MXPA98007247A - Triar compounds - Google Patents
Triar compoundsInfo
- Publication number
- MXPA98007247A MXPA98007247A MXPA/A/1998/007247A MX9807247A MXPA98007247A MX PA98007247 A MXPA98007247 A MX PA98007247A MX 9807247 A MX9807247 A MX 9807247A MX PA98007247 A MXPA98007247 A MX PA98007247A
- Authority
- MX
- Mexico
- Prior art keywords
- methoxy
- biphenyl
- phenyl
- pyridine
- carboxylic acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 46
- 239000002253 acid Substances 0.000 claims abstract description 40
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 238000007792 addition Methods 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 239000011780 sodium chloride Substances 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 13
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 10
- 206010054094 Tumour necrosis Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 230000000069 prophylaxis Effects 0.000 claims abstract description 8
- 206010061218 Inflammation Diseases 0.000 claims abstract description 7
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims abstract description 4
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 62
- -1 5-methylthiazol-2-yl Chemical group 0.000 claims description 49
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
- 239000004305 biphenyl Substances 0.000 claims description 16
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000004494 ethyl ester group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 200000000018 inflammatory disease Diseases 0.000 claims description 10
- 125000004429 atoms Chemical group 0.000 claims description 9
- 235000010290 biphenyl Nutrition 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 230000001506 immunosuppresive Effects 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- MAKAMIVXMYNFNT-UHFFFAOYSA-N 4-[3-(2,1,3-benzoxadiazol-5-yl)-4-methoxyphenyl]benzoic acid Chemical compound C1=C(C2=CC3=NON=C3C=C2)C(OC)=CC=C1C1=CC=C(C(O)=O)C=C1 MAKAMIVXMYNFNT-UHFFFAOYSA-N 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052718 tin Inorganic materials 0.000 claims description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- YDIUGKOMDDOFEW-UHFFFAOYSA-N 4-[4-methoxy-3-(3-nitrophenyl)phenyl]benzamide Chemical compound COC1=CC=C(C=2C=CC(=CC=2)C(N)=O)C=C1C1=CC=CC([N+]([O-])=O)=C1 YDIUGKOMDDOFEW-UHFFFAOYSA-N 0.000 claims description 3
- VZLMAQSQKGXFEU-UHFFFAOYSA-N 5-(5-imidazo[1,2-a]pyridin-6-yl-2-methoxyphenyl)-2,1,3-benzoxadiazole Chemical compound C1=CC2=NC=CN2C=C1C1=CC=C(OC)C(C2=CC3=NON=C3C=C2)=C1 VZLMAQSQKGXFEU-UHFFFAOYSA-N 0.000 claims description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- BCSYOXHHXVMQJO-UHFFFAOYSA-N 4-[4-methoxy-3-(3-nitrophenyl)phenyl]-2-methylbenzamide Chemical compound COC1=CC=C(C=2C=C(C)C(C(N)=O)=CC=2)C=C1C1=CC=CC([N+]([O-])=O)=C1 BCSYOXHHXVMQJO-UHFFFAOYSA-N 0.000 claims description 2
- 206010062016 Immunosuppression Diseases 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- CAOPLAKDEPBPGJ-UHFFFAOYSA-N ethyl 4-[3-(2,1,3-benzoxadiazol-5-yl)-4-methoxyphenyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C1=CC=C(OC)C(C2=CC3=NON=C3C=C2)=C1 CAOPLAKDEPBPGJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 150000003248 quinolines Chemical class 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- XWOUAKCUMZJUQF-UHFFFAOYSA-N 3-[4-methoxy-3-(3-nitrophenyl)phenyl]benzoic acid Chemical compound COC1=CC=C(C=2C=C(C=CC=2)C(O)=O)C=C1C1=CC=CC([N+]([O-])=O)=C1 XWOUAKCUMZJUQF-UHFFFAOYSA-N 0.000 claims 2
- MWNABMOZSIHFRI-UHFFFAOYSA-N 4-[4-methoxy-3-(3-nitrophenyl)phenyl]-N-methylbenzamide Chemical compound C1=CC(C(=O)NC)=CC=C1C1=CC=C(OC)C(C=2C=C(C=CC=2)[N+]([O-])=O)=C1 MWNABMOZSIHFRI-UHFFFAOYSA-N 0.000 claims 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N Phenyl acetate Chemical compound CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- 125000006501 nitrophenyl group Chemical group 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 29
- 208000006673 Asthma Diseases 0.000 abstract description 17
- 230000000414 obstructive Effects 0.000 abstract description 12
- 230000002757 inflammatory Effects 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 abstract description 9
- LQWHPYPUHPQSRX-UHFFFAOYSA-N 1,1'-biphenyl;pyridine Chemical class C1=CC=NC=C1.C1=CC=CC=C1C1=CC=CC=C1 LQWHPYPUHPQSRX-UHFFFAOYSA-N 0.000 abstract description 2
- KQNQGPDKRIUXPS-UHFFFAOYSA-N 2-(2-phenylphenyl)benzamide Chemical class NC(=O)C1=CC=CC=C1C1=CC=CC=C1C1=CC=CC=C1 KQNQGPDKRIUXPS-UHFFFAOYSA-N 0.000 abstract description 2
- UKJFDHQIVVKJTE-UHFFFAOYSA-N 2,6-diphenylbenzoic acid Chemical group OC(=O)C1=C(C=2C=CC=CC=2)C=CC=C1C1=CC=CC=C1 UKJFDHQIVVKJTE-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 23
- 239000012043 crude product Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 230000035492 administration Effects 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000000284 extract Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 14
- 101710031992 pRL90232 Proteins 0.000 description 14
- 101710035540 plaa2 Proteins 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cells Anatomy 0.000 description 13
- 239000012258 stirred mixture Substances 0.000 description 13
