HRP970503A2 - Novel carboxylic acid derivatives, their production and their use as mixed eta/etb receptor antagonists - Google Patents
Novel carboxylic acid derivatives, their production and their use as mixed eta/etb receptor antagonistsInfo
- Publication number
- HRP970503A2 HRP970503A2 HRP970503A HRP970503A2 HR P970503 A2 HRP970503 A2 HR P970503A2 HR P970503 A HRP970503 A HR P970503A HR P970503 A2 HRP970503 A2 HR P970503A2
- Authority
- HR
- Croatia
- Prior art keywords
- alkyl
- phenyl
- image
- substituted
- optionally substituted
- Prior art date
Links
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title claims description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 239000002464 receptor antagonist Substances 0.000 title claims 3
- 229940044551 receptor antagonist Drugs 0.000 title claims 3
- -1 alkali metal cation Chemical class 0.000 claims description 95
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 34
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000001624 naphthyl group Chemical group 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 239000011593 sulfur Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 11
- 102000002045 Endothelin Human genes 0.000 claims description 11
- 108050009340 Endothelin Proteins 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 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 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 5
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 230000036454 renin-angiotensin system Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000006850 spacer group Chemical group 0.000 claims description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
- 208000033626 Renal failure acute Diseases 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 201000011040 acute kidney failure Diseases 0.000 claims description 2
- 208000012998 acute renal failure Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 229940097320 beta blocking agent Drugs 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 4
- 102000003729 Neprilysin Human genes 0.000 claims 1
- 108090000028 Neprilysin Proteins 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 239000002792 enkephalinase inhibitor Substances 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 67
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 238000002844 melting Methods 0.000 description 40
- 230000008018 melting Effects 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- 238000000354 decomposition reaction Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 150000001735 carboxylic acids Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 5
- 102100033902 Endothelin-1 Human genes 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101800004490 Endothelin-1 Proteins 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- SRQAJMUHZROVHW-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)ethanol Chemical compound COC1=CC=C(CCO)C=C1OC SRQAJMUHZROVHW-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100040611 Endothelin receptor type B Human genes 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000001647 Renal Insufficiency Diseases 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 201000006370 kidney failure Diseases 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- RQJWOLFMWKZKCJ-CQSZACIVSA-N (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C([C@H](O)C(O)=O)(OC)C1=CC=CC=C1 RQJWOLFMWKZKCJ-CQSZACIVSA-N 0.000 description 2
- CLSJNXXMIVKULC-MUUNZHRXSA-N (2s)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-diphenylpropanoic acid Chemical compound C1=C(OC)C(OC)=CC=C1CCOC(C=1C=CC=CC=1)(C=1C=CC=CC=1)[C@@H](C(O)=O)OC1=NC(C)=CC(C)=N1 CLSJNXXMIVKULC-MUUNZHRXSA-N 0.000 description 2
- WHYZSISPOATNIY-HSZRJFAPSA-N (2s)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2-hydroxy-3,3-diphenylpropanoic acid Chemical compound C1=C(OC)C(OC)=CC=C1CCOC([C@H](O)C(O)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 WHYZSISPOATNIY-HSZRJFAPSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- VQUBCMKIGJZUME-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-bis(4-ethylphenyl)-3-[2-(4-methoxyphenyl)ethoxy]propanoic acid Chemical compound C1=CC(CC)=CC=C1C(C=1C=CC(CC)=CC=1)(C(OC=1N=C(C)C=C(C)N=1)C(O)=O)OCCC1=CC=C(OC)C=C1 VQUBCMKIGJZUME-UHFFFAOYSA-N 0.000 description 2
- QWDHLTWAAVZDIR-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-diphenyl-3-(2-phenylethoxy)propanoic acid Chemical compound CC1=CC(C)=NC(OC(C(O)=O)C(OCCC=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 QWDHLTWAAVZDIR-UHFFFAOYSA-N 0.000 description 2
- GNAQHSYROFORPJ-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-diphenyl-3-(3-phenylpropoxy)propanoic acid Chemical compound CC1=CC(C)=NC(OC(C(O)=O)C(OCCCC=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 GNAQHSYROFORPJ-UHFFFAOYSA-N 0.000 description 2
- INWOLNPQZCZDPJ-NTCAYCPXSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-diphenyl-3-[(E)-3-phenylprop-2-enoxy]propanoic acid Chemical compound CC1=CC(C)=NC(OC(C(O)=O)C(OC\C=C\C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 INWOLNPQZCZDPJ-NTCAYCPXSA-N 0.000 description 2
- SCDCKGHMQGDTNG-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-diphenyl-3-[2-(4-propylphenyl)ethoxy]propanoic acid Chemical compound C1=CC(CCC)=CC=C1CCOC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C(O)=O)OC1=NC(C)=CC(C)=N1 SCDCKGHMQGDTNG-UHFFFAOYSA-N 0.000 description 2
- LXBZYTQZRVITIB-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3,3-diphenyl-3-[3-(3,4,5-trimethoxyphenyl)propoxy]propanoic acid Chemical compound COC1=C(OC)C(OC)=CC(CCCOC(C(OC=2N=C(C)C=C(C)N=2)C(O)=O)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 LXBZYTQZRVITIB-UHFFFAOYSA-N 0.000 description 2
- WUNUEBZYLIUGHH-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3-[2-(4-ethoxy-3-methoxyphenyl)ethoxy]-3,3-diphenylpropanoic acid Chemical compound C1=C(OC)C(OCC)=CC=C1CCOC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C(O)=O)OC1=NC(C)=CC(C)=N1 WUNUEBZYLIUGHH-UHFFFAOYSA-N 0.000 description 2
- SPSAWQZZHBTXMJ-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3-[2-(4-ethoxyphenyl)ethoxy]-3,3-diphenylpropanoic acid Chemical compound C1=CC(OCC)=CC=C1CCOC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C(O)=O)OC1=NC(C)=CC(C)=N1 SPSAWQZZHBTXMJ-UHFFFAOYSA-N 0.000 description 2
- NPLNAUBFRRXHRY-UHFFFAOYSA-N 2-(4,6-dimethylpyrimidin-2-yl)oxy-3-[2-(4-methoxyphenyl)ethoxy]-3,3-diphenylpropanoic acid Chemical compound C1=CC(OC)=CC=C1CCOC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C(O)=O)OC1=NC(C)=CC(C)=N1 NPLNAUBFRRXHRY-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Predloženi izum odnosi se na nove derivate karbonske kiseline, njihovu proizvodnju i upotrebu. The proposed invention relates to new carboxylic acid derivatives, their production and use.
Endotelin je peptid izgrađen od 21 amino kiseline, kojeg sintetizira i oslobađa vaskularni endotel. Endotelin postoji u tri izomerna oblika, ET-1, ET-2 i ET-3. U nastavku se jedan ili svi izomerni oblici endotelina označavaju kao "endotelin" ili "ET". Endotelin je jaki vazokonstriktor i snažno djeluje na tonus krvnih žila. Poznato je, da tu vazokonstrikciju uzrokuje vezanje endotelina na njegov receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 i Biochem. Biophys. Res. Commun., 154, 868-875, 1988). Endothelin is a peptide made of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin exists in three isomeric forms, ET-1, ET-2 and ET-3. Hereinafter, one or all of the isomeric forms of endothelin are referred to as "endothelin" or "ET". Endothelin is a strong vasoconstrictor and has a strong effect on blood vessel tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988 ).
Povišeno ili nenormalno oslobađanje endotelina uzrokuje trajnu kontrakciju žila u perifernim, renalnim i cerebralnim krvnim žilama, koja može dovesti do bolesti. Kako je poznato iz literature, endotelin je uključen u niz bolesti. Tu spadajaju hipertonija, akutni infarkt miokarda, pulmonalna hipertonija, Raynaudov sindromom, cerebralne vazospazme, udar kapi, benigna hipertrofija prostate, ateroskleroza, i astma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996)) . Elevated or abnormal release of endothelin causes permanent vasoconstriction in peripheral, renal, and cerebral blood vessels, which can lead to disease. As is known from the literature, endothelin is involved in a number of diseases. These include hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, stroke, benign prostatic hypertrophy, atherosclerosis, and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264 , 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 328, 1732 (1993), Nephron 66, 373 (1994) ), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996)).
Zasada su u literaturi opisana najmanje dva podtipa endotelin-receptora, ETA- i ETB-receptor (Nature 348, 730 (1990), Nature 348, 732 (1990). Prema tome, tvari koje inhibiraju specifično vezanje endotelina na obadva receptora, također antagoniziraju fiziološke efekte endotelina i stoga predstavljaju dragocjene lijekove. So far, at least two subtypes of endothelin-receptor, ETA- and ETB-receptor, have been described in the literature (Nature 348, 730 (1990), Nature 348, 732 (1990). Therefore, substances that inhibit the specific binding of endothelin to both receptors also antagonize physiological effects of endothelin and therefore represent valuable drugs.
U WO 96/11914 opisani su derivati karbonske kiseline, koji se s visokim afinitetom vežu na ETA-receptor, a s bitno manjim afinitetom vežu se na ETB-receptor (tzv. ETA-specifični antagonisti). In WO 96/11914, carboxylic acid derivatives are described, which bind to the ETA-receptor with high affinity, and bind to the ETB-receptor with significantly lower affinity (so-called ETA-specific antagonists).
Kao ETA-specifični " antagonisti ovdje se označavaju takovi antagonisti čiji je afinitet prema ETA-receptoru najmanje dvadeseterostruko viši od njegovog afiniteta prema ETB-receptoru. "ETA-specific" antagonists are defined here as such antagonists whose affinity for the ETA-receptor is at least twenty times higher than its affinity for the ETB-receptor.
Postojala je potreba za pripravljanjem antagonista endotelin receptora, koji se vežu na ETA- i na ETB-receptor s približno jednakim afinitetom (tzv. miješani antagonisti). There was a need for the preparation of endothelin receptor antagonists, which bind to ETA- and ETB-receptor with approximately equal affinity (so-called mixed antagonists).
Otprilike jednak afinitet prema receptorima postoji ako je kvocijent afiniteta ETB: ETB veći od 0,1 i manji od 20, ponjaprije manji od 10. Approximately equal receptor affinity exists if the ETB:ETB affinity quotient is greater than 0.1 and less than 20, preferably less than 10.
Predmet izuma su derivati karbonskih kiselina formule I The subject of the invention are derivatives of carboxylic acids of formula I
[image] [image]
u kojoj where
R1 predstavlja tetrazol ili skupinu R1 represents a tetrazole or a group
[image] [image]
u kojoj R ima slijedeće značenje: where R has the following meaning:
a) ostatak OR7, gdje R7 ima slijedeće značenje: a) residue OR7, where R7 has the following meaning:
vodik, kation alkalijskog metala, kation zemno alkalijskog metala, fiziološki podnošljiv organski ion amonija, kaoC1-C4-alkilamonij ili amonijev ion; hydrogen, alkali metal cation, alkaline earth metal cation, physiologically tolerable organic ammonium ion, such as C1-C4-alkylammonium or ammonium ion;
C3-C8-cikloalkil, C1-C8-alkil, CH2-fenil, koji može biti supstituiran s jednim ili više slijedećih supstituenata: halogen, nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi, C1-C4-alkoksi, merkapto, C1-C4-alkiltio, amino, karboksi, NH (C1-C4-alkil) , N (C1-C4-alkil)2; C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl, which may be substituted with one or more of the following substituents: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4 -Alkoxy, mercapto, C1-C4-alkylthio, amino, carboxy, NH (C1-C4-alkyl), N (C1-C4-alkyl)2;
C3-C6-alkenilna ili C3-C6-alkinilna skupina, pri čemu ta skupina sa svoje strane može nositi jedan do pet halogenih atoma; C3-C6-alkenyl or C3-C6-alkynyl group, whereby this group can carry one to five halogen atoms;
R7 može nadalje biti fenilni ostatak koji može nosti jedan do pet halogenih atoma i/ili jedan do tri slijedeća ostatka: nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi, C1-C4-alkoksi, merkapto, C1-C4-alkiltiof amino, NH(C1-C4-alkil), N(C1-C4-alkil)2; R7 can further be a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl, hydroxy, C1-C4-alkoxy, mercapto, C1 -C4-alkylthiophene amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2;
b) preko dušikovog atoma povezan peteročlani heteroaromat kao pirolil, pirazolil, imidazolil i triazolil, koji može nositi jedan do dva halogena atoma, ili jedan do dva C1-C4-alkila ili jednu do dvije C1-C4-alkosi skupine; b) a five-membered heteroaromatic linked via a nitrogen atom such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which can carry one to two halogen atoms, or one to two C1-C4-alkyl or one to two C1-C4-alkoxy groups;
c) skupina c) group
[image] [image]
u kojoj where
k ima vrijednost 0, 1 i 2, k has the value 0, 1 and 2,
p ima vrijednost 1, 2, 3 i 4, a p has the value 1, 2, 3 and 4, a
R8 predstavlja C1-C4-alkil, C3-C8-cikloalkil, C3-C6-alkenil, C3-C6-alkinil ili fenil, koji može biti supstituiran s jednim ili više, npr. s jednim do tri slijedeća ostatka: halogen, nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi,C1-C4-alkoksi, C1-C4-alkiltio, merkapto, amino, karboksi, NH (C1-C4-alkil) , N (C1-C4-alkil) 2; R8 represents C1-C4-alkyl, C3-C8-cycloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or phenyl, which may be substituted with one or more, for example with one to three of the following residues: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxy, C1-C4-alkoxy, C1-C4-alkylthio, mercapto, amino, carboxy, NH (C1-C4-alkyl) , N (C1-C4-alkyl ) 2;
d) ostatak d) the remainder
[image] [image]
u kojem in which
R9 predstavlja C1-C4-alkil, C3-C6-alkenil, C3-C6-alkinil, C3-C8-cikloalkil, C1-C4-halogenalkil, pri čemu ti ostaci mogu nositi C1-C4-alkoksif C1-C4-alkiltio i/ili fenilni ostatak kao pod c); R9 represents C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, C1-C4-haloalkyl, whereby these residues can carry C1-C4-alkoxy C1-C4-alkylthio and/ or a phenyl radical as under c);
fenil, po potrebi supstituiran, posebno kako je prethodno navedeno, phenyl, optionally substituted, especially as previously stated,
e) R1 može nadalje biti e) R1 can also be
[image] [image]
gdje where
R13 i R14 mogu biti jednaki ili različiti i imaju slijedeće značenje: R13 and R14 can be the same or different and have the following meaning:
vodik, C1-C8-alkil, C3-C8-cikloalkil, C3-C8-alkenil, C3-C8-alkinil, benzil, fenil, koji može nositi jedan do tri slijedeća ostatka: nitro, cijano, C1-C4-alkil, C1-C4-halogenalkil, hidroksi, C1-C4-alkoksif merkapto, C1-C4-alkiltio, amino, NH (C1-C4-alkil) , N (C1-C4-alkil) 2; ili hydrogen, C1-C8-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl, benzyl, phenyl, which may bear one to three of the following residues: nitro, cyano, C1-C4-alkyl, C1 -C4-haloalkyl, hydroxy, C1-C4-alkoxy mercapto, C1-C4-alkylthio, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2; or
R13 i R14 zajedno tvore lanac C4-C7-alkila koji je zatvoren u prsten, koji je supstituiran sa C1-C4-alkilom i kojem jedna alkilenska skupina može biti nadomješten sa -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)2-O-(CH2)2-, -(CH2)7-, -CH2-S- (CH2) 2--CH2-NH- (CH2) 2-, - (CH2) 2-N- (CH2) 2-; R13 and R14 together form a C4-C7-alkyl chain which is closed in a ring, which is substituted with C1-C4-alkyl and in which one alkylene group can be replaced by -(CH2)4-, -(CH2)5-, - (CH2)6-, -(CH2)2-O-(CH2)2-, -(CH2)7-, -CH2-S- (CH2) 2--CH2-NH- (CH2) 2-, - ( CH2)2-N-(CH2)2-;
