group as defined above, substituted with 1, 2 or 3 groups of Ra. The alkyl group preferably contains 1, 2, 3
'0 or 4 carbons in the normal chain that also can be substituted with 1, 2 or 3 groups of Ra, which groups may be the same or different at any available point, as defined with respect to each variable. When such a substituted alkyl group is present, the preferred substitution is halogen such as in -CH2Cl, -CF3, -CH2I, -CHF2, -CH2Br, -CH2F, -CHFCH2F, -CHFCH2Cl, - CHFCHClCH3, -CHClCHBrCH2CF3, -CHClCBrICH2CF3, -CH2CH2CH2CH2I, and the like.
!5 The term "alkenyl" as used herein, alone or as part of another group, refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7 or 8 carbons, which contains at least one carbon to carbon double bond. Preferably only one carbon to carbon double bond is present, such as in the normal chain vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, and the like.
0 The alkenyl group preferably contains 2, 3 or 4 carbons in the normal chain. As described above with respect to the "alkyl", the straight or branched portion of the alkenyl group may be optionally substituted when a substituted alkenyl group is provided. Furthermore, unless
otherwise specified, the chain may be interrupted or terminated by a carbocyclyl group, in which case the total number of carbon atoms of the chain and the carbocyclyl is at most 8.
The term "alkynyl" as used herein by itself or as part of another group refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7 or 8 carbons, which contains at least one carbon to carbon triple bond. Preferably, only one carbon to carbon triple bond is present, such as in the normal chain 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3- pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, and the like. The alkynyl group preferably contains 1, 2, 3 or 4 carbons in the normal chain. As described above with respect to the "alkyl", the straight or branched portion of the alkynyl group may be optionally substituted when a substituted alkynyl group is provided. Furthermore, unless otherwise specified, the chain may be interrupted or terminated by a carbocyclyl group, in which case the total number of carbon atoms of the chain and the carbocyclyl is at most 8.
In one embodiment, in a compound according to formula (I), any alkyl, alkenyl, or alkynyl group having a number of p (p being an integer of 4 to 8) carbon atoms, optionally and independently from any other alkyl, alkenyl or alkynyl group present in the compound, includes a carbocyclic portion of a number of q (q being an integer of 3 to 7 and q being less than p) carbon atoms, which carbocyclic portion may be located so as to interrupt or terminate the straight or branched chain of the alkyl, alkenyl, or alkynyl group, whereby the number of carbon atoms in the straight or branched chain of the alkyl, alkenyl or alkynyl group equals p-q. In another embodiment, in a compound according to formula (I), any alkyl, alkenyl, or alkynyl group having p carbon atoms has all p carbon atoms in the straight or branched chain portion, i.e. does not include any terminating or interrupting carbocyclic portion.
The term "carbocyclyl" as employed herein alone or as part of another group includes saturated cyclic hydrocarbyl groups or unsaturated (at least 1 double bond) cyclic hydrocarbyl groups, containing at least one ring of in total of 3, 4, 5, 6, 7 or 8 ring carbons, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and the like. The cyclic hydrocarbyl may be monocyclic or bicyclic (i.e. containing two rings of 3 to 8 ring carbons each). For example, the carbocyclyl may be monocyclic and 3- to 6-membered. As described above with respect to the "alkyl", the carbocyclyl group may be optionally substituted by 1, 2 or 3 halogens, which may be the same or different.
As used herein, and unless otherwise specified, the term "heterocyclyl" mean a non- aromatic cyclic group that optionally might be unsaturated, containing one or more heteroatom(s) preferably selected from N, O and S, such as a 4 to 10-membered ring system containing at least one heteroatom, e.g. 1-4 heteroatoms. For example, a suitable heterocyclyl
may be a non-aromatic cyclic group that optionally might be unsaturated, containing one or more heteroatom(s) preferably selected from N, O and S, such as a 5 to 6-membered monocyclic ring system containing at least one heteroatom, e.g. 1-4 heteroatoms, 1-3 heteroatoms, or 1 or 2 heteroatoms. A heterocyclyl e.g. may be, but is not limited to, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl, imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, pyrrolidinyl, pyrrolidinonyl, piperidyl, piperazinyl, piperidinyl, pyrazolidinyl, quinuclidinyl, sulfalonyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl, tropanyl, lH-indazolyl and monosaccharide.
By the term "unsaturated", when referring to a bicyclic system, is meant a ring system comprising at least one double or triple bond in at least one ring. Thus, it is contemplated that both rings may be unsaturated or only one ring may be unsaturated, and the other one being saturated. Furthermore, the term "unsaturated bicyclic" also is intended to refer to a non- aromatic bicyclic system comprising a ring that is either unsaturated or saturated fused to a ring that by itself would be aromatic, such as in indane or 4,5-dihydro-l -indole.
The term "halogen" refers to fluorine, chlorine, bromine and iodine, where the preferred halogen radicals are fluorine and chlorine.
As used herein, the term "aryl" means an aromatic group, monocyclic or bicyclic such as phenyl or naphthyl, and the like. The aryl group is preferably a monocyclic C6 aryl (i.e. phenyl).
As used herein, the term "heteroaryl" means a mono- or bicyclic heteroaromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as, but not limited to, pyridyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, isoquinolinyl, naphthyridinyl, imidazolyl, phenazinyl, phenothiazinyl, phthalazinyl, indolyl, pyridazinyl, quinazolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, pyrazinyl, indazolyl, indolinyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, chromanyl, cinnolinyl, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl, benzofuranyl, benzothiazolyl, benzobenzoxadiazolyl, benzoxazinyl, benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl, benzothienyl, purinyl, and pteridinyl.
(I) as defined herein above.
In formula (I), n denotes the number of -CH2- linking X to R , and is either 0 or 1. In one 5 embodiment n is 1 ; however, more preferably n is 0.
The groups R and R2 are independently selected from hydrogen; branched or unbranched C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; monocyclic or bicyclic, saturated or unsaturated C3-C8 carbocyclyl; and monocyclic or bicyclic, saturated or unsaturated C1-C7 heterocyclyl wherein the heteroatoms are independently selected from N, O and S; and wherein said alkyl, 10 alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally are substituted with 1, 2, or 3 groups R . In one embodiment, R1 and R2 are independently selected from hydrogen and branched or unbranched C1-C8 alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein said alkyl, alkenyl, or alkynyl are substituted with 1, 2, or 3 groups Ra. In particular, R1 and R2 may be independently selected from hydrogen and branched or unbranched C1-C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl, said ^5 alkyl, alkenyl, or alkynyl optionally being substituted with 1, 2, or 3 groups R .
In another embodiment, R1 and R2 are independently selected from hydrogen and branched or unbranched C1-C8 alkyl, said alkyl optionally being substituted with 1, 2, or 3 groups Ra. In particular, R and R2 may be independently selected from hydrogen and branched or unbranched CJ-C4 alkyl, e.g. methyl, said alkyl, alkenyl, or alkynyl optionally being substituted with 1, 2, or !0 3 groups R , e.g. 1 or 2 groups R , or 1 group R , or no group R .
1 0 1
In one embodiment, R is hydrogen, and R is as defined herein above. For example, R is hydrogen, and R2 is as defined herein above, but is not hydrogen.
In one particular embodiment, R1 is hydrogen, and R2 is methyl.
In a compound of formula (I), R3 is selected from monocyclic or bicyclic C6-C10 aryl; and '5 monocyclic or bicyclic Ci -Cg heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups Rb.
In one embodiment, R3 is selected from monocyclic C6 (i.e. phenyl); and monocyclic C1-C5 heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups R .
In another embodiment, R is selected from monocyclic or bicyclic C6-CiO aryl; said aryl 5 optionally being substituted with 1, 2, 3, 4 or 5 groups R .
For example, R may be phenyl; optionally substituted with 1, 2, 3, 4 or 5 groups R . In one embodiment, R3 is selected from (unsubstituted) phenyl, fluorophenyl, chlorophenyl, isopropylphenyl, difluoromethoxyphenyl, dimethylphenyl and methoxyphenyl. For example, R may be selected from phenyl, 2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- 10 isopropylphenyl, 4-(difluoromethoxy)phenyl, 2,6-dimethylphenyl, and 3 -methoxyphenyl.