- 239000007832 Na2SO4 Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 210000003979 Eosinophils Anatomy 0.000 description 11
- 229940079593 drugs Drugs 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 206010006895 Cachexia Diseases 0.000 description 8
- 230000003110 anti-inflammatory Effects 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 108010044467 Isoenzymes Proteins 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- JOCCQFWHBVVRNV-UHFFFAOYSA-N 4-(3-bromo-4-methoxyphenyl)pyridine Chemical compound C1=C(Br)C(OC)=CC=C1C1=CC=NC=C1 JOCCQFWHBVVRNV-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 229940092253 Ovalbumin Drugs 0.000 description 5
- 108010058846 Ovalbumin Proteins 0.000 description 5
- HXITXNWTGFUOAU-UHFFFAOYSA-N Phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 238000004166 bioassay Methods 0.000 description 5
- 230000001684 chronic Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 210000004072 Lung Anatomy 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 230000003182 bronchodilatating Effects 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical class CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- QWMCFBNRPCHLHT-UHFFFAOYSA-N 2,3-dihydro-1H-inden-5-ylboronic acid Chemical compound OB(O)C1=CC=C2CCCC2=C1 QWMCFBNRPCHLHT-UHFFFAOYSA-N 0.000 description 3
- FATZLDXSDNBXKR-UHFFFAOYSA-N 3-(2,1,3-benzoxadiazol-5-yl)-5-bromophenol Chemical compound OC1=CC(Br)=CC(C2=CC3=NON=C3C=C2)=C1 FATZLDXSDNBXKR-UHFFFAOYSA-N 0.000 description 3
- YBRKVMNQIHNPPH-UHFFFAOYSA-N 4-(3-bromo-4-methoxyphenyl)benzoic acid Chemical compound C1=C(Br)C(OC)=CC=C1C1=CC=C(C(O)=O)C=C1 YBRKVMNQIHNPPH-UHFFFAOYSA-N 0.000 description 3
- BDXPUDLCSHDVGK-UHFFFAOYSA-N 4-(4-methoxyphenyl)pyridine Chemical compound C1=CC(OC)=CC=C1C1=CC=NC=C1 BDXPUDLCSHDVGK-UHFFFAOYSA-N 0.000 description 3
- MHDZUNDAGMJZEX-UHFFFAOYSA-N 4-[4-methoxy-3-(3-nitrophenyl)phenyl]-2-methylbenzoic acid Chemical compound COC1=CC=C(C=2C=C(C)C(C(O)=O)=CC=2)C=C1C1=CC=CC([N+]([O-])=O)=C1 MHDZUNDAGMJZEX-UHFFFAOYSA-N 0.000 description 3
- CBAZRTAXMMUUFT-UHFFFAOYSA-N 5-(3-bromo-5-methoxyphenyl)-2,1,3-benzoxadiazole Chemical compound COC1=CC(Br)=CC(C2=CC3=NON=C3C=C2)=C1 CBAZRTAXMMUUFT-UHFFFAOYSA-N 0.000 description 3
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 3
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- 206010060945 Bacterial infection Diseases 0.000 description 3
- 206010006451 Bronchitis Diseases 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 229940088598 Enzyme Drugs 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108010008211 N-Formylmethionine Leucyl-Phenylalanine Proteins 0.000 description 3
- 101700029476 PDE4A Proteins 0.000 description 3
- 102100003492 PDE4A Human genes 0.000 description 3
- 101700057678 PDE4B Proteins 0.000 description 3
- 102100018800 PDE4B Human genes 0.000 description 3
- 101700042596 PDE4C Proteins 0.000 description 3
- 102100018799 PDE4C Human genes 0.000 description 3
- 101700057277 PDE4D Proteins 0.000 description 3
- 102100018798 PDE4D Human genes 0.000 description 3
- 108060002038 Pde4 Proteins 0.000 description 3
- 206010035653 Pneumoconiosis Diseases 0.000 description 3
- 206010040070 Septic shock Diseases 0.000 description 3
- AJSTXXYNEIHPMD-UHFFFAOYSA-N Triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 3
- JEKNLOWIDYHORP-UHFFFAOYSA-N [4-(2,1,3-benzoxadiazol-5-yl)phenyl]boronic acid Chemical compound C1=CC(B(O)O)=CC=C1C1=CC2=NON=C2C=C1 JEKNLOWIDYHORP-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000001154 acute Effects 0.000 description 3
- 230000036428 airway hyperreactivity Effects 0.000 description 3
- 201000009961 allergic asthma Diseases 0.000 description 3
- 150000001543 aryl boronic acids Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- PRQROPMIIGLWRP-BZSNNMDCSA-N chemotactic peptide Chemical compound CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-BZSNNMDCSA-N 0.000 description 3
- 230000002354 daily Effects 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- LGFDQZCUDVWAIQ-UHFFFAOYSA-N ethyl 4-(4-methoxyphenyl)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C1=CC=C(OC)C=C1 LGFDQZCUDVWAIQ-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 108010047623 iridine Proteins 0.000 description 3
- 230000002969 morbid Effects 0.000 description 3
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Abstract
The compounds of (4-oxy-3- (aryl) phenyl-azaryloarylcarbonyloxy, in the free form of acid addition salt, are useful as pharmaceuticals for the treatment and prophylaxis of inflammation, particularly inflammatory or obstructive airway diseases, by example for asthma therapy The preferred compounds are novel biphenyl pyridines, biphenyl-benzamides, and phenylcarboxyl-biphenyl compounds.The compounds are selective inhibitors of the activity of the phosphodiesterase-4 isoenzyme, and also act to down-regulate or inhibit the release of factor-2. tumor necrosis
Description
COMPOSITIONS OF T TARILLO
