MXPA99008224A - Novel carboxylic acid derivatives, their preparation and use in treating cancer - Google Patents
Novel carboxylic acid derivatives, their preparation and use in treating cancerInfo
- Publication number
- MXPA99008224A MXPA99008224A MXPA/A/1999/008224A MX9908224A MXPA99008224A MX PA99008224 A MXPA99008224 A MX PA99008224A MX 9908224 A MX9908224 A MX 9908224A MX PA99008224 A MXPA99008224 A MX PA99008224A
- Authority
- MX
- Mexico
- Prior art keywords
- phenyl
- methyl
- alkyl
- ome
- och3
- Prior art date
Links
- 201000011510 cancer Diseases 0.000 title claims abstract description 19
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 16
- 238000002360 preparation method Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N Endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims abstract description 35
- 102000002045 Endothelin Human genes 0.000 claims abstract description 26
- 108050009340 Endothelin Proteins 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- 210000002307 Prostate Anatomy 0.000 claims abstract description 9
- 210000004556 Brain Anatomy 0.000 claims abstract description 5
- 210000003734 Kidney Anatomy 0.000 claims abstract description 4
- 210000000481 Breast Anatomy 0.000 claims abstract description 3
- 210000001072 Colon Anatomy 0.000 claims abstract description 3
- 210000004696 Endometrium Anatomy 0.000 claims abstract description 3
- 210000004185 Liver Anatomy 0.000 claims abstract description 3
- 210000004072 Lung Anatomy 0.000 claims abstract description 3
- 210000002418 Meninges Anatomy 0.000 claims abstract description 3
- 210000002784 Stomach Anatomy 0.000 claims abstract description 3
- 210000001550 Testis Anatomy 0.000 claims abstract description 3
- 210000001685 Thyroid Gland Anatomy 0.000 claims abstract description 3
- 210000003932 Urinary Bladder Anatomy 0.000 claims abstract description 3
- 210000000496 Pancreas Anatomy 0.000 claims abstract 2
- -1 alkyl ion Chemical class 0.000 claims description 348
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 116
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 116
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 125000004414 alkyl thio group Chemical group 0.000 claims description 62
- 125000003545 alkoxy group Chemical group 0.000 claims description 47
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 36
- 229910052717 sulfur Inorganic materials 0.000 claims description 36
- 125000005843 halogen group Chemical group 0.000 claims description 31
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 23
- 239000001301 oxygen Substances 0.000 claims description 23
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 23
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 239000011593 sulfur Substances 0.000 claims description 18
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000004434 sulfur atoms Chemical group 0.000 claims description 16
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
- 101710008828 UQCRB Chemical group 0.000 claims description 14
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 10
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 10
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000001105 regulatory Effects 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 5
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 229940079593 drugs Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 3
- 125000005038 alkynylalkyl group Chemical group 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 210000003635 Pituitary Gland Anatomy 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 2
- 230000001174 ascending Effects 0.000 claims 1
- 230000001817 pituitary Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 150000003254 radicals Chemical class 0.000 description 57
- 239000000203 mixture Substances 0.000 description 55
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 38
- 239000000460 chlorine Substances 0.000 description 38
- 239000000243 solution Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 238000004821 distillation Methods 0.000 description 19
- 238000001035 drying Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cells Anatomy 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 239000002585 base Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 229910052801 chlorine Inorganic materials 0.000 description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 230000037396 body weight Effects 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- 239000011737 fluorine Substances 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 102100004921 EDN1 Human genes 0.000 description 9
- 108010072834 Endothelin-1 Proteins 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 125000001188 haloalkyl group Chemical group 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 229960000583 Acetic Acid Drugs 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- 238000004166 bioassay Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 102100017696 EDNRB Human genes 0.000 description 4
- 102000010180 Endothelin Receptors Human genes 0.000 description 4
- 108050001739 Endothelin Receptors Proteins 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 230000003042 antagnostic Effects 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reduced Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- RAEVOBPXEHVUFY-LURJTMIESA-N 4187-53-5 Chemical compound C[C@H](N)C1=CC=C([N+]([O-])=O)C=C1 RAEVOBPXEHVUFY-LURJTMIESA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000004429 atoms Chemical group 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- DYDIMXGJVTUIIK-UHFFFAOYSA-N methyl 2-hydroxy-3-phenyl-3-phenylmethoxybutanoate Chemical compound C=1C=CC=CC=1C(C)(C(O)C(=O)OC)OCC1=CC=CC=C1 DYDIMXGJVTUIIK-UHFFFAOYSA-N 0.000 description 3
- 150000002829 nitrogen Chemical group 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- CUWLVAXYUJQMCZ-UHFFFAOYSA-N 2-hydroxy-3-methoxy-3,3-diphenylpropanenitrile Chemical compound C=1C=CC=CC=1C(C(O)C#N)(OC)C1=CC=CC=C1 CUWLVAXYUJQMCZ-UHFFFAOYSA-N 0.000 description 2
- RQJWOLFMWKZKCJ-UHFFFAOYSA-N 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C(O)C(O)=O)(OC)C1=CC=CC=C1 RQJWOLFMWKZKCJ-UHFFFAOYSA-N 0.000 description 2
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000035812 respiration Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 200000000008 restenosis Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- IOHXJTACMVJNFE-UHFFFAOYSA-M sodium;2-(4,6-dimethoxypyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoate Chemical compound [Na+].COC1=CC(OC)=NC(OC(C([O-])=O)C(OC)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 IOHXJTACMVJNFE-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- JIRRJTAAVDYFBH-ZWBIQZHISA-J tetrasodium;(7Z)-7-[[4-[4-[(2Z)-2-(6-anilino-1-oxo-3-sulfonatonaphthalen-2-ylidene)hydrazinyl]-3-hydroxyphenyl]-2-hydroxyphenyl]hydrazinylidene]-8-oxonaphthalene-1,3,6-trisulfonate;copper Chemical compound [Na+].[Na+].[Na+].[Na+].[Cu].[Cu].OC1=CC(C=2C=C(O)C(N\N=C\3C(=CC4=C(C(=CC(=C4)S([O-])(=O)=O)S([O-])(=O)=O)C/3=O)S([O-])(=O)=O)=CC=2)=CC=C1N\N=C(C(=CC1=C2)S([O-])(=O)=O)\C(=O)C1=CC=C2NC1=CC=CC=C1 JIRRJTAAVDYFBH-ZWBIQZHISA-J 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- LCKIEQZJEYYRIY-UHFFFAOYSA-N titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N triclene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
Abstract
This invention provides a method for treating cancer in an individual, wherein the cancer is a tumor in which endothelin is upregulated (e.g. tumors of the prostate, lung, liver, breast, brain, stomach, colon, endometrium, testicle, thyroid, pituitary, bladder, kidney, pancreas and meninges) by administering to the individual an effective amount of a compound of formula (I) or formula (Ia), as described therein.
Description
NOVEDOUS DERIVATIVES OF CARBOXYLIC ACID, ITS PREPARATION AND USE IN THE TREATMENT OF C NCER BACKGROUND OF THE INVENTION Cancer is a disease for which there are many potentially effective treatments. However, due to the prevalence of cancers of various types and the severe effects that cancer can have, more effective treatments are required, especially treatments with fewer side effects than the currently available forms of treatment. SUMMARY OF THE INVENTION This invention relates to novel carboxylic acid derivatives, their preparation and use for the treatment of cancer wherein endothelin is upregulated, in a mammal, for example, a human. Endothelin is a peptide composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. As used herein, the term "endothelin" or "ET" refers to one or all of the isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin on its receptor (Nature, 332, (1988) 411-415, FEBS Letters, 231, (1988) 440-444 and Biochem. Biophys. Res. Commun ,, 154 , (1988) 868-875). An insed or abnormal release of endothelin causes a persistent vasoconstriction of peripheral blood vessels, kidney and brain, which can cause diseases. It has been reported in the literature that high levels of endothelin were found in the plasma of patients with hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, atherosclerosis and in the airways of asthmatic patients (Japan J. Hypertension, 12 , (1989) 79, J. Vascular Med. Biology 2, (1990) 207, J. Am. Med. Association 264, (1990) 2868). Accordingly, substances that specifically inhibit the binding of endothelin to the receptor could also antagonize the various aforementioned physiological effects of endothelin and thus be valuable drugs. For example, the compounds of the present invention can be used for the treatment of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute liver failure, renal insufficiency, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, organic insufficiency induced by endotoxin, intravascular coagulation, restenosis after angioplasty, benign prostatic hyperplasia, or hypertension or renal failure caused by ischemia or intoxication in accordance with what is described in documents W096 / 11914 and W095 / 26716, whose teachings they are incorporated herein by reference in their entirety. We have found that certain carboxylic acid derivatives of formula I or that which are inhibitors of endothelin receptors are also useful for the treatment of cancer, such as prostate cancer. These carboxylic acid derivatives are described herein and also in documents W096 / 11914 and W095 / 26716, the teachings of which are hereby incorporated by reference in their entirety. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the treatment of cancer in a patient such as, for example, a human being, wherein the cancer is a tumor in which endothelin is upregulated (eg, tumors). of the prostate, liver, lung, breast, brain, stomach, colon, endometrium, testis, thyroid, pituitary gland, bladder, kidneys, pans and meninges). By treatment we mean the inhibition (total or partial) of the formation of a solid tumor in which endothelin is up-regulated, reversing the development of a solid tumor in which endothelin is up-regulated or reducing its additional progression, by administering to the patient an effective amount of one or more compounds of the formula I and / or the formula as described below. As used herein, the term "effective amount" is an amount sufficient to inhibit (partially or totally) the growth of a solid tumor in which endothelin is upregulated, reversing the development of a solid tumor in which the endothelin is up-regulated or reduce its additional progression. In the present invention, the formula la is a subgroup of the formula I. One or more compounds of the formula I and the formula can be administered alone or with a pharmaceutically acceptable carrier or diluent appropriate for the desired administration route. The administration can be by any conventional means for pharmaceutical agents, preferably oncological agents, including oral and parenteral media such as, for example, subcutaneous, intravenous, intramuscular, intraperitoneal, nasal or rectal. The dosage administered to a mammal, such as a human, includes an effective amount of a compound of the formula I or of the formula la. In the case of a particular condition or a particular treatment method, the dosage can be determined empirically, using known methods, and will depend on factors such as biological activity, toxicity profile, administration form, age, sex, condition of health and body weight of the patient, the nature and extent of symptoms, the frequency of treatment, the administration of other therapies and the desired effect. A typical daily dose of the compound of formula I or will be within a range of about 0.5 to about 5000 milligrams per kilogram of body weight per oral administration and from about 0.1 to about 1000 milligrams per kilogram of body weight in the case of parenteral administration. In one embodiment, when the administration is parenteral, a daily dose will be from about 50 to about 500 milligrams per kilogram of body weight. In a particular embodiment, in the case in which administration is parenteral, a daily dose will be from about 100 to about 300 milligrams per kilogram of body weight (eg, 100, 150, 220 milligrams per kilogram of body weight). The novel compounds can be used in conventional solid or liquid dosage forms, for example, in the form of coated (film) or uncoated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. They are produced in a conventional manner. The active substances can, for this purpose, be processed with conventional pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, slow-release agents. , antioxidants and / or driving gases (see H. Sucker et al .: Phar azeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way usually contain from 0.1 to 90% by weight of the active substance. The carboxylic acid derivatives useful in the method of the present invention are compounds of the formula I:
where R is formyl, tetrazolyl, cyano, a COOH group or a radical that can be hydrolyzed in COOH, and the other substituent has the following meanings: R2: hydrogen, hydroxyl, NH2, NH (C? -C4 alkyl), N ( Ci-C4 alkyl) 2 / halogen, C? -C alkyl, C? -C4 haloalkyl, C? -C alkoxy, C? -C haloalkoxy, or C? -C4 alkylthio; X: Nitrogen or CR14 where R14 is hydrogen or C1-C5 alkyl, or CR14 forms together with CR3 a 5-membered or 6-membered alkylene or alkenylene ring which may be substituted by one or two C alquilo-alkyl groups C4 and in which in each case a methylene group can be replaced by oxygen, sulfur, NH ion or N-C? -C alkyl ion; R3: hydrogen, hydroxyl, NH2, NH (C? -C4 alkyl), N (Ci-C4 alkyl) 2, halogen, C? -C4 alkyl, C? -C4 haloalkyl, C? -C alkoxy, haloalkoxy C? C4, -NH-O-C? -C alkyl, C? -C4 alkylthio or CR3 is linked to CR14 in accordance with that indicated above to provide a 5- or 6-membered ring; R4 and R5 (which may be identical or different): phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C? -C4 alkyl, C? -C haloalkyl / alkoxy C3-C4, haloalkoxy C? -C, phenoxy, C1-C4 alkylthio, amino, C1-C4 alkylamino, or C? -C4 dialkylamino; or phenyl or naphthyl, which are joined together in the ortho positions through a direct bond, a methylene group, ethylene or ethenylene, an oxygen or sulfur atom or a group S02-, NH- or N-alkyl , or C3-C7 cycloalkyl; or R 4 is C 1 -C 10 alkyl which can carry from one to five halogen atoms and / or one of the following radicals: C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, Ci-Cs alkylcarbonyl, Ci-Cβ alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals in turn can carry from one to five halogen atoms and / or from one to three of the following radicals: C? -C alkyl, C1-C4 haloalkyl, C1-C4 alkoxy , haloalkoxy Ci-C, and / or C1-C4 alkylthio. C1-C10 alkyl which can carry from one to five halogen atoms and carry one of the following radicals: a five-membered heteroaromatic ring containing one to three nitrogen atoms and / or a sulfur atom or an oxygen atom and which can carry from one to four halogen atoms and / or one or two of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio and / or phenyl; C 2 -C 12 cycloalkyl or C 3 -C 12 cycloalkenyl, each of which can contain an oxygen atom or a sulfur atom and can carry from one to five halogen atoms and / or one of the following radicals: C alquilo alkyl C, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 8 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals in turn can carry from one to five halogen atoms and / or from one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, Ci-C haloalkoxy, and C 1 -C 4 alkylthio; C3-C6 alkenyl or C3-C6 alkynyl, each of which can carry from one to five halogen atoms and / or one of the following radicals: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano , C 1 -C 8 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals, in turn, can carry from one to five halogen atoms and / or from one to three of the following radicals: alkyl C C 4, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and / or C 1 -C 4 alkylthio; a five-membered or six-membered heteroaromatic ring containing one to three nitrogen atoms and / or one sulfur atom or one oxygen atom and which may carry one to four halogen atoms and / or one or two the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, wherein the phenyl radicals in turn can carry from one to five atoms of halogen and / or from one to three of the following radicals: C3-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C? -C4, and / or C? -C4 alkylthio; R4 and R5, together with the adjacent carbon atom, a 3 to 8 membered ring which may contain an oxygen atom or a sulfur atom and may carry from one to three of the following radicals: C1-C4 alkyl, halogen, Ci-C4 haloalkyl, C3-C4 alkoxy, C1-C4 haloalkoxy, and / or C1-C4 alkylthio (sic); R 5 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 1 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkylthioalkyl, phenyl or R 5 is attached to R 4. in accordance with that indicated above to form a ring of 3 to 8 members; R6 is hydrogen, Ci-Cß alkyl, C3-C6 alkenyl, C3-Ce alkynyl, or C3-C8 cycloalkyl, wherein each of these radicals can be substituted once or several times by: halogen, nitro, cyano, C alco alkoxy? -C, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C1-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, C3-C8 alkylcarbonylalkyl, C3-C4 alkylamino, C1-C4 dialkylamino, phenyl , or phenyl or phenoxy which is substituted one or more times, for example one to three times, by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C 1 -C 4 alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C3- C 4, phenoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, methylenedioxy or ethylenedioxy; a five-membered or six-membered heteroaromatic portion containing one to three nitrogen atoms and / or one sulfur atom or one oxygen atom, which may carry one to four halogen atoms and / or one or two the following radicals: C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals themselves to carry from one to five atoms of halogen and / or from one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 4 haloalkoxy, and / or C 3 -C 4 alkylthio;