In formula (I), the moiety Y is - is selected from -C(O)-; -S(O)-; and -S(O)2-, but preferably is -C(O)-.
The moiety X is selected from -NR0-; -O-; and -S-; but preferably is -NRC-.
As mentioned herein above, any alkyl, alkenyl, or alkynyl in either of R and R optionally 15 may be substituted with 1, 2, or 3 groups Ra. For example, the number of substituents R e.g. may be 1 or 2, or 1, and each R is independently selected from halogen; hydroxy; carbonyl; methoxy; halomethoxy; dihalomethoxy; and trihalomethoxy; e.g. from halogen. In one embodiment Ra is absent.
In R , any aryl or heteroaryl optionally is substituted with 1, 2, 3, 4 or 5 groups R . For !0 example, the number of groups R present on any given ring in a monocyclic or bicyclic moiety may be 1-4, or 1-3, e.g.l or 2.
Each R is independently selected from halogen, branched or unbranched C1-C4 alkyl, C2- C4 alkenyl or C2-C4 alkynyl; branched or unbranched C1-C4 alkyloxy, C2-C4 alkenyloxy or C2-C4 alkynyloxy; branched or unbranched C1-C4 alkylthio, C2-C4 alkenylthio or C2-C4 alkynylthio; '.5 wherein any alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy alkynyloxy, alkylthio, alkenylthio or alkynylthio group optionally is substituted with 1, 2 or 3 halogens.
In one embodiment, each R is independently selected from halogen, branched or unbranched Ci-C4 alkyl; branched or unbranched C1-C4 alkyloxy; and branched or unbranched C1-C4 alkylthio; wherein any alkyl, alkyloxy or alkylthio group optionally is substituted with 1, 2 0 or 3 halogens. For example, each R may be independently selected from halogen, branched or unbranched C1-C4 alkyl; and branched or unbranched C1-C4 alkyloxy; wherein any alkyl or alkyloxy group optionally is substituted with 1, 2 or 3 halogens.
In another embodiment, each R is independently selected from halogen, branched or unbranched C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; and branched or unbranched C1-C4 alkyloxy, C2-C4 alkenyloxy or C2-C4 alkynyloxy; wherein any alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, or alkynyloxy group optionally is substituted with 1, 2 or 3 halogens. 5 In one embodiment, any C1-C4 alkyl moiety present in R is selected from C1- C3 alkyl.
Also, any C2-C4 alkenyl moiety in R may be selected from C2-C3 alkenyl. Any C2-C4 alkynyl moiety in R may be selected from C2-C3 alkynyl.
In one embodiment, each R is selected from halogen, e.g. fluoro, chloro and bromo, in particular fluoro and chloro.
LO In another embodiment of the invention, each R is independently selected from halomethyl; dihalomethyl and trihalomethyl.
In another embodiment, each R is selected from fluoro, chloro; methyl, isopropyl, and methoxy, the methyl, isopropyl and methoxy groups optionally being substituted by 1, 2 or 3 hhaallooggeennss.. FFoorr eexxaaimple, R may be selected from fluoro, chloro, methyl, isopropyl, methoxy, and difluoromethoxy.
The group Rc is selected from hydrogen and branched or unbranched C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl. In one embodiment, R is selected from hydrogen and branched or unbranched C1-C4 alkyl, e.g. hydrogen and methyl. In one embodiment, R is hydrogen.
In one particular embodiment of the invention, there is provided compounds of formula (I), ',0 wherein R1 and R2 are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl and C2- C4 alkynyl; Ra is halogen; X is -NRC- and n is 0 (zero).
In another embodiment of the invention, there is provided compounds of formula (I), wherein n is 0 (zero); R and R are independently selected from hydrogen and C1-C8 alkyl; R is a monocyclic C6 aryl; substituted with 1, 2, 3, 4 or 5 groups each independently selected from '5 R ; Y is -C(O)-; X is -NR0-; and R is independently selected from halogen; halomethyl; dihalomethyl; and trihalomethyl.
In another embodiment of the invention, there is provided compounds of formula (I), wherein R1 represents hydrogen; R2 represents C1-C4 alkyl; X represents NR0; R° represents hydrogen; R3 represents a monocyclic C6 aryl (phenyl), substituted with R ; R represents 0 halogen; and n represents 0 (zero).
In another embodiment of the invention, there is provided compounds of formula (I), wherein R represents hydrogen; R represents C1-C4 alkyl; X represents NR ; R represents hydrogen; R3 represents a monocyclic C6 aryl (phenyl), substituted with R ; R represents halomethyl; dihalomethyl or trihalomethyl; and n represents 0 (zero).
In any of the above embodiments, wherein any Cp alkyl, alkynyl or alkenyl group has a number p > 4 of carbon atoms, said alkyl, alkenyl or alkynyl group optionally includes a Cq carbocyclic portion of q of carbon atoms, whereby 3 < q < p.
In another embodiment of the invention, there is provided a compound of formula (I), which is:
4-(4-fluorophenylamino)-6-(methylcarbamoyl)quinoline-3 -carboxylic acid; or
4-(4-chlorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid;
4- [(4-isopropylphenyl)amino] -6-(methylcarbamoyl)quinoline-3 -carboxylic acid;
-[[4-(difluoromethoxy)phenyl]amino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid;
-benzylamino-6-methylcarbamoyl-quinoline-3 -carboxylic acid;
-(2,6-dimethyl-phenylamino)-6-methylcarbamoyl-quinoline-3-carboxylic acid;
-(3 -methoxy-phenylamino)-6-methylcarbamoyl-quinoline-3 -carboxylic acid;
4-(2-fluoro-phenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid;
6-niethylcarbamoyl-4-phenylamino-quinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
The compounds of the invention can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred.
For example, the inventive compounds can form acid addition salts, e.g. at the amino function. These may be formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid; strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (Ci-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene- sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a
mono-, di- or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts that are unsuitable for pharmaceutical uses but which can be employed, for example, for the
5 isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts are also included.
The present invention also includes prodrugs. In fact, the esters of formula I display improved uptake in vivo and are hydrolyzed to their corresponding carboxylic acids in vivo. The term "prodrug" is intended to represent a compound bonded to a carrier, which prodrug is
.0 capable of releasing the active ingredient when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs of compounds of the invention include compounds wherein a hydroxyl, amino, carboxylic, or a similar group is modified. Examples of prodrugs include, but are not limited to, esters (e.g. acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl of hydroxyl or amino functional
5 groups of the present invention), amides (e.g., trifluoroacetylamino, acetylamino, and the like), and the like.
The compounds of the invention may be administered as is or as an alternative prodrug, for example in the form of an in vivo hydrolysable ester or in vivo hydrolysable amide. An in vivo hydrolysable ester of a compound of the invention containing carboxy or hydroxyl group is, for
!0 example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Q-Cealkyloxymethyl esters (e.g., methoxymethyl) d-Cβalkanoyloxymethyl esters (e.g., pivaloyloxymethyl), phthalidyl esters, Ca-Cscycloalkyloxycarbonyloxy-Ci-Cδalkyl esters (e.g. 1- cyclohexylcarbonyloxyethyl), l,3-dioxolen-2-onylmethyl esters (e.g., 5 -methyl- 1,3 -dioxolen-2-
15 onylmethyl) and Cj-Cealkyloxycarbonyloxyethyl esters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at any appropriate carboxy group in the compounds of the invention.
An in vivo hydrolysable ester of a compound of the invention containing a hydroxyl group includes inorganic esters such as phosphate esters and acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent
0 hydroxy group. Examples of acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and 7V-(N,iV-dialkylamino- ethyl)-7V-alkylcarbamoyl (to give carbamates), A^N-dialkylaminoacetyl and carboxyacetyl.
Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring. A suitable value for an in vivo hydrolysable amide of a compound of the invention containing a carboxy group is, for example, an N-Ci-C6alkyl or 7V,7V-diCj-C6alkyl amide such as iV-methyl, iV-ethyl, JV-propyl, ΛyV-dimethyl, iV-ethyl-iV-methyl or N^/V-diethyl amide. Upon administration of a compound of the invention, or an alternative prodrug thereof, the prodrug undergoes chemical conversion by metabolic or chemical processes to yield another compound, for example a salt and/or solvate thereof. Solvates of the compounds of the present invention include, for example hydrates. An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and general condition, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to exactly specify an exact effective amount in advance. In the case of oral administration the dosage might, however, vary from about 0.01 mg to about 1000 mg per day of a compound of formula (I) or the corresponding amount of a pharmaceutically acceptable salt thereof.
The composition according to the invention may be prepared for any route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal. The precise nature of the carrier or other material will depend on the route of administration. For parenteral administration, a parenterally acceptable aqueous solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability. Those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature.
The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. The pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Examples of pharmaceutical formulations can be found in Remington: The Science and Practice of Pharmacy. A. R. Gennaro, Editor. Lippincott, Williams and Wilkins, 20th edition (2000).
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diasteromeric forms or in
5 mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diasteromers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, which for example is chromatographic or fractional crystallization.
The effectiveness of the compounds of the invention in preventing or treating disease may
[O be improved by administering the compounds in combination with another agent that is effective for those purposes, such as, but not limited to, another antiangiogenic compounds inhibiting VEGF, VEGFR tyrosine kinase, integrin inhibitors, phototherapies, antibodies against VEGF, or one or more conventional therapeutic agents such as, alkylating agents, folic acid antagonists, anti-metabolites of nucleic acid metabolism, pyrimidine analogs, 5-fluorouracil, purine
5 nucleosides. Such other agents may be present in the composition being administered or may be administered separately. Also, the compounds of the invention are suitably administered serially or in combination with radiological treatments, whether involving irradiation or administration of radioactive substances.
The term antiangiogenic as used herein by itself or as a part of another definition refers to a
!0 compound with the ability to inhibit angiogenesis, which is the growth of new blood vessels into a solid tumor.
The number of mechanisms for antiangiogenic agents is diverse and may include, but not limited to, compounds that inhibit cell proliferation, inhibit cell migration of endothelial cells, activate immune system, downregulate angiogenesis stimulators, stimulate angiogenesis
!5 inhibitor formation, inhibits binding of angiogenesis stimulators, inhibit basement membrane degradation, induce apoptosis of endothelial cells, inhibit survival of endothelial cells, inhibit cell adhesion and inhibit survival of endothelial cells.
The number of compounds or monoclonal antibodies that are antiangiogenic may include, but is not limited to, Avastin® (bevacizumab) carboxyamidotriazole (5-Amino-l-((3,5-dichloro-
0 4-(4-chlorobenzoyl)phenyl)methyl)- 1 H- 1 ,2,3 -triazole-4-carboxamide), TNP-470
((3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)-oxiranyl]-l-oxaspiro [2,5] oct-6-yl(chloroacetyl) carbamate), CM-IOl (a bacterial polysaccharide exotoxin produced by group B Streptococcus (GBS), also referred to as GBS toxin), Germanin® (also known as suramin, CAS number 145-63-1), SU5416 (semaxinib, (3Z)-3-[(3,5-dimethyl-lH-pyrrol-2-
yl)methylidene]-l,3-dihydro-2H-indol-2-one), TSP (thrombospondins, a group of secreted proteins with antiangiogenic abilities), angiostatic steroids and heparin in combination, matrix metalloproteinase inhibitors, Angiostatin™, Macugen® (pegaptanib sodium injection), Endostatin™, 2-methoxyestradiol, Tecogalan sodium (DS-4152, a bacterial polysaccharide), 5 prolactin (or luteotropic hormone (LTΗ), a peptide hormone), linomide (LS-2616, [N-methyl-N- phenyl-l,2-dihydro-4-hydroxy-l-methyl-2-oxo-quinoline-3-carboxamide]) and the like.
The term VEGF (vascular endothelial growth factor) as used herein refers to a sub-family of growth factors, which are platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in angiogenesis, as well as vasculogenesis (de 10 novo formation of the embryonic circulatory system).
The term VEGFR tyrosine kinase as used herein refers to the tyrosine kinase receptors that the members of the VEGF family bind to.
The term integrin as used herein by itself or as a part of another definition refers to a family of transmembrane glycoproteins consisting of noncovalent heterodimers. The integrins consist of .5 at least three identified families where each family contains a common beta-subunit combined with one or more distinct alpha-subunits. These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including oncogenic transformation.
The compounds according to formula (I) will be useful for treating various diseases such as cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic !0 myocardium, atherosclerosis, macular edema and psoriasis. The treatment may be preventive, palliative or curative.
The compounds of the invention provides a method of treating a mammal suffering from a disease or disorder related to VEGFR tyrosine kinase or integrin activity, comprising administering to said mammal in need thereof, a therapeutically effective amount of a compound 15 of formula (I). The said mammal can be a human.
The compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of hyperproliferative diseases, e.g. antiangiogenic agents, including both compounds and monoclonal antibodies, and a cytostatic agent. The components may be in the same formulation or in separate formulations for 0 administration simultaneously or sequentially. The compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
Examples of cytotstatic agents for use as indicated herein above are DNA alkylating compounds, topoisomerase I inhibitors, topoisomerase II inhibitors, compounds interfering with
RNA and DNA synthesis, compounds polymerising the cytoskeleton, and compounds depolymerising the cytoskeleton.
The invention is illustrated by the following non-limiting Examples.
EXAMPLES Example 1: 4-(4-fluorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid.
(a) Preparation of intermediary compound diethyl 2-((4-bromophenylamino)methylene)- malonate:
4-Bromoaniline (10 g) and diethoxymethylene malonate (12.6 g) were heated at 150°C for 3 hours in a sealed tube. The reaction mixture was then cooled and diluted with n-hexane when the solid product precipitated out. This solid was filtered, washed several times with n-hexane and dried under vacuum to afford 17.8 g of 2-[(4-bromo-phenylamino)methylene]-malonic acid diethyl ester. 1R NMR (300 MHz, CDCl3) δ 11.03 (d, IH, J = 13 Hz, -NH- ), 8.48 (d, IH, J =13 Hz, -CH=C), 7.49 (m, 2Η, aromatic), 7.10-7.01 (m, 2H, aromatic), 4.42-4.22 (m, 4H, -CH2-CH3), 1.45-1.26 (m, 6H, -CH2-CH5); LC-MS (rn/z) 343.9 (M+l).
(b) Preparation of intermediary compound 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester:
2-[(4-Bromophenylamino)methylene]malonic acid diethyl ester (5 g) was heated with POCl3 (phosphoryl chloride, 31.5 mL) at 1500C in a sealed tube for about 6 hours. The excess POCl3 was removed in vacuo and the reaction mixture was diluted with dichloromethane. The
dichloromethane extract was washed with aqueous sodium hydroxide solution (10 %), dried over sodium sulphate and purified by column chromatography (Silica gel, hexane/ethyl acetate 80:20) to give 2.3 g of 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester. H NMR (300 MHz, CDCl3) δ 9.22 (s, IH, aromatic), 8.60 (d, IH, J = 2.1 Hz, aromatic), 8.04 (d, IH, J = 9 Hz, aromatic), 7.95-7.85 (m, IH, aromatic), 4.53 (q, 2H, J = 7 Hz, -CH2-), 1.50 (t, 3H, J = 7 Hz, - CH5); LC-MS (m/z) 315.8 (M+ 1).
(c) Preparation of intermediary compound ethyl 6-bromo-4-(4-fluorophenylamino)- quinoline-3 -carboxylate:
/7-Fluoroaniline (0.106 g) and 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (0.3 g, 0.95 mmol) were mixed in dioxane and irradiated in a microwave reactor at 150°C for 30 minutes. The reaction mixture was diluted with petroleum ether. The solid product obtained was filtered and dried to give 0.33 g of ethyl 6-bromo-4-(4-fluorophenyl-amino)quinoline-3- carboxylate. LC-MS (m/z) 389.4 (M+l).