The present invention relates to triaryl compounds, particularly biphenyl pyridines, biphenyl-benzamides, and biphenyl carboxyphenyl compounds, to processes for their production, to their use as pharmaceuticals, and to pharmaceutical compositions comprising them. In a specific manner, the invention provides a compound of (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt, to be used as a pharmaceutical, by example, for use in the treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, for example asthma. In a further embodiment, the invention provides a pharmaceutical composition comprising a compound of (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt, for example, in combination with a pharmaceutically acceptable diluent or carrier. In a still further embodiment, the invention includes the use of a compound of (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt, for the preparation of a medicament for the treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, for example asthma. In a still further embodiment, the invention provides a method for the treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, for example asthma, which comprises administering an effective amount of a (4-OXY- 3- (aryl) phenyl) -azaryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt, to a subject in need of such therapy. The (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy compounds of the invention, and their pharmaceutically acceptable acid addition salt forms, are hereinafter referred to as "AGENTS" OF THE INVENTION. In these compounds, the 4-oxy fraction is suitably alkoxy
(optionally substituted by fluoro), for example, (fluoro-3-) -alkoxy from 1 to 4 carbon atoms, for example methyl, ethyl, difluoromethyl, or trifluoromethyl. The 3-aryl moiety is suitably a mono- or bi-cyclic moiety having at least one aromatic ring, for example, azaryl, for example pyridyl, alkyl of 1 to 4 carbon atoms-pyridyl, or quinolinyl; 2, 5-cyclohexadien-3,4-ylidin-1-yl aromatic, for example benzofurazanyl or benzofuranyl; or phenyl, preferably suitably substituted, eg, meta- and / or para-substituted, with (i) one or two substituents selected from nitro, carbamoyl, halogen (e.g., chloro), trifluoromethyl, alkoxy (e.g. , alkoxy of 1 to 4 carbon atoms), thioalkoxy (for example, thioalkoxy (of 1 to 4 carbon atoms)), alkylsulfoxyl (for example, alkyl of 1 to 4 carbon atoms-sulfoxyl), alkylsulfonyl (for example, alkyl of 1 to 4 carbon atoms-sulfonyl), cyano, or phenoxy, or (ii) a bridge substituent of 3 to 5 atoms in length, wherein the bridge atoms are selected from C, O, S, and N, for example indanyl, benzopyrrolidonyl, indanonyl, or benzodioxolanyl. "Azaryl" means an aromatic group containing nitrogen, for example pyridine, for example 3-pyridine or 4-pyridine, quinoline, isoquinoline, imidazopyridine (for example imidazo [1,2-a] pyridine) or benzamide, for example 3- or 4-benzamide. "aryloxycarbonyl" means an aryl moiety, for example as defined above for the 3-aryl moiety, bearing at least one oxycarbonyl substituent, for example in the form of free acid, ester, amide, or salt, preferably a phenylcarboxyl fraction, for example a phenyl-3 or phenyl-4-carboxyl moiety, such as an ester of phenylcarboxylic acid or of phenyl carboxylate (for example, lower alkylcarboxylate ester-phenyl), or a phenylcarboxamido moiety. Halo or halogen, as used herein, refers to F, Cl, Br, or I, unless otherwise indicated. The AGENTS OF THE INVENTION include compounds that are known per se, but for which a pharmaceutical activity has not been described or suggested. Accordingly, Jin et al. (Macromol. Symp. (1995), 96 [International Conference on Liquid Crystal Polymers 1994], 125-134) describe methyl-4'-methoxy-3'-phenylbiphenyl 4-carboxylate, and sodium 4-carboxylate. '-acetoxy-3'-phenylbiphenyl-4-carboxylic acid as intermediates in the preparation of copolyester liquid crystal materials. Buu-Hoi et al (J. Org. Chem. 21, [1956], 136-138) describe the preparation of 2- (6-methoxy-biphenyl-3-yl) -quinoline and analogs thereof, further substituted in the quinoline ring by methyl or phenyl in the 3-position, and / or by carboxyl in the 4-position, and (J. Org. Chem. 22, [1964], 762-763) also the preparation of 2- (6, 2'-dimethoxy-biphenyl-3-yl) -quinoline and analogues thereof, further substituted in the quinoline ring by methyl in the 3-position, and / or by carboxy in the 4-position. Buu Hoi et al. Do not identify a utility or activity for these quinoline compounds. The Belgian Patent of Du Pont No. 652,320, describes the preparation of 5- (6-methoxy-biphenyl-3-yl) -2-methylthiazole, as an intermediate in the preparation of 5,5'-diphenylthiazolecarbocyanine sensitizers of halide emulsions of silver for photographic use. Accordingly, the present invention provides a (4-oxy-3-aryl) phenyl) -aryl or -arylcarbonyloxy compound, for example, wherein the 4-oxyl, 3-aryl, random, and arylcarbonyloxy , are as defined above, with the understanding that the 3-aryl moiety is not unsubstituted phenyl, when: the arylcarbonyloxy moiety is phenyl-4-carboxylic acid or phenyl-4-methyl carboxylate, or the moiety azaryl is 5-methylthiazol-2-yl, or that the 3-aryl fraction is not unsubstituted phenyl or 2-methoxyphen-1-yl when: the azaryl fraction is unsubstituted 2-quinoline, or 2-quinoline substituted by methyl or phenyl in the 3-position, and / or by carboxy in the 4-position, or a pharmaceutically acceptable acid addition salt thereof.