provided that R6 can be hydrogen only when Z is not a single bond; And sulfur or oxygen or a single bond; Z sulfur or oxygen or a single bond. In particular embodiments, carboxylic acid derivatives useful in the method of the present invention are compounds of the formula which form a subgroup of the formula I:
where R is formyl, tetrazolyl, cyano, a COOH group or a radical that can be hydrolyzed in COOH, and the other substituents have the following meanings: R2: hydrogen, hydroxyl, NH2, NH (C? -C alkyl), N (C 1 -C 4 alkyl) 2, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C 1 -C 4 alkylthio; X: nitrogen or CR14 where R14 is hydrogen or alkyl
C1-C5, or CR14 forms together with CR3 a 5-membered or 6-membered alkenylene or alkenylene anvil which can be substituted by one or two C1-C4 alkyl groups and in which in each case a methylene group can be replaced by oxygen, sulfur, NH ion or N-C-C alkyl ion; R 3: hydrogen, hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 2) alkyl, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, haloalkoxy C? -C 4, -NH-O-C 1 -C 4 alkyl, C 1 -C 4 alkylthio or CR 3 is linked to CR 14 in accordance with that indicated above to provide a 5- or 6-membered ring; R4 and R5 (which may be identical or different): phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C? -C4 alkyl, C? -C4 haloalkyl, alkoxy C1-C4, haloalkoxy C? -C, phenoxy, C1-C4 alkylthio, amino, C1-C4 alkylamino, or C? -C4 dialkylamino; or phenyl or naphthyl, linked together in the ortho positions through a direct bond, a methylene group, ethylene or ethenylene, an oxygen or sulfur atom or a group S02-, NH- or N-alkyl, or C3-C7 cycloalkyl; R6 is hydrogen, Ci-Cs alkyl, C3-C6 alkenyl, C-Cß alkynyl, or C3-C8 cycloalkyl, wherein each of these radicals can be substituted once or several times by: halogen, nitro, cyano, C1-6 alkoxy C4, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C 1 -C 4 -alkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 4 alkylcarbonylalkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino , phenyl, or phenyl or phenoxy substituted one or more times, for example one to three times, by halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 4 haloalkoxy, or C 1 -C 4 alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C1-C4 , phenoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, methylenedioxy or ethylenedioxy; a five-membered or six-membered heteroaromatic portion containing one to three nitrogen atoms and / or one sulfur atom or one oxygen atom, which may carry from one to four halogen atoms and / or one or two of the following radicals: C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C4 haloalkoxy, C1-C4 alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals themselves to carry from one to five carbon atoms. halogen and / or from one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 2 -C 4 haloalkoxy, and / or C 1 -C 4 alkylthio; provided that R6 can be hydrogen only when Z is not a single bond; And sulfur or oxygen or a single bond; Z sulfur or oxygen or a single bond. The compounds, and the intermediates for the preparation of the compounds of the formula I and the, such as for example IV and VI, may have one or more carbon atoms substituted asymmetrically. Such compounds can have the form of pure enantiomers or of diastereomers - pure or a mixture thereof. The use of an enantiomerically pure compound as an active substance is preferred. The invention also relates to the use of the aforementioned carboxylic acid derivatives for the production of drugs, particularly for the production of endothelin receptor inhibitors. The invention also relates to the preparation of the compounds of the formula IV in enantiomerically pure form. Enantioselective epoxidation of an olefin with two phenyl substituents is known (J. Org Chem 59, 1994, 43784380). The preparation of the compounds according to the present invention wherein Z is sulfur or oxygen starts from the epoxides IV, which are obtained in conventional manner, for example, according to that described in J. March, Advanced Organic Chemistry, 2nd Edition, 1983, page 862 and page '750, from ketones II or olefins III:
III Carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (for example, with R = COOR 10) with alcohols or thiols of the formula V where Rd and Z have the meanings stated above .
OH VI
IV + dZH R- CH- R I V
To achieve this, compounds of the general formula IV are heated with compounds of the formula V, in the molar ratio of from about 1: 1 to 1: 7, preferably from 1 to 3 molar equivalents, at a temperature of 50 to 200 °. C, preferably 80 to 150 ° C. The reaction can also be carried out in the presence of a diluent. All solvents that are inert in relation to the reagents used can be used for this purpose. Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which can, in each case, be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform. , carbon tetraeloride, ethyl chloride, and trichlorethylene, ethers such as, for example, diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitriles as example acetonitrile and propionitrile, alcohols such as for example methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as for example ethyl acetate and amyl acetate, amides such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, sulfoxides and sulfones, for example dimethyl sulfoxide and sulfolane, bases such as for example pyridine, cyclic ureas such as 1,3-d imethylimidazolidin-2-one and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone. The reaction is preferably carried out at a temperature within the range of 0 ° C to the boiling point of the solvent or mixture of solvents. The presence of a catalyst can have advantages. Suitable catalysts are strong organic and inorganic acids and Lewis acids. Examples thereof are, among others, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and titanium (IV) alcoholates. Compounds of the formula IV wherein R 4 and R 5 are cycloalkyl can also be prepared by subjecting the compounds of the formula VI wherein R 4 and R 5 are phenyl, naphthyl or phenyl or naphthyl substituted in accordance with that described above, to a nuclear hydrogenation. Compounds of formula VI can be obtained in an enantiomerically pure form starting from the enantiomerically pure compounds of formula IV and reacting them in the manner described with compounds of formula V. It is also possible to obtain enantiomerically pure compounds of formula VI by carrying a resolution of classical racemate in racemic or diastereomeric compounds of formula VI using suitable enantiomerically pure bases such as for example brucine, sricin, quinine, quinidine, cinchonidine, cinchonin, yohimbine, morphine, dehydroabietylamine, ephedrine (-), (+ ), deoxiefedrine (+), (-), threo-2-amino-l- (p-nitrophenyl) -1, 3-propanediol (+), (-), threo-2- (N, N-dimethylamino) - 1- (p-nitrophenyl) -1,3-propanediol (+), (-), alpha- (2-naphthyl) ethylamine (+), (-), aminomethylpinnane, N, N-dimethyl-1-phenylethylamine, N -methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, deri amino acid fords, peptide derivatives. The compounds according to the present invention wherein Y is oxygen, and the remaining substituents have the meanings established under the general formulas I and the, and can be prepared, for example, by the reaction of the carboxylic acid derivatives of the general formula VI wherein the substituents have the meanings stated with the compounds of the general formula VII
VII wherein R15 is a halogen or R16-S02-, wherein R16 may be C1-C4 alkyl, C1-C4 haloalkyl or phenyl. The reaction is preferably carried out in one of the aforementioned inert diluents with the addition of a suitable base, that is, of a base which deprotonates the intermediates VI, in a range of temperatures ranging from room temperature to room temperature. boiling point of the solvent. Compounds of formula VII are known, some of them may be purchased, or they may be prepared in a generally known manner. It is also possible to use as the base an alkali metal or alkaline earth metal hydride such as, for example, sodium hydride, potassium hydride, calcium hydride, a carbonate such as, for example, sodium carbonate or, for example, alkali metal carbonate. potassium, an alkali metal or alkaline earth metal hydroxide, such as, for example, a sodium or potassium hydroxide, an organometallic compound with, for example, butyl lithium, or an alkali metal amide such as, for example, lithium diisopropylamide. The compounds according to the present invention where Y is sulfur, and the other substituents have the meanings established under the general formulas I and II, can be prepared as for example, by the reaction of carboxylic acid derivatives of the formula VIII, which they can be obtained in known manner from compounds of the general formula VI and wherein the substituents have the meanings mentioned above, with compounds of the general formula IX, wherein R2, and R3 and X have the meanings established under the general formulas I and the.
The reaction is preferably carried out in one of the aforementioned inert diluents with the addition of a suitable base which is a base that deprotonates intermediate IX, within a range of temperatures ranging from room temperature to the point of boiling of the solvent. It is possible to use as a base, in addition to those mentioned above, organic bases such as for example triethylamine, pyridine, imidazole or diazabicycloundecene. Carboxylic acid derivatives of the formula Via (Z in formula VI = direct bond) can be prepared by reaction of epoxides of formula IV with cuprates of formula XI:
IV + R, Cu (CN) Li2 - * - R • CH-OH I. R *
XI Vía
Cuprates can be prepared in accordance with that described in Tetrahedron Letters 23, (1982) 3755. Compounds of formulas I and can also be prepared by starting from the corresponding carboxylic acid, ie compounds of formulas I and where R is COOH, and initially converting these compounds in conventional manner into an activated form, such as for example a halide, an anhydride or an imidazolide, and then reacting the latter with an appropriate HOR10 hydroxy compound. This reaction can be carried out in the usual solvents and frequently requires the addition of a base, in which case the bases mentioned above are suitable. These two steps can also be simplified, for example by allowing the carboxylic acid to act on the hydroxy compound in the presence of a dehydrating agent such as a carbodiimide. Furthermore, it is also possible that compounds of the formula I are prepared by starting from the salts of the corresponding carboxylic acids, ie from compounds of the formulas I and where R is COR1 and R1 is OM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can react with many compounds of the formula R1-A where A is a conventional nucleophobic labile group, for example, halogen such as for example chlorine, bromine, iodine or arylsulfonyl or unsubstituted alkylsulfonyl or substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R1-A with a reactive substituent A are known or can be obtained easily with the general knowledge of an expert. This reaction can be carried out in conventional solvents and is advantageously carried out with the addition of a base, in which case the bases mentioned above are suitable. The radical R in formula I and can vary widely. For example, R is a group II C-R1 where R1 has the following meanings: a) hydrogen; b) succinimidyloxy; c) a five-membered heteroaromatic portion linked by a nitrogen atom such as for example pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms, particularly fluorine and chlorine and / or one or two of the following radicals: C3-C4 alkyl such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl; C1-C4 haloalkyl, particularly C1-C2 haloalkyl such as for example fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro -2, 2-difluoroethyl, 2,2-chloro-2-fluoroethyl, 2,2,2-trichloroethyl and penta-luoroethyl; C1-C4 haloalkoxy, particularly C?-C2 haloalkoxy such as for example difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2, 2, 2- trifluoroethoxy, 2-chloro-l, 1,2-trifluoroethoxy, and pentafluoroethoxy, particularly trifluoromethoxy; C1-C4 alkoxy, such as, for example, methoxy, ethoxy, propoxy, 1-ethylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, particularly methoxy, ethoxy, 1-methylethoxy; C 1 -C 4 alkylthio, such as, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, particularly methylthio and ethylthio; d) R1 is also a radical
/ (O) N * \ R "
where m is 0 or 1, and R7 and R8, which may be identical or different, have the following meanings: hydrogen, C? -C8 alkyl, particularly C? -C4 alkyl according to the above mentioned; C3-C6 alkenyl such as for example 2-propenyl, 2-bute-yl, 3-butenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, l, 1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-methyl-4-pentenyl, 2- methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, l-dimethyl-2-butenyl, 1,1-dimethyl-1,3-butenyl, 1,2-dimethyl-2 -butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2 -butenyl, 2,3-dimethyl-3-butenyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2 -trimethyl-2-propenyl, 1-ethyl-l-methyl-2-propenyl and l-ethyl-2-methyl-2-propenyl, particularly 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl; C3-C6 alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl -3-butynyl, l-methyl-2-butynyl, l, l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, l-methyl -2-pentynyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4 -pentinyl, 4-methyl-2-pentynyl, 1, 1-dimethyl-2-butynyl, 1, 1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl , l-ethyl-2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3-butynyl and l-ethyl-l-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, l-methyl -2-propynyl and 1-methyl-2-butynyl, particularly 2-propynyl;