(d) Preparation of intermediary compound ethyl 4-(4-fiuorophenylamino)-6- (methylcarbamoyl)quinoline-3 -carboxylate :
Ethyl 6-bromo-4-(4-fluorophenyl-amino)quinoline-3-carboxylate (0.3 g) was added to tetrahydrofuran followed by trørø-di(μ-acetato)-bis[o-(di-ø-tolylphosphino)- benzyl]dipalladium(II) (Herrmann's palladacycle, 0.038 mmol), tri tertiarybutyl phosphonium hexafluoborate) ([(/-Bu)3PH]BF4, 0.0385 mmol), molybdenum hexacarbonyl (Mo(CO)6, 1.54 mmol), methylamine (4.6 mmol, 2N in tetrahydrofuran) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 7.7 mmol). The reaction mixture was irradiated at 130°C for 5 minutes in a microwave reactor. The reaction mixture was concentrated and then purified on column (silica gel, dichloromethane/methanol 98:2) to give 0.39 g of ethyl 4-(4-fluorophenylamino)-6-
(methylcarbamoyltøuinoline-S-carboxylate as a solid. 1H NMR (300 MHz, CDCl3) δ 9.88(s, IH, -CONH-), 8.89(s, IH, aromatic), 8.72(s, IH, aromatic), 8.59(d, 1H,J=4 Hz, aromatic), 8.15(d,lH, J= 8.7 Hz, aromatic), 7.98(d, IH, J=8.7 Hz, aromatic), 7.16(m, 4H, aromatic), 3.98(g, 2H, J=7 Hz, -CH2-), 2.80(s, 3H5-NCH3), 1.16(t, 2Η, J=7 Hz, -CH3); LC-MS (m/z) 368.1 (M+l). (e) Ethyl 4-(4-fluorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylate (0.03 g) was stirred with lithium hydroxide (0.128 g) in a mixture of 6 mL of methanol/tetrahydrofuran /water (2:2:2,) overnight. The reaction mixture was concentrated and the aqueous layer was washed with ethyl acetate. The aqueous layers were collected and acidified with aqueous hydrochloric acid and the precipitate formed was filtered and dried to give 0.022 g of 4-(4- fluorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 12.47(bs, IH5-COOH), 9.12(s, IH, aromatic), 8.46(s, IH, aromatic), 8.23(s, IH, aromatic), 8.07(d, IH, J=8.4 Hz, aromatic), 7.92(d, IH, J=8.4 Hz, aromatic), 7.15(m, 4H, aromatic), 2.17(s, 3H, -NCH3) ; LC-MS (m/z) 340.2 (M+l).
Example 2: 4-(4-chlorophenylamino)-6-(methylcarbamoyl)quinoIine-3-carboxylic acid.
(a) Preparation of intermediary compound ethyl 6-bromo-4-(4-chlorophenylamino)- quinoline-3 -carboxylate :
/7-Chloroaniline (0.2 g) and 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (0.5 g) were mixed in dioxane and irradiated in a microwave reactor at 150°C for 30 minutes. The reaction mixture was diluted with petroleum ether. The solid product obtained was filtered and dried to give 0.565 g of ethyl 6-bromo-4-(4-chlorophenylamino)-quinoline-3-carboxylate. LC- MS (m/z) 406.7 (M+l).
(b) Preparation of intermediary compound ethyl 4-(4-chlorophenylamino)-6- (methylcarbamoyl)quinoline-3 -carboxylate :
Ethyl 6-bromo-4-(4-chlorophenylamino)-quinoline-3-carboxylate (0.52 g) was added to tetrahydrofuran followed by /rαo>s'-di(μ-acetato)-bis[o-(di-o- tolylphosphino)benzyl]dipalladium(II) (Herrmann's palladacycle, 0.06 g), [(t-Bu)3PH]BF4 (tri tertiarybutyl phosphonium hexafluoborate) (0.074 mg), molybdenum hexacarbonyl (Mo(CO)6, 0.677 mg), methylamine (7.6 mmol, 2N in tetrahydrofuran) and l,8-diazabicyclo[5.4.0]undec-7- ene (DBU, 1.95 g). The reaction mixture was irradiated at 130°C for 5 minutes in a microwave reactor. The reaction mixture was concentrated and then purified on column (silica gel, dichloromethane/methanol 98:2) to give 0.25 g of ethyl 4-(4-chlorophenylamino)-6-(methyl- carbamoyl)quinoline-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ 9.83(s, IH, -CONH-), 8.92(s, IH, aromatic), 8.75(s, IH, aromatic), 8.61(d, IH, J= 4.5Hz, aromatic), 8.17(d, IH, J=8.7Hz, aromatic), 8.01(d, IH, J=8.7 Hz, aromatic), 7.35(d, 2H, J= 8.7 Hz, aromatic), 7.09(d, 2H, J= 8.7 Hz, aromatic), 3.98(q, 2H, J= 7Hz, -CH2-), 2.81(s, 3Η, N-CH3), 1.41(t, J= 7Ηz, -CH3)LC-MS im/z) 384.1 (M+l).
(c) Ethyl 4-(4-chlorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylate (0.025 g) was stirred with lithium hydroxide (10 mg) in a mixture of 3 mL of methanol/ tetrahydrofuran/water (2:2:2,) overnight. The reaction mixture was concentrated and the aqueous layer was washed with ethyl acetate. The aqueous layers were collected and acidified with aqueous hydrochloric acid and the precipitate formed was filtered and dried to give 0.02 g of 4- [(4-chloro-phenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylic acid as a solid. Η NMR (300 MHz, MeOD) δ 11.8 (broad s, IH5-COOH), 9.05 (s, 1Η, aromatic), 8.68(m, 2Η, aromatic), 8.66 (d, IH, J=4.5 Hz, aromatic), 8.24 (d, IH, J=9 Hz, aromatic), 8.02 (d, IH, J=9 Hz, aromatic), 7.42 (d, 2H, J=8.4 Hz, aromatic), 7.23 (d, 2H, J=8.4 Hz, aromatic), 2.77 (s, 3H, -NCH3) ; LC- MS (m/z) 356.4 (M+l).
Example 3: 4-[(4-Isopropylphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid
(a) Preparation of intermediary compound ethyl 6-bromo-4-[(4-isopropylphenyl)- amino] quinoline-3 -carboxylate :
4-Isopropyl aniline (0.195 g, 1.4 mmol) and 6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (1.0 g, 3.2 mmol) were dissolved in dioxane (7 mL) and irradiated in a microwave reactor at 150°C for 30 minutes. The reaction mixture was diluted with petroleum ether, and the precipitate formed filtered off and dried. This gave 0.5 g (85 % yield) of ethyl 6-bromo-4-[(4- isopropylphenyl)-amino]quinoline-3-carboxylate. LC-MS (m/z) 413.3 (M+l). 1H NMR (300 MHz, CDCl3) δ 9.15 (d, IH, J= 3 Hz), 8.06 (d, IH, J= 9 Hz), 7.86 (d, IH, J= 9 Hz), 7.79 (s, IH), 7.49 (d, 2H, J= 8.4 Hz), 7.35 (d, 2H, J= 8.4 Hz), 4.46 (dd, 2H, J= 7 Hz), 3.10 (m, IH), 1.45 (t, 3H, J= 7 Hz), 1.35 (d, 6H, J= 5 Hz).
(b) Preparation of intermediary compound ethyl 6-bromo-4-[(4-isopropylphenyl)- amino]quinoline-3-carboxylate:
Ethyl 6-bromo-4-[(4-isopropylphenyl)amino]quinoline-3-carboxylate (0.45 g, 1.08 mmol) was added to tetrahydrofuran followed by trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)-
benzyl]dipalladium(II) (50 mg, 0.054 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.063 g, 0.2 mmol), molybdenum hexacarbonyl (0.575 g, 2.17 mmol), methyl amine (2 N in tetrahydrofuran, 3.2 mL, 6.5 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (1.7 mL, 10 mmol). The reaction mixture was irradiated at 130 °C for 5 minutes in a microwave reactor. The reaction mixture was concentrated and the crude product was purified on column (flash chromatography, silica gel, dichloromethane/methanol 98:2). This gave 0.33 g (79% yield) of ethyl 6-bromo-4- [(4-isopropylphenyl)amino]quinoline-3-carboxylate. LC-MS (m/z) 392.1 (M+l). 1H NMR (MeOD) δ 9.11 (s, IH), 8.23 (s, IH), 8.03 (d, IH, J= 4.5 Hz), 7.91 (d, IH, J= 8 Hz), 7.27 (d, 2H, J= 8.5 Hz), 7.10 (d, 2H, J= 8.5 Hz), 4.41 (dd, 2H, J= 7 Hz), 2.96 (m, IH), 2.82 (s, 3H), 1.43 (triplett, 3H, J= 7 Hz), 1.29 (d, J= 7 Hz).