R2 predstavlja vodik, hidroksi, NH(C1-C4-alkil), n(C1-C4-alkil)2, halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C1-C4-hidroksialkil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio, ili je skupina CR2 zajedno sa CR10, kako je dolje navedeno, povezana u petero- ili šesteročlani prsten; R2 represents hydrogen, hydroxy, NH(C1-C4-alkyl), n(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-hydroxyalkyl , C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio, or the group CR2 together with CR10, as indicated below, is connected in a five- or six-membered ring;
X je dušik ili metin; X is nitrogen or methine;
Y je dušik ili metih; Y is nitrogen or methine;
Z je dušik ili CR10, gdje CR10 predstavlja vodik ili C1-C4-alkil ili CR10 zajedno sa CR2 ili CR3 tvori petero-ili šesteročlani alkilenski ili akenilni prsten, koji može biti supstituiran s jednom ili dvije C1-C4-alkilne skupine i gdje jedna ili više metilenskih skupina može biti nadomješteno s kisikom, sumporom, -NH ili N (C1-C4-alkilom) 2; Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl or CR10 together with CR2 or CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted with one or two C1-C4-alkyl groups and where one or more methylene groups may be substituted with oxygen, sulfur, -NH or N (C1-C4-alkyl) 2 ;
najmanje jedan od članova prstena, X, Y ili Z je dušik; at least one of the ring members, X, Y or Z is nitrogen;
R3 je vodik, hidroksi, NH2, NH (C1-C4-alkil) , N(C1-C4-alkil)2, halogen, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil,C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi, C1-C4-hidroksialkil, C1-C4-alkiltio ili je CR3 je zajedno sa CR10 kako je gore navedeno, povezan u petero- ili šesteročlani prsten; R3 is hydrogen, hydroxy, NH2, NH (C1-C4-alkyl), N(C1-C4-alkyl)2, halogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4 -haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy, C1-C4-hydroxyalkyl, C1-C4-alkylthio or CR3 is together with CR10 as mentioned above, connected in a five- or six-membered ring;
R4 i R5 (koji mogu biti jednaki ili različiti) predstavljaju: R4 and R5 (which can be the same or different) represent:
fenil ili naftil, koji može biti supstituiran s jednim ili više slijedećih ostataka: halogen, nitro, cijano, hidroksi, merkapto, C1-C4-alkil, C2-C4-alkenil, C1-C4-hidroksialkil, C2-C4-alkinil, C1-C4-halogenalkil, C1-C4-alkoksi, fenoksi, karboksi, C1-C4-halogenalkoksi, C1-C4-alkiltio, amino, NH (C1-C4-alkil) , N (C1-C4-alkil) 2 ili fenil koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenal kilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; ili phenyl or naphthyl, which may be substituted with one or more of the following radicals: halogen, nitro, cyano, hydroxy, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-hydroxyalkyl, C2-C4-alkynyl, C1 -C4-haloalkyl, C1-C4-alkoxy, phenoxy, carboxy, C1-C4-haloalkoxy, C1-C4-alkylthio, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2 or phenyl which may be mono- or multi-substituted, eg mono- to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halogenal alkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or
fenil ili naftil, koji su međusobno povezani u orto položaju preko izravne veze, metilenske, etilenske ili etenilne skupine, kisikovog ili sumpornog atoma ili jedne SO2-, NH- ili N-alkilne skupine; phenyl or naphthyl, which are connected to each other in the ortho position via a direct bond, a methylene, ethylene or ethenyl group, an oxygen or sulfur atom or one SO2-, NH- or N-alkyl group;
C3-C8-cikloalkil; C3-C8-cycloalkyl;
R6 predstavlja C3-C8-cikloalkil, pri čemu ti ostaci mogu biti jednostruko ili višestruko supstituirani s halogenim hidroksi, merkapto, karboksi, nitro, cijano, C1-C4-alkoksi, C1-C4-alkilom, C2-C4-alkenilom, C2-C4-alkinilom, C3-C6-alkeniloksi, C3-C6-alkiniloksi, C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkilkarbonilom, C1-C4-alkoksi-karbonilom, C3-C8-alkilkarbonilalkilom, NH (C1-C4-alkilom) , R6 represents C3-C8-cycloalkyl, whereby these residues can be mono- or multi-substituted with halogen hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2- ( C1-C4-alkyl),
N (C1-C4-alkilom) 2 ili s fenilom koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogen-alkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; N (C1-C4-alkyl) 2 or with phenyl which can be mono- or multi-substituted, e.g. mono- to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halo-alkyl, C1-C4-alkoxy , C1-C4-halogenalkoxy or C1-C4-alkylthio;
fenil ili naftil, koji može biti supstituiran s jednim ili više slijedećih ostataka: halogen, R15 , nitro, merkapto, karboksi, cijano, hidroksi, amino, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C3-C6-alkeniloksi, C1-C4-halogenalkil, C3-C6-alkiniloksi, C1-C4-alkilkarbonil, C1-C4-alkoksikarbonil, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi,C1-C4-alkiltio, NH (C1-C4-alkil) , N (C1-C4-alkil) 2, dioksometilen, dioksoetilen ili fenil koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; phenyl or naphthyl, which may be substituted with one or more of the following residues: halogen, R15 , nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3 -C6-Alkenyloxy, C1-C4-Haloalkyl, C3-C6-Alkynyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C1-C4-Alkoxy, C1-C4-Haloalkyloxy, Phenoxy, C1-C4-Alkylthio, NH (C1-C4-alkyl) , N (C1-C4-alkyl) 2 , dioxomethylene, dioxoethylene or phenyl which may be singly or multiply substituted, e.g. singly to triply with halogen nitro, cyano, C1-C4-alkyl, C1- C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;
peteročlani ili šesteročlani heteroaromat koji sadrži jedan do tri dušikova atoma i/ili sumporni ili kisikov atom, koji može nositi jedan do četiri halogena atoma i/ili jedan do dva slijedeća ostatka: C1-C4-alkil, C2-C4-alkenil,C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi, C1-C4-alkiltio, fenil ili fenoksi, pri čemu fenilni ostaci sa svoje strane mogu nositi jedan do pet halogenih atoma i/ili jedan do tri slijedeća ostatka: C1-C4-alkil, C1-C4-halogenalkil,C1-C4-alkoksi, C1-C4-halogen-alkoksi i/ili C1-C4-alkiltio; a five-membered or six-membered heteroaromatic containing one to three nitrogen atoms and/or a sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following residues: C1-C4-alkyl, C2-C4-alkenyl, C1- C4-Haloalkyl, C1-C4-Alkoxy, C1-C4-Halo-Alkoxy, C1-C4-Alkylthio, phenyl or phenoxy, whereby the phenyl residues can carry one to five halogen atoms and/or one to three of the following residues: C1 -C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy and/or C1-C4-alkylthio;
R15 je C1-C4-alkil, C1-C4-alkiltio, C1-C4-alkoksi, koji mogu nositi jedan od slijedećih ostataka: hidroksi, karboksi, amino, NH (C1-C4-alkil) , N (C1-C4-alkil) 2, karboks-amid ili CON (C1-C4-alkil) 2; R15 is C1-C4-alkyl, C1-C4-alkylthio, C1-C4-alkoxy, which can carry one of the following residues: hydroxy, carboxy, amino, NH (C1-C4-alkyl), N (C1-C4-alkyl ) 2, carboxamide or CON (C1-C4-alkyl) 2;
W je sumpor ili kisik; W is sulfur or oxygen;
Q je razmačna skupina, koja odgovara duljini C2-C4-lanca. Funkcija skupine Q u spojevima formule I je stvaranje definiranog razmaka između skupina R6 i W. Razmak mora odgovarati duljini C2-C4-alkilnog lanca. To se može postići s mnoštvom kemijskih ostataka, primjerice sa C2-C4-al kilom, C3-C4-alkenilom, C3-C4-alkinilom,-S-CH2-CH2-, -O-CH2-CH2-, -N-CO-CH2-O-, pri čemu ti ostaci mogu biti jednostruko ili višestruko supstituirani s halogenim, hidroksi, merkapto, C1-C4-alkilom, C2-C4-alkenilom, C2-C4-alkinilom, karboksi, nitro, cijano, C1-C4-alkoksi, C3-C6-alkeniloksi, C3-C6-alkiniloksi, C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkilkarbonilom,C1-C4-alkoksikarbonilom, C3-C8- alkilkarbonilalkilom, NH (C1-C4-alkilom) , N (C1-C4-alkilom) 2, fenilom koji može biti jednostruko ili višestruko supstituiran npr. jednostruko do trostruko s halogenim, nitro, cijano, C1-C4-alkilom,C1-C4-halogen-alkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio. Q is a spacer group, which corresponds to the length of the C2-C4 chain. The function of the group Q in the compounds of formula I is to create a defined distance between the groups R6 and W. The distance must correspond to the length of the C2-C4-alkyl chain. This can be achieved with a variety of chemical residues, for example with C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -S-CH2-CH2-, -O-CH2-CH2-, -N-CO -CH2-O-, whereby these residues can be singly or multiply substituted with halogen, hydroxy, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, carboxy, nitro, cyano, C1-C4 -Alkoxy, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Haloalkyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C3-C8- Alkylcarbonylalkyl, NH (C1-C4 -alkyl), N (C1-C4-alkyl) 2, phenyl which can be single or multiple substituted, e.g. single to triple with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-halo-alkyl, C1- C4-Alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio.
Ili, razmačna skupina Q predstavlja dio petero- do sedmeročlanog, hetero- ili karbocikličkog prstena, koji je aneliran na R6 . Or, the spacer group Q represents part of a five- to seven-membered, hetero- or carbocyclic ring, which is fused to R 6 .
Pri tome u nastavku vrijede slijedeće definicije: The following definitions apply below:
Alkalijski metal je npr. litij, natrij, kalij. An alkali metal is, for example, lithium, sodium, potassium.
Zemno alkalijski metal je npr. kalcij, magnezij, barij. Alkaline earth metal is, for example, calcium, magnesium, barium.
C3-C8-cikloalkil je npr. ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil ili ciklooktil; C3-C8-cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
C1-C4-halogenalkil može biti linearan ili razgranat, kao npr. fluormetil, difluormetil, trifluormetil, klor-difluormetil, diklorfluormetil, triklormetil, 1-fluoretil, 2-fluoretil, 2,2-difluoretil, 2,2,2-trifluoretil, 2-klor-2,2-difluoretil, 2,2-diklor-2 -fluoretil, 2,2,2-trikloretil ili pentafluoretil. C1-C4-haloalkyl can be linear or branched, such as fluoromethyl, difluoromethyl, trifluoromethyl, chloro-difluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl.
C1-C4-halogenalkoksi može biti linearan ili razgranat, kao npr. difluormetoksi, trifluormetoksi, klordifluor metoksi,1-fluoretoksi, 2,2-difluoretoksi, 1,1,2,2-difluoretsoki, 1,1,2,2-tetrafluoretoksi, 2,2,2-trifluoretoksi, 2-klor-1,1,2- trifluoretoksi, 2-fluoretoksi ili pentafluoretoksi. C1-C4-halogenalkoxy can be linear or branched, such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy , 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy, 2-fluoroethoxy or pentafluoroethoxy.
C1-C4-alkil može biti linearan ili razgranat, kao npr. metil, etil, 1-propil, 2-propil, 2-metil-2-propil, 2-metil-1-propil, 1-butil ili 2-butil. C1-C4-alkyl may be linear or branched, such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl.
C2-C4-alkenil može biti linearan ili razgranat, kao npr. etenil, 1-propen-3-il, 1-propen-2-il, 1-propen-1-il, 2-metil-1 -propenil, 1-butenil ili 2-butenil. C2-C4-alkenyl can be linear or branched, such as ethenyl, 1-propen-3-yl, 1-propen-2-yl, 1-propen-1-yl, 2-methyl-1-propenyl, 1- butenyl or 2-butenyl.
C2-C4-alkinil može biti linearan ili razgranat, kao npr. etinil, 1-propin-1-il, 1-propin-3-il, 1-butin-4-il ili 2-butin-4-il. C2-C4-alkynyl can be linear or branched, such as ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl.
C1-C4-alkoksi može biti linearan ili razgranat, kao npr. metoksi, etoksi, propoksi, 1-metiletoki, butoksi, 1-metilpropoksi, 2-metilpropoksi ili 1,1-dimetiletoksi. C1-C4-Alkoxy can be linear or branched, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.
C3-C6-alkeniloksi može biti linearan ili razgranat, kao npr. aliloksi, 2-buten-1-iloksi ili 3-buten-2-iloksi. C3-C6-alkenyloxy can be linear or branched, such as allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy.
C1-C4-hidroksialkil može biti linearan ili razgranat, kao npr. hidroksimetil, 1-hidroksieter-2-il. C1-C4-hydroxyalkyl may be linear or branched, such as hydroxymethyl, 1-hydroxyether-2-yl.
C3-C6-alkiniloksi može biti linearan ili razgranat, kao npr. 2-propin-1-iloksi, 2-butin-1-iloksi ili 3-butin-2-iloksi. C3-C6-alkynyloxy can be linear or branched, such as 2-propyn-1-yloxy, 2-butyn-1-yloxy or 3-butyn-2-yloxy.
C1-C4-alkiltio može biti linearan ili razgranat, kao npr. metiltio, etiltio, propiltio, 1-metiletiltio, butiltio, 1-metilpropiltio, 2-metilpropiltio ili 1/1-dimetiletiltio. C1-C4-alkylthio can be linear or branched, such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1/1-dimethylethylthio.
C1-C4-alkilkarbonil može biti linearan ili razgranat, kao npr. acetil, etilkarbonil ili 2-propilkarbonil. C1-C4-alkylcarbonyl may be linear or branched, such as acetyl, ethylcarbonyl or 2-propylcarbonyl.
C1-C4-alkoksikarbonil može biti linearan ili razgranat, kao npr. metoksikarbonil, etoksikarbonil, n-propoksikarbonil, i-propoksikarbonil ili n-butoksi-karbonil. C1-C4-Alkoxycarbonyl can be linear or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbonyl.
C3-C8-alkilkarbonilalkil može biti linearan ili razgranat, kao npr. 2-okso-prop-1-il, 3-okso-but-1-il ili 3-okso-but-2-il. C3-C8-alkylcarbonylalkyl can be linear or branched, such as 2-oxo-prop-1-yl, 3-oxo-but-1-yl or 3-oxo-but-2-yl.
C1-C8-alkil može biti linearan ili razgranat, kao npr. pentil, heksil, heptil ili okstil. C1-C8-alkyl may be linear or branched, such as pentyl, hexyl, heptyl or oxytyl.
Halogen je npr. fluor, klor, brom, jod. Halogen is, for example, fluorine, chlorine, bromine, iodine.
Daljnji predmet izuma su takovi spojevi iz kojih se spojevi formule I mogu osloboditi (tzv. pred-lijekovi). A further subject of the invention are such compounds from which the compounds of formula I can be released (so-called prodrugs).
Prednost se daje takovim pred-lijekovima kod kojih se oslobađanje odvija pod takovim uvjetima kao što su oni koji vladaju u određenim dijelovima tijela, npr. u želucu, crijevima, krvotoku, jetri. Preference is given to such prodrugs in which the release takes place under such conditions as those prevailing in certain parts of the body, eg in the stomach, intestines, blood stream, liver.
Spojevi, a također i meduproizvodi za njihovu proizvodnju, kao npr. II, III i IV mogu imati jedan ili više asimetrično supstituiranih ugljikovih atoma. Takovi spojevi mogu postojati kao čisti enantiomeri ili kao njihove smjese. Pri upotrebi kao aktivne tvari, prednost se daje upotrebi enantiomerno čistog spoja. Compounds, and also intermediate products for their production, such as II, III and IV can have one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers or as mixtures thereof. When used as an active substance, preference is given to using an enantiomerically pure compound.
Predmet izuma je "nadalje upotreba gore navedenih derivata karbonskih kiselina za proizvodnju lijekova, naročito za proizvodnju inhibitora ETA i ETB receptora. Spojevi prema izumu posebno su prikladni kao miješani antagonisti, kako su definirani uvodno. The subject of the invention is "further use of the above-mentioned carboxylic acid derivatives for the production of drugs, especially for the production of ETA and ETB receptor inhibitors. The compounds according to the invention are particularly suitable as mixed antagonists, as defined in the introduction.
Proizvodnja spojeva opće formule IV, u kojima Z predstavlja sumpor ili kisik, može se provesti - također i u enatiomerno čistom obliku - kako je opisano u WO 96/11914. The production of compounds of the general formula IV, in which Z represents sulfur or oxygen, can be carried out - also in enantiomerically pure form - as described in WO 96/11914.
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Spojevi opće fprmule III su poznati ili se mogu sintetizirati npr. redukcijom odgovarajućih karbonskih kiselina, odnosno njihovih estera, ili također nekom drugom opće poznatom metodom. Compounds of general formula III are known or can be synthesized, for example, by reduction of the corresponding carboxylic acids, i.e. their esters, or also by some other generally known method.
Derivati karbonskih kiselina opće formule IV mogu se proizvesti tako da se spoj formule IVa dovede u reakciju s alkoholom ili tiolom formule VII pod uvjetima kisele katalize. Derivatives of carboxylic acids of general formula IV can be prepared by reacting a compound of formula IVa with an alcohol or thiol of formula VII under acid catalyzed conditions.