C3-C8 cycloalkyl, such as for example cyclopropyl, cyclobutyl, cycloopentyl, cyclohexyl and cycloheptyl, cyclooctyl, wherein these alkyl, cycloalkyl, alkenyl and alkynyl groups may each carry from one to five halogen atoms, particularly fluorine or chlorine and / or or one or two of the following groups: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, in accordance with the above, C 3 -C 6 alkenyloxy, C 3 -C 6 alkenylthio, C 3 alkynyloxy C6, C3-C6 alkynylthio, wherein the alkenyl and alkynyl constituents present in these radicals preferably have the meanings mentioned above; C 1 -C 4 alkylcarbonyl, such as, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl; C 1 -C 4 alkoxycarbonyl, such as, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, 1,1-dimethylethoxycarbonyl; C3-C6 alkenylcarbonyl, C3-C6 alkynylcarbonyl, C3-C6 alkenyloxycarbonyl and C3-C6 alkynyloxycarbonyl, wherein the alkenyl and alkynyl radicals are preferably defined in accordance with the above; phenyl, unsubstituted or substituted one or more times, for example, one to three times, by halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C? -C4 alkoxy, Ci-C4 haloalkoxy, or Cilt-C 4 alkylthio, such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2 , 4-dichlorophenyl, 2-methoxy-3-methyl-phenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl, 2,6-difluorophenyl; dialkylamino C? ~ C4, such as, for example, dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino, N-isopropy1-N-ethylamino, N-isopropyl-N-propylamino; R7 and R8 further phenyl which may be substituted by one or several, for example, from one to three, of the following radicals: halogen, nitro, cyano, C? -C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C 4 -C 4 or C 3 -C 4 alkylthio according to the above mentioned in particular; or R7 and R8 together form a C1-C4 alkylene chain, which is closed to form a ring, is unsubstituted or substituted, for example, substituted by C1-C4 alkyl, and may contain a heteroatom selected from the group consists of oxygen, sulfur or nitrogen such as - (CH2) 4-, - (CH2) 5-, - (CH2) e-, - (CH2) 7-, (CH2) 2-0- (CH2) 2- , -CH2-S- (CH2) 3-, - (CH2) 2-0- (CH2) 3-, -NH- (CH2) 3-, -CH2-NH- (CH2) 2-, -CH2-CH = CH-CH2-, -CH = CH- (CH2) 3-;
e) R1 is also a group
where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R9 is C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, or unsubstituted or substituted phenyl, in accordance with the above mentioned in particular, f) R1 is also a radical OR10, where R10 is: hydrogen, the cation of an alkali metal such as for example lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium or an environmentally compatible organic ammonium ion such as, for example, C 1 -C 4 alkyl-tertiary ammonium or the ammonium ion; C3-Cs cycloalkyl, according to the aforementioned, which can carry from one to three C? -C4 alkyl groups; Ci-Cß alkyl, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1, 3- dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 2-ethylbutyl, l-ethyl-2-methylpropyl, which can carry from one to five halogen atoms, particularly fluorine and chlorine and / or one of the following radicals: C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, alkylcarbonyl C1-C4, C3-C8 cycloalkyl, C1-C4 alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, wherein the aromatic radicals in turn can each carry from one to five halogen atoms and / or from one to three of the following radicals: nit ro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and / or C1-C4 alkylthio, in accordance with the above-mentioned in particular; Ci-Cs alkyl according to the aforementioned, which can carry from one to five halogen atoms, particularly fluorine and / or chlorine, and bears one of the following radicals: a 5-membered heteroaromatic portion containing from one to three atoms of nitrogen, or a 5-membered heteroaromatic portion containing a nitrogen atom and an oxygen or sulfur atom, which can carry from one to four halogen atoms and / or one or two of the following radicals: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, phenyl, C 1 -C 4 haloalkoxy, and / or C 1 -C 4 alkylthio. Mention may be made in particular of the following: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1 -pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1, 2, -triazol-1-yl, 3-methyl-1, 2, 4-triazole- 1-yl, 5-methyl-l, 2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2- imidazolyl, 3-ethyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 3-tert-butyl-5-isoxazolyl; a C2-C2 alkyl group, which bears one of the following radicals in the 2-position: C?-C alkoxyimino, C 3 -C 6 alkynyloxyimino, haloalkenyloxyimino or benzyloxyimino; a C3-C6 alkenyl group, or C3-C6 alkynyl, it being possible for these groups, in turn, to carry from one to five halogen atoms; R10 furthermore a phenyl radical which can carry from one to five halogen atoms and / or from one to three of the following radicals: nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C1-C4 , and / or C1-C4 alkylthio, in accordance with that mentioned above particularly; a 5-membered heteroaromatic portion which is attached through a nitrogen atom, contains one to three nitrogen atoms and can carry one or two halogen atoms and / or one or two of the following radicals: C1-C4 alkyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, phenyl, C 1 -C 4 haloalkoxy, and / or C 1 -C 4 alkylthio. Particularly may be mentioned the following: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3, 5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl- l-pyrazolyl, 4-chloro-l-pyrazolyl, 4-bromo-l-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1, 2,4-triazol-1-yl, 3-methyl-l, 2, 4- tri-azole-l-yl, 5-methyl-l, 2,4-triazol-l-yl, 1-benzotriazolyl, 3,4-dichloro-l-imidazolyl; R10 is also a group
where R11 and R12, which may be identical or different, are: C? -C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl, these radicals possibly carrying a C1-C4 alkoxy radical, alkylthio C? -C4, and / or an unsubstituted or substituted phenyl radical, in accordance with the above mentioned particular-entity; phenyl which may be substituted by one or more, for example from one to three of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C1-C4 alkylthio, where these radicals are, in particular, those mentioned above;
or R11 and R12 together form a C3-C2 alkylene chain which can carry from one to three C1-C4 alkyl groups, and can contain a heteroatom of the group consisting of oxygen, sulfur and nitrogen, in accordance with particularly mentioned for R7 and R8. g) R1 is also a radical
OR
where R 13 is: C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, cycloalkyl
C3-C8, in accordance with the above-mentioned particularly, it being possible for these radicals to carry a C1-C4 alkoxy, C1-C4 alkylthio and / or phenyl radical in accordance with that mentioned above; phenyl, unsubstituted or substituted, particularly in accordance with that mentioned above. h) R1 is a radical
II 13 CH? s- IoI where R13 has the meaning mentioned above. R may also be: tetrazolyl or cyano. In a specific embodiment, the carboxylic acid derivatives of the general formula I, both as pure enantiomers and pure diastereomers or as a mixture thereof, are the derivatives wherein the substituents have the following meanings: R2 hydrogen, hydroxyl, N (C-alkyl) C4) 2, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, and halogen atoms mentioned with details for R 1, especially chloro, methyl, methoxy, ethoxy , difluoromethoxy, trifluoromethoxy; X nitrogen or CR14 where R14 is hydrogen or alkyl, or CR14 together with CR3 forms a 5-membered alkylene or alkenylene ring in which, in each case, a methylene group can be replaced by oxygen or sulfur, for example -CH2-CH2-0-, -CH = CH-0-, -CH2-CH2-CH2-O-, -CH = CH-CH20, particularly hydrogen, -CH2-CH2-O-, -CH (CH3) - CH (CH3) -0-, -C (CH3) = C (CH3) -0-, -CH = C (CH3) -O- or -C (CH3) = C (CH3) -S; R 3 is hydrogen, hydroxyl, N (C 1 -C 4 alkyl), C 3 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio groups and halogen atoms mentioned for R 1. , especially chloro, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or is bound to R14 in accordance with that mentioned above to provide a 5- or 6-membered ring; R 4 and R 5 are phenyl or naphthyl, which may be substituted by one or more, for example, from one to three, of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C 1 -C 4 alkyl, haloalkyl C C 4, C 3 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl; particularly, as in the case of the aforementioned for R7 and R8, and, for example, 3-hydroxyphenyl, 4-dimethylamino-phenyl,
2-mercapto phenyl, 3-methoxycarbonyl phenyl, 4-acetyl phenyl, 1-naphthyl, 2-naphthyl, 3-bromo-2-naphthyl, 4-methyl-1-naphthyl, 5-methoxy-1-naphthyl, 6-trifluoromethyl- 1-naphthyl, 7-chlor-1-naphthyl, 8-hydroxy-1-naphthyl; or R4 and R5 together with the adjacent carbon atom form a 3- to 6-membered ring which can contain an oxygen atom or a sulfur atom and is unsubstituted or carries from one to three, depending on the size of the ring, of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, in accordance with that mentioned above in general and in particular; and phenyl or naphthyl, linked together in the ortho positions through a direct bond, a methylene group, ethylene or ethenylene, an oxygen or sulfur atom or a S02, NH or N-alkyl group, or C3 cycloalkyl. -C7; R4 is C1-C10 alkyl, in accordance with what is specifically mentioned for R1, which can carry from one to five halogen atoms such as, for example, fluorine, chlorine, bromine, iodine, particularly fluorine and chlorine, and / or one of the following radicals : alkoxy, alkylthio, cyano, alkylcarbonyl, alkoxycarbonyl, phenyl, phenoxy, phenylcarbonyl according to the aforementioned in general and in particular to R1; C.sub.1 -C.sub.10 alkyl, in accordance with that mentioned above, which can carry from one to five halogen atoms as mentioned above, particularly fluorine and chlorine, and which bears an unsubstituted or substituted 5-membered heteroaromatic ring, as mentioned above in the case of R1; C3-C12 cycloalkyl, particularly C3-C7 cycloalkyl, or C3-C12 cycloalkenyl, particularly C4-C7 cycloalkenyl, it being possible for a methylene group in the saturated or unsaturated ring to be replaced by an oxygen or sulfur atom, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, cyclopropenyl, dihydrofuranyl, dihydrothienyl, dihydropyranyl, dihydrothiopyranyl, wherein the cycloalkyl and cycloalkenyl radicals may be substituted by one to five halogen atoms in accordance with mentioned above, especially fluorine or chlorine and / or one of the following radicals: C? -C4 alkyl, C? -C4 alkoxy, C1-C4 alkylthio, cyano, Ci-Cs alkylcarbonyl, Ci-C? alkoxycarbonyl, phenyl, phenoxy, phenylcarbonyl as mentioned above in general and in particular; C3-C6 alkenyl, or C3-C6 alkynyl according to that mentioned for R1, which can carry from one to five halogen atoms as mentioned above, particularly fluorine and chlorine, and / or one of the following radicals: C1 alkyl -C4, C1-C4 alkoxy, C1-C4 alkylthio, cyano, C? -C8 alkylcarbonyl, C? -C8 alkoxycarbonyl, phenyl, phenoxy, phenylcarbonyl as mentioned above in general and in particular; a 5 or 6 membered hetaryl such as furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, isothioazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, for example 2-furanyl, 3- furanyl, 2-thienyl, 3-thienyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothizolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, oxa-2, -diazolyl, oxa-3,4-diazolyl, thia-2,4-diazolyl, thia-3,4-diazolyl (sic) and triazolyl, where the heteroaromatic rings can carry from one to five carbon atoms. halogen as mentioned above, particularly fluorine and chlorine, and / or one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, nitro, C 1 -C 4 alkylcarbonyl, alkoxycarbo nyl Ci-Cß, phenyl, phenoxy, phenylcarbonyl as mentioned above in general and in particular; R 5 is hydrogen, C 1 -C 4 alkyl, C 3 -C 5 alkenyl, C 3 -C 3 alkynyl, C 3 -C 4 cycloalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 1 -C 4 alkylthioalkyl or phenyl as mentioned above for R 4 in particular; Rs is C? -C8 alkyl, C3-Ce alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl in accordance with the above mentioned in particular, it being possible for these radicals in each case to be replaced one or more times by: halogen, hydroxyl, nitro, cyano, C 1 -C 4 alkoxy, C 3 -C 6 alkenyloxy, C 3 -C alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyl, hydroxycarbonyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyl, alkoxycarbonyl, C1-C4 alkylamino, dialkylamino C? ~ C or phenyl or unsubstituted or substituted phenoxy, as mentioned above in particular; Phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy , alkylthio Cj.-C4, alkylamino Ci-C4, or dialkylamino C-C4, as mentioned in particular for R7 and R; a 5 or 6 membered heteroaromatic portion containing 1 to 3 nitrogen atoms and / or one sulfur atom or one oxygen atom and which may carry one to four halogen atoms and / or one or two of the following radicals : C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals themselves to carry from one to five carbon atoms. halogen and / or from one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and / or C 1 -C 4 alkylthio, in accordance with that for R 4 in particular; And it is sulfur, oxygen or a simple bond; Z is sulfur, oxygen, -SO-, -S02- or a single bond. In a further embodiment, compounds of the formula I and the, both as pure enantiomers and pure diastereomers or mixture thereof, are the compounds in which the substituents have the following meanings: R 2 is C 1 -C 4 alkyl, C 1 alkoxy C4, X is nitrogen or CR14, where R14 is hydrogen or alkyl, or CR14 forms, together with CR3, a 4 or 5 membered alkylene or alkenylene ring such as -CH2-CH2-0-, -CH = CH-0-, -CH2-CH2-CH2-0-, -CH-CH-CH20-, particularly hydrogen, -CH2-CH2-0-, -CH (CH3) -CH (CH3) -O-, - c (CH3) = C (CH3) -0-, -CH = C (CH3) -0- or -C (CH3) = C (CH3) -S; R 3 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, at R 14 as mentioned above to provide a 5- or 6-membered ring; R4 and R5 are phenyl (identical or different) which may be substituted by one or more, for example, from one to three, of the following radicals: halogen, nitro, hydroxyl, alkyl
C1-C4, C1-C4 alkoxy, C1-C4 alkylthio or R4 and R5 are phenyl groups which are connected together in the ortho positions by means of a direct bond, a methylene group, ethylene or ethenylene, an oxygen or sulfur atom or a group S02, NH or N-alkyl; or R4 and R5 are C? -C4 cycloalkyl; R6 is C?-C8 alkyl, C3-C6 alkenyl, or C3-C8 cycloalkyl, it being possible for these radicals in each case to be replaced one or more times by: halogen, hydroxyl, nitro, cyano, C alco ~C alkoxy, , C3-C6 alkenyloxy, alkylthio C? ~ c4; phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, d-C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy , alkylthio C? -C4, alkylamino C?
C4, or dialkylamino C? -C4; a five or six member heteroaromatic portion containing nitrogen atoms and / or a sulfur or oxygen atom and which may carry from one to four halogen atoms and / or one or two of the following radicals: C? -C4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals, in turn, to carry from one to five halogen atoms and / or from one to three the following radicals: C3-C4 alkyl, C1-C4 haloalkyl, C3-C4 alkoxy and / or C1-C4 alkylthio,; And it is sulfur, oxygen or a simple bond; Z is sulfur, oxygen, -SO-, -S02- or a single bond. The beneficial effect of the compounds can be shown in the following tests: EVALUATION OF IN VIVO BIOLOGICAL ACTIVITY Compounds of the present invention can be further tested in any of several preclinical assays for in vivo anticancer activity. For example, human tumors that have been cultured in nude mice can be transplanted into new recipient mice using tumor fragments that are approximately 50 mg in size. The day of the transplant is designated as day zero. Five to fifteen days later, the mice are treated with the test compounds provided in the form of an intravenous or intraperitoneal injection, in groups of 5 to 10 mice in each dose. The compounds are administered daily either for 5, 10 or 15 days in doses of 0.1 to 1000 mg / kg of body weight. The diameters of tumors and body weights are measured periodically. The tumor mass is calculated using the diameters measured with Vernier calipers, the formula: (length x width?) / 2 = mg of tumor weight. The mean tumor weights are calculated for each treatment group in relation to untreated control tumors. The DU-145 model is a specific example of this type of test and is described below. Model DU-145 Fragment of human prostate tumor (HTB 81), cultured in nude mice were implanted subcutaneously via trocar, on the dorsal side of new nude recipient mice, as is well known in the art. The day of the implant is known as day zero. The treatment was started on day 11 after implantation using compound 1.1 of Table I. Six mice were assigned to each treatment group with the mode of administration and the amounts administered (mg / kg body weight) described in Table XI . Compound 1-1 was administered once a day for 10 days starting, as mentioned above, on day 11 after implantation (Q1D x 10:11). Table IX shows that all the groups of. treatment responded to the administration of compound 1-1, in accordance with what was evidenced by a reduction of the value of% / T / C of mean tumor weight MT).