(c) Ethyl 4-[(4-isopropylphenyl)amino]-6-(methylcarbamoyl)-quinoline-3-carboxylate (30 mg, 0.77 mmol) was stirred with lithium hydroxide monohydrate (128 mg, 3.0 mmol) in a mixture of methanol, tetrahydrofuran and water (6 mL, 2:2:2) overnight. The reaction mixture was concentrated and the aqueous layer washed with ethyl acetate. The aqueous layers were collected, acidified with aqueous hydrochloric acid and the precipitate formed was filtered off and dried to afford 22 mg (80 %) of 4-(4-isopropyl-phenylamino)-6-methylcarbamoyl-quinoline- 3-carboxylic acid as a yellow solid. LC-MS (m/z) 364.2 (M+1).1H NMR (MeOD) δ 12.08 (broad s, IH), 8.99 (s, IH), 8.82 (s, IH), 8.35 (d, IH, J= 8.7 Hz), 8.14 (d, IH, J= 8.7 Hz), 7.35 (m, 4H), 3.54 (m, IH), 2.50 (s, 3H), 1.23 (d, 6H, J= 5.1 Hz).
Example 4: 4-[[4-(Difluoromethoxy)phenyl]amino]-6-(methylcarbamoyl)quinoline-3- carboxylic acid.
(a) Preparation of intermediary compound ethyl-6-bromo-4-[[4-(difluoromethoxy)- phenyl]amino]quinoline-3-carboxylate:
6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (0.30 g, 0.95 mmol) and 4- difluoromethoxyaniline (0.23 g, 1.43 mmol) was mixed in dioxane (4 mL) and heated under microwave conditions at 150°Cfor 20 minutes. The reaction mixture was cooled, concentrated in vacuo and suspended in dichloromethane. The reaction mixture was filtered, the residue evaporated and triturated with diethyl ether. The yellow crystals were washed twice with cold diethyl ether and dried in vacuo to afford ethyl-6-bromo-4-[[4-(difluoromethoxy)phenyl] amino] - quinoline-3-carboxylate in 90% purity (monitored by LC-MS). Yield: 250 mg (60 %). LC-MS (m/z) 437 (M+l).
(b) Preparation of intermediary compound ethyl 4-[[4-(difluoromethoxy)phenyl]amino]-6- (methylcarbamoyl)quinoline-3 -carboxylate :
Ethyl 6-bromo-4-[[4-(difluoromethoxy)phenyl]amino]quinoline-3-carboxylate (0.100 g, 0,21 mmol) , /rø«s-di(i-acetato)-bis[ø-(di-ø-tolylphosphino)benzyl]dipalladium(II) (Herrmann's palladacycle, 10.0 mg, 0.01 mmol), tri-tert-butylphosphonium tetrafluoroborate ([(^-Bu)3PH]BF4, 11.5 mg, 0.04 mmol) and molybdenum hexacarbonyl (111 mg, 0,42 mmol) were dissolved in tetrahydrofuran (2 mL), followed by and methylamine in tetrahydrofuran (2N, 0.7 mL, 1.4 mmol) and l,8-diazabicyclo[5.4.0]-undec-7-ene (32 mg, 0,21 mmol). The mixture irradiated under microwave conditions at 120 0C for 5 minutes. The reaction mixture was evaporated and the crude product purified by column (flash chromatography on silica gel, dichloromethane/
methanol 97.5 : 2.5). This gave 25 mg (26 %) of ethyl 4-[[4-(difluoromethoxy)-phenyi]amino]-6- (methylcarbamoyl)quinoline-3-carboxylate in 95% purity as a yellow solid. LC-MS (m/z) 416 (M+l). 1NMR (CDCl3) δ 9.53 (s, IH), 8.46-8.38 (m, 2H), 8.20 (s, IH), 7.49 (s, 4H), 7.05-6.68 (triplett, IH, J= 73.1 Hz), 4.74 (dd, 2H, J= 7.2 Hz), 3.16 (d, 3H, J= 5.07 Hz), 1.74 (triplett, 3H, J= 7.2 Hz).
(c) Lithium hydroxide monohydrate (3.6 mg, 0.09 mmol) was added to a solution of ethyl 4-[[4-(difluoromethoxy)phenyl]amino]-6-(methylcarbamoyl)quinoline-3-carboxylate (15 mg, 0.036 mmol) in a mixture of tetrahydrofuran and water (1.5 mL, 8:2 mL) at room temperature. The reaction mixture was stirred overnight, acidified with aqueous hydrochloric acid (2N) and concentrated in vacuo. The yellow solid was suspended in water, filtered, washed twice with water and dried to give 5 mg (36 % yield) of 4-[[4-(difluoromethoxy)phenyl]amino]-6- (methylcarbamoyl)quinoline-3-carboxylic acid with a purity of 95%. LC-MS (m/z) 388 (M+l). NMR (CD3OD) δ 9.19 (s, IH), 8.24-8.17 (m, 2H), 7.94 (d, IH, J= 8.6 Hz), 7.46 (d, 2H, J= 8.7 Hz), 7.32 (d, 2H, J= 8.7 Hz), 6.95 (triplett, IH, J= 73.5 Hz), 2.83 (s, 3H).
Example 5. 4-Ben2ylamino-6-methylcarbamoyl-quinoline-3-carboxylic acid:
(a) Preparation of intermediary compound iV-methyl-4-nitrobenzamide:
To a solution of aqueous methylamine (1.09 g, 35.1 mmol) and sodium hydroxide (1.2 g, 29.7 mmol) in water (27.5 mL) was added a solution of 4-nitrobenzoyl chloride (5.0 g, 27.0 mmol) in 2-butanone (6.5 mL) in such a way that the temperature of the reaction mixture not increased above 40 0C. After completion of addition, water (20 mL) was added and the reaction mixture was stirred well for 3 hours. The solid precipitate was filtered, washed with cold water (2 x10 mL) and cold methanol (2 χ5 mL) to afford 3.5 (72 % yield) of Λ^-methyl-4-nitro-
benzamide as a brown solid. 1H-NMR (300 MHz, DMSO-d6) δ 8.78 (bs, IH), 8.31 (d, J= 8.7 Hz, 2H), 8.06 (d, J= 8.7 Hz, 2H), 2.82 (d, J= 4.5 Hz, 3H). LC-MS (m/z, 0A): 180.5 (M+l, 99), 202.5 (M+Na).
(b) Preparation of intermediary compound 4-amino-iV-methylbenzamide:
To a solution of 7V-methyl-4-nitrobenzamide (23.0 g, 127.8 mmol) in ethanol (460 rnL) was added palladium on carbon (Pd/C, 10%, 50% moistened, 15.0 g). The mixture was hydrogenated under 2.0 atmospheric pressure at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered through Celite and thoroughly washed with ethanol. The filtrate was evaporated and the residue washed with diisopropyl ether to give 16.0 g (84 % yield) of 4-amino-N-methylbenzamide as an off-white solid. 1H-NMR (300 MHz, DMSOd6) δ 7.94 (bs, IH), 7.54 (d, J= 8.7 Hz, 2H), 6.52 (d, J= 8.7 Hz, 2H), 5.57 (s, 2H), 2.72 (d, J= 4.5 Hz, 3H). LC-MS 172.5 (M+Na).