The novel compounds of that aspect of the invention are encompassed by the AGENTS OF THE INVENTION. The AGENTS OF THE INVENTION may exist in free form or in the form of pharmaceutically acceptable acid addition salts. The pharmaceutically active acid addition salts for use in the present invention include, for example, hydrochlorides, oxalates, and fumarates. In particular, the invention provides an AGENT OF THE INVENTION which is a 4- (oxy-3- [phenyl- (2,5-cyclohexadien-3,4-ylidin-1-yl)] - phenyl-azaryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt Optionally, the 3-phenyl fraction is substituted, for example, 3- and / or 4-substituted The fraction of 2,5-cyclohexadien-3,4-ylidin The l-yl is preferably a fraction of 2,5-cyclohexadien-3,4-N-ylidin-1-yl, preferably aromatic, Preferably, the oxy-moiety is alkoxy, for example, alkoxy of 1 to 4 atoms The fraction of azaryl is preferably pyridine, for example pyridine, imidazopyridine, for example 6-imidazo [1,2-a] pyridine, or benzamide, for example 3-or 4-benzamide. of aryloxycarbonyl is phenylcarboxy, for example phenyl-3- or 4-carboxyl For example, the AGENTS OF THE INVENTION include a [2- (alkoxy of 1 to 4 carbon atoms) -biphenyl-5-yl] pyri dina, [2- (alkoxy of 1 to 4 carbon atoms) -biphenyl-5-yl] benzamide, or [2- (alkoxy of 1 to 4 carbon atoms-biphenyl-5-yl] phenylcarboxy, where the fraction of biphenyl is optionally 3'- and / or 4'-substituted, or optionally 3 ', 4' -condensed with a second aromatic ring, preferably a compound of the formula la or of the formula Ib:
wherein in the formula la, W is N or C-CO-R, wherein R is OH, O-alkyl (of 1 to 6 carbon atoms), or NR3R4, wherein Rj and R, which may be the same or different, they are H or alkyl (of 1 to 6 carbon atoms), or in the formula Ib, Az is a randomyl group containing one or more nitrogen atoms, such as quinoline, isoquinoline, indole, imidazopyridine, for example imidazo [ 1,2-a] pyridine, and both in the formula la and Ib: Rx is alkyl (of 1 to 4 carbon atoms), preferably methyl; and R2 is a phenyl moiety, for example of the formula
wherein R 5 and R are independently H, nitro, halogen (e.g., chloro), trifluoromethyl, alkoxy (1 to 4 carbon atoms), cyano, or phenoxy; or Rs and. together form a bridge of 3 to 5 atoms in length, wherein the bridge atoms are selected from S, O, N, and C, for example -OCH20-, or propylene; or R2 is a 2,5-cyclohexadien-3,4-ylidene-1-yl fraction, for example of the formula III:
wherein R7 and R8 together form an aromatic bridge of 3 to 5 carbon atoms in length, wherein the bridge atoms are selected from S, 0, N, and C, for example = N-0- N =; in free form or pharmaceutically acceptable acid addition salt.