Table IX USE OF THE COMPOUND 1-1 IN THE PROSTATE TUMOR MODEL
DU-145 Dose Days for weight Average weight of Tumor weight = tumor (MTW) MTW 1000 mg on day 33 (mg)% (T / C)
Control 32.6 1232 100.00
100 mg / kg IV, QlDxlOrll 39.3 561 45.54
150mg / kg IV, Q1DX10: 11 37.4 793 64.37
150mg / kg IP, Q1DX10: 11 59.3 407 33.04
220mg / kg IP, Q1DX10: 11 50.9 470 38.15
LINK STUDY WITH RECEIVER CHO cells expressing cloned human ETA receptor and guinea pig brain membranes from India with > 60% of
ETB compared to ETA receptors were used for link studies. CHO cells expressing the ETA receptor were cultured in Fi2 medium containing 6% fetal calf serum, 1% glutamine, 100 U / ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, MD, United States). from America) . After 48 hours the cells were washed with PBS and incubated with PBS containing 0.05% trypsin for 5 minutes. The neutralization was then carried out with F? 2 / medium and the cells were harvested by centrifugation at 300 x g. To lyse the cells, the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4 with 10% glycerol) and then the pellet was incubated at a concentration of 107 cells / ml of lysis buffer at temperature of 4 ° C for 30 minutes. The membranes were centrifuged at 2000 x g for 10 minutes, and the pellet was stored in liquid nitrogen. Guinea pig cerebellum were homogenized in a Potter-Elvejhem homogenizer, and membranes were obtained by centrifugation at 1000 x g difference for 10 minutes and the centrifugation of the supernatant was repeated at 20,000 x g for 10 minutes. LINK TESTING For the assay of ETA and ETB receptor binding, the membranes were suspended in incubation buffer (50 mM tris-HCl, pH 7.4 with 5 mM MnCl2, 40 μg / ml, bacitracin and 0.2% BSA) a concentration of 50μg of protein per assay mixture and the membranes were incubated with 25 pM (125I) -ET? (ETA receptor assay) or 25 pM (125I) -RZ3 (the ETB receptor assay) in the presence and absence of test substance at a temperature of 25 ° C. The non-specific binding was determined using 10"'M of ETi.After 30 minutes, the free ligand and bound radio were separated by filtration through glass fiber filters GF / B (Whatman, England) in a cell harvester Skatron (Skatron, Lier, Norway) and the filters were washed with a Tris-HCl regulator at wire temperature, pH 7.4, with 0.2% BSA.The radioactivity collected in filters was quantified using a Packard 2200 liquid scintillation counter CA. The Kx values shown in Table A were determined by non-linear regression analysis using the LIGAND program Table A shows the effect of the compounds of the formula I as the K (mol / 1) determined in the experiments. A Ki (mol / 1) Compound ET-A ET-B 4.42 2.5 x 10"7 3.0 x 10" 6 4.58 1.6 x 10"7 4.7 x 10" 6 FUNCTIONAL TEST SYSTEM in vitro TO SEARCH ENDOTHELINE RECEPTOR ANTAGONISTS ( SUBTYPE A) This test system is a functional test, based on in cells for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes.
Fibroblast 1 that had been isolated from rats and in which an endogenous endothelin receptor of subtype A had been detected were loaded with the fluorescent dye Fura 2-an in the following manner: after trypsinization, the cells were resuspended in regulator A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl2, 1 mM CaCl2, 25 mM HEPES, 10 mM glucose, pH 7.4) at a density of 2 x 10'Vml and incubated with Fura 2-a (2uM), Pluronics F-127 (0.044.) And DMSO (0.2%) at a temperature of 37 ° C in the dark for 30 minutes. The cells were then washed twice with regulator A and resuspended at 2 x 106 / l. The fluorescence signal of 2 x 10 5 cells per ml with Ex / Em 380/510 was continuously recorded at 30 ° C. The test substances and, after a 3 minute incubation time, ET1 were added to the cells, and the maximum change in fluorescence was determined. The response in the cells to ET1 without prior addition of a test substance was used as a control and was set equal to 100%. Table B indicates the effect of some compounds of formula I such as IC50 (mol / 1) determined in the experiments. Table B Compounds IC50 (mol / 1) 4.42 7.4 x 10 ~ 7 4.58 1.0 x 10 ~ 6 ET ANTAGONIST TEST in vivo SD male rats weighing 250 to 300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and their marrow removed. The carotid artery and the jugular vein were catheterized. In control animals, an intravenous administration of lμg / kg of ET1 caused an evident rise in blood pressure that persisted for a long period of time. The test animals received an i.v. of the test compounds (1 ml / kg) 5 minutes before ET1 administration. To determine the antagonist properties of ET, the elevation of blood pressure in the test animals was compared with the elevation of blood pressure in the control animals. SUDDEN DEATH INDUCED BY ENDOTHELIN-1 IN MICE The principle of the test is this inhibition of the sudden cardiac death caused in mice by the endothelin, probably induced, by the constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. An intravenous injection of lOnmol / kg of endothelin in a volume of 5 ml / kg of body weight results in the death of the animals in a period of a few minutes. The lethal dose of endothelin 1 is reviewed in each case in a small group of animals. If the test substance is administered intravenously, the injection of endothelin-1 that was lethal in the reference group is usually performed 5 minutes later. With other modes of administration, the times before administration are extended, if appropriate up to several hours. The survival rate is recorded and the effective doses that protect 50% of the animals (ED 50) against cardiac death induced by endothelin during a period of 24 hours or more are determined. FUNCTIONAL TEST ON GLASSES FOR ENDOTHELINE RECEPTOR ANTAGONISTS. After an initial tension of 2 g and a relaxation time of 1 hour in a solution of Krebs-Henseleit at 37 ° C and pH 7.3-7.4, segments of rabbit aorta are first induced to contract with K +. After washing, the endothelin-effect dose graph is constructed up to the maximum. Potential endothelin antagonists are administered to other preparations of the same vessel 15 minutes before the start of the endothelin-effect dose graph. The effects of endothelin are calibrated as a percentage of the contraction induced by K +. Effective endothelin antagonists result in a shift to the right of the endothelin-effect dose plot. Examples of synthesis of compound of the formula Example 1 Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved 5 g (19.6 mmoles) of 3,3-diphenyl-2,3-epoxypropionate methyl in 50 ml of absolute methanol and 0.1 ml of boron trifluoride heterate was added at a temperature of 0 ° C. The mixture was stirred at a temperature of 0 ° C for 2 hours and at room temperature for an additional 2 hours. Respiration of the solution was removed by distillation, the residue was taken up in ethyl acetate, washed with a solution of sodium bicarbonate and water and dried over magnesium sulfate. After the solvent was removed by distillation, 5.5 g (88%) of a pale yellow oil remained. Example 2 Methyl 2-hydroxy-3-phenoxy-3, 3-diphenyl propionate 5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6 g (60 mmol) of phenol were heated together to 100 g. ° C for 6 hours. Removal of the excess phenol by distillation under high vacuum and purification of the residue by chromatography on silica gel with hexane / ethyl acetate mixtures resulted in 4.9 g (77%) of a pale yellow oil. EXAMPLE 3 Methyl 2- (4A-6-dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3-diphenyl-propionate 2.86 g (10 mmol) of 2-hydroxy-3-methoxy-3, 3-diphenyl were dissolved. methyl propylate in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for one hour and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methyl-diffonylpyrimidine were added. After stirring at temperature, environment for 24 hours, a cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was removed by distillation. The residue was mixed with 10 ml of ether, and the resulting precipitate was removed by suction filtration. After drying, 3.48 g (82%) of white powder remained. EXAMPLE 4 2- (4,6-Dimethoxy-pyrimidin-2-yloxy) -3-methoxy-3, 3-diphenylpropionic acid 2.12g (5m-mol) of 2- (4,6-dimethoxy-pyrimidine) were dissolved. Methyl 2-yl-oxy) -3-methoxy-3-diphenyl-propionate in 50 ml of dioxane, 10 ml of a 1 N KOH solution was added, and the mixture was stirred at 100 ° C for 3 hours. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove the unreacted ester. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and said phase was extracted with ethyl acetate.
After drying in magnesium sulfate and after the solvent was removed by distillation, the residue was mixed with an ester / hexane mixture, and the precipitate that formed was removed by suction filtration. After drying, 1.85g (90%) of white powder remained. Melting point: 167 ° C Example 5 Sodium 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methoxy-3,3-diphenyl-propionate 1.68g (4 mmol) of 2- ( 4,6-dimethoxy-2-pyrimidinyloxy-) -3-methoxy-3, 3-diphenylpropionic acid in 4 ml of IN NaOH + 100 μl of water. The solution was diofilized, and the sodium salt of the carboxylic acid used is obtained quantitatively. 10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3-diphenyl-propionate were dissolved in 50 ml each of methanol and glacial acetic acid, 1 ml of RuO (OH) in dioxane was added, and carried out hydrogenation with H2 in an autoclave at a temperature of 100 ° C under a pressure of 100 bar for 30 hours. The catalyst was removed by filtration, the mixture was concentrated, mixed with ether and washed with a NaCl solution, and the organic phase was dried and concentrated. '10. lg of 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate methyl was obtained in the form of an oil. Example 7 Methyl 2- (4,6-dimethoxy-pyrimidin-2-ylthio) -3-methoxy-3-diphenyl-propionate 7.16 g (25 mmol) of 2-hydroxy-3-methoxy-3, 3- were dissolved Methyl diphenyl propionate in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine were added, and 3.2 g (28 mmol) of methanesulphonyl chloride were added dropwise with stirring. The mixture was stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and added dropwise at a temperature of 0 ° C to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidin-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate. in 100 ml of DMF. After stirring at room temperature for 2 hours and at 60 ° C for two additional hours, the mixture was poured into one liter of ice water, and the resulting precipitate was removed by suction filtration. After drying, 3.19 g (29%) of a white powder remained. EXAMPLE 8 Methyl 2-hydroxy-3, 3-diphenylbutyrate was added dropwise 1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-hepoxypropionate dissolved in 10 ml of absolute ether to a solution of cuprate which had been prepared from 635 mg (7 mmoles) of copper (I) cyanide dissolved in 10 ml of absolute ether and 8.14 ml (13 mmoles) of a 1.6-normal methyllithium solution and cooled to -78 ° C. The solution was stirred at a temperature of -78 ° C for 1 hour and then allowed to warm to room temperature. The solution was subsequently diluted with 100 ml of ether and 100 ml of water, and the ether phase was washed with dilute citric acid and with a solution of sodium bicarbonate and said solution was dried in magnesium sulfate. The crude product was purified by chromatography on silica gel with mixtures of cyclohexane / ethyl acetate to result in 250 mg (16%) of a pale yellow oil. Example 9 2-Hydroxy-3-methoxy-3, 3-diphenylpropionic acid 91. llg (0.5 mole) of benzophenone and 45.92g (0.85 mole) of sodium methoxide were suspended in 150 ml of methyl tert-butyl ether (MTB) ) at room temperature. After cooling to 10 ° C, 92.24 g (0.85 mol) of methyl chloroacetate were added in such a way that the internal temperature will rise to 40 ° C while continuing to cool in a bath at a temperature of -10 ° C. The mixture was then stirred without cooling at autogenous temperature for one hour. After the addition of 250 ml of water and after a brief stirring, the aqueous phase was separated. The MTB phase was washed with 250 ml of a diluted sodium chloride solution. After changing the solvent to methanol (250 ml), a solution of lg of p-toluenesulfonic acid in 10 ml of methanol was added at room temperature. The mixture was stirred at autogenous temperature for 1 hour and then heated to reflux. While distilling methanol, 400 g of a 10% sodium hydroxide solution were added dropwise, and finally 60 ml of water was added. The methanol was distilled until the bottom temperature reached 97 ° C. After cooling to 55 ° C, 190 ml of MTB was added and the mixture was acidified to a pH of 2 with about 77 ml of concentrated HCL. After cooling to room temperature, the aqueous phase was separated and the organic phase was concentrated by distilling off 60 ml of MTB. The product was crystallized by the addition of 500 ml of heptane and said product was cooled slowly to room temperature. The approximately crystalline solid was removed by suction filtration, washing with heptane and drying to constant weight in a vacuum oven at a temperature of 40 ° C. Yield: 108.9 g (80%), HPLC >99.5% area. Example 10 S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid (resolution of racemate with L-proline methyl ether) 148.8 g of a 30% methanolic sodium methanolate solution (0.826 mol) were added. dropwise to 240 g of a 57% methanolic methanolic methyl ester hydrochloride solution (0.826 mol) at room temperature, and 2.4 1 of MTB and 225 g (0.826 mol) of 2-hydroxy-3- acid were added. methoxy-3, 3-diphenylpropionic. After the distillation of 2680 moles of the MTB / methanol mixture, with the simultaneous dropwise addition of 2.4 1 of MTB, the mixture was slowly cooled to room temperature, the crystals (R-2-hydroxy-3- acid) methoxy-3, 3-diphenylpropionic x L-proline methyl ester) were removed by suction filtration, and the solid was washed with 150 ml of MTB. The filtrate was concentrated by distillation from 1.5 1 of MTB, and 1.0 1 of water was added. The pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature and, after stirring and phase separation, the aqueous phase was separated and extracted with 0.4 1 of MTB. The combined organic phases were extracted with 0.4 1 of water. The residue, after the removal of MTB, was dissolved in 650 ml of toluene under reflux, and the product was crystallized by seeding and slow cooling. Filtration, suction, washing with toluene and drying in a vacuum oven resulted in 78.7 g of S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid (35% yield based on racemate). Chiral HPLC: 100% pure HPLC: 99.8% Example 11 S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid (resolution of racemate with (S) -1- (4-nitrophenyl) ethylamine) 30.5 g were added (o.184 mol) of (S) -l- (4-nitrophenyl) ethylamine at 100 g (0.368 mol) of 2-dihydroxy-methoxy-3, 3-diphenylpropionic acid in 750 ml of acetone and 750 ml of low MTB Reflux. The mixture was centered, boiled under reflux for one hour and cooled slowly to room temperature for crystallization. The crystals (S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid x (S) -l- (4-nitrophenyl) ethylamine) were removed by suction filtration and washed with MTB. The residue was suspended in 500 ml of water and 350 ml of MTB and then the pH was adjusted to 1.2 with concentrated hydrochloric acid at room temperature, and, after stirring and phase separation, the aqueous phase was separated and extracted with 150 ml. of MTB. The combined organic phases were extracted with 100 ml of water. 370 ml of MTB were removed by distillation and then 390 ml of n-heptane was added under reflux, and the mixture was cooled slowly to room temperature while the product crystallized. Filtration with suction, washing with n-heptane and drying in a vacuum oven resulted in the production of 35.0 g of S-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid (35% yield based on the racemate). Chiral HPLC: 100% pure HPLC: 99.8% Example 12 3-methoxy-2- (4-methoxy-β, 7-dihydroxy-5H-cyclopentapyrimidin-2-yloxy) -3,3-diphenylpropionate benzyl was dissolved 24.48 g ( 90 mmoles) of 3-methoxy-3, 3-diphenyl-2-hydroxypropionic acid in 150 ml of DMF, and 13.7g (99 mmoles) of potassium carbonate was added. The suspension was stirred at room temperature for 30 minutes. Then 10.7 ml (90 mmol) of benzyl bromide was added dropwise in the course of 5 minutes, and the mixture was stirred for 1 hour, during which time the temperature rose to 32 ° C. To this mixture, 24.84 g (180 mmol) of K2C03 and 20.52 g (90 mmol) of 2-methanesulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine were successively added, and the mixture was stirred at 80 ° C. 3 hours. For the treatment, the contents of the bottle were diluted with approximately 600 ml of H20 and cautiously acidified with concentrated HCl, and 250 ml of ethyl acetate were added. 31.4g of pure product was precipitated and was removed by filtration. The ethyl acetate phase was separated from the mother liquor, the aqueous phase was extracted again with ethyl acetate, the combined organic phases were concentrated. The oily residue (19 g) was purified by chromatography (cyclohexane / ethyl acetate = 9/1) to result in an additional 10.5 g of pure product.