(c) Preparation of intermediary compound 2-[(4-Methylcarbamoyl-phenylamino)- methylenejmalonic acid diethyl ester:
To a solution of 4-amino-iV-methyl-benzamide (7.5 g, 50 mmol) in anhydrous toluene (15 mL) was added diethoxymethylene malonate (11.88 g, 55.0 mmol) at room temperature. The reaction mixture was stirred at 100 0C for 3 hours, cooled to 40 0C and petroleum ether (200 mL) was added and the reaction mixture was subsequently stirred for 30 minutes. The solid formed, was collected by filtration, washed with diisopropylether and dried in vacuo to afford 15.0 g (94 % yield) of 2-[(4-methylcarbamoylphenylamino)methylene]malonic acid diethyl ester as a white solid. 1H-NMR (300 MHz, CDCl3) δ 11.09 (d, J= 13.5 Hz, IH), 8.54 (d, J= 13.5 Hz, 2H), 7.81 (d, J= 8.4 Hz, 2H), 7.18 (d, J= 8.7 Hz, 2H), 6.20 (bs, IH), 4.36-4.24 (m, 4H), 3.03 (d, J= 4.8 Hz, 3H), 1.41-1.33 (m, 6H). LC-MS (m/z, 0A): 319.6 (M-I, 99.7).
(d) Preparation of intermediary compound 4-hydroxy-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester:
A mixture of 2-[(4-methylcarbamoylphenylamino)methylene]malonic acid diethyl ester (6.0 g, 18.8 mmol) and "Dowtherm A" (synthetic organic heat transfer fluid consisting of an eutectic mixture of biphenyl (C12H10) and diphenyl oxide (C12H10O), 60 mL) was heated to 2000C for 30 minutes. The temperature was raised to 24O0C and stirred for another 30 minutes. The reaction mixture was allowed to cool to room temperature and petroleum ether (50 mL) was added. A solid (0.6 g) precipitated out, was filtered and washed with dichloromethane (2 χ5 mL). The combined filtrates were concentrated in vacuo, the residue obtained mixed with "Dowtherm A" (60 mL) and heated to 240 0C for 30 minutes. The reaction mixture was cooled to room temperature and treated with petroleum ether (50 mL). The formed solid precipitate was filtered and washed with dichloromethane (2 x10 mL) to afford 2.6 g (51 % yield) of 4-hydroxy-6- methylcarbamoylquinoline-3-carboxylic acid ethyl ester as a pale blue solid. IH-NMR (300 MHz, DMSOd6) δ 12.46 (bs, IH), 8.68 (d, J= 4.5 Hz, IH), 8.65 (d, J= 1.8 Hz, 1H),8.58 (s, IH), 8.11 (dd, J= 9.9, 1.8 Hz, IH), 7.66 (d, J= 8.7 Hz, IH), 4.23 (q, J= 6.9 Hz, 2H), 2.81 (d, J = 4.5 Hz, 3H), 1.29 (triplet, J= 6.9 Hz, 3H). LC-MS (m/z, %): 275.2 (M+l, 98.7).
(e) Preparation of intermediary compound 4-chloro-6-methylcarbamoyl-quinoline-3- carboxylic acid ethyl ester:
4-Hydroxy-6-methylcarbamoyl-quinoline-3-carboxylic acid ethyl ester (1.0 g, 3.65 mmol) was added to phosphorus oxychloride (16.75 g, 109.2 mmol) at room temperature. The stirred mixture was heated at 100 0C for 3 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in the tetrahydrofuran (10 mL) and the reaction mixture was neutralized (pH 7) by addition of triethylamine. The reaction mixture was diluted with dichloromethane (4 χ20 mL) and concentrated in vacuo. The crude residue was purified on column (flash chromatography on silica gel, chloroform/methanol 98:2) to give 0.8 g (75 % yield) of 4-chloro-6-methylcarbamoylquinoline-3-carboxylic acid ethyl ester as an off-white
solid. 1H-NMR (300 MHz, CDCl3) δ 9.27 (s, IH), 8.79 (s, IH), 8.26-8.19 (m, 2H), 8.58 (s, IH), 6.48 (bs, IH), 4.53 (dd, J= 7.2 Hz, 2H), 3.13 (d, J= 4.8 Hz, 3H), 1.49 (triplett, J= 7.2 Hz, 3H). LC-MS (m/z, %): 293.1 (M+l, 98), 315 (M+Na).
(f) Preparation of intermediary compound 4-benzylamino-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester:
A 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (150 mg, 0.514 mmol), benzylamine (0.082 g, 0.765 mmol), triethylamine (0.011 mL, 0.077 mmol) and dry AζiV-dimethylamine (10 mL). The vial was capped and the mixture irradiated with microwaves for 30 minutes at 160°C. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ice-cold diisopropyl ether to give 90 mg (48 %) of 4-benzylamino- δ-methylcarbamoylquinoline-S-carboxylic acid ethyl ester. 1H-NMR (300 MHz, CDCl3) δ 9.87 (bs, IH), 9.19 (s, IH), 8.56 (d, J= 1.8 Hz, IH), 8.05- 7.96 (m, 2H), 7.52-7.37 (m, 5H), 5.62 (bs, IH), 5.05 (d, J= 6.0 Hz, 2H), 4.42 (q, J= 7.2 Hz, 2H), 2.9 (d, J= 4.8 Hz, 3H), 1.44 (t, J= 7.2 Hz, 3H). LC-MS (m/z, %): 364 (M+l, 98).
(g) To a solution of 4-benzylamino-6-methylcarbamoyl-quinoline-3-carboxylic acid ethyl ester (130 mg, 0.358 mmol) in a mixture of tetrahydrofuran (6 mL), methanol (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (60 mg, 1.43 mmol) in one portion at room temperature. The clear solution was then stirred for 3 hours, during which time the reaction progress was monitored with thin layer chromatography. After completion of the reaction, the solvents were evaporated under reduced pressure. The highly viscous residue was treated with ice-cold aqueous hydrochloric acid (1.5 N) until the pH of the reaction mixture reached 1-2. The colourless solid precipitated out was filtered and washed with cold dichloromethane (3 mL) followed by cold diisopropyl ether (5 mL) to give 80 mg (75 % yield) of 4-benzylamino-6- methyl-carbamoylquinoline-3-carboxylic acid as an off-white solid. 1H-NMR (300 MHz, CDCl3) δ 11.31 (bs, IH), 9.04 (s, IH), 8.87 (d, J= 4.5 Hz, IH), 8.38 (d, J= 8.7 Hz, IH), 8.06 (d, J= 8.7
Hz, IH), 7.51-7.36 (m, 5H), 5.42 (bs, IH), 2.85 (d, J= 4.5 Hz, 3H). LC-MS (m/z, %): 336.2 (M+l, 98).
Example 6: 4-(2,6-Dimethyl-phenylamino)-6-methylcarbamoyl-quinoline-3-carboxyIic acid.
(a) Preparation of intermediary compound 4-(2,6-dimethyl-phenylamino)-6-methyl- carbamoyl-quinoline-3-carboxylic acid ethyl ester:
A 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (400 mg, 1.370 mmol), 2,6-dimethylaniline (0.25 g, 2.066 mmol), triethylamine (0.028 mL, 2.06 mmol) and dry N,N-dimethylformamide (10 mL). The vial was capped and the mixture was irradiated with microwaves for 30 minutes at 160 °C. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ice-cold diisopropyl ether to give 320 mg (62 % yield) of 4-(2,6- dimethylphenylamino)-6-methylcarbamoylquinoline-3 -carboxylic acid ethyl ester. H-NMR (300 MHz, CDCl3) δ 10.98 (bs, IH), 9.28 (s, IH), 8.07 (dd, J= 8.7, 2.1 Hz, IH), 7.96 (d, J= 8.7 Hz, IH), 7.45 (d, J= 1.8 Hz, IH), 7.35-7.26 (m, 2H), 5.18 (d, J= 3.9 Hz, IH), 4.49 (dd, J= 7.2 Hz, 2H), 2.82 (d, J= 4.8 Hz, 3H), 2.18 (s, 6H), 1.50 (t, J= 7.2 Hz, 3H). LC-MS (m/z, %): 275.2 (M+l, 98.7).