More preferably, R 2 is selected from 3-nitrophenyl, 3- (trifluoromethyl) phenyl, 3-cyanophenyl, 3- or 3,4-halophenyl (e.g. 3-chlorophenyl or 3-chloro-4-fluorophenyl) ), indan-5-yl, benzofurazan-5-yl, and 1,3-benzo [d] dioxolan-5-yl. Accordingly, the compounds of the formula I: 1. 4- [2- (methoxy) -biphenyl-5-yl] pyridine, 2. 4- [2- (methoxy) -3 '- (nitro) biphenyl-5- il] pyridine, 3. 4- [2- (methoxy) -3 '- (trifluoromethyl) biphenyl-5-yl] pyridine,
4. 4- [2- (methoxy) -3 ', 4' - (propylene) biphenyl] pyridine, 5- 4- [4- (methoxy) -3- (benzofurazan-5-yl) phenyl] pyridine,
6. 4- [2- (methoxy) -3 '- (cyano) biphenyl-5-yl] pyridine, 7. 4- [2- (methoxy) -3' - (chloro) biphenyl-5-yl] pyridine, 8. 4- [2- (methoxy) -3 ', 4' - (methylenedioxy) biphenyl-5-yl] pyridine
9. 4- [2- (methoxy) -3 '- (phenoxy) biphenyl-5-yl] pyridine, 10. 4- [2- (methoxy) -4' - (phenoxy) biphenyl-5-yl] pyridine, 11. 4- [2- (methoxy) -3 '- (chloro) -4' - (f 1ooro) biphenyl-5-yl] pyridine, 12. 4 '-methoxy-3' - (benzofurazan-5-yl) - [ 1, 1'-biphenyl] -4- carboxamide, 13. Ethyl ester of 4'-methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid, 14. Ethyl ester of acid 4'-methoxy-3 '- (3-nitrophenyl) - [1, l' -biphenyl] -3-carboxylic acid, ethyl ester of 4'-methoxy-3-methyl-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid, 16. 3 '- (5-Benzofurazanyl) -4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid ethyl ester, 17. Ester 2, 2-dimethylpropyl 3 '- (5-benzofurazanyl) -4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid,
18. 3 '- (5-Benzofurazanyl) -4' -methoxy- [1,1'-biphenyl] -4-carboxylic acid, 19. 4 '-methoxy-3' - (3-nitrophenyl) - [1,1 '] acid -biphenyl] -3-carboxylic acid, 20. 4 '-methoxy-3-methyl-3' - (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid, 21. 3 '- (5 -benzofurazanyl) -4 '-methoxy- [1,1'-biphenyl] -4-carboxylic acid, 22. 4' -methoxy-3 '- (3-chlorophenyl) - [1,1'-biphenyl] -4- acid carboxylic acid, 23. 4 '-methoxy-3' - (3-cyanophenyl) - [1,1 '-biphenyl] -4-carboxylic acid, 24. 4' -methoxy-3 '- (3-nitrophenyl) - [1 , 1'-biphenyl] -4-carboxamide, 25. 4'-methoxy-3 '- (3-nitrophenyl) - [1, 1-biphenyl] -3-carboxamide, 26. 4'-methoxy-3-methyl -3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide, 27. N-methyl-4' -methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] ] -4- carboxamide, 28. 6- [4-methoxy-3- (5-benzofurazanyl) phenyl] imidazo [1,2- a] pyridine.
in free form or pharmaceutically acceptable acid addition salt, for example, hydrochloride. The compounds of the formula I are suitably prepared by the reaction of a compound of the formula I 'a or of the formula I'b:
wherein X is halogen (preferably bromine) or an exit group, such as a group containing tin or boron (preferably -B (0H) 2), and Rlf W, and Az are as defined above for the formulas la and Ib, with the desired activated aryl, for example aryl halide or arylboronic acid, for example a compound of the formula Ia or Illa:
wherein Y is halogen (preferably bromine) or an exit group, such as a group containing tin or boron (preferably -B (0H) 2), and the R groups are as defined above for Formulas II and III; and the compound resulting from the invention is recovered, for example of the formula la or Ib, in free form or acid addition salt. Preferably, one of X or Y is halogen, for example bromine, and the other is an leaving group, for example -B (OH) 2. Suitable reaction conditions may include the reaction in the presence of one or more of the following: a nucleophile, such as triarylphosphine (preferably tri-o-tolylphosphine or tri-2-furylphosphine); a base such as sodium carbonate, a solvent such as toluene, acetonitrile, or dimethyl formamide, and / or a suitable catalyst, such as a palladium catalyst. Suitable reaction temperatures include from room temperature to the boiling point of the solvent, for example from 20 ° C to 150 ° C, preferably from 70 ° C to 90 ° C. The novel intermediates, especially of the formulas I 'a and I'b, are within the scope of the invention. The compounds of the formulas I 'and I'b can be prepared by a Suzuki or Stille type coupling reaction, for example, between a 4-alkoxyboronic acid derivative and the suitably substituted haloaromatic system, or alternatively, are prepared from 4-halopyridine and the corresponding Grignard reagent, for example by the reaction of 4-bromopyridine with a compound of the formula R-LO-CgH ^ MgBr, wherein R? it is as defined above, in the presence of a suitable catalyst, for example, a nickel catalyst, to obtain the 4-aryl-pyridine, which is then halogen, for example by its reaction with Br2, to obtain the compound of the formula I 'a or I'b, wherein X is halogen, and optionally further reacted with one or more alkyl metal reagents, for example with alkyl lithium, for example butyl lithium, followed by the reaction with alkyl borate, for example, triethyl borate, to obtain the compound of the formula I 'a or I'b, wherein X is -B (OH) 2. The compounds of the formula Ia or Illa can be prepared in an analogous manner, by halogenation of the aryl, for example bromination, optionally followed by exchange of the halogen by an exit group, for example -B (OH) 2.
EXAMPLES
EXAMPLE 1: 4- [2- (methoxy) biphenyl-5-ill pyridine a) 4- (4-methoxyphenyl) pyridine A solution of 4-methoxyphenyl magnesium bromide, prepared from 4-bromoanisol (150 grams, 0.80 moles) and magnesium (20 grams, 0.83 moles) in dry tetrahydrofuran (300 milliliters), filtered, cooled to -10 ° C, and added with caution to a stirring mixture of bis- (triphenylphosphine) nickel (II) chloride (1.5 grams, 2.25 mmol) and 4-bromopyridine hydrochloride (65 grams, 0.334 mol) in dry tetrahydrofuran (300 milliliters) at 10 ° C under an argon atmosphere . After 50 percent of the Grignard reagent has been added, a vigorous exothermic reaction is established, and the temperature of the mixture between 50 ° C and 60 ° C is maintained throughout the remainder of the addition, by the Use of a cooling bath with ice-cold methanol. When the addition is complete, the mixture is stirred for 60 minutes at 50 ° C. The solvent is evaporated under reduced pressure to give a residue, which is treated with methyl tertiary butyl ether (500 milliliters), and extracted with hydrochloric acid (3 x 300 milliliters of 5. The combined extracts are washed (methyl ether tertiary butyl), basify (aqueous NaOH), and extract with tertiary butyl methyl ether (4 x 300 milliliters) .The combined extracts are dried (Na2SO4), and the solvent is evaporated under reduced pressure, to give the crude product , which is purified by recrystallization from methyl tertiary butyl cyclohexane methyl ether, to give 4- (4-methoxyphenyl) pyridine as a colorless crystalline solid, mp 94-96 ° C.