Total yield: 41.9g (82.2 mmoles) = 91% Melting point: 143-147 ° C MS: MH + = 511 Example 13 '3-Methoxy-2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine) acid -2-yl-oxy) -3,3-diphenylpropionic 40 g (78.4 mmoles) of 3-methoxy-2- (4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy) -3 were dissolved, Benzyl 3-diphenyl propionate in 400 ml of ethyl acetate / methanol (4: 1), approximately 500 mg of palladium in activated charcoal (10%) was added, and the mixture was exposed to a hydrogen atmosphere until it would not bring it closer gas. The catalyst was removed by filtration, the solution was evaporated, and the residue was crystallized from ether. Example 14 Ethyl 2S-3, 3-diphenyloxirane-2-carboxylate 2.57g (10.2 mmol) of ethyl 3, 3-diphenylacrylate and 464 mg of 4-phenylpyridine N-oxide were dissolved in 24 ml of methylene chloride, and 4.32 mg (6.5 mol%) of (S, S) - (+) - N, N'-bis (3,5-ditert-butyl-alylidene) -1,2-cyclohexanediaminomanganese (III) chloride was added. While cooling on ice, 6.4 ml of a 12% sodium hypochlorite solution was added, and the mixture was stirred while it was cooling on ice for 30 minutes and at room temperature overnight. The solution was diluted to 200 ml with water, extracted with ether, dried and evaporated. 2.85 g of a colorless oil were obtained. Purification by MPLC (cyclohexane: ethyl acetate = 9: 1) resulted in 1.12 g of oil with an enantiomer ratio of about 8: 1 in favor of the S configuration. 1 H- = NMR (CDC13) d 0 1.0 (t, 3H); 3.9 (m, 3H); 7.3 (, 10H) Example 15 2-Methylthio-6,7-dihydro-5H-cyclopentapyrimidin-4-ol 46.9g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5g (192 mmol) of sulfate were successively added. of S-methylisothiourea at 29.6 g (528 mmol) of KOH in 396 ml of methanol, and the mixture was stirred at room temperature overnight acidified with 1 N hydrochloric acid and diluted with water. The crystals that separated were removed by filtration with suction and dried. 20 grams of crystals were obtained. Example 16 4-Chloro-2-methylthio-6,7-dihydro-5H-cyclopentapyrimidine 255 ml of phosphorus oxychloride was added at 20 g (110 mmol) of Example 15, and the mixture was stirred at 80 ° C for 3 hours. The phosphorus oxychloride was removed by evaporation, ice was added to the residue, and the crystals that separated were removed by filtration with suction. 18.5 g of a brown solid were obtained.
Example 17 4-methoxy-2-methylthio-6,7-dihydro-5H-cyclopentapyrimidine 18.05g (90 mmol) of 4-chloro-2-methylthio-6,7-dihydro-5H-cyclopentapyrimidine were dissolved in 200 ml of methanol . At a temperature of 45 ° C, 16.7 g of sodium methoxide (in the form of a 30% solution in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate, and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. They remained 15.5g of an oil. XH-NMR (DMSO), d = 2.1 (quintet, 2H); 2.5 (s, 3H); 2.8 (dt, 4H); 3.9 (s, 3H) ppm Example 18 2-Methylthio-4-methoxy-6,7-dihydro-5H-cyclopentapyrimidine 15g (76.2 mmoles) of 4-methoxy-2-methylthio-6,7-dihydro-5H- were dissolved. Cyclo-pentapyrimidine in 160 ml of glacial acetic acid / methylene chloride (1: 1) and 1.3 g of sodium tungstate were added. At a temperature of 35 ° C, 17.5 ml (170 mmol) of a 30% H202 solution was added dropwise. The mixture was then diluted with 500 ml of water and 100 ml of methylene chloride, and the organic phase was separated, dried and evaporated. 14 g of oil remained and were crystallized from ether.
1 H = NMR (CDCla), d = 2.2 (quintet, 2H); 3.0 (dt., 4H); 3.3 (s, 3H); 4.1 (s, 3H) ppm Example 19 l-Benzylsulfonyl-3- (4,6-dimethoxy-2-pyrimidinyloxy) -4-methoxy-4,4-diphenyl-2-butanone 0.37g (2.4 mmoles) of phenyl was dissolved methyl sulfone in 10 ml of dry THF and then, at a temperature of -70 ° C, 2 equivalents of butyllithium (2.94 ml) were added.; 1.6 molar solution in hexane), drop by drop. After 1 hour at a temperature of -70 ° C, 1 gram (2.4 mmoles) of methyl 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methoxy-3-diphenyl-propionate was added dropwise. dissolved in 5 ml of THF. The reaction mixture was then stirred at a temperature of -70 ° C for one hour, and at a temperature of -10 ° C for one hour, and then said mixture was heated to room temperature. For the treatment, approximately 10 ml of an NH 4 Cl solution was added dropwise, a complete extraction was carried out with ethyl acetate, and the combined organic phases were washed with a saturated NaCl solution and dried in NA 2 SO 4. The residue obtained after drying and concentration was purified by chromatography on silica gel (n-heptane / ethyl acetate 15% -> 30%) and subsequently MPLC on silica gel RP (acetonitrile / H20 + TFA); 0.3 g of a white amorphous powder obtained as a product. EXAMPLE 3 3-3-diphenyloxyran-2-carbonitrile 3.1 g (54.9 mmol) of sodium methoxide were suspended in 20 ml of dry THF and then, at a temperature of -10 ° C, a mixture of sodium methoxide was added dropwise. g (27.4 mmoles) of benzophenone and 4.2 g (54.9 mmoles) of chloroacetonitrile. The reaction mixture was stirred at a temperature of -10 ° C for about 2 hours, and then said mixture was poured into water and extracted several times with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated, and the residue was purified by chromatography on silica gel (n-heptane / ethyl acetate). Yield: 1.2 g (20%) 1 H-NMR (CDC1) d = 3.9 (s, ÍH); 7.4-7.5 (m, 10 H) ppm Example 21 2-Hydroxy-3-methoxy-3,3-diphenylpropionitrile was dissolved 6.5g (29.4 mmol) of 3,3-diphenyloxyran-2-carbonitrile in 60 ml of methanol and, at a temperature of 0 ° C, approximately 2 ml of a boron trifluoride etherate solution was added. The mixture was further stirred at a temperature of 0 ° C for 1 hour, and then at room temperature overnight. For the preparation, the mixture was diluted in diethyl ether and washed with a saturated solution of NaCl, and the organic phase was dried on
Na 2 SO 4 and concentrated. The residue consisted of 7.3 g of an amorphous white powder that was used directly in the subsequent reactions. ^ -H-NMR (CDC13) d = 2.95 (broad s, OH), 3.15 (s, 3H), 5.3 (s, ÍH), 7.3-7.5 (m, 10) ppm Example 22 2- (4, 6- Dimethoxy-2-pyrimidinyloxy) -3-methoxy-3, 3-diphenylpropionitrile 7.3g (28.8 mmoles) of 2-hydroxy-3-methoxy-3, 3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4g (28.8 mgs) were added. mmoles) of K2C03 and 6.3 g (28 mmoles) of 2-methanesulfonyl-4,6-dimethoxypyrimidine. The mixture was stirred at room temperature for approximately 12 hours, then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H20, dried and concentrated, the residue obtained in this way was then purified by chromatography on silica gel (n-heptane / ethyl acetate). Yield: 6.9 g of an amorphous white powder. FAB-MS: 392 (M + H1) d = 3.3 (s, 3H); 4.95 (s, 6H), 5.85 (s, ÍH);
6. 3 (s, ÍH); 7.3-7.5 (, 10H) ppm Example 23 5- (1- (4,6-Dimethoxy-2-pyrimidinyloxy) -2-methoxy-2,2-diphenyl-ethyl) -lH-tetrazole 0.5 g (1.3 mmol) was dissolved ) of nitrile in 10 ml of toluene, and 85 mg (1.3 mmol) of NaN3 and 460 mg (1.4 mmol) of BusSnCl were successively added and then the mixture was refluxed for about 40 hours. Cooling was followed by dilution with ethyl acetate and washing with a 10% aqueous KF solution and with a NaCl solution. After drying in MgSO4 and concentration, 1.0 g of a yellow oil remained, which was purified by chromatography on silica gel (n-heptane / ethyl acetate). The concentration of the fractions resulted in 60 mg of 1H-tetrazole and 110 mg of 1-methyltetrazole, each as amorphous white solids. 5- (1- (4,6-Dimethoxy-2-pyrmidinyloxy) -2-methoxy-2,2-diphenylethyl-1H-tetrazole Electrorocio-MS: 435 (M + H1) ^ - MR (CDClj): d (ppm ) 3.28 (s, 3H), 3.85 (s, 6H), 5.75 (s, ÍH), 7.25-7.40 (m, 10H), 7.50 (s, ÍH) 5- (1- (4,6-Dimethoxy-) 2-pyrimidinyloxy) -2-methoxy-2, 2-diphenylethyl) -1-methyltetrazole Electrorho-MS; 471 (M + H 1) 1 H-NMR (CDCl 3): d (ppm) 3.0 (s, 3H), 3 35 (s, 3H), 3.80 (s, 6H), 5.75 (s, ÍH) 7. 30-7.40 (m, 11H) eg 24 Acid 2- (4, 6-D) methoxy-2-pyrimidinyloxy) -3-methylsulfinyl-3, 3-diphenylpropionic 1.2g (2.9 mmol) of 2- (4,6-dimethoxy-2-pyrimidinyloxy) -3-methylthio-3,3-diphenylpropionic acid were introduced in 15 ml of glacial acetic acid at a temperature of 0 ° C and 294 μl of 30% H20 were added dropwise The mixture was stirred at room temperature overnight, poured into water, extracted with CH2Cl2 and washed with a solution of sodium thiosulfate and brine, after drying, substance Ig was isolated in the form of a white foam. Example 25 2- (4,6-Dimethoxy-2-pyrimidinyloxy) -3-methylsulfonyl-3,3-diphenylpropionic acid 0.6 g (1.45 mmol) of 2- (4,6-diemethoxy-2-pyrimidinyloxy) - 3-methyl-sulfinyl-3, 3-diphenylpropionic acid in 15 ml of glacial acetic acid at room temperature, and 294μl of 30% H202 were added dropwise. The mixture was stirred at room temperature overnight, heated to a temperature of 50 ° C for an additional 3 hours, poured into water and washed with a solution of sodium thiosulfate and brine. After drying, 400 mg were isolated as a white solid. The compounds listed in Table I can be prepared in a similar manner. Table I
No. R1 R4, R5 R6 1-1 OMe Phenyl Methyl 1-2 OH Phenyl Methyl 1-3 OH Phenyl CH2-CH2-S-CH3 1-4 OH Phenyl Ethyl 1-5 OH Phenyl Iso-Propyl 1-6 OH Phenyl Methyl 1-7 OH Phenyl CH2-CH2-S02-CH (CH3) 2 1-8 OH Phenyl CH2-CH2-S02-CH (CH3) 2 1-9 OH Phenyl CH2-CH2-S02-CH (CH3) 2 1 -10 OH Phenyl CH2-CH2-S02-CH (CH3) 2 1-11 OH Phenyl CH2-CH2-S02-CH (CH3) 2 1-12 OH Phenyl n-Propyl 1-13 OMe Phenyl n-Propyl 1-14 OH Phenyl n-Propyl 1-15 OH Phenyl n-Butyl 1-16 OH Phenyl butyl 1-17 OH Phenyl iso-Butyl 1-18 OH Phenyl Tert. -Butyl 1-19 OH Phenyl Cyclopropyl 1-20 OH Phenyl Cyclopentyl 1-21 OH Phenyl Cycloxyld 1-22 OH Phenyl (CH3) 3C-CH2-CH2