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Navedeni ostaci imaju slijedeća značenja: The listed residues have the following meanings:
R1 ima značenje navedeno za opću formulu I; R 1 has the meaning given for the general formula I;
R16 i R17, koji mogu biti jednaki ili različiti, predstavljaju vodik ili alkil, alkenil, alkinil, fenil, naftil, cikloalkil, koji po potrebi mogu biti supstituirani, R16 and R17, which may be the same or different, represent hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, which may be substituted if necessary,
R18 predstavlja vodik ili alkil, alkenil, alkinil, fenil, naftil, cikloalkil, koji po potrebi mogu biti supstituirani, R18 represents hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, which can be substituted if necessary,
R19 predstavlja vodik ili alkil, alkenil, alkinil, fenil, naftil, cikloalkil, koji po potrebi mogu biti supstituirani, R19 represents hydrogen or alkyl, alkenyl, alkynyl, phenyl, naphthyl, cycloalkyl, which can be substituted if necessary,
Predosna značenja ostataka su slijedeća: The following meanings of the rests are:
R1 je COOR7; R1 is COOR7;
R16 i R17, koji mogu biti jednaki ili različiti, predstavljaju alkil, fenil, naftil, cikloalkil, koji po potrebi mogu biti supstituirani, R16 and R17, which can be the same or different, represent alkyl, phenyl, naphthyl, cycloalkyl, which can be substituted if necessary,
R18 predstavlja alkil, fenil, cikloalkil, koji po potrebi mogu biti supstituirani, R18 represents alkyl, phenyl, cycloalkyl, which can be substituted if necessary,
R19 predstavlja alkil, alkenil, alkinil, fenil, cikloalkil, koji po potrebi mogu biti supstituirani, R19 represents alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, which can be substituted if necessary,
Posebna predosna značenja ostataka su slijedeća: The special meanings of the rests are as follows:
R1 je COOR7; R1 is COOR7;
R16 je R4; R 16 is R 4 ;
R17 je R5; R17 is R5;
R18 je alkil, po potrebi supstituiran, naročito metil, R18 is alkyl, optionally substituted, especially methyl,
R19 je Q. R19 is Q.
Derivati karbonskih kiselina opće formule IV mogu se proizvesti postupkom po kojem se spoj formule IVa dovede u reakciju s jednim alkoholom ili tiolom formule III pod uvjetima kisele katalize Derivatives of carboxylic acids of the general formula IV can be produced by a process in which a compound of the formula IVa is reacted with an alcohol or a thiol of the formula III under conditions of acid catalysis
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U tu svrhu pomiješaju se spojevi IVa i III kao tvari ili se pomiješaju u otapalu inertnom za tu reakciju i doda se katalitičku količinu jedne kiseline, npr. p-toluol-sulfonske kiseline. Primjeri inertnih otapala jesu metilenklorid, benzol ili toluol. Prikladna su također i takova inertna otapala koja s alkoholom R18OH tvore 1 fi azeotropnu smjesu. U slučaju metanola (R18 = CH3) to su, na primjer, kloroform ili metil ester octene kiseline. For this purpose, compounds IVa and III are mixed as substances or mixed in a solvent inert for this reaction and a catalytic amount of an acid, for example p-toluenesulfonic acid, is added. Examples of inert solvents are methylene chloride, benzene or toluene. Also suitable are such inert solvents that form a 1 fi azeotropic mixture with alcohol R18OH. In the case of methanol (R18 = CH3) these are, for example, chloroform or acetic acid methyl ester.
Zatim se reakcijsku smjesu miješa pri temperaturi između sobne temperature i vrelišta otapala. Nastali i p alkohol R18OH se izdestilira ili se odstrani pomoću vakuuma. Ta metoda je prikladna za proizvodnju enantiomerno čistih spojeva IV ako se polazi od enantiomerno čistih spojeva IVa. The reaction mixture is then stirred at a temperature between room temperature and the boiling point of the solvent. The resulting i-p alcohol R18OH is distilled off or removed using a vacuum. This method is suitable for the production of enantiomerically pure compounds IV if starting from enantiomerically pure compounds IVa.
Spojevi formule IVa su poznati i opisani su primjerice u WO 96/11914. Compounds of formula IVa are known and are described, for example, in WO 96/11914.
Spojevi prema izumu, u kojima supstituenti imaju značenja navedena za opću formulu I, mogu se proizvesti primjerice tako, da se derivat karbonske kiseline opće formule IV, u kojem supstituenti imaju navedeno značenje, dovede u reakciju sa spojem opće formule V. Compounds according to the invention, in which the substituents have the meanings specified for the general formula I, can be produced, for example, by reacting the carboxylic acid derivative of the general formula IV, in which the substituents have the specified meanings, with the compound of the general formula V.
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U formuli V R11 predstavlja halogen ili R12-SO2-, pri čemu R12 može biti C1-C4-alkil, C1-C4-halogenalkil ili fenil. Nadalje, najmanje jedan od članova prstena, X ili Y ili Z, je dušik. Reakcija se odvija ponajprije u inertnoj otopini ili sredstvu za rezređenje uz dodatak prikladne baze, tj . baze koja potpomaže deprotoniranje međuproizvoda, u temperaturnom području od sobne temperature do vrelišta otapala. In formula V, R11 represents halogen or R12-SO2-, where R12 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. Furthermore, at least one of the ring members, X or Y or Z, is nitrogen. The reaction takes place primarily in an inert solution or diluent with the addition of a suitable base, i.e. of bases that support the deprotonation of intermediate products, in the temperature range from room temperature to the boiling point of the solvent.
Spojevi tipa I sa R1 = COOH mogu se dobiti nadalje izravno ako se medusproizvod IV, u kojem R1 predstavlja COOH, s dva ekvivalenta odgovarajuće baze deprotonira i spojevi opće formule V dovedu se u reakciju. Reakcija se također odvija u inertnom otapalu i u temperaturnom području od sobne temperature do vrelišta otapala. Compounds of type I with R1 = COOH can also be obtained directly if the intermediate IV, in which R1 is COOH, is deprotonated with two equivalents of the appropriate base and the compounds of the general formula V are reacted. The reaction also takes place in an inert solvent and in the temperature range from room temperature to the boiling point of the solvent.
Primjeri takovih otapala, odnosno sredstava za razredenje jesu alifatski, aliciklički i aromatski ugljikovodici, koji po potrebi mogu biti klorirani, kao npr. heksan, cikloheksan, petroleter, ligroin, benzol, toluol, ksilol, metilenklorid, kloroform, tetraklorugljik, etilenklorid i trikloretilen, eteri, kao na primjer diizopropil eter, dibutil eter, metil-terc.butil eter, propilen oksid, dioksan i tetrahidrofuran, nitrili kao na primjer acetonitril i propionitril, kiselinski amidi kao na primjer dimetilformamid, dimetilacetamid i N-metil-pirolidon, sulfoksidi i sulfoni, kao na primjer dimetilsulfoksid i sulfolan. Examples of such solvents, i.e. diluents, are aliphatic, alicyclic and aromatic hydrocarbons, which can be chlorinated if necessary, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethylene chloride and trichloroethylene, ethers, such as diisopropyl ether, dibutyl ether, methyl tert.butyl ether, propylene oxide, dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, acid amides such as dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, sulfoxides and sulfones, such as dimethylsulfoxide and sulfolane.
Spojevi formule V su poznati, djelomično su komercijalno dostupni ili se mogu proizvesti po opće poznatim metodama. Compounds of formula V are known, are partially commercially available or can be produced by generally known methods.
Kao baza može poslužiti hidrid alkalijskog ili zemno alkalijskog metala, kao natrijev hidrid, kalijev hidrid ili kalcijev hidrid, karbonat kao alkalijski karbonat, npr. natrijev ili kalijev karbonat, hidroksid alkalijskog ili zemno alkalijskog, metala kao natrijev ili kalijev hidroksid, metaloorganski spoj kao butil-litij ili alkalijski amid, kao litijev diizopropilamid ili litijev amid. Alkaline or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, carbonate such as alkali carbonate, e.g. sodium or potassium carbonate, alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, organometallic compound such as butyl can serve as a base. -lithium or alkali amide, such as lithium diisopropylamide or lithium amide.
Spojevi formule I mogu se proizvesti također i tako da se pode od odgovarajućih karbonskih karbonskih kiselina, tj . spojeva formule I u kojima R1 predstavlja COOH i oni se najprije na uobičajen način prevedu u aktivirani oblik, kao što je kiselinski halogenid, anhidrid ili imidazol, a oni se zatim kemijski pretvaraju s odgovarajućim hidroksilnim spojem HOR7 . Ta pretvorba se može provesti u uobičajenim otapalima i često je potreban dodatak baze, pri čemu u obzir dolaze gore navedene. Obadva stupnja mogu se također pojednostavniti time da se karbonsku kiselinu pusti djelovati na hidroksilni spoj u prisutnosti sredstva koje oslobađa vodu, kao što je karbodiimid. Compounds of formula I can also be produced by dividing them from the corresponding carboxylic acids, i.e. compounds of formula I in which R1 represents COOH and they are first converted in the usual way into an activated form, such as an acid halide, anhydride or imidazole, and they are then chemically converted with the corresponding hydroxyl compound HOR7. This conversion can be carried out in common solvents and often requires the addition of a base, where the above come into play. Both steps can also be simplified by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a water releasing agent such as carbodiimide.
Osim toga, spojevi formule I mogu se također proizvesti i tako da se pode od soli odgovarajućih karbonskih kiselina, tj. spojeva formule I u kojima R predstavlja skupinu COR, a R je OM, pri čemu M može biti kation alkalijskog metala ili ekvivalent kationa zemno alkalijskog metala. Te soli mogu se dovesti u reakciju s mnogim spojevima formule R-A, pri čemu A predstavlja uobičajenu nukleofilnu polaznu skupinu, primjerice halogen, kao klor, brom, jod, ili po potrebi s halogenim, alkilom ili s halogenalkilom supstituirani aril ili alkil sulfonil, kao npr. toluolsulfonil i metilsulfonil ili neku drugu ekvivalentnu polaznu skupinu. Spojevi formule R-A sa supstituentima A, sposobnim za reakciju, su poznati ili se lako mogu dobiti na osnovi općeg stručnog znanja. Ta se pretvorba može provesti u uobičajenim otapalima i vrši se ponajprije uz dodatak baze, pri čemu u obzir dolaze gore navedene. In addition, the compounds of formula I can also be prepared by dividing them from the salts of the corresponding carboxylic acids, i.e. compounds of formula I in which R represents the group COR and R is OM, where M can be an alkali metal cation or an equivalent of an earth cation. alkali metal. These salts can be reacted with many compounds of the formula R-A, where A represents a common nucleophilic starting group, for example halogen, such as chlorine, bromine, iodine, or, if necessary, halogen, alkyl or haloalkyl substituted aryl or alkyl sulfonyl, such as e.g. toluenesulfonyl and methylsulfonyl or some other equivalent starting group. Compounds of the formula R-A with substituents A, capable of reaction, are known or can be easily obtained on the basis of general expert knowledge. This conversion can be carried out in common solvents and is carried out primarily with the addition of a base, whereby the above mentioned are taken into account.
U nekim slučajevima za proizvodnju spojeva I prema izumu treba primijeniti opće poznate postupke zaštitnih skupina. Ako primjerice R6 predstavlja 4-hidroksifenilnu skupinu, tada hidroksi skupinu treba najprije zaštititi kao benzil eter, koji se zatim odcjepljuje u prikladnom stupnju reakcije. In some cases, for the production of compounds I according to the invention, generally known methods of protecting groups should be applied. If, for example, R6 represents a 4-hydroxyphenyl group, then the hydroxy group should first be protected as a benzyl ether, which is then cleaved off in a suitable reaction step.
Spojevi formule I, u kojima R1 predstavlja tetrazol, mogu se proizvesti na način opisan u WO/11914. Compounds of formula I, in which R 1 represents a tetrazole, can be prepared as described in WO/11914.
Što se tiče biološkog djelovanja, prednost se daje derivatima karbonskih kiselina opće formule I - također kao čistim enantiomerima, odnosno čistim diastereomerima ili kao njihovim smjesama -, u kojima supstituenti imaju slijedeće značenje: As far as biological action is concerned, preference is given to derivatives of carboxylic acids of the general formula I - also as pure enantiomers, i.e. pure diastereomers or as their mixtures -, in which the substituents have the following meaning:
R2 predstavlja vodik, hidroksi, halogen, N(C1-C4-alkil)2, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio, C1-C4-halogenalkil, C1-C4-halogenalkoksi ili je CR2 zajedno sa CR10, kako je dolje navedeno, povezana u petero- ili šesteročlani prsten; R 2 represents hydrogen, hydroxy, halogen, N(C 1 -C 4 -alkyl) 2 , C 1 -C 4 -alkyl, C 1 -C 4 -Alkoxy, C 1 -C 4 -Alkylthio, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Haloalkyl, or is CR 2 together with CR10, as indicated below, linked in a five- or six-membered ring;
X je dušik ili metin; X is nitrogen or methine;
Y je dušik ili metin; Y is nitrogen or methine;
Z je dušik ili CR10, gdje CR10 predstavlja vodik ili C1-C4-alkil ili CR10 zajedno sa CR2 ili sa CR3 tvori petero-ili šesteročlani alkilenski ili akenilni prsten, koji može biti supstituiran s jednom ili dvije metilne skupine i gdje metilenska skupina može biti nadomješteno s kisikom ili sa sumporom, kao -CH2-CH2-O-, -CH2-CH2-CH2-O-, Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl or CR10 together with CR2 or with CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted with one or two methyl groups and where the methylene group can be substituted with oxygen or with sulfur, as -CH2-CH2-O-, -CH2-CH2-CH2-O-,
-CH=CH-O-, -CH=CH-CH2-O-, -CH (CH3) -CH (CH3) -O-, -CH=CH-O-, -CH=CH-CH2-O-, -CH (CH3) -CH (CH3) -O-,
-CH=C(CH3)-O-, -C(CH3)=C(CH3)-O-, ili -C (CH3) =C (CH3)-S; -CH=C(CH3)-O-, -C(CH3)=C(CH3)-O-, or -C(CH3)=C(CH3)-S;
najmanje jedan od članova prstena, X, Y ili Z, je dušik; at least one of the ring members, X, Y or Z, is nitrogen;
R3 je vodik, hidroksi, halogen, N (C1-C4-alkil) 2, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio, C1-C4-halogenalkil, C1-C4-halogenalkoksi ili je CR3 zajedno sa CR10, kako je gore navedeno, povezan u petero- ili šesteročlani prsten; R 3 is hydrogen, hydroxy, halogen, N (C 1 -C 4 -alkyl) 2 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkyloxy or is CR 3 together with CR10, as above, linked in a five- or six-membered ring;
R4 i R5 (koji mogu biti jednaki ili različiti) predstavijaju: R4 and R5 (which can be the same or different) represent:
fenil ili naftil, koji može biti supstituiran s jednim ili više slijedećih ostataka: halogen, nitro, cijano, hidroksi, merkapto, amino, C1-C4-alkil, C1-C4-halogenalkil, karboksi, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi, C1-C4-alkiltio, NH (C1-C4-alkil) ili N (C1-C4-alkil) 2 ili fenil, koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko, s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili sa C1-C4-alkiltio; ili phenyl or naphthyl, which may be substituted with one or more of the following residues: halogen, nitro, cyano, hydroxy, mercapto, amino, C1-C4-alkyl, C1-C4-halogenoalkyl, carboxy, C1-C4-alkoxy, C1-C4 -halogenalkoxy, phenoxy, C1-C4-alkylthio, NH (C1-C4-alkyl) or N (C1-C4-alkyl) 2 or phenyl, which can be mono- or multi-substituted, e.g. mono to tri-substituted, with halogen nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or with C1-C4-alkylthio; or
fenil ili naftil, koji su u orto položaju međusobno povezani preko izravne veze, metilenske, etilenske ili etenilne skupine, kisikovog ili sumpornog atoma ili jedne S02-, NH- ili N-alkilne skupine; phenyl or naphthyl, which are connected to each other in the ortho position via a direct bond, a methylene, ethylene or ethenyl group, an oxygen or sulfur atom or a SO2-, NH- or N-alkyl group;