(b) To a solution of 4-(2,6-dimethyl-phenylamino)-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (0.36 g, 0.954 mmol) in a mixture of tetrahydrofuran (6 mL), methanol (6 mL) and water (6 mL), was added lithium hydroxide monohydrate (0.16 g, 3.81 mmol) in one portion at room temperature. The clear solution was stirred for 3 hours, during
which time the reaction progress was monitored with thin layer chromatography. After completion of the reaction, the solvents were evaporated under reduced pressure. The highly viscous residue was treated with ice-cold aqueous hydrochloric acid (1.5 N) until the pH of the reaction mixture reached 1-2. The colourless solid precipitated out was filtered and washed with cold dichloromethane (3 mL) followed by cold diisopropyl ether (5 mL) to give 0.19 g (57 % yield) of 4-(2,6-dimethyl-phenylamino)-6-methylcarbamoyl-quinoline-3-carboxylic acid as off- white solid. 1H-NMR (300 MHz, CDCl3) δ 12.37 (bs, IH), 9.15 (s, IH), 8.56 (s, IH), 8.33 (d, J= 8.7 Hz, IH), 8.07(d, J= 8.7 Hz, IH), 7.36-7.26 (m, 3H), 2.71 (d, J= 3.6 Hz, 3H), 2.13 (s, 6H). LC-MS im/z, %): 350.1 (M+l, 97.6).
Example 7: 4-(3-Methoxy-phenylamino)-6-methyIcarbamoyl-quinoIine-3-carboxylic acid.
(a) Preparation of intermediary compound 4-(3-methoxy-phenylamino)-6-methyl- carbamoyl-quinoline-3-carboxylic acid ethyl ester.
A 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (150 mg, 0.514 mmol), w-anisidine (0.095 g, 0.771 mmol), triethylamine (0.010 mL, 0,51 mmol) and dry iV,JV-dimethylformamide (10 mL). The vial was capped and the mixture was irradiated with microwaves for 30 minutes at 160°C. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ice-cold diisopropyl ether to give 85 mg (43 % yield) of 4-(3- methoxyphenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid ethyl ester. 1H-NMR (300
MHz, CDCl3) δ 10.65 (bs, IH), 9.30 (s, IH), 8.07-7.99 (m, 2H), 7.95 (s, IH), 7.30-7.25 (m, IH), 6.83-6.80 (m, IH), 6.72-6.70 (m, IH), 5.54 (bs, IH), 4.47 (dd, J= 7.2 Hz, 2H), 3.78 (s, 3H), 2.88 (d, J= 4.8 Hz, 3H), 1.48 (triplet., J= 7.2 Hz, 3H).
(b) To a solution of 4-(3-methoxyphenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid ethyl ester (115 mg, 0.303 mmol) in a mixture of tetrahydrofuran (6 niL), methanol (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (51 mg, 1.2 mmol) in one portion at room temperature. The clear solution was then stirred for 3 hours, during which time the reaction was monitored with thin layer chromatography. After completion of the reaction, the solvents were evaporated under reduced pressure. The highly viscous residue was treated with ice-cold aqueous hydrochloric acid (1.5 N) until the pH of the reaction mixture reached 1-2. The colourless solid precipitated out was filtered and washed with cold dichloromethane (3 mL) followed by cold diisopropyl ether (5 mL) to give 67 mg (63 % yield) of 4-(3-methoxy- phenylamino)-6-methylcarbamoyl-quinoline-3-carboxylic acid as an off-white solid. 1H-NMR (300 MHz, DMSOd6) δ 11.85 (bs, IH), 9.11 (s, IH), 8.82 (s, IH), 8.73 (d, J= 4.2 Hz, IH), 8.34 (d, J= 8.7 Hz, IH), 8.09 (d, J= 8.7 Hz, IH), 7.35 (t, J= 8.1 Hz, IH), 6.99 (s, IH), 6.91 (d, J= 8.1 Hz, 2H), 3.74 (s, 3H), 2.78 (d, J= 4 .5 Hz, 3H). LC-MS (m/z, %): 352.1 (M+l, 98.1).
Example 8: 4-(2-Fluoro-phenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid.
(a) Preparation of intermediary compound 4-(2-fluorophenylamino)-6-methylcarbamoyl- quinoline-3-carboxylic acid ethyl ester:
A 20 mL microwave vial was charged with 4-chloro-6-methylcarbamoylquinoline-3- carboxylic acid ethyl ester (360 mg, 1.233 mmol), 2-fluoroaniline (0.206 g, 1.853 mmol), triethylamine (0.025 mL, 1.85 mmol) and dry N^V-dimethylformamide (10 mL). The vial was
capped and the mixture was irradiated with microwaves for 30 minutes at 160 °C. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ice-cold diisopropyl ether to give 95 mg (21 % yield) of 4-(2- fluorophenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid ethyl ester. H-NMR (300 MHz, CDCl3) δ: 10.54 (bs, IH), 9.32 (s, IH), 8.01 (d, J= 10.8 Hz, 3H), 7.28-7.09 (m, 4H), 5.68 (bs, IH), 4.48 (dd, J= 7.2 Hz, 2H), 2.89 (d, J= 4.5 Hz, 3H), 1.49 (t, J= 7.2 Hz, 3H).
(b) To a solution of 4-(2-fluorophenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid ethyl ester (115 mg, 0.313 mmol) in a mixture of tetrahydrofuran (6 mL), methanol (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (53 mg, 1.3 mmol) in one portion at room temperature. The clear solution was stirred for 3 hours, during which time the reaction was monitored with thin layer chromatography. After completion of the reaction, the solvents were evaporated under reduced pressure. The highly viscous residue was treated with ice-cold aqueous hydrochloric acid (1.5 N) until the pH of the reaction mixture reached 1-2. The colourless solid precipitated out was filtered and washed with cold dichloromethane (3 mL) followed by cold diisopropyl ether (5 mL) to give 70 mg (66 % yield) of 4-(2-fluoro- phenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid as a pale yellow solid. H-NMR (300 MHz, CDCl3) δ 12.09 (bs, IH), 9.32 (s, IH), 9.09 (s, IH), 8.84 (s, 2H), 8.38 (d, J= 8.7 Hz, IH), 8.15 (d, J= 8.7 Hz, IH), 7.48-7.38 (m, 3H), 7.30-7.24 (m, IH), 2.76 (d, J= 4.2 Hz, 3H). LC-MS (m/z, %): 340.1 (M+l, 98.9).
Example 9: 6-Methylcarbamoyl-4-phenylamino-quinoline-3-carboxyIic acid.
(a) Preparation of intermediary compound 6-methylcarbamoyl-4-phenylaminoquinoline-3- carboxylic acid ethyl ester:
A 20 mL microwave vial was charged with compound 4-chloro-6-methylcarbamoyl- quinoline-3-carboxylic acid ethyl ester (150 mg, 0.514 mmol), aniline (0.072 g, 0.774 mmol), triethylamine (0.011 mL, 0.077 mmol) and dry ΛζjV-dimethylfbrmamide (10 mL). The vial was capped and the mixture was irradiated with microwaves for 30 minutes at 160 °C. The reaction
5 mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was washed with ice-cold diisopropyl ether to give 90 mg (50 % yield) of 6- methylcarbamoyl-4-phenylaminoquinoline-3-carboxylic acid ethyl ester. 1H-NMR (300 MHz, CDCl3) δ 10.71 (bs, IH), 9.30 (s, IH), 8.06-7.99 (m, 2H), 7.86 (d, J= 1.5 Hz, IH), 7.44-7.38 (m,
10 2H), 7.31-7.27 (m, IH), 7.17 (d, J= 7.8 Hz, 2H), 5.47 (bs, IH), 4.47 (q, J= 7.2 Hz, 2H), 2.85 (d, J= 4.8 Hz, 3H), 1.48 (t, J= 7.2 Hz, 3H).
(b) To a solution of 6-methylcarbamoyl-4-phenylaminoquinoline-3-carboxylic acid ethyl ester (120 mg, 0.344 mmol) in a mixture of tetrahydrofuran (6 mL), methanol (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (60 mg, 1.43 mmol) in one portion at room
5 temperature. The clear solution was then stirred for 3 hours, during which time the reaction was monitored with thin layer chromatography. After completion of the reaction, the solvents were evaporated under reduced pressure. The highly viscous residue was treated with ice-cold aqueous hydrochloric acid (1.5 N) until the pH of the reaction mixture reached 1-2. The colourless solid precipitated out was filtered and washed with cold dichloromethane (3 mL) followed by cold i0 diisopropyl ether (5 mL) to give 63 mg (57 % yield) of 6-methylcarbamoyl-4-phenylamino- quinoline-3-carboxylic acid 1H-NMR (300 MHz, DMSO-d6) δ 11.95 (bs, IH), 9.11 (s, IH), 8.58- 8.57 (m, 2H), 8.23 (d, J= 8.4 Hz, IH), 8.01 (d, J= 8.7 Hz, 1H),7.42 (triplet, J= 7.8 Hz, 2H), 7.29-7.27 (m, 3H), 2.74 (d, J= 4.5 Hz, 3H). LC-MS (m/z, %): 322.1 (M+l, 96.4).