1-23 OH Phenyl (CH3) 2CH-CH2-CH2-CH2
1-24 OH Phenyl HO-CH2-CH2 1-25 OH Phenyl H02C- (CH2) 2- 1-26 OH Phenyl Cyclopropylmethyl
1-27 OH Phenyl R 1-28 OH Phenyl Methyl 1-29 OH Phenyl Phenyl 1-30 OH Phenyl Phenyl 1-31 OMe Phenyl Phenyl 1-32 OH Phenyl 4-Isopropyl phenyl
1-33 OH Phenyl 4-Me-S-Phenyl 1-34 OH Phenyl 4-Me-O-Phenyl 1-35 OH Phenyl 3-Et-Phenyl 1-36 OH Phenyl 2-Me-Phenyl 1-37 OH Phenyl 2 -Cl-Phenyl 1-38 OH Phenyl 3-Br-Phenyl 1-39 OH Phenyl 4-F-Phenyl 1-40 OH Phenyl 4-F-Phenyl 1-41 OH Phenyl 4-CH 3-Phenyl 1-42 OH Phenyl 3 -N02-Phenyl 1-43 OH Phenyl 2-HO-Phenyl 1-44 OH. Phenyl 3, 4-dimethoxyphenyl
1-45 OH Phenyl 3, 4-Methylenedioxyphenyl
1-46 OH Phenyl 3, 4, 5-trimethoxyphenyl
1-47 OH Phenyl Benzyl 1-48 OH Phenyl 2-Cl-Benzyl 1-49 OH Phenyl 3-Br-Benzyl 1-50 OH Phenyl 4-F-Benzyl 1-51 OH Phenyl 2-Me-Benzyl 1-52 OH Phenyl 2-Me-Benzyl 1-53 OH Phenyl 3-Et-Benzyl 1-54 OH Phenyl 4-iso-Propyl-Benzyl
1-55 OH Phenyl 4-N02-Propyl-Benzyl
1-56 OH Phenyl 2-Me-5-Propyl-Benzyl
1-57 OH Phenyl 2-Me-5-Propyl-Benzyl
1-58 OH Phenyl 4-Me-2-Propyl-Benzyl
1-59 OH Phenyl 3, 4-Methylenedioxybenzyl
1-60 OH 4-F-Phenyl Methyl 1-61 OMe 4-F-Phenyl Methyl 1-62 OH 4-Cl-Phenyl Methyl 1-63 OH 4-Me-O-Phenyl Methyl 1-64 OH 4-Me -O- • Phenyl Ethyl 1-65 OH 4-Me-Phenyl Methyl
1-66 OH 4-Me-Phenyl Methyl
1-67 OH 3-CF3-n-Propyl Phenyl
1-68 OH 3-CF3-n-Propyl Phenyl
1-69 OH 4-N02-Phenyl Methyl
1-70 OH 4-N02-Phenyl Methyl
1-71 OH 3-Cl-Phenyl Ethyl
1-72 OH 2-F-Phenyl Methyl
1-73 OH 2-F-Phenyl Methyl
1-74 OH 2-Me-O-Phenyl Methyl
1-75 OH 2-Me-O-Phenyl Methyl
1-76 OH 3, 4-Dimethoxyphenyl Methyl
1-77 OH 3, 4-Methylene-phenyl-Methyl phenyl 1-78 OH p-CF3-Phenyl Methyl
1-79 OH Phenyl, Methyl
1-80 OMe Phenyl Methyl
1-81 OH Phenyl Ethyl
1-82 OH p-Me-O-Phenyl n-Propyl
1-83 OH Phenyl, Methyl
1-84 OH Phenyl, Methyl
1-85 OH 3, 4-Dimethoxyphenyl Benzyl
1-86 OH 3, 4-Dimethoxyphenyl Methyl
1-87 OH Phenyl, Methyl
1-88 OH Phenyl Methyl 1-89 OH Phenyl Methyl
1-90 OH Phenyl, Methyl
1-91 OH Phenyl, Methyl
1-92 OH Phenyl, Methyl 1-93 OH Phenyl, Methyl
1-94 OH 4-F-Phenyl Methyl
1-95 OH 4-F-Phenyl H
1-96 OH Phenyl, Methyl
1-97 OH Phenyl, Methyl 1-98 OH Phenyl, Methyl
1-99 OH _ Phenyl Methyl
1-100 OH Phenyl, Methyl
1-101 OH Phenyl, Methyl
1-102 OH Phenyl, Methyl 1-103 OH Phenyl, Methyl
1-104 OH Cycloexyl Methyl
1-105 OH Cycloexyl Methyl
1-106 OH Phenyl, Methyl
1-107 OH Phenyl Methyl 1-108 OCH3 Phenyl Methyl
1-109 OH Phenyl, Methyl
1-110 OCH3 2-Fluorophenyl Methyl
1-111 OC2H5 3-Chlorophenyl Methyl
1-112 ON (CH3) 2 4-Bromophenyl Methyl 1-113 0-CH2- Phenyl Ethyl C = CH 1-114 OH Phenyl Propyl 1-115 OCH3 Phenyl I-Propyl 1- 116 OC2H5 Phenyl-butyl 1- 117 ON (CH 3) 2 2-Metiphenyl Methyl 1-118 ON (CH 3) 2 3-Methoxyphenyl Methyl 1-119 ON = C 4-Nitrophenyl Methyl (CH 3) 2 1-120 ON (CH 3) 2 Phenyl 1-Phenylpropin-3 1- 121 ON = C 2-Hydroxyphenyl Methyl (CH 3) 2 1- 122 ONS02 3-Trifluoromethyl-Methyl C6H5 phenyl 1-123 NH 4-Dimethylamino-Methyl Phenyl phenyl 1-124 OC2H5 Phenyl Trifluoromethyl 1- 125 ON Phenyl Benzyl 1-126 ON Phenyl 2-Methoxyethyl (CH3) 2 1- 127 OH Phenyl Phenyl 1-128 OH Phenyl Phenyl 1- 129 OH Phenyl Phenyl 1-130 OH Phenyl Phenyl 1-131 OH Phenyl Phenyl 1-132 OH Phenyl Phenyl 1-133 OH Phenyl Phenyl 1-134 OH Phenyl Phenyl 1-135 OH - (CH 2) 5- Phenyl 1-136 OH- Phenyl 2-Thiazolyl
1-137 OCH3 2-Fluorophenyl Phenyl 1-138 OC2H5 3-Chlorophenyl Phenyl 1-139 ON (CH3) 24-Bromophenyl Phenyl 1-140 0-CH2 = CH Phenyl 2-Fluorophenyl
1-141 OH Phenyl 3-Chlorophenyl- 1-142 OCH 3 Phenyl 4-Bromophenyl
1-143 OC2H5 Phenyl 4-thiazolyl
1-144 ON (CH3) 2: 2-Methylphenyl Phenyl 1-145 ON = C 3-Methoxyphenyl Phenyl (CH 3) 2 1-146 OH Phenyl Methyl 1-147 OH 4-Fluorophenyl Methyl 1-148 OH 4-Fluorophenyl Methyl 1 -149 NH-SO- 4-Nitrophenyl Phenyl C6H5 1-150 OCH3 3-Imidazolyl Phenyl
1-151 OC2H5 4-Imidazolyl Phenyl
1-152 ON (CH3) 2: Phenyl 2-pyrazolyl
1-153 ON = C 2 -hydroxyphenyl Phenyl (CH 3) 2 1-154 NH-S02- 3-Trifluoromethyl Phenyl C6H5 phenyl 1-155 NH Phenyl 4-Dimethylamino- Phenyl Phenyl 1-156 ONa Phenyl Phenyl 1-157 0-CH2- Phenyl Phenyl C = C 1-158 OH Phenyl Phenyl 1-159 OCH3 Phenyl Phenyl 1-160 OC2H5 Phenyl 2-Dimethylaminophenyl 1-161 ON (CH3) 2 Phenyl 3-Hydroxyphenyl 1-162 ON = C Phenyl 4-Trifluoromethylphenyl (CH3) 2 1-163 NH-S02- Phenyl 2-Oxazolyl C6H5 1-164 OH Phenyl Methyl 1- 165 OH Cycloexyl Methyl 1-166 OH Cycloexyl Methyl 1-167 OH Phenyl Methyl 1-168 OH Phenyl Methyl 1-169 OH Phenyl Methyl 1-170 OH 3-F-Phenyl Me 1-171 OH 3-F-Phenyl Me 1- 172 OH 4-F-Phenyl Me 1-173 OH 3-MeO-Phenyl Me 1-174 OH 3-MeO-Phenyl Me 1-175 OH 3-MeO. Phenyl Et 1-176 OH Phenyl HO-CH2-CH2
1-177 OH Phenyl I 1-178 OH Phenyl Phenyl
1-179 OH 1-180 NH-S02- Phenyl Me Phenyl 1-181 NH-S02 Phenyl Me -Me 1-182 CH2-So2- Phenyl Me Phenyl 1-183 CH2-S02- Phenyl Me Me 1-184 -CN Phenyl I 1-185 Tetrazo- Phenyl I Lyl 1-186 NH-S02- Phenyl Me Phenyl 1-187 N-Methyl- Phenyl Me tetrazolyl 1-188 ONa Phenyl I 1-189 OH oF-Phenyl Me 1-190 OH m-Me -Fenyl Me 1-191 OH m-Me-Phenyl, 1-192 OH, pF-Phenyl, 1-193 OH, m-F-Phenyl, 1-194 OH, p-F-Phenyl, or R2 R2, XYZ pf (C °) 1-1 OMe OMe CH 0 0 81 1-2 OMe OMe CH 0 0 167 1-3 OMe OMe CH 0 0 1-4 OMe OMe CH 0 0 81 (decomposition)
1-5 OMe OMe CH 0 0 182 1-6 OMe OMe CH 0 S 168 1-7 OMe OMe CH 0 0 1-8 OMe OMe CH S 0 1-9 OMe OMe C-CH (CH3) 2 0 0 1- 10 OMe OMe C-CH (CH3) 3 0 0 1-11 OMe NH-OCH3 CH 0 0 1-12 OMe OMe CH 0 0 174 1-13 OMe OMe CH 0 0 1-14 OEt OEt CH 0 0 1-15 OMe OMe CH 0 0 1-16 OMe OMe CH 0 0 1-17 OMe 0-CH2CH2-C 0 0 1-18 OMe OMe CH 0 0 1-19 OMe OMe CH 0 0 1-20 OMe OMe CH 0 0 1- 21 OMe OMe CH 0 0 1-22 OEt OEt CH oo 1-23 OMe OMe CH 0 0 173
1-24 OMe OMe CH 0 0 1-25 OMe OMe CH 0 0 1-26 OMe OMe CH 0 0 115
1-27 OMe OMe CH 0 0 1-28 OMe OMe CH 0 - 1-29 OMe OMe CH 0 0 136
1-30 OMe 0 - CH (CH3) -CH2-C 0 0 1-31 OMe OMe CH 0 0 1-32 OMe OMe CH 0 0 1-33 OMe OMe CH 0 0 1-34 OMe OMe CH 0 0 1 -35 OMe OMe CH 0 0 1-36 OMe OMe CH 0 0 1-37 OMe OMe CH 0 0 1-38 OMe OMe CH 0 0 1-39 OMe OMe CH 0 0 1-40 OMe OMe CH S 0 1-41 OMe OMe CH 0 0 1-42 OMe OMe CH 0 0 1-43 OMe OMe CH 0 0 1-44 OMe OMe CH 0 0 1-45 OMe OMe CH 0 0 1-46 OMe OMe CH 0 0 1-47 OMe OMe CH 0 0 1-48 OMe OMe CH 0 0 1-49 OMe OMe CH 0 0 1-50 OMe OMe CH 0 0 1-51 OMe OMe CH 0 0 1-52 OMe 0-CH = CH-C 0 0 1- 53 OMe OMe CH 0 0 1-54 OMe OMe CH 0 0 1-55 OMe OMe CH 0 0 1-56 OMe OMe CH 0 0 1-57 OEt OEt CH 0 0 1-58 OMe OMe CH 0 0 1-59 OMe OMe CH 0 0 1-60 OMe OMe CH 0 0 163-165 (decomposition)
1-61 OEt OEt CH O o 1-62 OMe OMe CH oo 1-63 OMe OMe CH oo 1-64 OMe OMe CH oo 1-65 OMe OMe CH oo 1-66 OMe 0-CH2-CH2-C oo 1- 67 OMe OMe CH oo 1-68 OMe O-CH (CH3) -CH2-C oo 1-69 OMe OMe CH oo 1-70 OMe 0-CH = CH-C oo 1-71 OMe OMe CH oo 1-72 OMe OMe CH 0 0 193-194 (decomposition)
1-73 OMe OMe CH S 0 1-74 OMe OMe CH 0 0 1-75 OMe OMe CH 0 s 1-76 OMe OMe CH 0 0 1-77 OMe OMe CH 0 or 1-78 OMe OMe CH 0 0 1- 79 OMe OEt CH 0 0 1-80 OMe OEt CH s 0 1-81 OMe NH-OMe ¡CH 0 0 1-82 OMe OCF3 CH 0 0 1-83 OMe CF3 CH 0 0 1-84 OMe CF3 N 0 0 1 -85 Me Me 0 0 1-86 OMe 0- • CH2-CH2-C 0 0 1-87 OMe 0 - CH2-CH2-C 0 0 126 (decomposition)
I - 88 OMe 0-CH (CH3) -CH2-C 0 0 I - 89 OMe N (CH3) -CH = CH-C 0 0 118 I - 90 OMe SC (CH3) = C (CH3) - C 0 0 I - 91 OMe 0-G (CH3) = CH-C 0 or I - 92 Me OC (CH3) = CH-C 0 0 I - 93 Me 0-CH = CH-C 0 0 I - 94 Me S-CH = CH-C 0 0 1-95 OMe OMe CH O 0 1-96 OMe CH2 - CH2- • CH2 - c O 0 149-151 (decomposition)
1-97 Methyl CH2 - CH2 - CH2 - c O 0 175 (decomposition)
1-98 Ethyl CH2 - CH2-CH2-CH2-CO 0 1-99 OMe CH2. CH2-CH2-CH2-CO 0 1-100 Me Me CH 0 0 1-101 Et Et CH O 0 1-102 Me Me C-CH3 O 0 1-103 OMe OMe CH O 0 1-104 OMe OMe CH O 0 1-105 OMe CH2 - CH2 - CH2 - c O or 1-106 OCH3 OCH3 CH S s 1-107 OCH3 OCH3 CH O s 134 1-108 OCH3 OCH3 CH S s 1-109 OCH3 OCH3 CH O 0 1 -110 OCH3 OCH3 CH 0 0 1-111 OCH3 OCH3 N 0 0 1-112 CF3 CF3 CH s 0 1-113 OCH3 CF3 CH 0 0 1-114 OCH3 OCF3 CH 0 s 1-115 OCH3 CH3 CH 0 0 1-116 OCH3 Cl CH s 0 1-117 OCH3 OCH3 CH 0 0 1-118 OCH3 OCH3 CH 0 0
1-119 OCH3 OCH3 CH 0 0
1-120 OCH3 OCF3 N 0 S
1-121 OCH3 CH3 N 0 0
1-122 OCH3 Cl N 0 0
1-123 OCH3 OCH3 CH s 0
1-124 CH3 CH3 CH 0 0 i-125 Cl Cl CH 0 0
1-126 OCH3 -o - CH2-CH2- S 0
1-127 OCH3 OCH3 CH 0 0
1-128 OCH3 -0 - CH2-CH2- 0 0
1-129 OCH3 OCH3 N 0 0
1-130 OCH3 OCH3 CH S 0
1-131 OCH3 OCH3 CH S s
1-132 OCH3 OCH3 CH 0 s
1-133 OCH3 OCH3 CH 0 0
1-134 OCH3 OCH3 CH 0 0
1-135 Phenyl OCH3 CH 0 0
1-136 OCH3 OCH3 CH 0 0
1-137 OCH3 OCH3 CH 0 0
1-138 OCH3 OCH3 N 0 0
1-139 CF3 CF3 CH 0 0
1-140 OCH3 CF3 CH 0 0
1-141 OCH3 OCF3 CH 0 s
1-142 OCH3 CH3 CH 0 0 1-143 OCH3 Cl CH S 0 1-144 OCH3 OCH3 CH 0 0 1-145 OCH3 OCH3 CH 0 0 1-146 OCH3 -CH2 -CH2 -CH2-C 0 or • 1-147 OCH3 OCH3 CH 0 0 168 (decomposition)
1-148 OCH3 -CH2 -CH2 -CH2-C 0 0 1-149 OCH3 OCH3 CH 0 0 1-150 OCH3 -o-CH2-CH2 0 0 1-151 OCH3 CF3 N 0 0 1-152 OCH3 OCF3 N 0 S 1-153 OCH3 CH3 N 0 0 1-154 OCH3 Cl N 0 0 1-155 OCH3 OCH3 CH S 0 1-156 OCH3 OCH3 CH S s 1-157 OCH3 OCH3 NS s 1-158 CF3 CF3 CH 0 s 1-159 OCF3 OCF3 CH 0 0 1-160 CH3 CH3 CH 0 or 1-161 Cl Cl CH 0 0 1-162 OCH3 -0-CH2-CH2 S 0 1-163 OCH3 CF3 NS s 1-164 CH3 CH3 CH 0 0 1- 165 OCH3 OCH3 CH 0 0 1-166 OCH3 CH2-CH2-CH-C 0 or 1-167 N (CH3) 2N (CH3) 2 CHOO 1-168 OCH3 OCH3 CH O S02 1-169 OCH3 OCH3 CH O S02 1 -170 OMe OMe CH OO 1-171 OMe CH2-CH2-CH2-COO 1-172 OMe CH2-CH2-CH2-COO 142-143 191 ° C 1-173 OMe CH2-CH2-CH2-COO 158-161 (decomposition )
1-174 OMe OMe CH OO 1-175 OMe CH2 - CH2 - CH2 - COO 1-176 OMe CH2 - CH2 - CH2 - cOO 1-177 NMe2 NMe2 NOO 181 1-178 OMe OMe NO 0 1-179 1-180 OMe OMe CH O 0 1-181 OMe OMe CH O 0 1-182 OMe OMe CH O 0 1-183 OMe OMe CH O 0 1-184 OMe OMe CH O 0 1-185 OMe OMe CH O 0 1-186 OMe OMe CH O 0 167 1-187 OMe OMe CH O 0 1-188 OMe -O - CH2 - CH2 - c - O 0 122-139 (decomposition) 1-189 OMe -0-CH2 -CH2-C- 0 0 140-144 (dec.)