C3-C8-cikloalkil; C3-C8-cycloalkyl;
R6 predstavlja C3-C8-cikloalkil, pri čemu ti ostaci mogu biti jednostruko ili višestruko supstituirani s halogenim hidroksi, merkapto, karboksi, nitro, cijano, C1-C4-alkoksi, C1-C4-alkilom, C2-C4-alkenilom, C2-C4-alkinelom, C3-C6-alkeniloksi, C3-C6-alkiniloksi, C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkilkarbonilom, C1-C4-alkoksi-karbonilom, NH (C1-C4-alkilom) , N (C1-C4-alkilom) 2 ili fenilom, koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko, s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; R6 represents C3-C8-cycloalkyl, whereby these residues can be mono- or multi-substituted with halogen hydroxy, mercapto, carboxy, nitro, cyano, C1-C4-alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2- C4-Alkynel, C3-C6-Alkenyloxy, C3-C6-Alkynyloxy, C1-C4-Alkylthio, C1-C4-Haloalkyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxy-carbonyl, NH (C1-C4-Alkyl) , N (C1-C4-alkyl) 2 or phenyl, which can be mono- or multi-substituted, e.g. mono- to tri-substituted, with nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy , C1-C4-halogenalkoxy or C1-C4-alkylthio;
fenil ili naftil, koji može biti supstituiran s jednim ili više slijedećih ostataka: halogen, R15, nitro, merkapto, karboksi, cijano, hidroksi, amino, C1-C4-alkil, C2-C4-alkenil, C2-C4-alkinil, C3-C6-alkeniloksi, C1-C4-halogenalkil,C3-C6-alkiniloksi, C1-C4-alkilkarbonil, C1-C4-alkoksikarbonil, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi,C1-C4-alkiltio, NH (C1-C4-alkil) , N (C1-C4-alkil) 2, dioksometilen, dioksoetilen ili fenil, koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenal kilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; phenyl or naphthyl, which may be substituted with one or more of the following residues: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3 -C6-Alkenyloxy, C1-C4-Haloalkyl, C3-C6-Alkynyloxy, C1-C4-Alkylcarbonyl, C1-C4-Alkoxycarbonyl, C1-C4-Alkoxy, C1-C4-Haloalkyloxy, Phenoxy, C1-C4-Alkylthio, NH (C1-C4-alkyl) , N (C1-C4-alkyl) 2 , dioxomethylene, dioxoethylene or phenyl, which may be singly or multiply substituted, e.g. singly to triply with halogenated nitro, cyano, C1-C4-alkyl, C1 -C4-halogenal alkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio;
petero- ili šesteročlani heteroaromat, koji sadrži jedan do tri dušikova atoma i/ili sumporni ili kisikov atom, koji može nositi jedan do četiri halogena atoma i/ili jedan do dva slijedeća ostatka: C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi, C1-C4-alkiltio, fenil, fenoksi ili fenilkarbonil, pri čemu fenilni ostaci sa svoje strane mogu nositi jedan do pet halogenih atoma i/ili jedan do tri slijedeća ostatka: C1-C4-alkil, C1-C4-halogenalkil, C1-C4- alkoksi,C1-C4-halogen-alkoksi i/ili C1-C4-alkiltio; a five- or six-membered heteroaromatic, containing one to three nitrogen atoms and/or a sulfur or oxygen atom, which can carry one to four halogen atoms and/or one to two of the following residues: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-Alkoxy, C1-C4-Halo-Alkoxy, C1-C4-Alkylthio, phenyl, phenoxy or phenylcarbonyl, whereby the phenyl residues can carry one to five halogen atoms and/or one to three of the following residues: C1-C4 -alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy, C1-C4-halo-alkoxy and/or C1-C4-alkylthio;
R15 je metil, etil, metoksi ili etoksi, koji nosi jedan od slijedećih ostataka: hidroksi, karboksi, amino, NH(C1-C4-alkil) ,N (C1-C4-alkil) 2, karboksamid ili CON(C1-C4-alkil)2; R15 is methyl, ethyl, methoxy or ethoxy, bearing one of the following residues: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N (C1-C4-alkyl) 2, carboxamide or CON(C1-C4- alkyl)2;
W je sumpor ili kisik; W is sulfur or oxygen;
Q je C2-C4-alkil, C3-C4-alkenil, C3-C4-alkinil, -S-CH2-CH2-, -O-CH2-CH2-, pri čemu ti ostaci mogu biti jednostruko ili višestruko supstituirani s halogenim, hidroksi, merkapto, karboksi, nitro, cijano, C1-C4-alkilom, C1-C4- alkoksi,C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkoksikarbonilom, NH (C1-C4-alkil) , N (C1-C4-alkil) 2 ili s fenilom, koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim, nitro, cijano, C1-C4- alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; ili Q is C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -S-CH2-CH2-, -O-CH2-CH2-, where these residues can be mono- or multi-substituted with halogen, hydroxy . C1-C4-alkyl) 2 or with phenyl, which can be singly or multiply substituted, e.g. singly to triply with halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1 -C4-halogenalkoxy or C1-C4-alkylthio; or
Q zajedno s R6 tvori slijedeće prstenaste sisteme: indan-2-il, indan-3-il, 1,2,3,4-tetrahidro naft-2-il,1,2,3,4-tetrahidronaft-3-il, pri čemu fenilni prsten može biti supstituiran s halogenim, hidroksi, merkapto, karboksi, nitro, cijano, C1-C4-alkoksi, C1-C4-alkilom, C2-C4-alkenilom, C2-C4-alkinilom, C3-C6-alkeniloksi, C3-C6- alkiniloksi, C1-C4-alkiltio, C1-C4-halogenalkoksi, C1-C4-alkilkarbonilom, C1-C4-alkoksikarbonilom, amino, NH (C1-C4-alkil),N(C1-C4-alkil) 2 ili s fenilom. Q together with R6 forms the following ring systems: indan-2-yl, indan-3-yl, 1,2,3,4-tetrahydro naphth-2-yl, 1,2,3,4-tetrahydronaphth-3-yl, wherein the phenyl ring may be substituted with halogen, hydroxy, mercapto, carboxy, nitro, cyano, C1-C4- alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-halogenalkoxy, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, amino, NH (C1-C4-alkyl),N(C1-C4-alkyl) 2 or with phenyl.
Posebno prednosni spojevi opće formule I - također kao čisti enantiomeri, odnosno čisti diastereomeri ili kao njihove smjese - su oni u kojima supstituenti imaju slijedeća značenja: Particularly preferred compounds of the general formula I - also as pure enantiomers, i.e. pure diastereomers or as their mixtures - are those in which the substituents have the following meanings:
R2 predstavlja trif luormetil, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio ili je CR2 zajedno sa CR10, kako je dolje navedeno, povezana u peteročlani ili šesteročlani prsten; R 2 represents trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or CR 2 together with CR 10 , as indicated below, is connected in a five- or six-membered ring;
X je dušik ili metin; X is nitrogen or methine;
Y je dušik ili metin; Y is nitrogen or methine;
Z je dušik ili CR10, gdje CR10 predstavlja vodik ili C1-C4-alkil ili CR10 zajedno sa CR2 ili sa CR3 tvori peteročlani ili šesteročlani alkilenski ili akenilni prsten, koji može biti supstituiran s jednom ili dvije metilne skupine i gdje metilenska skupina može biti nadomještena s kisikom ili sa sumporom, kao -CH2-CH2-O-, Z is nitrogen or CR10, where CR10 represents hydrogen or C1-C4-alkyl or CR10 together with CR2 or with CR3 forms a five- or six-membered alkylene or akenyl ring, which can be substituted with one or two methyl groups and where the methylene group can be substituted with oxygen or with sulfur, as -CH2-CH2-O-,
-CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2O-, -CH2-CH2-CH2-O-, -CH=CH-O-, -CH=CH-CH2O-,
-CH (CH3) -CH (CH3) -O-, -CH=C (CH3) -O-, -C (CH3) -C (CH3) -O- ili -CH (CH3) -CH (CH3) -O-, -CH=C (CH3) -O-, -C (CH3) -C (CH3) -O- or
-C(CH3) = (CH3)-S; -C(CH3) = (CH3)-S;
najmanje jedan od članova prstena, X, Y ili Z je dušik; at least one of the ring members, X, Y or Z is nitrogen;
R3 je trifluormetil, C1-C4-alkil, C1-C4-alkoksi, C1-C4-alkiltio ili je CR3 zajedno sa CR10 , kako je gore navedeno, povezan u peteročlani ili šesteročlani prsten; R 3 is trifluoromethyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio or CR 3 together with CR 10 , as mentioned above, is connected in a five-membered or six-membered ring;
R4 i R5 (koji mogu biti jednaki ili različiti) predstavljaju; R4 and R5 (which may be the same or different) represent;
fenil ili naftil, koji može biti supstituiran s jednim ili više slijedećih ostataka: halogen, nitro, cijano, hidroksi, merkapto, amino, C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi, C1-C4-alkiltio, NH (C1-C4-alkil) ili N (C1-C4-alkil) 2 ili fenilom, koji može biti jednostruko ili višestruko supstituiran, npr, jednostruko do trostruko s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; ili phenyl or naphthyl, which may be substituted with one or more of the following residues: halogen, nitro, cyano, hydroxy, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4- alkoxy, C1-C4-haloalkyloxy . -C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or
fenil ili naftil, koji su u orto položaju međusobno povezani preko izravne veze, metilenske, etilenske ili etenilne skupine, kisikovog ili sumpornog atoma ili jedne SO2-, NH- ili N-alkilne skupine; phenyl or naphthyl, which are connected to each other in the ortho position via a direct bond, methylene, ethylene or ethenyl group, oxygen or sulfur atom or one SO2-, NH- or N-alkyl group;
C5-C7-cikloalkil; C5-C7-cycloalkyl;
R6 predstavlja C5-C7-cikloalkil, pri čemu ti ostaci mogu biti jednostruko ili višestruko supstituirani sa C1-C4-alkoksi,C1-C4-alkilom, C1-C4-alkiltio, halogenim hidroksi, karboksi, cijano, trifluormetilom, acetilom ili fenilom, koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko supstituiran s halogenim, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; R6 represents C5-C7-cycloalkyl, whereby these residues can be mono- or multi-substituted with C1-C4-alkoxy, C1-C4-alkyl, C1-C4-alkylthio, halogen hydroxy, carboxy, cyano, trifluoromethyl, acetyl or phenyl, which may be mono- or multi-substituted, for example mono- to tri-substituted with halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;
fenil ili naftil, koji može biti supstituiran s jednim ili više slijedećih ostataka: halogen, R15, nitro, merkapto, karboksi, cijano, hidroksi, amino, C1-C4-alkil, C1-C4-halogenalkil, acetil, C1-C4-alkoksikarbonil, C1-C4-alkoksi, C1-C4-halogenalkoksi, fenoksi, C1-C4-alkiltio, NH (C1-C4-alkil) , N (C1-C4-alkil) 2, dioksometilen, diokso-etilen ili fenil koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim nitro, cijano, C1-C4-alkilom, C1-C4-halogenalkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; phenyl or naphthyl, which may be substituted with one or more of the following radicals: halogen, R15, nitro, mercapto, carboxy, cyano, hydroxy, amino, C1-C4-alkyl, C1-C4-halogenoalkyl, acetyl, C1-C4-alkoxycarbonyl . mono- or multi-substituted, eg mono to tri-halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkyloxy or C1-C4-alkylthio;
peteročlani ili šesteročlani heteroaromat, koji sadrži jedan do tri dušikova atoma i/ili sumporni ili kisikov atom, koji može nositi jedan do četiri halogena atoma i/ili jedan do dva slijedeća ostatka: C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkoksi, trifluormetoksi, C1-C4-alkiltio, fenil ili fenoksi, pri čemu fenilni ostaci sa svoje strane mogu nositi jedan do pet halogenih atoma i/ili jedan do tri slijedeća ostatka: C1-C4-alkil, C1-C4-halogenalkil, C1-C4-alkoksi, C1-C4-halogenalkoksi i/ili C1-C4-alkiltio; a five-membered or six-membered heteroaromatic, containing one to three nitrogen atoms and/or a sulfur or oxygen atom, which may carry one to four halogen atoms and/or one to two of the following residues: C1-C4-alkyl, C1-C4-haloalkyl, C1 -C4-Alkoxy, trifluoromethoxy, C1-C4-alkylthio, phenyl or phenoxy, whereby the phenyl residues can carry one to five halogen atoms and/or one to three of the following residues: C1-C4-alkyl, C1-C4- haloalkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy and/or C1-C4-alkylthio;
R15 je metoksi ili etoksi, koji može nositi jedan od slijedećih ostataka: hidroksi, karboksi, amino, NH(C1-C4-alkil), N(C1-C4-alkil)2, karboksamid ili CON (C1-C4-alkil) 2; R15 is methoxy or ethoxy, which can carry one of the following residues: hydroxy, carboxy, amino, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, carboxamide or CON (C1-C4-alkyl)2 ;
W je sumpor ili kisik; W is sulfur or oxygen;
Q je C2-C4-alkil, C3-C4-alkenil, C3-C4-alkinil, -S-CH2-CH2-, -O-CH2-CH2-, pri čemu ti ostaci mogu biti jednostruko ili višestruko supstituirani s halogenim, hidroksi, merkapto, karboksi, C1-C4-alkilom, C1-C4-alkoksi, C1-C4-alkiltio ili fenilom, koji može biti jednostruko ili višestruko supstituiran, npr. jednostruko do trostruko s halogenim, nitro, cijano, C1-C4-alkilom, C1-C4-halogen-alkilom, C1-C4-alkoksi, C1-C4-halogenalkoksi ili C1-C4-alkiltio; ili Q is C2-C4-alkyl, C3-C4-alkenyl, C3-C4-alkynyl, -S-CH2-CH2-, -O-CH2-CH2-, where these residues can be mono- or multi-substituted with halogen, hydroxy , mercapto, carboxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio or phenyl, which may be singly or multiply substituted, e.g. singly to triply with halogen, nitro, cyano, C1-C4-alkyl , C1-C4-halo-alkyl, C1-C4-alkoxy, C1-C4-halogenalkoxy or C1-C4-alkylthio; or
Q zajedno s R6 tvori slijedeći prstenasti sistem: indan-2-il, indan-3-il, 1,2,3,4-tetrahidronaft-2-il, 1,2,3,4- tetrahidronaft-3-il, pri čemu fenilni prsten može biti supstituiran s halogenim, hidroksi, merkapto, karboksi, cijano, C1-C4- alkoksi,C1-C4-alkilom, C2-C4-alkenilom, C2-C4-alkinilom, C3-C6-alkeniloksi, C3-C6-alkiniloksi, C1-C4-alkiltio, C1-C4- alogenalkoksi, C1-C4-alkilkarbonil, NH (C1-C4-alkil) , N (C1-C4-alkil) 2 ili s fenilom. Q together with R6 forms the following ring system: indan-2-yl, indan-3-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-3-yl, at where the phenyl ring may be substituted with halogen, hydroxy, mercapto, carboxy, cyano, C1-C4- alkoxy, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-alkenyloxy, C3-C6 -alkynyloxy, C1-C4-alkylthio, C1-C4-halogenalkoxy, C1-C4-alkylcarbonyl, NH (C1-C4-alkyl), N (C1-C4-alkyl) 2 or with phenyl.
Spojevi predloženog izuma nude novu terapeutsku mogućnost za liječenje hipertonije, pulmonalnog visokog tlaka, infarkta miokarda, kronične srčane insuficijencije, angine pectoris, akutnog/kroničnog otkazivanja bubrega, insuficijencije bubrega, cerebralnih vazospazmi, cerebralne ishemije, subarahnoidnih krvarenja, migrene, astme, ateroskleroze, "endotoksičkog šoka, otkazivanja organa induciranih endotoksinom, intravaskularne koagulacije, restenoze nakon angioplastije, benigne hiperplazije prostate, ishemijskog i otkazivanja bubrega uzrokovanog intoksikacijom, odnosno hipertonije, metastaziranja i rasta mezenhimalnih tumora, otkazivanja bubrega induciranog kontratstnim sredstvom, pankreatitisa, gastrointestinalnog čira. The compounds of the proposed invention offer a new therapeutic option for the treatment of hypertension, pulmonary hypertension, myocardial infarction, chronic heart failure, angina pectoris, acute/chronic renal failure, renal failure, cerebral vasospasm, cerebral ischemia, subarachnoid hemorrhage, migraine, asthma, atherosclerosis, " endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostatic hyperplasia, ischemic and intoxication-induced kidney failure, i.e. hypertension, metastasis and growth of mesenchymal tumors, contrast agent-induced kidney failure, pancreatitis, gastrointestinal ulcer.
Spojevi prema izumu pokazuju iznenađujuće, povremeno također antagonističke djelovanje prema neurokinin-receptoru. The compounds according to the invention show a surprising, occasionally also antagonistic action against the neurokinin receptor.
To se posebno susreće kod spojeva formule I u kojima R1 predstavlja This is particularly the case with compounds of formula I in which R1 represents
[image] [image]
Daljni predmet izuma su kombinirani pripravci od antagonista endotelin-receptora formule I i inhibitora sistema renin-angiotenzina. Inhibitori sistema renin-angiotenzina su inhibitori renina, angiotenzin-II-antagonista i prije svega enzima koji pretvara angiotenzin, (AGE)-inhibitora. A further subject of the invention are combined preparations of endothelin-receptor antagonists of formula I and inhibitors of the renin-angiotensin system. Inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin-II-antagonists and, above all, angiotensin-converting enzyme (AGE)-inhibitors.