bj 4- (-bromo-4-methoxyphenyl) iridine Bromine (26.0 grams, 163 mmol) is added to a stirred solution of 4- (4-methoxyphenyl) pyridine (13.6 grams, 73.5 mmol) in acetic acid (500 milliliters), and it is heated at 60 ° C for 72 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue is treated with aqueous ammonia (400 milliliters of 6M), and extracted with ethyl acetate (3 x 200 milliliters). The combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure to give the crude product, which is purified by chromatography.
(silica gel, 95 percent tertiary butyl methyl ether / 4.5 percent methanol / 0.5 percent aqueous NH3 (25 percent)), and recrystallized from ether-cyclohexane, to give 4- (3 -bromo-4-methoxyphenyl) pyridine as a pale yellow crystalline solid, mp 82-84 ° C.
c) 4- f2- (methoxy) biphenyl-5-ill pyridine A stirred mixture of 4- (3-bromo-4-methoxyphenyl) pyridine (1.32 grams, 5 mmol), phenylboronic acid (0.67 grams, 5.5 mmol), tri -o-tolylphosphine (0.152 grams, 0.50 millimoles), palladium (II) acetate (0.056 grams, 0.25 millimoles), sodium carbonate (1.06 grams, 10 millimoles), and water (10 milliliters) in dimethyl formamide (20 milliliters) , it is heated at 80 ° C for 3 hours. The mixture is then treated with water (100 milliliters), and extracted with ethyl acetate (3 x 80 milliliters). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by chromatography
(silica gel, 98 percent ethyl acetate / 1.8 percent ethanol / 0.2 percent aqueous NH3 (25 percent)), to give the base of 4- [4-methoxy-3- (phenyl) phenyl] ] pyridine. The base is dissolved in diethyl ether (5 milliliters), treated with methanolic HCl (excess), evaporated to dryness under reduced pressure, and recrystallized from isopropanol-diethyl ether, to give 4- [2-methoxy] hydrochloride. - (1,1-biphenyl) -5-yl] pyridine as a pale yellow crystalline solid, mp 180-200 ° C, and having the following physical characteristics: -H-NMR (d DMSO-d6): 3.89 (s, 3H), 7.35 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.45 (dd, J = 7.1 Hz, J = 7.2 Hz, 2H), 7.58 (d, J = 7.1 Hz, 2H), 7.95 (d, J = 2.3 Hz, 1H), 8.08 (dd) , J = 8.7 Hz, J = 2.3 Hz, 1H), 8.2 (broad s, 1H), 8.36 (d, J = 6.0 Hz, 2H), and 8.83 (d, J = 6.0 Hz, 2H).
EXAMPLE 2: 4- [2- (methoxy) -3 # - (nitro) biphenyl-5-yl] pyridine This compound is prepared in a manner analogous to Example 1, using 3- (nitro) phenyl boronic acid instead of phenylboronic acid , to give the compound of the title, pf 145-150 ° C.
EXAMPLE 3: 4- .2- (methoxy) -3 '- (trifluoromethyl) biphenyl-5-yl] pyridine This compound is prepared in a manner analogous to Example 1, using 3- (trifluoromethyl) phenyl boronic acid instead of phenylboronic acid , to obtain the title compound as the hydrochloride, mp 103-106 ° C.
EXAMPLE 4: 4- [2- (methoxy) -3 ', 4'- (propylene) bifinyl pyridine a) Indan-5-boronic acid A solution of normal butyl lithium in hexane (13.2 milliliters of 1.6M, 21 millimoles) is add to a stirred solution of 5-bromo-indane (1.06 grams, 4 mmol) in dry tetrahydrofuran (30 milliliters) at -75 ° C, under an argon atmosphere. The mixture is stirred for 30 minutes at -65 ° C, then treated with triethyl borate (3.07 grams, 21 mmol), and stirred for 60 minutes at -50 ° C. The resulting mixture is allowed to warm to 0 ° C, and then treated with a saturated aqueous solution of ammonium chloride (60 milliliters), and extracted with ethyl acetate (2 x 80 milliliters). The combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure to give the crude product, which is purified by chromatography (silica gel, 50 percent ethyl acetate in hexane), and recrystallize from ethyl acetate-hexane, to give indan-5-boronic acid as a colorless crystalline solid.