1-190 OMe OMe CH 0 0 169-177 1-191 OMe -0-CH2-CH2-C-0 0 119-135 (dec.)
1-192 OMe OMe CH 0 0 137-140 (dec.)
1-193 Me -0-CH2-CH2-C- 0 0 150-152 1-194 Me -0-CH2-CH2-C- 0 0 169-170 Table II
No. R1 A R6 R2 II-l OH Link Methyl OMe II-2 OH CH2 Methyl OMe II-3 OH CH2-CH2 Methyl OMe II-4 OH CH = CH Methyl OMe II-5 OH 0 Methyl OMe II-6 OH S Methyl OMe II-7 OH GH (CH3) Methyl OMe II-8 OH Link Isopropyl OMe II-9 OH Link p-Isopropylphenyl OMe 11-10 OH Link Benzyl OMe 11-11 OH CH = CH Ethyl OMe 11-12 OH CH = CH (CH3) 2-CH2-CH2 OMe 11-13 OH CH = CH Cycloprojylmethyl OMe
11-14 OH CH = CH Methyl OMe
11-15 OH CH2 -CH2 Ethyl OMe
11-16 OH CH2 = CH2 Methyl OMe
11-17 OH Link Methyl OMe
No. R3 X Y Z p.f. (° C)
II-l OMe CH 0 0 96-98
II-2 OMe CH 0 0 II-3 OMe CH 0 0 II-4 OMe CH 0 0 II-5 OMe CH 0 0 II-6 OMe CH 0 or II-7 OMe CH 0 0 II-8 OMe CH 0 0 137 -139 V
II-9 OMe CH 0 0 11-10 OMe CH 0 0 11-11 OMe CH 0 0 11-12 OMe CH 0 0 11-13 OMe CH 0 0 11-14 OMe 0-CH2-CH2-C 0 0 11- 15 OMe O- 'CH = CH-C 0 0 11-16 OMe CH2 ~ CH2 - CH2 -C 0 0 11-17 OMe CH2 -CH2 - CH2 -C 0 0 147
Table IV O- CH3 R6-O-- R1 R4 R5 R6 OH Phenyl Methyl Methyl OH Phenyl Methyl OCH3 Phenyl Methyl Methyl OH Phenyl I-Propyl Methyl OCH3 2-Fluorophenyl Ethyl Methyl OC2H5 3-Chlorophenyl Propyl Methyl ON (CH3) 2 4 -Bromophenyl i-Propyl Methyl ON = C (CH3) 2 2-Thienyl Methyl Methyl HNS02C6H5 3-Thienyl Methyl Methyl NHPhenyl 2-Furyl Methyl Methyl ONa 3-Furyl Methyl Methyl 0-CH2-C = CH Phenyl Ethyl Ethyl OH Phenyl Propyl Propyl OCH3 Phenyl I-Propyl i-Propyl OC2H5 Phenyl Methyl s-Butyl ON (CH3) 2 2-Methylphenyl Methyl Methyl ON (CH3) 2 3-Methoxyphenyl Methyl Methyl ON = C (CH3) 2 4-Nitrophenyl Methyl Methyl NH-Phenyl 2-Oxazolyl Methyl Methyl ONa 4-Oxazolyl Methyl 3-Propinyl (sic)
0-CH2-G = CH 5-Oxazolyl Methyl 3-Propinyl (sic)
OH 3-Isoxazolyl Methyl Cyclopentyl 0CH3 4-Isoxazolyl Methyl Cycloexyl 0C2H5 5-Isoxazolyl Methyl Cyclopropylmethyl
ON (CH3) 2 Phenyl Methyl l-Phenyl-3-propynyl (sic) ON = C (CH 3) 2 2-Hydroxyphenyl Methyl Methyl ONS02C6H5 3-Trifluoromethyl-Methyl Methyl phenyl NH Phenyl 4-Dimethylaminophenyl Methyl Methyl ONa 2-Imidazolyl Ethyl Methyl 0 -CH2-C = CH 4-Imidazolyl Propyl Methyl OH 3-Pyrazolyl i-Propyl Methyl 0 CH 3 4-Pyrazolyl Methyl Methyl 0 C 2 H 5 Phenyl Methyl Trifluoroethyl
ON (CH3) 2 Phenyl Methyl Benzyl ON (CH3) 2 Phenyl Methyl 2-Methoxyethyl
ON = C (CH3) 2 Phenylpropyl Methyl 3-Methoxycarbonyl (sic) NH-Phenyl or 2-Pyridyl Methyl 2-Chloroethyl
ONa 3-Pyridyl Methyl Methyl 0-CH2 - C = CH 4-Pyridyl Methyl OCH 3 Phenyl CH 3 Phenyl Phenyl CH 3 Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl Phenyl OH Phenyl I-Propyl Phenyl OH CH 3 CH 3 Phenyl OH- (CH 2) 5- Phenyl OH Phenyl CH 3 2-Thiazolyl
OH 2-Thienyl CH3 Phenyl OCH3 2-Fluorophenyl Ethyl Phenyl OC2H5 3-Chlorophenyl Propyl Phenyl O (CH3) 2 4-Bromophenyl i-Propyl Phenyl ON = C (CH3) 2 2-Thienyl Methyl Phenyl NH-S02-C6H5 3-Thienyl Methyl Phenyl NHFenyl 2-Furyl Methyl Phenyl ABa 3-Furyl Methyl Phenyl 0-CH2 = CH Phenyl Ethyl 2-Fluorophenyl
OH Phenyl Propyl 3-Chlorophenyl
OCH3 Phenyl I-Propyl 4-Bromophenyl
OC2H5 Phenyl 4-thiazolyl methyl
ON (CH3) 2 2-Methylphenyl Methyl Phenyl ON = C (CH3) 2 3-Methoxyphenyl Methyl Phenyl NH-SO-C6H5 4-Nitrophenyl Methyl Phenyl NHPhenyl Methyl Methyl Phenyl O N Methyl Methyl 2-Methylphenyl
0-CH2-C = CH Methyl Methyl 3-Methoxyphenyl OH Methyl Methyl 4-Nitrophenyl
OCH3 3-Imidazolyl Methyl Phenyl
OC2H5 Phenyl 4-Imidazolyl Methyl
ON (CH3) 2 Phenyl Methyl 2-Pyrazolyl
ON = C (CH3) 2 2-Hydroxyphenyl Methyl Phenyl NH-S02-C6H5 3-Trifluromethylphenyl Methyl Phenyl NHPhenyl 4-Dimethylaminophenyl Methyl Phenyl ABa 3-Imidazolyl Ethyl Phenyl 0-CH2-C = CH 4-Imidazolyl Propyl Phenyl OH 3-Pyrazolyl i-Propyl Phenyl OCH3 4-Pyrazolyl Methyl Phenyl OC2H5 Phenyl Methyl 2-Dimethylaminophenyl ON (CH3) 2 Phenyl Methyl 3-Hydroxyphenyl
ON = C (CH3) 2 Phenyl Methyl 4-Trifluoromethyl Phenyl NH-S02-C6H5 Phenyl Methyl 2-Oxazolyl
NH-Phenyl 2-Pyridyl Methyl 4-Isoxazolyl
ONa 3-Pyridyl Methyl Phenyl 0-CH2-C = CH 4-Pyridyl Methyl Phenyl R2 R3 X Y Z OCH 3 OCH 3 CH S S OCH 3 OCH 3 CH 0 S OCH 3 OCH 3 CH S S OCH 3 OCH 3 CH 0 0 OCH 3 OCH 3 CH 0 0
OCH3 OCH3 N 0 0
CF3 CF3 CH S 0
OCF3 OCF3 CH 0 s
CH3 CH3 CH 0 0
Cl Cl CH 0 0
OCH3 -OCH2-CH2- S 0
OCH3 CF3 CH 0 0
OCH3 OCF3 CH 0 s
OCH3 CH3 CH 0 0
OCH3 Cl CH S 0
OCH3 OCH3 CH 0 0
OCH3 OCH3 CH 0 0
OCH3 OCH3 CH 0 0
CF3 CF3 N S 0
OCF3 OCF3 N 0 s
CH3 CH3 N 0 0
Cl Cl N 0 0
OCH3 -0-CH2-CH2- O or
OCH3 CF3 N S 0
OCH3 OCF3 N 0 s
OCH3 CH3 N 0 0
OCH3 Cl N 0 0
OCH3 OCH3 CH s 0
OCH3 OCH3 CH s s OCH3 0CH3 N S s
CF3 CF3 CH 0 s
OCF3 0CF3 CH 0 0
CH3 CH3 CH 0 0
Cl Cl CH 0 0
OCH3 -o - CH2-CH2- S 0
OCH3 CF3 N S s
OCH3 0CF3 N S s
OCH3 CH3 N 0 0
OCH3 Cl N 0 0
OCH3 0CH3 CH 0 0
OCH3 0CH3 CH 0 0
OCH3 -0 - CH2-CH2- 0 0
OCH3 0CH3 N 0 0
OCH3 0CH3 CH S 0
OCH3 0CH3 CH S s
OCH3 0CH3 CH 0 s
OCH3 0CH3 CH 0 0
OCH3 0CH3 CH 0 0
OCH3 0CH3 CH 0 0
Phenyl 0CH3 CH 0 0
0CH3 0CH3 CH 0 0
OCH3 0CH3 CH 0 0
OCH3 0CH3 CH 0 0
0CH3 0CH3 N 0 0 CF3 CF3 CH S 0
OCF3 OCF3 CH 0 s
CH3 CH3 CH 0 0
Cl Cl CH 0 0
OCH3 -0 -CH2-CH2- S 0
OCH3 CF3 CH 0 0
OCH3 OCF3 CH 0 s
OCH3 CH3 CH 0 0
OCH3 Cl CH S 0
OCH3 OCH3 CH 0 0
OCH3 OCH3 CH 0 0
OCH3 OCH3 CH 0 0
CF3 CF3 N S 0
OCF3 OCF3 N 0 s
CH3 CH3 N 0 0
Cl Cl N 0 0
OCH3 -0-CH2-CH2- 0 0
OCH3 CF3 N S 0
OCH3 OCF3 N 0 s
OCH3 CH3 N 0 0
OCH3 Cl N 0 0
OCH3 OCH3 CH S 0
OCH3 OCH3 CH S s
OCH3 OCH3 N S s
CF3 CF3 CH 0 s OCF3 OCF3 CH 0 0 CH3 CH3 CH 0 0 Cl Cl CH 0 0 OCH3 -0-CH2-CH2- s 0 OCH3 CF3 NSS OCH3 OCF3 NSS OCH3 CH3 N 0 0 OCH3 Cl N 0 0 Synthesis of compounds of Formula VI Example 26 Methyl 3-ethoxy-3- (3-methoxyphenyl) -2-hydroxybutyrate 19.5 g (88 mmoles) of methyl 3- (3-methoxyphenyl) -2,3-epoxybutyrate were dissolved in 200 ml of absolute methanol, and 0.1 ml of boron trifluoride etherate was added. The mixture is stirred at room temperature for 12 hours and the solvent is removed by distillation. The residue is taken up in ethyl acetate, washed with a solution of sodium bicarbonate and water and dried over sodium sulfate. After removal of the solvent by distillation, 21.1 g grams of a pale yellow product remain. Yield: 94% (1: 1 mixture of diastereomers) Example 27 Methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate 9.6 g (50 mmoles) of methyl 3-phenyl-2,3-epoxybutyrate are dissolved in 150 ml of benzyl alcohol, and 0.5 ml of concentrated sulfuric acid is added. The mixture is stirred at a temperature of 50 ° C for 6 hours and allowed to cool to room temperature. After neutralization with a solution of sodium bicarbonate. Excess benzyl alcohol is removed by distillation under vacuum, and the residue is purified by flash chromatography on silica gel with 9: 1 n-hexane / ethyl acetate. After removal of the solvent by distillation, 6.9 g of a colorless oil remain. Yield: 43% (3: 2 mixture of diastereomers). All the compounds mentioned in Table V were prepared in a similar manner. Table V: intermediate products of the formula VI with R1 = OCH3
R4 R6-O C- CH --- OH Rs COOCH3
No. Rb R4 R5 DR * p.f. (° C)
1. 1 Methyl 3-Methoxyphenyl Methyl 1: 1 oil
1. 2 Benzyl Phenyl Methyl 3: 2 oil
1. 3 Methyl 2-Fluorophenyl Methyl 1: 1 oil
1. 4 Methyl 4-i-Propylphenyl Methyl 1.5 Methyl 2-Methylphenyl Methyl 2: 1 oil
1. 6 Methyl 3-Methylphenyl Methyl 1.7 Methyl 4-Methylphenyl Methyl 3 :: 2 oil
1. 8 Methyl 3-Nitrophenyl Methyl 1.9 Methyl 4-Bromophenyl Methyl 3:: 1 oil
1. 10 Methyl 2-Furyl Methyl 1.11 Methyl 3-Furyl Methyl 1.12 Methyl 2-Thienyl Methyl 1.13 Methyl 3-Thienyl Methyl 1.14 Methyl 2-Pyridyl Methyl 1.15 Methyl 3-Pyridyl Methyl 1.16 Methyl 4-Pyridyl Methyl 1.17 Methyl 2-thiazolyl Methyl 1.18 Methyl 3-Isoxazolyl Methyl 1.19 Methyl 4-Imidazolyl Methyl 1.20 Methyl 2-Pyrazolyl Methyl 1.21 Methyl 4-Chlorophenyl Methyl 2:: 1 oil
1. 22 Benzyl 3-Methylphenyl Methyl 1:: 1 oil
1. 23 Methyl 4-Fluorophenyl Methyl 1: 1 oil
1. 24 Benzyl 4-Bromophenyl Methyl 1:: 1 oil
1. 25 Benzyl 4-Chlorophenyl Methyl 3:: 2 oil
1. 26 Benzyl 4-Fluorophenyl Methyl 1:: 1 oil
1. 27 Methyl Phenyl Ethyl 1:: 1 oil
1. 28 Methyl 3-Nitrophenyl Methyl 2:: 1 oil
1. 29 Ethyl 4-Methylphenyl Methyl 1:: 1 oil
1. 30 Benzyl 4-Methylphenyl Methyl 1:: 1 oil
1. Benzyl Phenyl Ethyl 1:: 0 oil oil * ratio of diastereomers Synthesis of compound of the general formula I: Example 28 Methyl 3-benzyloxy-3-phenyl-2- (4,6-dimethoxy-2-pyrimidinyl) oxybutyrate 3 g (10 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (compound 1.1) were dissolved in 40 ml of dimethylformamide, and 0.3 (12 mmol) of sodium hydride was added. The mixture is stirred for 1 hour and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. The mixture is stirred at temperature for 24 hours and then carefully hydrolysed with 10 ml of water, the pH is adjusted to 5 with acetic acid, and the solvent is removed by distillation under high vacuum. The residue is taken up in 100 ml of ethyl acetate, washed with water, dried in sodium sulphate and distilled to remove solvents. 10 moles of methyl t-butyl ether are added to the residue, and the precipitate is removed by suction filtration. The drying results in obtaining 2.4 g of a white powder. Yield: 55% (1: 1 diastereomer mixture) Melting point: 115-117 ° C Example 29 3-Benzyloxy-3-phenyl-2- (4,6-dimethoxy-2-pyrimidinyl) -oxibutyric acid Dissolve 1.4 g (3 mmol) of methyl 3-benzyloxy-3-phenyl-2- (4,6-dimethoxy-2-pyridinyl) oxybutyrate of Example 3 (now 37) in 20 ml of methanol and 20 ml of tetrahydrofuran, and add 3.7g of a 10% NaOH solution. The mixture is stirred at a temperature of 60 ° C for 6 hours and at room temperature for 12 hours. The solvent is removed by distillation under reduced pressure, and the residue is taken up in 100 ml of water. The mixture is extracted with ethyl acetate to remove unreacted ester. The aqueous phase is then adjusted to a pH of 1-2 with dilute hydrochloric acid and said aqueous phase is extracted with ethyl acetate. After drying in magnesium sulfate and after removal of the solvent by distillation, a small amount of acetone is added to the residue, and the precipitate is removed by filtration with suction. Drying results in obtaining 1.2g of a white powder. Yield: 88% (3: 2 diastereomer mixture) Melting point: 165 ° C (decomposition) Example 30 3-benzyloxy-3-phenyl-2- ((4,6-dimethoxy-2-pyrimidinyl) thio) butyrate methyl IIg (25 mmol) of methyl 3-benzyloxy-3-phenyl-2-hydroxybutyrate (compound 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, are added drop by drop 3.2 g (28 mol) of methanesulfonyl chloride. The mixture is stirred at room temperature, 6-dimethoxypyrimidin-2-thiol and 8.4g (100 mmol) of sodium bicarbonate in 100 moles of DMF at a temperature of 0 ° C. After stirring at room temperature for 2 hours and at 70 ° C for two additional hours, the mixture is drained in one liter of ice water and the precipitate is removed by suction filtration. Drying results in obtaining 3.2g of a white powder. Yield: 29% (1: 1 diastereomer mixture) The compounds specified in Table VI were prepared in a manner similar to the previous examples. Table VI
DO NOT . Rb R4 Ra Y 2.1 Benzyl Phenyl Methyl O 2.2 Benzyl Phenyl Methyl 0
2. 3 Benzyl Phenyl Methyl S
2. 4 Benzyl Phenyl Methyl S
2. 5 Methyl 2-Fluorophenyl Methyl 0
2. 6 Methyl 2-Fluorophenyl Methyl 0
2. 7 Methyl 3-Methoxyphenyl Methyl 0
2. 8 Methyl 3-Methoxyphenyl Methyl 0
2. 9 Methyl 4-i-Propylphenyl Methyl 0
2. 10 Methyl 4-i-Propylphenyl Methyl 0
2. 11 Methyl 2-Methylphenyl Methyl 0
2. 12 Methyl 2-Methylphenyl Methyl O
2. 13 Methyl 3-Methylphenyl Methyl 0
2. 14 Methyl 3-Methylphenyl Methyl 0
2.