Daljnji predmet izuma su kombinirani pripravci iz β-blokera i gore navedenih antagonista endotelin-receptora kao i miješanih ACE-neutralnih (NEP)-inhibitora endopeptidaze i gore navedenih antagonista endotelin-receptora. A further subject of the invention are combined preparations from β-blockers and the above-mentioned endothelin-receptor antagonists, as well as mixed ACE-neutral (NEP) endopeptidase inhibitors and the above-mentioned endothelin-receptor antagonists.
Kombinirani pripravci mogu se dati u jednom jedinstvenom galenskom obliku ili također u prostorno odvojenim oblicima. Davanje se može izvršiti istovremeno ili vremenski stupnjevano. Combined preparations can be given in a single galenic form or also in spatially separate forms. Administration can be done simultaneously or time-graded.
U slučaju kombinacije doziranje može ići sve do najveće količine dotične pojedinačne doze. Međutim, također se mogu primijeniti manje doze nego kod dotične pojedinačne terapije. In the case of a combination, the dosage can go up to the highest amount of the individual dose in question. However, lower doses can also be administered than with the individual therapy concerned.
Ti kombinirani pripravci prikladni su prije svega za liječenje i suzbijanje hipertenzije i bolesti koje iz nje proizlaze, te za liječenje srčane insuficijencije. These combined preparations are suitable above all for the treatment and suppression of hypertension and diseases resulting from it, and for the treatment of heart failure.
Dobro djelovanje spojeva može se pokazati u slijedećim pokusima: The good performance of the compounds can be demonstrated in the following experiments:
Proučavanje vezanja receptora Study of receptor binding
Za proučavanje vezanja koriste se klonirane CHO-stanice koje eksprimiraju ETA- ili ETB-receptor. Cloned CHO cells expressing the ETA- or ETB-receptor are used for binding studies.
Priprava membrana Preparation of membranes
CHO-stanice, koje eksprimiraju ETA- ili ETB-receptor, umnožene su DMEM NUT MIX F12-mediju (Gibco, br. 21331-020) s 10% fetalnog telećeg seruma (PAA Laboratories GmbH, Linz, br. A15-022), 1 mM glutamina (Gibco br. 25030-024), 100 E/ml penicilina i 100 µg/ml streptomicina (Gibco, Sigma br. P-0781) . Nakon 48 sati stanice se isperu sPBS-om i inkubiraju se 5 minuta s PBS-om koji sadrži 0,05% tripsina. Nakon toga se neutraliziraju s medijem i stanice se skupe centrifugiranjem pri 300 x g. CHO cells expressing the ETA- or ETB-receptor were propagated in DMEM NUT MIX F12-medium (Gibco, no. 21331-020) with 10% fetal calf serum (PAA Laboratories GmbH, Linz, no. A15-022), 1 mM glutamine (Gibco no. 25030-024), 100 U/ml penicillin and 100 µg/ml streptomycin (Gibco, Sigma no. P-0781). After 48 hours the cells are washed with PBS and incubated for 5 minutes with PBS containing 0.05% trypsin. After that, they are neutralized with the medium and the cells are harvested by centrifugation at 300 x g.
Za pripravljanje membrana stanice se namjeste na koncentraciju od 108 stanica/ml pufera (50 ml Tris HCl pufer, pH 7,4) i zatim se dezintegriraju ultrazvukom (Branson Sonifier 250, 40-70 sekundi/konstatno/učin 20). To prepare the membranes, cells are adjusted to a concentration of 108 cells/ml buffer (50 ml Tris HCl buffer, pH 7.4) and then disintegrated by ultrasound (Branson Sonifier 250, 40-70 seconds/constant/power 20).
Ispitivanja vezanja Binding tests
Za ispitivanje vezanja ETA- i ETB-receptora membrane se suspendiraju u inkubacijskom puferu (50 mM tris-HCl, pH 7,4 s 5 mM MnCl2, 40 µg/ml bacitracina i 0,2% BSA) u koncentraciji od 50 µg proteina po ispitnoj smjesi i inkubiraju se pri 25°C s 25 pM 125J-ET1 (ispitivanje ETA-receptora) ili 25 pM 125J-RZ3 (ispitivanje ETB-receptora) u prisutnosti i odsutnosti ispitne tvari. Nespecifično vezanje određuje se s 10-7 M ET1. Nakon 30 minuta razdvoje se slobodan i vezani radioligand filtriranjem preko filtera od staklenih vlakana GF/B (Whatman, Engleska) na skupljaču stanica Skatron (Skatron, Lier, Norveška) i filter se ispere s ledeno hladnim puferom tris-HCl, pH 7,4 s 0,2% BSA. Radioaktivnost skupljena na filterima kvantitativno se odredi pomoću scintilacijskog brojača za tekućine Packard 2200 CA. To test the binding of ETA- and ETB-receptors, membranes are suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl2, 40 µg/ml bacitracin and 0.2% BSA) at a concentration of 50 µg protein per test mixture and are incubated at 25°C with 25 pM 125J-ET1 (ETA-receptor assay) or 25 pM 125J-RZ3 (ETB-receptor assay) in the presence and absence of the test substance. Non-specific binding is determined by 10-7 M ET1. After 30 minutes, free and bound radioligand are separated by filtration through a GF/B glass fiber filter (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway) and the filter is washed with ice-cold Tris-HCl buffer, pH 7.4 with 0.2% BSA. Radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Ispitivanje ET-antagonista in vivo Testing of ET-antagonists in vivo
Mužjaci SD štakora težine 250 - 300 g narkotizirani su s amobarbitalom, priključeni na umjetno disanje, vagotomizirani i despinalizirani. Arteria carotis i vena jugularis bile su katetezirane. Male SD rats weighing 250-300 g were anesthetized with amobarbital, connected to artificial respiration, vagotomized and de-spinalized. The carotid artery and jugular vein were catheterized.
U skupini kontrolnih životinja intravensko davanje 1 µg/kg ET1 dovelo je do jasnog porasta krvnog tlaka, koji se je održao tijekom duljeg vremena. In a group of control animals, intravenous administration of 1 µg/kg ET1 led to a clear increase in blood pressure, which was sustained over a longer period of time.
Pokusnim životinjama, 30 minuta prije davanja ET1, ubrizgani su ispitni spojevi i.v. (1 mg/kg). Za određivanje ET-antagonističkih svojstava porast krvnog tlaka pokusnih životinja bio je uspoređen s onim kod kontrolnih životinja. Experimental animals, 30 minutes before the administration of ET1, were injected with the test compounds i.v. (1 mg/kg). To determine the ET-antagonistic properties, the increase in blood pressure of experimental animals was compared with that of control animals.
p.o. - ispitivanje miješanih ETA- i ETB-antagonista: per. - testing of mixed ETA- and ETB-antagonists:
Mužjaci normoton štakora težine 250-350 g (Sprague Dawley, Janvier) najprije se oralno primili ispitne tvari. 80 minuta kasnije životinje su narkotizirane s uretanom, a arteria carotis (za mjerenje krvnog tlaka) kao i vena jugularis (aplikacija big endotelin/endotelin 1) bile su katetezirane. Male normotensive rats weighing 250-350 g (Sprague Dawley, Janvier) were first orally administered the test substances. 80 minutes later the animals were anesthetized with urethane, and the carotid artery (for blood pressure measurement) as well as the jugular vein (big endothelin/endothelin 1 application) were catheterized.
Nakon faze stabilizacije, intravenski je dat big endotelin (20 µg/kg, apl. vol. 0,5 ml/kg), odnosno ET1 (0,3 µg/kg, apl . vol. 0,5 ml/kg). Krvni tlak i srčana frekvencija registrirani su kontinuirano tijekom 30 minuta. Jasne i trajne promjene krvnog tlaka računate su kao površine ispod krivulje (AUC). Za određivanje antagonističkog djelovanja ispitnih tvari AUC životinja koje su primile ispitne tvari uspoređen je s kontrolnim životinjama. After the stabilization phase, big endothelin (20 µg/kg, apl. vol. 0.5 ml/kg) or ET1 (0.3 µg/kg, apl. vol. 0.5 ml/kg) was given intravenously. Blood pressure and heart rate were registered continuously for 30 minutes. Clear and persistent changes in blood pressure were calculated as area under the curve (AUC). To determine the antagonistic effect of the test substances, the AUC of the animals that received the test substances was compared with the control animals.
Spojevi prema izumu mogu se davati na uobičajen način oralno ili parenteralno (subkutano, intravenski, intramuskularno, intraperitonealno). Aplikacije se također mogu izvršiti s parama ili sprejevima putevima nos-ždrijelo. The compounds according to the invention can be administered in the usual way orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Applications can also be made with vapors or sprays through the nasopharyngeal route.
Doziranje ovisi o starosti, stanju i težini pacijenta, te o načinu aplikacije. U pravilu dnevna doza aktivne tvari iznosi između 0,5 i 50 mg/kg tjelesne težine kod oralnog davanja i između 0,1 i 10 mg/kg tjelesne težine kod parenteralnog davanja. The dosage depends on the age, condition and weight of the patient, and on the method of application. As a rule, the daily dose of the active substance is between 0.5 and 50 mg/kg of body weight for oral administration and between 0.1 and 10 mg/kg of body weight for parenteral administration.
Novi spojevi mogu se primijeniti u upotrebljivim galenskim oblicima aplikacija čvrsti ili tekući, npr. kao tablete, filmske tablete, kapsule, prašak, granule, dražeje, čepići, otopine, masti, kreme ili sprejevi. Oni se pripremaju na uobičajen način. Pri tome, aktivne tvari mogu se preraditi s uobičajenim galenskim pomoćnim sredstvima kao vezivima za tablete, punilima, konzervansima, sredstvima za rastvaranje tableta, sredstvima za regulaciju tečenja, omekšivačima, sredstvima za umreživanje, sredstvima za dispergiranje, emulgatorima, otapalima, sredstvima za produženo oslobađanje aktivne tvari, antioksidantima i/ili potisnim plinovima (usporedi H. Sucker et al.; Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). Tako dobiveni aplikacijski oblici sadrže aktivnu tvar obično količinom od 0,1 do 90 mas. %. The new compounds can be administered in usable solid or liquid galenic application forms, eg as tablets, film-coated tablets, capsules, powder, granules, dragees, suppositories, solutions, ointments, creams or sprays. They are prepared in the usual way. In doing so, the active substances can be processed with the usual galenic auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow control agents, softeners, cross-linking agents, dispersing agents, emulsifiers, solvents, extended-release agents. active substances, antioxidants and/or propellant gases (compare H. Sucker et al.; Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). Application forms obtained in this way contain the active substance usually in an amount of 0.1 to 90 wt. %.
Primjeri sinteze Examples of synthesis
Primjer 1 Example 1
2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-difenil-propionska kiselina metil ester 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid methyl ester
7 g (27,5 mmolova) metil estera 3,3-epoksipropionske kiseline i 5,5 g (30,2 mmolova) 2-(3,4-dimetoksifenil)-etanola otopi se u 20 ml diklormetana i pri sobnoj temperaturi doda se 5 kapi bor-trifluorid-eterata. Otopinu se miješa dva sata. Zatim se otapalo izdestilira i ostatak (10,7 g, 89%) se izravno dalje pretvara. 7 g (27.5 mmol) of methyl ester of 3,3-epoxypropionic acid and 5.5 g (30.2 mmol) of 2-(3,4-dimethoxyphenyl)-ethanol are dissolved in 20 ml of dichloromethane and added at room temperature 5 drops of boron trifluoride etherate. The solution is stirred for two hours. The solvent is then distilled off and the residue (10.7 g, 89%) is converted directly further.
Primjer 2 Example 2
2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3, 3-difenil-propionska kiselina 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3, 3-diphenyl-propionic acid
12 g (27,5 mmolova) metil estera 2-hidroksi-3-(2-(3,4-dimetoksi-fenil)etoksi)-3,3-difenilpropionske kiseline otopi se u 110 ml dioksana i pomiješa se s 55 ml 1N otopinom NaOH. Smjesu se miješa dva sata pri 80°C. K smjesi se doda vodu i vodenu fazu se ekstrahira dva puta s eterom. Vodenu fazu se zakiseli s 1N vodenom octenom kiselinom, ekstrahira se s eterom, organsku fazu se osuši preko magnezijevog sulfata i otapalo se izdestilira. Ostatak se prekristalizira izeter/n-heksana i može se izolirati 10,2 g (87%) bezbojnih kristala. 12 g (27.5 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid methyl ester are dissolved in 110 ml of dioxane and mixed with 55 ml of 1N with NaOH solution. The mixture is stirred for two hours at 80°C. Water is added to the mixture and the aqueous phase is extracted twice with ether. The aqueous phase is acidified with 1N aqueous acetic acid, extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is distilled off. The residue was recrystallized from ether/n-hexane and 10.2 g (87%) of colorless crystals could be isolated.
Talište: 133-135°C. Melting point: 133-135°C.
Primjer 3 Example 3
2-(4-metoksi-6-metil)-pirimidin-2-iloksi)-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-482) 2-(4-Methoxy-6-methyl)-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-482)
1 g (2,3 mmola) 2-hidroksi-3-(2-(3,4-dimetoksifenil)-etoksi)-3,3-difenilpropionske kiseline stavi se u 10 ml DMF-a i doda se 340 mg NaH (50%-tna suspenzija) . Nakon 15 minuta miješanja smjesu se pomiješa s 526 mg 4-metoksi-6-metil-2-metilsulfonilpirimidina i miješa se tri sata pri sobnoj temperaturi. Smjesu se pomiješa s vodom i reakcijsku smjesu se ekstrahira s eterom. Vodenu fazu se zakiseli s 1N vodenom HCl, ekstrahira s eterom i osuši preko magnezijevog sulfata. Otapalo se izdestilira, ostatak se očisti pomoću MPLC i nakon prekristalizacije iz eter/n-heksana izolira se 655 mg (52%) bezbojnog praha. 1 g (2.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)-ethoxy)-3,3-diphenylpropionic acid is placed in 10 ml of DMF and 340 mg of NaH (50 % suspension). After stirring for 15 minutes, the mixture was mixed with 526 mg of 4-methoxy-6-methyl-2-methylsulfonylpyrimidine and stirred for three hours at room temperature. The mixture was mixed with water and the reaction mixture was extracted with ether. The aqueous phase is acidified with 1N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent is distilled off, the residue is purified by MPLC and after recrystallization from ether/n-hexane, 655 mg (52%) of a colorless powder is isolated.
1H-NMR (200 MHz) : 7,2 ppm (10 H, m); 6, 8 (3H, m); 6,2 (1H, s); 6,18 (1H, s); 3,9 (9H, m); 3,8 (1H, m); 3,7 (1H, m); 2,85 (2H, tr); 2,2 (3H, s) . 1H-NMR (200 MHz): 7.2 ppm (10 H, m); 6, 8 (3H, m); 6.2 (1H, s); 6.18 (1H, s); 3.9 (9H, m); 3.8 (1H, m); 3.7 (1H, m); 2.85 (2H, tr); 2.2 (3H, s) .
ESI-MS: M+ = 544 ESI-MS: M+ = 544
Primjer 4 Example 4
3,3-di(4-etilfenil)-2,3-epoksipropionska kiselina metil ester 3,3-di(4-ethylphenyl)-2,3-epoxypropionic acid methyl ester
K suspenziji od 9,1 g (168 mmolova) natrijevog metanolata u 80 ml THF-a pri -10°C dokaplje se otopinu od 15 ml (168 mmolova) metil estera kloroctene kiseline i 20 g (84 mmola) 4,4' -dietilbenzofenona u 20 ml THF-a. Smjesu se miješa 2 sata pri sobnoj temperaturi. Zatim se smjesu prenese na vodu i ekstrahira s eterom. Organsku fazu se ispere s otopinom natrijevog hidrogen karbonata i s otopinom limunske kiseline, osuši se preko magnezijevog sulfata i otapalo se izdestilira. Može se izolirati 15,4 g sirovog ulja, koje se izravno dalje koristi. A solution of 15 ml (168 mmol) methyl ester of chloroacetic acid and 20 g (84 mmol) of 4,4'- of diethylbenzophenone in 20 ml of THF. The mixture is stirred for 2 hours at room temperature. The mixture is then transferred to water and extracted with ether. The organic phase is washed with sodium hydrogen carbonate solution and citric acid solution, dried over magnesium sulfate and the solvent is distilled off. 15.4 g of crude oil can be isolated, which is directly used further.