:5 BIOLOGICAL ASSAYS
Chemotaxis assay
Cell migration is a fundamental function of normal cellular processes, including embryonic development, angiogenesis, wound healing, immune response, and inflammation. Microporous membrane inserts are widely used for cell migration and invasion assays. The most widely 0 accepted of which is the Boyden Chamber assay. The Boyden chamber assay, is based on a chamber of two medium-filled compartments separated by a microporous membrane. Cells are placed in the upper compartment and are allowed to migrate through the pores of the membrane into the lower compartment, in which chemotactic agents are present. After an appropriate incubation time, the membrane between the two compartments is fixed and stained, and the
number of cells that have migrated to the lower side of the membrane is determined. Therefore, the Boyden chamber-based cell migration assay has also been called chemotaxis assay. The compounds were tested for their capacity of influencing chemotaxis, using porcine aorta endothelial (PAE) cells expressing VEGFR2 and VEGFR3 (PAE/VEGFR-2 and PAE/VEGFR- 3) with VEGF-A and VEGF-C, respectively, as chemotactic agent. The method used a modified Boyden chamber assay. The migration of the PAE cells expressing VEGFR2 and VEGFR3 receptors toward VEGF-A and VEGF-C respectively used as chemo-attractant was studied though micropore polycarbonate filter and was scored in the absence of serum. The assay was performed in the presence of compounds at 10 μM concentrations and the quantified measure of the inhibiton activity of compounds is expressed in %.
Cell adhesion assay:
The cell adhesion assay is a measure of the ability of a compound to inhibit adhesion to fibronectin. Therefore a high % inhibition value indicates that the compounds inhibit adhesion to flbronectine and are therefore integrin antagonists for α5β 1.
Day 1 : Flat-bottomed microwell plates (Maxisorb, Nunc) are coated with 20 μg/ml of fibronectin (FN) and incubated over night at room temperature in a humified box.
Day 2: The excess of coating agent (fibronectin) is removed by washing three times in PBS. After washing, 50 μl 2 % PVP (polyvinylpyrrolidone) is added as a blocking agent and the plates are incubated one hour at room temperature. The blocking agent is then removed by washing 3 times in PBS. In the meantime HT1080 human fibrosarcoma cells (2 x 10 cells/ml) are pre-incubated 20 minutes at room temperature with substances to a final concentration of 100 μM (maximum DMSO concentration is 0.1%). The pre-incubated cells are added to the plates and incubated 20 minutes at 37 °C. After incubation the plates are washed 5 times in pre-warmed EMEM medium and the cells that had adhered to fibronectin is fixated in 4 % paraformaldehyde for 30 minutes in the humified box. To the fixated cells 0.5 % toluidine blue is added and the plates are incubated over night in the humified chamber.
Day 3: The plates are washed three times in deionised water and then 100 μl 2 % SDS is added to release the dye from the cells. After 20 minutes the plates are ready to be analysed by an ELISA-reader at 630 rim.
In Table 1, data from both the chemotaxis assay and the cell adhesion assay are shown. Thus, "Chemotaxis VEGFR-2 % inhibition of cell migration" and "Chemotaxis VEGFR-3 % inhibition of cell migration" show the percentage inhibition of PAE cells expressing VEGFR-2
or 3 in the presence of 10 μM of the indicated inventive compound. Data under "Cell adhesion assay % inhibition to fibronectin" show the percentage of inhibition of the compound at lOOμM.
Claims
1. A compound of formula (I)
(I) wherein: n is 0 (zero) or 1 ;
1 0
R and R are independently selected from hydrogen; branched or unbranched C]-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; monocyclic or bicyclic, saturated or unsaturated C3-C8 carbocyclyl; and monocyclic or bicyclic, saturated or unsaturated Ci-C7 heterocyclyl wherein the heteroatoms are independently selected from N, O and S; said alkyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally being substituted with 1, 2, or 3 groups Ra'
R is selected from monocyclic or bicyclic C6-C10 aryl; and monocyclic or bicyclic C1-C9 heteroaryl, wherein the heteroatoms independently are selected from N, O and S; said aryl or heteroaryl optionally being substituted with 1, 2, 3, 4 or 5 groups R ;
Y is selected from -C(O)-; -S(O)-; and -S(O)2-;
X is selected from -NR0-; -0-; and -S-; each Ra is independently selected from halogen; hydroxy; carbonyl; methoxy; halomethoxy; dihalomethoxy; and trihalomethoxy; each R is independently selected from halogen, branched or unbranched C1-C4 alkyl, C2- C4 alkenyl or C2- C4 alkynyl; branched or unbranched C1-C4 alkyloxy, C2-C4 alkenyloxy or C2-C4 alkynyloxy; branched or unbranched Cj-C4 alkylthio, C2-C4 alkenylthio or C2-C4 alkynylthio; said alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy alkynyloxy, alkylthio, alkenylthio or alkynylthio group optionally being substituted with 1, 2 or 3 halogens;
R° is selected from hydrogen and branched or unbranched C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein n is 0.
3. A compound according to claim 1 or claim 2, wherein R and R are independently selected from hydrogen and branched or unbranched C1-C8 alkyl, C2-C8 alkenyl and C2-C8 alkynyl, said alkyl, alkenyl, or alkynyl optionally being substituted with 1, 2, or 3 groups R .
4. A compound according to claim 3, wherein R and R are independently selected from hydrogen and branched or unbranched Cj-C8 alkyl, said alkyl optionally being substituted with 1, 2, or 3 groups R .
5. A compound according to claim 3, wherein R is hydrogen and R is selected from C1-C4 alkyl.
6. A compound according to any one of claims 1 to 5, wherein R3 is phenyl, optionally substituted with 1, 2, 3, 4 or 5 groups R .
7. A compound according to any one of claims 1 to 6, wherein Y is -C(O)-.
8. A compound according to any one of claims 1 to 7, wherein X is -NR0-.
9. A compound according to any one of claims 1 to 8, wherein each Ra is halogen.
10. A compound according to any of claims 1 to 9, wherein each R is independently selected from halogen; and Ci-C4 alkyl; and C1-C4 alkyloxy; wherein any alkyl or alkyloxy optionally is substituted with 1, 2 or 3 halogens.
11. A compound according to any one of claims 1 to 10, wherein R is hydrogen.
12. A compound according to claim 1 which is:
4-(4-fluorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid; 4-(4-chlorophenylamino)-6-(methylcarbamoyl)quinoline-3-carboxylic acid; 4-[(4-isopropylphenyl)amino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid; 4-[[4-(difluoromethoxy)phenyl]amino]-6-(methylcarbamoyl)quinoline-3-carboxylic acid; 4-benzylamino-6-methylcarbamoyl-quinoline-3 -carboxylic acid; 4-(2,6-dimethyl-phenylamino)-6-methylcarbamoyl-quinoline-3-carboxylic acid; 4-(3-methoxy-phenylamino)-6-methylcarbamoyl-quinoline-3-carboxylic acid;
4-(2-fluoro-phenylamino)-6-methylcarbamoylquinoline-3-carboxylic acid; 6-methylcarbamoyl-4-phenylamino-quinoline-3 -carboxylic acid, or a pharmaceutically acceptable salt thereof.
13. A compound according to any one of claims 1 to 12 for use in therapy.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient.
15. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder selected from cancer, diabetic retinopathy, age- related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
16. The use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the manufacturing of a medicament for use in the treatment of a disorder selected from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema and psoriasis.
17. A method of treating a mammal suffering from cancer, diabetic retinopathy, age-related macular degeneration, inflammation, stroke, ischemic myocardium, atherosclerosis, macular edema or psoriasis, comprising administering to said mammal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
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