2. 26 ONa 175-176
2. 27 OCH3 2.28 OH 2.29 OCH3 2.30 OH 2.31 OCH3 2.32 OH 2.33 OCH3 2.34 OH 2.35 OCH3 2.36 OH 2.37 OCH3 2.38 OH 2.39 OCH3 2.40 OH 2.41 OCH3 1: 1 112-114
2. 42 OH 2.43 OCH3 4: 1 115-120
2. 44 OH 2: 1 143-145
2. 45 OCH3 1: 1 122-125
2. 46 OH 3: 1 170-172 2.47 OCH3 1: 1 94-95
2. 48 OH 1: 1 154-156
2. 49 OCH3 1: 1 125-127
2. 50 OH 5: 1 206-207
2. 51 OCH3 1: 0 95-100
2. 52 OH 1: 0 140-142
2. 53 OCH3 1: 1 95-98
2. 54 OH 4: 1 153-154
2. 55 OCH3 1: 0 152-153
2. 56 OH 7: 3 160-162
2. 57 OCH3 9: 1 158-160
2. 58 OH 1: 0 203-204
2. 59 OCH3 1: 0 129-130
2. 60 OH 1: 0 200-201
2. 61 OCH3 1: 1 78- 79
2. 62 OH 1: 1 156-158
2. 63 OCH3 1: 1 oil
2., the pH is adjusted to 5 with acetic acid, and the solvent is removed by distillation under high vacuum. The residue is taken up in 100 moles of ethyl acetate, washed with water, dried in sodium sulfate and distilled to remove the solvents. 10 ml of methyl t-butyl ether are added to the residue, and the precipitate is removed by suction filtration. Drying results in 1.6g of a white powder. Yield: 24.5% MP: 143-145 ° C Example 34 3-Phenoxy-3-phenyl-2- (4,6-dimethoxy-2-pyrimidinyl) -oxibutyric acid 1.3 g of 3-phenoxy-3-phenyl- are dissolved Methyl 2- (4,6-dimethoxy-2-pyrimidinyl) oxybutyrate (Example 6, changed to 42) in 20 ml of MeOH and 40 ml of THF, and 3.7 g of a 10% NaOH solution are added. The mixture is stirred at a temperature of 60 ° C for 6 hours and at room temperature for 12 hours, the solvent is removed by distillation under reduced pressure, and the residue is taken up in 100 ml of water. The unreacted ester is extracted with ethyl acetate. The aqueous phase is then adjusted to a pH of 1-2 with dilute hydrochloric acid and extracted with ethyl acetate. Drying in magnesium sulfate and removal of the solvent by distillation results in 1.0 g of a white powder.
Yield: 79.7% P.F. : 50-55 ° C Example 35 3-Phenoxy-3-phenyl-2- ((4,6-dimethoxy-2-pyrimidinyl) thio) Methyl butyrate 7.2 g (25 mmol) of 3-phenoxy-3 are dissolved methyl phenyl-2-hydroxybutyrate (compound 1.1) in 50 ml of dichloromethane, add 3 g (30 mmole of triethylamine and, while stirring, 3.2 g (28 mmoles) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure.The residue is taken up in 100 moles of DMF, and added dropwise to a suspension of 12.9 g (75 mmol). of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium bicarbonate in 100 ml of DMF at a temperature of 0 ° C. After stirring at room temperature for 2 hours and at 70 ° C. for 2 hours The mixture is then emptied into one liter of ice water, and the precipitate is removed by suction filtration.Drying results in 4.2 g of a white powder. o Yield: 38% The compounds specified in Table VIII were prepared in a manner similar to the previous examples. Table VIII No. Ex. R6 R4 R5 R1
4. 1 Phenyl Phenyl Methyl OCH3
4. 2 Phenyl Phenyl Methyl OH
4. 3 Phenyl Phenyl Methyl OCH3
4. 4 Phenyl Phenyl Methyl OH
4. 5 Phenyl Phenyl i-Propyl OCH3
4. 6 Phenyl Phenyl i-Propyl OH
4. 7 Phenyl Methyl Methyl OCH3
4. 8 Phenyl Methyl Methyl OH
4. 9 4-Bromophenyl Phenyl Methyl OCH3
4. 10 4-Bromophenyl Phenyl Methyl OH
4. 11 2-Fluorophenyl Phenyl Methyl OCH3
4. 12 2-Fluorophenyl Phenyl Methyl OH
4. 13 3-Fluorophenyl Phenyl Methyl OCH3
4. 14 3-Fluorc enyl Phenyl Methyl OH
4. 15 4-Fluorophenyl Phenyl Methyl OCH3
4. 16 4-Fluorophenyl Phenyl Methyl OH
4. 17 4-Chlorophenyl Phenyl Methyl OCH3
4.
4. 31 0 4.32 0 4.33 0 4.34 0 4.35 0 4.36 0 4.37 0 4.38 0 4.39 0 155
4. 40 0 100-101
4. 41 0 130-131
4. 42 0 230
4. 43 0 143-144
4. 44 0 90-92 4.45 0 179-180 4.46 0 4.47 0 95-114 4.48 0 80-85 4.49 0 110-112 4.50 0 156-157 4.51 0 oil 4.52 0 158-160 4.53 0 157-158 4.54 0 106-107 4.55 0 _ 160-165 4.56 0 99-100 4.57 0 160-163 4.58 0 248-250 4.59 0 106-110 4.60 0 250 4.61 0 115-117 4.62 0 84-85 4.63 0 157-159 4.64 0 80-90 Example 36 The receptor binding data were measured by the binding assay described above for the compounds presented below. The results appear in Table III.
Table III Receptor binding data (K-values) Compound ETA [nM] ETB [nM] 1-2 6 34 1-29 86 180 1-5 12 160 1-4 7 2500 1-87 1 57 1-89 86 9300 1-103 0.4 29 1-107 3 485 1-12 19 1700 1-26 23 2000 1-23 209 1100 1-47 150 1500 1-60 33 970 1-96 0.6 56
II-3 107 7300 II-1 28 2300 Equivalents Those skilled in the art will recognize, or may determine using only routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are encompassed by the following claims.
15 20 25
Claims (12)
- CLAIMS A method for the treatment of cancer in a human being that requires treatment, comprising the administration to the human being of a compound of the formula la in sufficient quantity to inhibit the growth of a solid tumor in which endothelin is regulated from ascending way, where the formula is: where R is formyl, tetrazolyl, cyano, a COOH group or a radical which may be hydrolyzed in COOH, and the other substituent has the following meanings: R2 is hydrogen, hydroxyl, NH2, NH (C1-C4 alkyl), N ( C? -C) 2alkyl / halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, or C 1 -C 4 alkylthio; X is nitrogen or CR14 where R14 is hydrogen or C1-C5 alkyl, or CR14 together with CR3 forms a 5-membered or 6-membered alkylene or alkenylene ring which may be substituted by one or two C1-C4 alkyl groups and in which, in each case, a methylene group can be replaced by oxygen, sulfur, NH ion or N-C alquilo-C4 alkyl ion; R 3 is hydrogen, hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 haloalkoxy C 4, -NH-O-C 1 -C 4 alkyl, Cth-C 4 alkylthio or CR 3 is linked to CR 14 in accordance with that indicated above to provide a 5- or 6-membered ring; R 4 and R 5 (which may be identical or different): phenyl or naphthyl, which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, alkoxy C 1 -C 4, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, or C 1 -C 4 dialkylamino; or phenyl or naphthyl, which are joined together in the ortho positions through a direct bond, a methylene group, ethylene or ethenylene, an oxygen or sulfur atom or a group S02-, NH- or N-alkyl , or C3-C7 cycloalkyl; or R6 is hydrogen, Ci-Cs alkyl, C3-C6 alkenyl, C3-C6 alkynyl, or C3-C8 cycloalkyl, where each of these radicals can be substituted once or several times by: halogen, nitro, cyano, alkoxy C 1 -C 4, C 3 -C 6 alkenyloxy, C 3 -C 8 alkynyloxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, C 3 -C 8 alkylcarbonylalkyl, C 1 -C 4 alkylamino, dialkylamino C 1 - C4, phenyl, or phenyl or phenoxy which is substituted one or more times, for example one to three times, by halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C1-C4 or C1-C4 alkylthio; phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C1-C4 , phenoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, methylenedioxy or ethylenedioxy; a five-membered or six-membered heteroaromatic portion containing one to three nitrogen atoms and / or one sulfur atom or one oxygen atom, which may carry from one to four halogen atoms and / or one or two of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals themselves to carry from one to five halogen atoms and / or from one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and / or C 1 -C 4 alkylthio; provided that Rd can be hydrogen only when Z is not a single bond; And it is sulfur or oxygen or a simple bond; Z is sulfur or oxygen or a simple bond.
- 2. The method of claim 1 wherein for the compound of the formula R is a group COOH, R2 is -OMe, R3 is -OMe, R4 is phenyl, Re is phenyl, R5 is methyl, X is CR14, R14 is H, Y is oxygen, and Z is oxygen.
- 3. The method of claim 1 wherein for the compound of the formula R is a COOH group, R2 is methyl, R3 is methyl, R4 is phenyl, R5 is phenyl, R6 is methyl, X is CR14, R14 is H, Y is oxygen, and Z is oxygen.
- 4. The method of claim 1 wherein in the case of the compound of the formula R is a COOH group, R2 is methyl, R3 is methyl, R4 is phenyl, R5 is phenyl, Rd is methyl, X is CR14, R14 is H, Y is oxygen, and Z is a simple bond.
- 5. The method of claim 1 wherein the cancer is prostate cancer.
- 6. The method of claim 2 wherein the cancer is cancer of the prostate.
- The method of claim 3 wherein the cancer is cancer of the prostate.
- 8. The method of claim 4 wherein the cancer is cancer of the prostate.
- 9. The use of a compound of the formula according to any one of claims 1 to 4 for administration to a human being for the purpose of inhibiting the growth of a solid tumor wherein endothelin is regulated in a manner upward.
- 10. A process for the manufacture of a drug for inhibiting the growth in a human of a solid tumor wherein the endothelin is up-regulated, the process is characterized by the use, as an essential constituent of said drug, of a compound of the formula according to the one defined in any of claims 1 to The use according to claim 9, or a method according to claim 10, wherein the solid tumor is selected from tumors of the prostate, lung, liver, breast, brain, stomach, colon, endometrium, testis, thyroid. , pituitary gland, bladder, kidney, pancreas and meninges. The use or method according to claim 11, wherein said solid tumor is cancer of the prostate.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US08818622 | 1997-03-14 |
Publications (1)
Publication Number | Publication Date |
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MXPA99008224A true MXPA99008224A (en) | 2000-02-02 |
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