Primjer 5 Example 5
2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-di(4-etil-fenil)propionska kiselina metil ester 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethyl-phenyl)propionic acid methyl ester
6 g (19,3 mmola) metil estera 3,3-di(4-etilfenil)-2,3-epoksipropionske kiseline (sirovog) i 3,52 g (19,3 mmolova) 2-(3,4-dimetoksifenil)etanola otopi se u 20 ml diklormetana i pri sobnoj temperaturi doda se 5 kapi bortrifluorid eterata. Otopinu se miješa 1,5 sata. Zatim se otapalo izdestilira i ostatak, slabo žuto ulje (8,66 g, 91%) se izravno dalje kemijski pretvara. 6 g (19.3 mmol) methyl ester of 3,3-di(4-ethylphenyl)-2,3-epoxypropionic acid (crude) and 3.52 g (19.3 mmol) 2-(3,4-dimethoxyphenyl) of ethanol is dissolved in 20 ml of dichloromethane and 5 drops of boron trifluoride ether are added at room temperature. The solution is stirred for 1.5 hours. The solvent is then distilled off and the residue, a pale yellow oil (8.66 g, 91%) is directly further chemically converted.
Primjer 6 Example 6
2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-di(4-etil-fenil)propionska kiselina 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethyl-phenyl)propionic acid
9,2 g (19,3 mmolova) metil estera 2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-di(4-etilfenil)propionske kiseline otopi se u 26 ml dioksana i pomiješa se s 13 ml 3N otopine NaOH. Smjesu se miješa 3 sata pri 60°C. K reakcijskoj smjesi doda se vodu i vodenu fazu se ekstrahira dva puta s eterom. Vodenu fazu se zakiseli s 1N vodenom HCl, i ekstrahira s eterom, organsku fazu se osuši preko magnezijevog sul'fata i otapalo se izdestilira. Izolira se 6,5 g (71%) žućkastog ulja, koje se izravno dalje kemijski pretvara. 9.2 g (19.3 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid methyl ester were dissolved in 26 ml of dioxane and it is mixed with 13 ml of 3N NaOH solution. The mixture is stirred for 3 hours at 60°C. Water is added to the reaction mixture and the aqueous phase is extracted twice with ether. The aqueous phase is acidified with 1N aqueous HCl and extracted with ether, the organic phase is dried over magnesium sulfate and the solvent is distilled off. 6.5 g (71%) of a yellowish oil is isolated, which is directly further chemically converted.
Primjer 7 Example 7
2- (4-metoksi-6-metil-pirimidin-2-iloksi) -3-(2-(3, 4-dimetoksifenil) etoksi)-3,3-di(4-etil-fenil)propionska kiselina(I-116) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(3, 4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethyl-phenyl)propionic acid (I- 116)
1,8 g (3,8 mmola) 2-hidroksi-3-(2-(3,4-dimetoksi-fenil)etoksi)-3,3-di(4-etilfenil)propionske kiseline stavi se u 20 ml DMF-a i doda se 554 mg NaH (50%-tna suspenzija) . Nakon 15 minuta miješanja smjesu se pomiješa s 855 mg (4,2 mmola) 4-metoksi-6-metil-2-metilsulfonil-pirimidina i miješa se 3 sata pri sobnoj temperaturi. Smjesu se pomiješa s vodom i ekstrahira s eterom. Vodenu fazu se zakiseli s 1N vodenom HCl, ekstrahira s eterom i osuši preko magnezijevog sulfata. Otapalo se izdestilira i nakon prekristalizacije iz eter/n-heksana izolira se 540 mg (23%) bezbojnog praha. 1.8 g (3.8 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid is placed in 20 ml of DMF- and 554 mg of NaH (50% suspension) is added. After stirring for 15 minutes, the mixture was mixed with 855 mg (4.2 mmol) of 4-methoxy-6-methyl-2-methylsulfonyl-pyrimidine and stirred for 3 hours at room temperature. The mixture is mixed with water and extracted with ether. The aqueous phase is acidified with 1N aqueous HCl, extracted with ether and dried over magnesium sulfate. The solvent is distilled off and after recrystallization from ether/n-hexane, 540 mg (23%) of a colorless powder is isolated.
1H-NMR (200 MHz) : 7,0-7,4 ppm (10 H, m); 6,8 (2H, d); 6,2 (1H, s); 6,15 (1H, s); 3,9 (3H, s); 3,8 (3H, s); 3,7 (1H, m); 3,5 (1H, m); 2,9 (2H, tr) ; 2,6 (4H, m); 2,3 (3H, s); 1,2 (6H, m). 1H-NMR (200 MHz): 7.0-7.4 ppm (10 H, m); 6.8 (2H, d); 6.2 (1H, s); 6.15 (1H, s); 3.9 (3H, s); 3.8 (3H, s); 3.7 (1H, m); 3.5 (1H, m); 2.9 (2H, tr) ; 2.6 (4H, m); 2.3 (3H, s); 1.2 (6H, m).
ESI-MS: M+ = 600 ESI-MS: M+ = 600
Primjer 8 Example 8
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(3-fenilprop- (2E)-enoksi)-3,3-difenilpropionska kiselina (I-27) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-phenylprop-(2E)-enoxy)-3,3-diphenylpropionic acid (I-27)
K suspenziji od 432 mg (9 mmolova, 50%) NaH u 20 ml DMF-a doda se 1,12 g (3 mmola) 2-hidroksi-3- (3-fenilprop-(2E)-enoksi)-3,3-difenilpropionske kiseline i miješa se 10 minuta pri sobnoj temperaturi. Nakon dodatka 614 mg (3,3 mmola) 4, 6-dimetil-1-metil-sulfonilpirimidina miješa se 16 sati, zatim se razrijedi s 200 ml vode, zakiseli se s 1N solnom kiselinom i esktrahira s eterom. Fazu u eteru se ekstrahira s 1N natrijevom lužinom, vodenu fazu se ponovno zakiseli i proizvod se ekstrahira s eterom. Organsku fazu se osuši preko magnezijevog sulfata, filtrira i otapalo se izdestilira. Ostatak se prekristalizira iz eter/heksana i izolira se 927 mg (65%) kristaliničnog proizvoda. To a suspension of 432 mg (9 mmol, 50%) of NaH in 20 ml of DMF was added 1.12 g (3 mmol) of 2-hydroxy-3-(3-phenylprop-(2E)-enoxy)-3,3 -diphenylpropionic acid and mixed for 10 minutes at room temperature. After the addition of 614 mg (3.3 mmol) of 4, 6-dimethyl-1-methyl-sulfonylpyrimidine, it is stirred for 16 hours, then diluted with 200 ml of water, acidified with 1N hydrochloric acid and extracted with ether. The ether phase is extracted with 1N sodium hydroxide solution, the aqueous phase is acidified again and the product is extracted with ether. The organic phase is dried over magnesium sulfate, filtered and the solvent is distilled off. The residue was recrystallized from ether/hexane and 927 mg (65%) of the crystalline product was isolated.
Talište: 128-133°C. Melting point: 128-133°C.
1H-NMR (200 MHz) : 7,3 ppm (15 H, m); 6,74 (1H, s); 6,7 (1H, d); 6,3 (1H, s); 6,2 (1H, dtr) ; 4,3 (1H, dd) ; 4,1 (1H, dd); 2,3 (6H, s). 1H-NMR (200 MHz): 7.3 ppm (15 H, m); 6.74 (1H, s); 6.7 (1H, d); 6.3 (1H, s); 6.2 (1H, dtr) ; 4.3 (1H, dd) ; 4.1 (1H, dd); 2.3 (6H, s).
ESI-MS: M+ = 480 ESI-MS: M+ = 480
Primjer 9 Example 9
4,6-dimetil-1-metiltio-pirimidin 4,6-dimethyl-1-methylthio-pyrimidine
15 g (107 mmolova) 4,6-dimetil-1-merkaptopirimidina i 5,14 g NaOH otopi se u 175 ml vode. K toj smjesi, pri sobnoj temperaturi tijekom 10 minuta, dokaplje se 12 ml (128 mmolova) dimetil sulfata. Nakon jednog sata vodenu fazu ekstrahira se tri puta s eterom, osuši preko magenzijevog sulfata i otapalo se izdestilira. Može se izolirati 15,9 g (97%) sirovog proizvoda. 15 g (107 mmol) of 4,6-dimethyl-1-mercaptopyrimidine and 5.14 g of NaOH are dissolved in 175 ml of water. 12 ml (128 mmol) of dimethyl sulfate was added dropwise to this mixture at room temperature for 10 minutes. After one hour, the aqueous phase is extracted three times with ether, dried over magnesium sulfate and the solvent is distilled off. 15.9 g (97%) of crude product can be isolated.
1H-NMR (270 MHz): 6,7 (1H, s); 2,5 (3H, s); 2,3 (6H, s). 1H-NMR (270 MHz): 6.7 (1H, s); 2.5 (3H, s); 2.3 (6H, s).
Primjer 10 Example 10
4, 6-dimetil-1-metilsulfonil-pirimidin 4, 6-dimethyl-1-methylsulfonyl-pyrimidine
15,9 g (103 mmola) 4,6-dimetil-1-metiltio-pirimidina stavi se u 120 ml diklormetana i 110 ml vode. Pri 0°C uvodi se plinoviti klor do zasićenja (žuto obojenje). Nakon potpune kemijske pretvorbe klor se istjera s dušikom, vodenu fazu se ekstrahira s diklormetanom i skupljenu organsku fazu se osuši preko magnezijevog sulfata. Otopinu se zgusne i proizvod izkristalizira dodatkom etera (14,0 g, 73%). 15.9 g (103 mmol) of 4,6-dimethyl-1-methylthio-pyrimidine are placed in 120 ml of dichloromethane and 110 ml of water. At 0°C, gaseous chlorine is introduced until saturation (yellow coloration). After complete chemical conversion, chlorine is expelled with nitrogen, the aqueous phase is extracted with dichloromethane and the collected organic phase is dried over magnesium sulfate. The solution is concentrated and the product is crystallized by adding ether (14.0 g, 73%).
Talište: 79-80°C. Melting point: 79-80°C.
1H-NMR (270 MHz): 7,2 ppm (1H, s); 3,4 (3H, s); 2,6 (6H, s) . 1H-NMR (270 MHz): 7.2 ppm (1H, s); 3.4 (3H, s); 2.6 (6H, s) .
Primjer 11 Example 11
(S)-2-hidroksi-3-metoksi-3,3-difenilpropionska kiselina metil ester (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester
U 300 ml DMF-a stavi se 54,4 g (200 mmolova) (S)-2-hidroksi-3-metoksi-3,3-difenilpropionske kiseline s 10,8 g (200 mmolova) natrijevog metilata. K toj suspenziji dokaplje se tijekom 15 minuta 21 ml (210 mmolova) dimetil sulfata, pri čemu temperatura poraste na 50°C i suspenzija postane nisko viskozna. Smjesu se miješa preko noći i zatim se prelije na 1,5 l vode i leda. Vodenu fazu ekstrahira se dva puta s 500 ml etera i etersku fazu ispere se opet dva puta s 200 ml vode. Organsku fazu se osuši preko magnezijevog sulfata, sredstvo za sušenje se odfiltrira i otapalo se izdestilira. Izolira se 55,8 g ulja koje se izravno dalje prerađuje. 54.4 g (200 mmol) of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid with 10.8 g (200 mmol) of sodium methylate are added to 300 ml of DMF. 21 ml (210 mmol) of dimethyl sulfate are added dropwise to this suspension over 15 minutes, during which the temperature rises to 50°C and the suspension becomes low-viscosity. The mixture is stirred overnight and then poured over 1.5 l of water and ice. The aqueous phase is extracted twice with 500 ml of ether and the ether phase is washed again twice with 200 ml of water. The organic phase is dried over magnesium sulfate, the drying agent is filtered off and the solvent is distilled off. 55.8 g of oil is isolated, which is further processed directly.
Primjer 12 Example 12
(S)-2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-difenil-propionska kiselina metil ester (S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid methyl ester
Inačica A: Version A:
U tikvici se pomiješa 27,9 g metil estera (S)-2-hidroksi-3-metoksi-3,3-difenil-propionske kiseline (100 mmolova) s 1 g p-toluolsulfonske kiseline i 18,2 g 2-(3,4-dimetoksifenil) etanola (100 mmolova) i zagrije se na 60°C. Na tikvicu se priključi vakuum da se izdestilira nastali metanol i miješa se dalje još 5 sati pri 60°C. Za obradu smjesu se ohladi, razrijedi se s 300 ml etera i organsku fazu se najprije ispere s otopinom natrijevog hidrogen karbonata i zatim više puta s vodom. Zatim se osuši s magnezijevim sulfatom, otapalo se odfiltrira i otapalo se izdestilira. Izolira se ostatak od 43 g ulja, koje se može izravno upotrijebiti u slijedećoj sintezi. In a flask, 27.9 g of (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid methyl ester (100 mmol) are mixed with 1 g of p-toluenesulfonic acid and 18.2 g of 2-(3 ,4-dimethoxyphenyl) ethanol (100 mmol) and heated to 60°C. A vacuum is connected to the flask to distill off the resulting methanol and it is stirred for another 5 hours at 60°C. For processing, the mixture is cooled, diluted with 300 ml of ether and the organic phase is first washed with sodium hydrogen carbonate solution and then several times with water. It is then dried with magnesium sulfate, the solvent is filtered off and the solvent is distilled off. A residue of 43 g of oil is isolated, which can be used directly in the next synthesis.
Inačica B: Version B:
U tikvici se otopi 27,9 g metil estera (S)-2-hidroksi-3-metoksi-3,3-difenil-propionska kiselina (100 mmolova), 1 g p-toluolsulfonske kiseline i 18,2 g (100 mmolova) 2-(3,4-dimetoksifenil)etanola u 75 ml diklor-metana. Otopinu se zagrije i diklormetan se izdestilira uz istovremeno dokapavanje diklormetana da se izdestilira nastali metanol i miješa se dalje još 5 sati pri 60°C. Za obradu smjesu se ohladi, razrijedi se s 300 ml etera i organsku fazu se najprije ispere s otopinom natrijevog hidrogen karbonata i zatim više puta s vodom. Zatim se osuši s magnezijevim sulfatom, sredstvo za sušenje se odfiltrira i otapalo se izdestilira. Izolira se ostatak od 43 g ulja, koje se može izravno upotrijebiti u slijedećoj sintezi. 27.9 g of methyl ester (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid (100 mmol), 1 g of p-toluenesulfonic acid and 18.2 g (100 mmol) are dissolved in the flask. of 2-(3,4-dimethoxyphenyl)ethanol in 75 ml of dichloromethane. The solution is heated and dichloromethane is distilled off while dichloromethane is added dropwise to distill off the resulting methanol and it is stirred for another 5 hours at 60°C. For processing, the mixture is cooled, diluted with 300 ml of ether and the organic phase is first washed with sodium hydrogen carbonate solution and then several times with water. It is then dried with magnesium sulfate, the drying agent is filtered off and the solvent is distilled off. A residue of 43 g of oil is isolated, which can be used directly in the next synthesis.
Primjer 13 Example 13
(S)-2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-difenil-propionska kiselina (S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid
K otopini od 74 g (170 mmolova) metil estera (S)-2-hidroksi-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-difenil-propionske kiseline u 510 ml dioksana doda se 255 ml 1N natrijeve lužine i suspenziju se miješa dva sata pri 50°C. Smjesu se razrijedi s 2,5 l vode i neutralizira se s limunskom kiselinom. Vodene faze se ekstrahiraju dva puta s 500 ml etera. Zatim se vodenu fazu ispere s vodom, osuši preko magnezijevog sulfata i nakon filtracije eter se izdestilira. Ostatak se očisti kristalizacijom iz eter/n-heksana i izolira se 70 g kristala. To a solution of 74 g (170 mmol) methyl ester (S)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl-propionic acid in 510 ml of dioxane, add 255 ml 1N sodium hydroxide solution and the suspension is stirred for two hours at 50°C. The mixture is diluted with 2.5 l of water and neutralized with citric acid. The aqueous phases are extracted twice with 500 ml of ether. Then the aqueous phase is washed with water, dried over magnesium sulfate and after filtration the ether is distilled off. The residue was purified by crystallization from ether/n-hexane and 70 g of crystals were isolated.
1H-NMR (200 MHz) : 7,3 ppm, (10H, m); 6,8 (1H, dbr) ; 6,7 (1H, dbr); 6,6 (1H, sbr) ; 5,0 (1H, s); 3,9 (3H, s); 3,85 (3H, s); 3,6 (1H, dt) ; 3,4 (1H, OH) ; 3,2 (1H, dt) ; 2,8 (2H, t) . 1H-NMR (200 MHz): 7.3 ppm, (10H, m); 6.8 (1H, dbr) ; 6.7 (1H, dbr); 6.6 (1H, sbr) ; 5.0 (1H, s); 3.9 (3H, s); 3.85 (3H, s); 3.6 (1H, dt) ; 3.4 (1H, OH) ; 3.2 (1H, dt) ; 2.8 (2H, t) .
[α]20 - 8,3 (1; etanol) . [α]20 - 8.3 (1; ethanol) .