b) 4- [2- (methoxy) -3 '.4' - (propylene) biphenyl] pyridine Using the procedure described in Example 1 c), but using indan-5-boronic acid instead of phenylboronic acid, a crude product, which is purified by chromatography (silica gel, 98 percent ethyl acetate / 1.8 percent ethanol / 0.2 percent aqueous NH3 (25 percent)) to give the base of 4- [2 - (methoxy) -3 ', 4' - (propylene) biphenyl] pyridine. The base is dissolved in acetone (5 milliliters), treated with methanolic HCl (excess), evaporated to dryness under reduced pressure, and recrystallized from isopropanol-ether, to give 4- [2- (methoxy) hydrochloride. -3 ', 4' - (propylene) biphenyl] pyridine as a pale yellow crystalline solid, mp 185-205 ° C, and having the following physical characteristics: 1H-NMR (d DMS0-d6): 2.06 (m, 2H), 2.91 (m, 4H), 3.07 (s, 3H), 7.27-7.32 (m , 2H), 7.33 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 7.93 (d, J = 2.5 Hz, 1H), 8.07 (dd, J = 8.7 Hz, J = 2.5 Hz, 1H ), 8.42 (d, J = 6.0 Hz, 2H), and 8.86 (d, J = 6.0 Hz, 2H).
EXAMPLE 5: 4- r4-Mβtoxy-3- (5-benzofurazanyl) phenyl pyridine to 4- (5-benzofurazanyl) phenylboronic acid Using the procedure described in Example 1 c), but using 5-bromobenzofuran instead of 4- ( 3-bromo-4-methoxyphenyl) pyridine, a crude product was produced, which is purified by recrystallization from ethyl acetate-hexane, to give 4- (5-benzofurazanyl) phenyl boronic acid as a beige crystalline solid, mp. > 300 ° C, and having the following physical characteristics: -RMN (d DMSO-d6 + D20): 3.66 (s, 3H), 7.84 (d, J = 9.1 Hz, 1H), 7.95 (d, J = 9.1 Hz , 1H), and 8.37 (s, 1H).
b 4- f4-methoxy-3- (5-benzofurazanyl) phenyl pyridine Using the procedure described in Example 1 c), but using 4- (5-benzofurazanyl) phenylboronic acid in place of phenylboronic acid, a crude product was produced, which is purified by chromatography (silica gel, 98 percent ethyl acetate / 1.8 percent ethanol / 0.2 percent aqueous NH3 (25 percent)), and recrystallized from ethyl acetate-hexane, to give 4- [4-methoxy-3- (5-benzofurazanyl) phenyl] pyridine as a beige crystalline solid, mp 187-192 ° C.
EXAMPLE 6: 4- r 2 -methoxy-3'-cyano- (1,1'-biphenyl) -S-illpyridine a) 2-methoxy-5- (4-pyridinyl) phenylboronic acid A solution of normal butyl lithium in hexane (1.7 milliliters) 2.5M, 4.25 mmol) is added to a stirred solution of 4- (3-bromo-4-methoxyphenyl) pyridine (Example 1, 1.06 grams, 4 mmol) and triethyl borate (0.62 grams, 4.2 mmol) in dry tetrahydrofuran. (20 milliliters) at -85 ° C under an argon atmosphere. The mixture is stirred for 15 minutes at -80 ° C, then treated with a saturated aqueous solution of ammonium chloride (60 milliliters), and extracted with ethyl acetate (2 x 80 milliliters). The combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure to give the crude product, which is purified by recrystallization from ethyl acetate-hexane, to give 2-methoxy-5-acid. (pyridin-4-yl) phenylboronic acid as a beige crystalline solid, mp 194-200 ° C, and having the following physical characteristics: XH-NMR (d DMSO-d6): 3.88 (s, 3H), 7.13 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 6.1 Hz, 2H), 7.88 (s, 1H), 7.85 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), and 8.60 (d, J = 6.1 Hz , 2H).
b 4- f2- (methoxy) - '- (cyano) biphenyl-5-yl] pyridine A stirred mixture of 3-bromobenzonitrile (0.91 grams, 5.0 mmol), 2-methoxy-5- (pyridin-4-yl) acid ) phenylboronic (0.50 grams, 2.3 millimoles), tri-o-tolylphosphine (0.152 grams, 0.50 millimoles), palladium (II) acetate (0.056 grams, 0.25 millimoles), sodium carbonate (1.59 grams, 15 millimoles), and water
(15 milliliters) in dimethyl formamide (46 milliliters), is heated at 80 ° C for 5 hours. The mixture is then treated with water (100 milliliters), and extracted with ethyl acetate (3 x 80 milliliters). The combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure to give the crude product, which is purified by chromatography.
(silica gel, ethyl acetate), to give the base of 4- [4-methoxy-3- (phenyl) phenyl] pyridine. The base is dissolved in diethyl ether (5 milliliters), treated with ethanolic HCl (excess), evaporated to dryness under reduced pressure, and recrystallized from ethanol-ether, to give 4- [2-methoxy] hydrochloride. -3'-cyano-phenyl-5-yl] pyridine as a pale yellow crystalline solid, mp 142-150 ° C.
The following compounds are prepared in an analogous manner, using the appropriate aryl bromides:
EXAMPLE 7: 4- [2- (methoxy) -3"- (chloro) biphenyl-5-ill-pyridine hydrochloride, mp 156-210 ° C.
EXAMPLE 8: 4- .2- (methoxy) -3 *. 4 '- (methyl-b-phenyloxy) biphenyl-5-ylpyridine. p.f. 168-171 ° C.
EXAMPLE 9: 4- [2- (Methoxy) -3 '- (phenoxy) biphenyl-5-pyridine hydrochloride, m.p. 184-204 ° C.