Primjer 14 Example 14
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(3,4-dimetoksi-fenil)etoksi)-3,3-difenilpropionska kiselina (I-445) i 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-445) and
(S)-2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-445 (S)-enantiomeri) (S)-2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-445 (S)-enantiomers )
U posudu s 9 g (390 mmolova) litijevog amida u 35 ml DMF-a doda se 55 g (130 mmolova) 2-hidroksi-3- (2- (3,4-dimetoksifenil)etoksi)-3,3-difenil-propionske kiseline, otopljene u 150 ml DMF-a. K tome se polako dokaplje 25 g (137 mmolova) 2-metilsulfon-4,6-dimetilpirimidina otopljenog u 75 ml DMF-a i miješa se 18 sati pri sobnoj temperaturi. Za obradu smjesu se prelije na 2 litre ledene vode i za neutralizaciju doda se limunsku kiselinu. Izlučeni kristali se odsisaju i isperu s vodom. Vlažni kristali se otope u diklormetanu, otopinu se osuši preko magnezijevog sulfata, profiltrira i otapalo se izdestilira. Uljasti ostatak se preuzme u eter, ekstrahira sa 130 ml 1 N otopine natrijeve lužine i vodenu fazu se neutralizira sa 130 ml 1 N solne kiseline, pri čemu se izlučuju kristali. Nakon sušenja izolira se 64 g proizvoda. 55 g (130 mmol) of 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenyl- of propionic acid, dissolved in 150 ml of DMF. To this, 25 g (137 mmol) of 2-methylsulfone-4,6-dimethylpyrimidine dissolved in 75 ml of DMF were slowly added dropwise and stirred for 18 hours at room temperature. For processing, the mixture is poured over 2 liters of ice water and citric acid is added for neutralization. The secreted crystals are sucked off and washed with water. Wet crystals are dissolved in dichloromethane, the solution is dried over magnesium sulfate, filtered and the solvent is distilled off. The oily residue is taken up in ether, extracted with 130 ml of 1 N sodium hydroxide solution and the aqueous phase is neutralized with 130 ml of 1 N hydrochloric acid, during which crystals are separated. After drying, 64 g of the product is isolated.
1H-NMR (200 MHz) : 7,3 ppm, (10H, m); 6,7 (4H, m); (6,3 (1H, s); 3,9 (3H, s); 3,85 (3H, s); 3,7 (1H, dt) ; 3,6 (1H, dt) ; 2,8 (2H, t); 2,3 (6H, s). 1H-NMR (200 MHz): 7.3 ppm, (10H, m); 6.7 (4H, m); (6.3 (1H, s); 3.9 (3H, s); 3.85 (3H, s); 3.7 (1H, dt) ; 3.6 (1H, dt) ; 2.8 ( 2H, t); 2.3 (6H, s).
Talište: 125-130°C (rasp.). Melting point: 125-130°C (approx.).
ESI-MS: M+ = 528 ESI-MS: M+ = 528
Analogno je iz (S)-2-hidroksi-3-(3,4-dimetoksi-fenil)etoksi)-3,3-difenilpropionske kiseline i 2-metil-sulfon-4,6- dimetilpirimidina u prisutnosti litijevog amida proizvedena (S)-2-(4, 6-dimetil-pirimidin-2- iloksi)-3-(2-(3,4- dimetoksifenil)etoksi)-3,3-difenilpropionska kiselina. Analogously, (S)-2-hydroxy-3-(3,4-dimethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid and 2-methyl-sulfone-4,6-dimethylpyrimidine in the presence of lithium amide was produced (S )-2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionic acid.
[α]20 = 111 (1; etanol) . [α]20 = 111 (1; ethanol) .
Primjer 15 Example 15
Slijedeći spojevi proizvedeni su analogno primjeru 8. The following compounds were produced analogously to example 8.
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-metoksifenil)etoksi)-3,3-di(4-etilfenil)propionska kiselina (I-147) Talište: 150-155°C 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid (I-147) Melting point: 150-155°C
ESI-MS: M+ = 570 ESI-MS: M+ = 570
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(4-klorfenil)etoksi)-3,3-difenilpropionska kiselina (I-651) Talište: 150-152°C 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid (I- 651) Melting point: 150-152°C
ESI-MS: M+ = 546 ESI-MS: M+ = 546
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(4-klorfenil)etoksi)-3,3-difenilpropionska kiselina (I-713) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid (I-713)
Talište: 108°C (rasp.) Melting point: 108°C (dec.)
ESI-MS: M+ = 502 ESI-MS: M+ = 502
2-(4,6-dimetoksi-pirimidin-2-iloksi)-3-(2-(4-klorfenil) etoksi)-3,3-difenilpropionska kiselina 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid
Talište: 165-167°C Melting point: 165-167°C
ESI-MS: M+ = 534 ESI-MS: M+ = 534
2- (4-metoksi-6-metil-pirimidin-2-iloksi) -3- (2- (4-klorfenil) etoksi)-3,3-difenilpropionska kiselina (I-746) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-chlorophenyl)ethoxy)-3,3-diphenylpropionic acid (I-746)
Talište: 93-98°C Melting point: 93-98°C
ESI-MS: M+ = 518 ESI-MS: M+ = 518
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(4-metoksi-fenil)etoksi)-3,3-di(4-etilfenil)propionska kiselina (I-148) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methoxy-phenyl)ethoxy)-3,3-di(4-ethylphenyl)propionic acid (I-148)
Talište: 130-133°C Melting point: 130-133°C
ESI-MS: M+ = 554 ESI-MS: M+ = 554
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-metilfenil)etoksi)-3,3-di(klorfenil)propionska kiselina (I-710) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-di(chlorophenyl)propionic acid (I-710)
Talište: 90-100°C Melting point: 90-100°C
ESI-MS: M+ = 566 ESI-MS: M+ = 566
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3- (3,3-difenilpropoksi)-3,3-di(klorfenil)propionska kiselina 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3,3-diphenylpropoxy)-3,3-di(chlorophenyl)propionic acid
1H-NMR (200 MHz) : 7,3 ppm, (18H, m); 6,25 (1H, s); 6,0 (1H, s); 4,0 (1H, tr) ; 3,8 (3H, s); 3,4 (2H, m); 2,2 (5H, m). ESI-MS: M+ = 642 1H-NMR (200 MHz): 7.3 ppm, (18H, m); 6.25 (1H, s); 6.0 (1H, s); 4.0 (1H, tr) ; 3.8 (3H, s); 3.4 (2H, m); 2.2 (5H, m). ESI-MS: M+ = 642
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-di(klorfenil)propionska kiselina (1-699) Talište: 100-110°C 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(chlorophenyl)propionic acid (1-699) Melting point: 100-110°C
ESI-MS: M+ - 612 ESI-MS: M+ - 612
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(2-metoksifenil)etoksi)-3,3-di(klorfenil)propionska kiselina (I-487) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(chlorophenyl)propionic acid (I-487)
Talište: 85-90°C Melting point: 85-90°C
ESI-MS: M+ = 582 ESI-MS: M+ = 582
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(3-metoksifenil)etoksi)-3,3-di(klorfenil)-propionska kiselina (I-486) 2-(4-methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(3-methoxyphenyl)ethoxy)-3,3-di(chlorophenyl)- propionic acid (I-486)
Talište: 190-195°C Melting point: 190-195°C
ESI-MS: M+ = 610 ESI-MS: M+ = 610
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-feniletiltio)-3,3-di(klorfenil)propionska kiselina 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-phenylethylthio)-3,3-di(chlorophenyl)propionic acid
Talište: 173-175°C Melting point: 173-175°C
1H-NMR (200 MHz): 7,0-7,4 ppm, (13H, m); 6,0 (1H, s); 4,7 (2H, tr); 3,8 (3H, s); 3,1 (2H, tr); 2,5 (4H, m). 1H-NMR (200 MHz): 7.0-7.4 ppm, (13H, m); 6.0 (1H, s); 4.7 (2H, tr); 3.8 (3H, s); 3.1 (2H, tr); 2.5 (4H, m).
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-di(klorfenil)-propionska kiselina (I-635) 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(chlorophenyl )-propionic acid (I-635)
Talište: 100-110°C Melting point: 100-110°C
ESI-MS: M+ = 640 ESI-MS: M+ = 640
2-(4-metoksi-5,6-dihidrofuro-(2, 3d)-pirimidin-2-il-oksi)-3-(2-(3,5-dimetoksifenil)etoksi)-3, 3-di(klorfenil) propionska kiselina (I-593) 2-(4-Methoxy-5,6-dihydrofuro-(2, 3d)-pyrimidin-2-yl-oxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3, 3-di(chlorophenyl ) propionic acid (I-593)
Talište: 90-100°C Melting point: 90-100°C
ESI-MS: M+ = 640 ESI-MS: M+ = 640
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(2-metoksifenil)etoksi)-3,3-di(4-klorfenil)-propionska kiselina (I-164) 2-(4-methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl )-propionic acid (I-164)
Talište: 135-145°C Melting point: 135-145°C
ESI-MS: M+ = 610 ESI-MS: M+ = 610
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(3,3-difenilpropoksi)-3,3-di(4-klorfenil)-propionska kiselina Talište: 125-127°C 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)-propionic acid Melting point: 125-127°C
ESI-MS: M+ = 670 ESI-MS: M+ = 670
2-(4-metoksi-5,6-dihidrofuro-5H-ciklopentilpirimidin-2-iloksi)-3-(3,3-difenilpropoksi)-3,3-di(4-klorfenil)-propionska kiselina 2-(4-Methoxy-5,6-dihydrofuro-5H-cyclopentylpyrimidin-2-yloxy)-3-(3,3-diphenylpropoxy)-3,3-di(4-chlorophenyl)-propionic acid
Talište: 135-140°C Melting point: 135-140°C
ESI-MS: M+ = 668 ESI-MS: M+ = 668
2-(4-metoksi-6,7-dihidro-5H-ciklopentapirimidin-2-il-oksi)-3-(2-feniletiltio)-3, 3-di(4-klorfenil)propionska kiselina 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-phenylethylthio)-3, 3-di(4-chlorophenyl)propionic acid
Talište: 135-140°C Melting point: 135-140°C
1H-NMR (200 MHz) : 7,0-7,5 ppm, (13H, m); 5,9 (1H, s); 3,9 (3H, s); 2,6-2,8 (8H, m); 2,1 (2H, m). 1H-NMR (200 MHz): 7.0-7.5 ppm, (13H, m); 5.9 (1H, s); 3.9 (3H, s); 2.6-2.8 (8H, m); 2.1 (2H, m).
2-(4-metoksi-6,7-dihidro-5H-ciklopentapirimidin-2-il-oksi)-3-(2-(2-metoksifenil)etoksi)-3,3-di(4-klorfenil)-propionska kiselina 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(2-methoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)-propionic acid
Talište: 105-115°C Melting point: 105-115°C
ESI-MS: M+ = 608 ESI-MS: M+ = 608
2-(4-metoksi-6,7-dihidro-5H-ciklopentapirimidin-2-il-oksi)-3-(2-(3-metoksifenil)etoksi)-3, 3-di(4-klorfenil)-propionska kiselina 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(3-methoxyphenyl)ethoxy)-3, 3-di(4-chlorophenyl)-propionic acid
Talište: 110-120°C Melting point: 110-120°C
ESI-MS: M* = 608 ESI-MS: M* = 608
2-(4-metoksi-6,7-dihidro-5H-ciklopentapirimidin-2-il-oksi)-3-(2-(4-dimetilaminofenil)etoksi)-3,3-di(4-klorfenil) propionska kiselina 2-(4-Methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(4-dimethylaminophenyl)ethoxy)-3,3-di(4-chlorophenyl) propionic acid
Talište: 135-140°C Melting point: 135-140°C
ESI-MS: M+ = 621 ESI-MS: M+ = 621
2-(4-metoksi-6,7-dihidro-5H-ciklopentapirimidin-2-il-oksi)-3-(2-(3,4-dimetoksifenil)etoksi)-3,3-di(4-klorfenil)-propionska kiselina 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)- propionic acid
Talište: 125-130°C Melting point: 125-130°C
ESI-MS: M+ = 638 ESI-MS: M+ = 638
2-(4-metoksi-6,7-dihidro-5H-ciklopentapirimidin-2-il-oksi)-3-(2-(3,5-dimetoksifenil)etoksi)-3,3-di(4-klorfenil)-propionska kiselina 2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yl-oxy)-3-(2-(3,5-dimethoxyphenyl)ethoxy)-3,3-di(4-chlorophenyl)- propionic acid
Talište: 125-130°C Melting point: 125-130°C
ESI-MS: M+ - 638 ESI-MS: M+ - 638
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(4-metilfenil)etoksi)-3,3-difenilpropionska kiselina(1-370) 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic acid (1- 370)
Talište: 128-130°C Melting point: 128-130°C
ESI-MS: M+ = 526 ESI-MS: M+ = 526
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3- (2-fenil-etoksi)-3,3-difenilpropionska kiselina (I-719) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-phenyl-ethoxy)-3,3-diphenylpropionic acid (I-719)
Talište: 155°C (rasp.) Melting point: 155°C (exp.)
ESI-MS: M+ = 484 ESI-MS: M+ = 484
2-(4,6-dimetoksi-pirimidin-2-iloksi)-3-(2-fenil-etoksi)-3,3-difenilpropionska kiselina 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(2-phenyl-ethoxy)-3,3-diphenylpropionic acid
Talište: 203°C (rasp.) Melting point: 203°C (dec.)
ESI-MS: M+ = 500 ESI-MS: M+ = 500
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-feniletoksi)-3,3-difenilpropionska kiselina(I-720) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic acid (I-720)
Talište: 130-133°C Melting point: 130-133°C
ESI-MS: M+ = 468 ESI-MS: M+ = 468
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-feniletoksi)-3,3-difenilpropionska kiselina (I-657) 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-phenylethoxy)-3,3-diphenylpropionic acid (I-657)
Talište: 138-142°C Melting point: 138-142°C
ESI-MS: M+ = 512 ESI-MS: M+ = 512
2-(4,6-dimetoksi-pirimidin-2-iloksi)-3-(2-(4-metilfenil) etoksi)-3,3-difenilpropionska kiselina 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic acid
Talište: 155-158°C Melting point: 155-158°C
ESI-MS: M+ = 514 ESI-MS: M+ = 514
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-metilfenil)etoksi)-3,3-difenilpropionska kiselina (I-465) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methylphenyl)ethoxy)-3,3-diphenylpropionic acid (I-465)
Talište: 145-147°C Melting point: 145-147°C
ESI-MS: M+ = 498 ESI-MS: M+ = 498
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-metoksifenil)propoksi)-3,3-difenilpropionska kiselina (I-554) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-554)
Talište: 160-165°C Melting point: 160-165°C
ESI-MS: M+ = 528 ESI-MS: M+ = 528
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(4-metoksi-fenil)propoksi)-3,3-difenilpropionska kiselina (I-555) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methoxy-phenyl)propoxy)-3,3-diphenylpropionic acid (I-555)
Talište: 165-170°C Melting point: 165-170°C
ESI-MS: M+ = 512 ESI-MS: M+ = 512
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(3-(3,4,5-trimetoksifenil)propoksi)-3,3-difenilpropionska kiselina (I-335) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-335)
1H-NMR (200 MHz) : 7,2-7,4 ppm, (10H, m); 6,3 (2H, s); 6,2 (2H, s); 3,8 (1H, s); 3,75 (10H, s); 3,4 (2H, m); 2,6 (2H, m); 2,25 (3H, s); 1,9 (2H, m). 1H-NMR (200 MHz): 7.2-7.4 ppm, (10H, m); 6.3 (2H, s); 6.2 (2H, s); 3.8 (1H, s); 3.75 (10H, s); 3.4 (2H, m); 2.6 (2H, m); 2.25 (3H, s); 1.9 (2H, m).
ESI-MS: M+ = 588 ESI-MS: M+ = 588
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(3-(3,4,5-trimetoksifenil)propoksi)-3,3-difenilpropionska kiselina (I-336) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(3,4,5-trimethoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-336)
1H-NMR (200 MHz): 7,2-7,5 ppm, (10H, m); 6,6 (IH, s); 6,3 (3H, s); 3,8 (9H, s); 3,4 (2H, m); 2,6 (2H, m); 2,3 (6H, s); 1,9 (2H, m) . 1H-NMR (200 MHz): 7.2-7.5 ppm, (10H, m); 6.6 (IH, s); 6.3 (3H, s); 3.8 (9H, s); 3.4 (2H, m); 2.6 (2H, m); 2.3 (6H, s); 1.9 (2H, m) .
ESI-MS: M+ = 572 ESI-MS: M+ = 572
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(3-(2-klorfenil)propoksi)-3,3-difenilpropionska kiselina (I-383) 2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(2-chlorophenyl)propoxy)-3,3-diphenylpropionic acid (I-383)
1H-NMR (200 MHz): 7,1-7,5 ppm, (14H, m); 6,24 (1H, s); 6,23 (1H, s); 3,8 (3H, s); 3,4 (2H, m); 2,75 (2H, m); 2,25 (3H, s); 1,9 (2H, m) . 1H-NMR (200 MHz): 7.1-7.5 ppm, (14H, m); 6.24 (1H, s); 6.23 (1H, s); 3.8 (3H, s); 3.4 (2H, m); 2.75 (2H, m); 2.25 (3H, s); 1.9 (2H, m) .
ESI-MS: M+ = 532 ESI-MS: M+ = 532
2-(4, 6-dimetil-pirimidin-2-iloksi)-3-(3-(2-klorfenil)-propoksi)-3,3-difenilpropionska kiselina (I-384) 2-(4, 6-dimethyl-pyrimidin-2-yloxy)-3-(3-(2-chlorophenyl)-propoxy)-3,3-diphenylpropionic acid (I-384)
Talište: 172-178°C Melting point: 172-178°C
ESI-MS: M+ = 516 ESI-MS: M+ = 516
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(3-(4-klorfenil)-propoksi)-3,3-difenilpropionska kiselina (I-251) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(4-chlorophenyl)-propoxy)-3,3-diphenylpropionic acid (I-251)
1H -NMR (200 MHz) : 7,0-7,4 ppm, (14H, m); 6,6 (1H, s); 6,3 (1H, s); 3,5 (2H, s); 2,7 (2H, m); 2,3 (6H, s); 1,9 (2H, m). 1H-NMR (200 MHz): 7.0-7.4 ppm, (14H, m); 6.6 (1H, s); 6.3 (1H, s); 3.5 (2H, s); 2.7 (2H, m); 2.3 (6H, s); 1.9 (2H, m).
ESI-MS: M+ = 516 ESI-MS: M+ = 516
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(3-(3,4-dimetoksifenil)propoksi)-3,3-difenilpropionska kiselina (I-490) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(3,4-dimethoxyphenyl)propoxy)-3,3-diphenylpropionic acid (I-490)
1H-NMR (200 MHz): 7,1-7,5 ppm, (10H, m); 6,74 (IH, s); 6,7 (3H, s); 6,3 (1H, s); 3,8 (6H, s); 3,5 (2H, m); 2,7 (2H, m); 2,3 (6H, s); 1,9 (2H, m). 1H-NMR (200 MHz): 7.1-7.5 ppm, (10H, m); 6.74 (IH, s); 6.7 (3H, s); 6.3 (1H, s); 3.8 (6H, s); 3.5 (2H, m); 2.7 (2H, m); 2.3 (6H, s); 1.9 (2H, m).
ESI-MS: M+ = 542 ESI-MS: M+ = 542
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-propoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-69) 2-(4-methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-propoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-69)
Talište: 115-119°C Melting point: 115-119°C
ESI-MS: M+ = 542 ESI-MS: M+ = 542
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-butoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-71) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-butoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-71)
Talište: 118-122°C Melting point: 118-122°C
ESI-MS: M+ = 556 ESI-MS: M+ = 556
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(4-butoksi-fenil)etoksi)-3,3-difenilpropionska kiselina (I-70) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-butoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-70)
Talište: 122-125°C Melting point: 122-125°C
ESI-MS: M+ = 540 ESI-MS: M+ = 540
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(3-fenil-prop-(2E)-enoksi)-3,3-difenilpropionska kiselina (I-44) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-phenyl-prop-(2E)-enoxy)-3,3-diphenylpropionic acid (I-44)
Talište: 171-174°C Melting point: 171-174°C
ESI-MS: M+ = 496 ESI-MS: M+ = 496
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(3-(2-metilfenil)-propoksi-3,3-difenilpropionska kiselina (I-107) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(2-methylphenyl)-propoxy-3,3-diphenylpropionic acid (I-107)
Raspadanj e: 144-146°C Decomposition: 144-146°C
ESI-MS: M+ = 512 ESI-MS: M+ = 512
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(3-(2-metil-fenil)-propoksi-3,3-difenilpropionska kiselina (I-90) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(2-methyl-phenyl)-propoxy-3,3-diphenylpropionic acid (I-90)
Raspadanje: 173-176°C Decomposition: 173-176°C
ESI-MS: M+ = 496 ESI-MS: M+ = 496
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(3-(4-metilfenil)-propoksi-3,3-difenilpropionska kiselina (I-363) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(3-(4-methylphenyl)-propoxy-3,3-diphenylpropionic acid (I-363)
Raspadanje: 158-161°C Decomposition: 158-161°C
ESI-MS: M+ = 512 ESI-MS: M+ = 512
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(3-(4-metil-fenil)-propoksi-3, 3-difenilpropionska kiselina (I-346) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(3-(4-methyl-phenyl)-propoxy-3, 3-diphenylpropionic acid (I-346)
Raspadanje: 163-167°C Decomposition: 163-167°C
ESI-MS: M+ = 496 ESI-MS: M+ = 496
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3- (2- (4-metiltio-fenil)etoksi-3,3-difenilpropionska kiselina (I-246) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methylthio-phenyl)ethoxy-3,3-diphenylpropionic acid (I-246)
Raspadanje: 136-138°C Decomposition: 136-138°C
ESI-MS: M+ = 530 ESI-MS: M+ = 530
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(4-metiltio-fenil)-etoksi-3,3-difenilpropionska kiselina (I-217) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methylthio-phenyl)-ethoxy-3,3-diphenylpropionic acid (I-217)
Raspadanje: 166-169°C Decomposition: 166-169°C
ESI-MS: M+ = 514 ESI-MS: M+ = 514
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-etoksi-3-metoksifenil)etoksi-3,3-difenilpropionska kiselina (I-145) Raspadanje: 141-145°C 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy-3,3-diphenylpropionic acid (I-145) Decomposition: 141-145 °C
ESI-MS: M+ = 558 ESI-MS: M+ = 558
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-etoksifenil)etoksi-3,3-difenilpropionska kiselina (I-510) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-ethoxyphenyl)ethoxy-3,3-diphenylpropionic acid (I-510)
Raspadanje: 131-135°C Decomposition: 131-135°C
ESI-MS: M+ = 528 ESI-MS: M+ = 528
2-(4-metsoki-6-metil-pirimidin-2-iloksi)-3- (2- (4-i-propilfenil)etoksi)-3,3-difenilpropionska kiselina (I-705) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic acid (I-705)
1H-NMR (200 MHz, DMSO) : 7,0-7,35 ppm, (14H, m); 6,35 (1H, s); 6,1 (1H, s); 4,0 (1H, m); 3,9 (3H, s); 3,8 (3H, s); 3,7 (1H, m); 2,9 (3H, m); 2,2 (3H, s); 1,1 (6H, d). 1H-NMR (200 MHz, DMSO): 7.0-7.35 ppm, (14H, m); 6.35 (1H, s); 6.1 (1H, s); 4.0 (1H, m); 3.9 (3H, s); 3.8 (3H, s); 3.7 (1H, m); 2.9 (3H, m); 2.2 (3H, s); 1.1 (6H, d).
ESI-MS: M+ = 526 ESI-MS: M+ = 526
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(3,4-metilendioksifenil)etoksi)-3,3-difenilpropionska kiselina (I-568) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-568)
Raspadanje: 146-148°C Decomposition: 146-148°C
ESI-MS: M+ = 528 ESI-MS: M+ = 528
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(3,4-metilendioksifenil)etoksi)-3,3-difenilpropionska kiselina (I-501) 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic acid ( I-501)
Raspadanje: 145-149°C Decomposition: 145-149°C
ESI-MS: M+ = 556 ESI-MS: M+ = 556
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-iloksi)-3-(2-(4-etoksi-3-metoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-735) 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionic acid ( I-735)
1H-NMR (200 MHz, DMSO): 7,1-7,4 ppm, (10H, m); 6,85 (2H, m); 6,7 (1H, d); 6,1 (1H, s); 4,6 (2H, tr) ; 4,0 (3H, m); 3,85 (3H, s); 3,75 (3H, s); 3,65 (1H, m); 3,05 (2H, tr) ; 2,8 (2H, m) ; 1,25 (3H, m-) . 1H-NMR (200 MHz, DMSO): 7.1-7.4 ppm, (10H, m); 6.85 (2H, m); 6.7 (1H, d); 6.1 (1H, s); 4.6 (2H, tr) ; 4.0 (3H, m); 3.85 (3H, s); 3.75 (3H, s); 3.65 (1H, m); 3.05 (2H, tr) ; 2.8 (2H, m); 1.25 (3H, m-) .
ESI-MS: M+ = 586 ESI-MS: M+ = 586
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(4-etoksifenil)etoksi)-3, 3-difenilpropionska kiselina 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-ethoxyphenyl)ethoxy)-3, 3-diphenylpropionic acid
(I-407) (I-407)
1H-NMR (270 MHz, DMSO): 7,1-7,4 ppm, (12H, m); 6,8 (2H, d); 6,1 (1H, s); 4,65 (2H, tr) ; 3,95 (3H, m); 3,8 (3H, s); 3,65 (1H, m); 3,05 (2H, tr) ; 2,8 (2H, m); 1,25 (3H, m). 1H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (12H, m); 6.8 (2H, d); 6.1 (1H, s); 4.65 (2H, tr); 3.95 (3H, m); 3.8 (3H, s); 3.65 (1H, m); 3.05 (2H, tr) ; 2.8 (2H, m); 1.25 (3H, m).
ESI-MS: M+ - 556 ESI-MS: M+ - 556
2-(4,6-dimetilpirimidin-2-iloksi)-3-(2-(4-etoksi-3-metoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-146) 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(4-ethoxy-3-methoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-146)
Raspadanje: 129-134°C Decomposition: 129-134°C
ESI-MS: M+ - 542 ESI-MS: M+ - 542
2-(4,6-dimetilpirimidin-2-iloksi)-3-(2-(3,4-metilen-dioksifenil)etoksi)-3,3-difenilpropionska kiselina (I-569) 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(3,4-methylenedioxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-569)
1H-H-NMR (270 MHz, DMSO) : 7,1-7,4 ppm, (10H, m); 6,9 (1H, s); 6,8 (2H, m); 6,7 (1H, d); 6,0 (2H, s); 3,95 (3H, m); 3,65 (1H, m); 2,8 (2H, m); 2,3 (6H, s). 1H-H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (10H, m); 6.9 (1H, s); 6.8 (2H, m); 6.7 (1H, d); 6.0 (2H, s); 3.95 (3H, m); 3.65 (1H, m); 2.8 (2H, m); 2.3 (6H, s).
ESI-MS: M+ = 512 ESI-MS: M+ = 512
2-(4,6-dimetilpirimidin-2-iloksi)-3-(2-(4-etoksi-fenil)etoksi)-3,3-difenilpropionska kiselina (I-473) 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(4-ethoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-473)
Raspadanje: 145-148°C Decomposition: 145-148°C
ESI-MS: M+ = 512 ESI-MS: M+ = 512
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(4-i-propilfenil)etoksi)-3,3-difenilpropionska kiselina 2-(4-Methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-i-propylphenyl)ethoxy)-3,3-diphenylpropionic acid
(I-604) (I-604)
1H-NMR (270 MHz, DMSO): 7,1-7,4 ppm, (14H, m); 6,1 (1H, s); 4,6 (2H, tr) ; 3,9 (3H, s); 3,8 (3H, s); 3,6 (1H, m); 3,0 (2H, tr); 2,8 (3H, m); 1,1 (6H, d). 1H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (14H, m); 6.1 (1H, s); 4.6 (2H, tr) ; 3.9 (3H, s); 3.8 (3H, s); 3.6 (1H, m); 3.0 (2H, tr); 2.8 (3H, m); 1.1 (6H, d).
ESI-MS: M+ = 554 ESI-MS: M+ = 554
2-(4,6-dimetilpirimidin-2-iloksi)-3-(2-(4-i-propil-fenil)etoksi)-3,3-difenilpropionska kiselina (I-672) 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-(4-i-propyl-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-672)
Raspadanje: 156-160°C Decomposition: 156-160°C
ESI-MS: M+ = 510 ESI-MS: M+ = 510
2-(4-metoksi-5,6-dihidrofuro-(2,3d)-pirimidin-2-il-oksi)-3-(2-(4-metoksifenil)etoksi)-3,3-di(4-metilfenil)-propionska kiselina (I-517) 2-(4-methoxy-5,6-dihydrofuro-(2,3d)-pyrimidin-2-yl-oxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-di(4-methylphenyl )-propionic acid (I-517)
1H-NMR (200 MHz, DMSO): 7,0-7,3 ppm, (10H, m); 6,8 (2H, d); 6,0 (1H, s); 4,6 (2H, tr) ; 3,85 (3H, s); 3,8 (1H, m); 3,7 (3H, s); 3,6 (1H, m); 3,0 (2H, tr); 2,8 (3H, tr); 1,1 (6H, d) . 1H-NMR (200 MHz, DMSO): 7.0-7.3 ppm, (10H, m); 6.8 (2H, d); 6.0 (1H, s); 4.6 (2H, tr) ; 3.85 (3H, s); 3.8 (1H, m); 3.7 (3H, s); 3.6 (1H, m); 3.0 (2H, tr); 2.8 (3H, tr); 1.1 (6H, d) .
ESI-MS: M+ - 570 ESI-MS: M+ - 570
2-(4-metoksi-6-metil-pirimidin-2-iloksi)-3-(2-(4-metoksifenil)etoksi)-3,3-difenilpropionska kiselina (I-622) 2-(4-Methoxy-6-methyl-pyrimidin-2-yloxy)-3-(2-(4-methoxyphenyl)ethoxy)-3,3-diphenylpropionic acid (I-622)
1H-NMR (270 MHz, DMSO) : 7,1-7,4 ppm, (12H, m); 6,8 (2H, d); 6,4 (1H, s); 6,1 (1H, s); 4,0 (1H, m); 3,7 (3H, s); 3,7 (1H, m); 2,8 (2H, tr); 2,3 (3H, s). 1H-NMR (270 MHz, DMSO): 7.1-7.4 ppm, (12H, m); 6.8 (2H, d); 6.4 (1H, s); 6.1 (1H, s); 4.0 (1H, m); 3.7 (3H, s); 3.7 (1H, m); 2.8 (2H, tr); 2.3 (3H, s).
ESI-MS: M+ = 514 ESI-MS: M+ = 514
2-(4,6-dimetil-pirimidin-2-iloksi)-3-(2-(4-metoksi-fenil)etoksi)-3,3-difenilpropionska kiselina (I-585) 2-(4,6-dimethyl-pyrimidin-2-yloxy)-3-(2-(4-methoxy-phenyl)ethoxy)-3,3-diphenylpropionic acid (I-585)
1H-NMR (200 MHz, DMSO): 7,1-7,4 ppm, (12H, m); 6,8 (3H, m); 6,1 (1H, s); 4,0 (1H, m); 3,7 (3H, s); 3,6 (1H, m); 2,8 1 H-NMR (200 MHz, DMSO): 7.1-7.4 ppm, (12 H, m); 6.8 (3H, m); 6.1 (1H, s); 4.0 (1H, m); 3.7 (3H, s); 3.6 (1H, m); 2.8
(2H, tr); 2,3 (3H, s). (2H, tr); 2.3 (3H, s).
ESI-MS: M+ - 498 ESI-MS: M+ - 498
2-(4-metoksi-6-metilpirimidin-2-iloksi)-3-(3-fenil-propoksi)-3,3-difenilpropionska kiselina (I-499) 2-(4-Methoxy-6-methylpyrimidin-2-yloxy)-3-(3-phenyl-propoxy)-3,3-diphenylpropionic acid (I-499)
Raspadanje: 153-155°C Decomposition: 153-155°C
ESI-MS: M+ = 498 ESI-MS: M+ = 498
2-(4,6-dimetilpirimidin-2-iloksi)-3-(3-fenil-propoksi)-3,3-difenilpropionska kiselina (I-500) 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(3-phenyl-propoxy)-3,3-diphenylpropionic acid (I-500)
Raspadanje: 148-151°C Decomposition: 148-151°C
ESI-MS: M+ = 482 ESI-MS: M+ = 482
Analogno, ili kako je opisano u općem dijelu se mogu proizvesti spojevi navedeni u tablici 1. Analogously, or as described in the general section, the compounds listed in Table 1 can be produced.
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Primjer 16 Example 16
U skladu s gore opisanim ispitivanjem vezanja, vrijednosti vezanja receptora izmjerene su za slijedeće navedene spojeve. In accordance with the binding assay described above, receptor binding values were measured for the following listed compounds.
Rezultati su prikazani u slijedećoj tablici. The results are shown in the following table.
Tablica 2 Table 2
Vrijednosti vezanja receptora (Ki-vrijednosti) Receptor binding values (Ki-values)
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Claims (10)
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