EXAMPLE 10: 4- [2- (Methoxy) -4 '- (phenoxy) biphenyl-5-yl] pyridine hydrochloride. p.f. 173-218 ° C.
EXAMPLE 11: 4- £ 2- (methoxy) -3 '- (chloro) -4' - (fluoro) biphenyl-5-yl] iridine hydrochloride, m.p. 115 ° C.
The compounds of Formula I which have benzamide or phenylcarboxy instead of pyridyl, are prepared in an analogous manner.
EXAMPLE 12: 4'-methoxy-3 '- (benzofurazan-5-yl) - [1,1'-biphenyl] -4-carboxamide
a) 4'-methoxy-1,1'-biphenyl-4-carboxylic acid ethyl ester
A stirred mixture of 4-bromobenzoic acid ethyl ester (23.6 grams, 103 millimoles), 4-methoxyphenylboronic acid (15.6 grams, 103 millimoles), tetrakis (triphenylphosphine) palladium (0) (2.0 grams, 1.73 millimoles), and fluoride cesium powder (30.0 grams, 200 millimoles) in 1,2-dimethoxyethane (300 milliliters), heated at 85 ° C for 3 hours. The mixture is then treated with water (500 milliliters), and extracted with ethyl acetate (3 x 100 milliliters). The combined extracts are washed (saturated NaCl), dried (Na2SO4), and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by chromatography (silica gel, 5 percent ethyl acetate / 95 percent cyclohexane), to give 4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid ethyl ester as a colorless crystalline solid, mp 103-104 ° C.
The following compounds are prepared in an analogous manner, using the appropriate bromobenzoic acid esters and arylboronic acids: 4'-methoxy- [1,1'-biphenyl] -3-carboxylic acid ethyl ester,
Ethyl ester of 4'-methoxy-3-methyl- [1,1'-biphenyl] -3-carboxylic acid.
b '-bromo-4'-methoxy- [1,1'-bi-enyl-1,4-carboxylic acid ethyl ester A solution of bromine (14.6 grams, 91.3 millimoles) in carbon tetrachloride (100 milliliters) is added to a stirred mixture of 4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid ethyl ester (23.4 grams, 91.3 millimoles) and silica gel (100 grams of a particle size of 0.040 to 0.063 millimeters;
Merck 1.09385) in carbon tetrachloride (350 milliliters). The mixture is stirred at 20 ° C for 4 hours, after which the silica gel is removed by filtration. The filtrate is washed with aqueous sodium hydrogen carbonate (200 milliliters of IN), followed by aqueous sodium thiosulfate (50 milliliters of 2 M), dried (Na 2 SO 4), filtered and evaporated to dryness under reduced pressure, to give the crude product, which is recrystallized from ether-cyclohexane, to give 3'-bromo-4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid ethyl ester as a colorless crystalline solid, mp. 114-115 ° C. The following compounds are prepared in an analogous manner, using the appropriate esters: 3'-Bromo-4'-methoxy- [1,1'-biphenyl] -3-carboxylic acid ethyl ester, m.p. 88-90 ° C. 3'-Bromo-4'-methoxy-3-methyl- [1,1'-biphenyl] -4-carboxylic acid ethyl ester, m.p. 84-87 ° C.
c) 3'-Bromo-4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid A stirred mixture of 3'-bromo-4'-methoxy- [1,1'-biphenyl] ethyl ester ] - carboxylic acid (28.8 grams, 86 mmol) and aqueous sodium hydroxide (35 milliliters of 2 M) in ethanol (690 milliliters), is heated at 90 ° C for 2 hours. The cooled mixture is then acidified with hydrochloric acid (200 milliliters of 1.0 M), and the resulting precipitate is filtered and dried to give 3'-bromo-4'-methoxy- [1,1'-biphenyl] -4- acid. carboxylic acid as a colorless crystalline solid.
d) Ester 2, 2-dimethylpropyl 3'-bromo-4'-methoxy- [1,1'-biphenyl-4-carboxylic acid A stirred mixture of 3'-bromo-4'-methoxy- [1, 1 '- biphenyl] -4-carboxylic acid (19.2 grams, 62.5 millimoles) and dimethyl formamide (0.1 milliliters) in toluene (200 milliliters) at 20 ° C, treated with oxalyl chloride (11.0 milliliters, 126 millimoles). The mixture is then heated at 50 ° C for 1 hour, and then evaporated to dryness under reduced pressure. The resulting crude acid chloride is dissolved in dry tetrahydrofuran (250 milliliters), and added dropwise to a stirred solution of tertiary lithium butylate in tetrahydrofuran (prepared by the slow addition of 32.5 milliliters of normal butyl lithium to a solution of 23.5 milliliters of dry tertiary butanol in 200 milliliters of dry tetrahydrofuran at 20 ° C). The mixture is stirred for a further 2 hours, then treated with a saturated aqueous solution of ammonium chloride (400 milliliters), and extracted with tertiary butyl ethyl ether (2 x 300 milliliters). The combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by chromatography (silica gel, 20 percent ethyl acetate in cyclohexane), and is recrystallized from tertiary butyl ethyl ether hexane to give 2,2-dimethylpropyl ester of 3'-bromo-4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid as a colorless crystalline solid. .
e) 4 - (3-bromo-4-methoxy-enyl) benzamide Using the procedure of Example 1 b), but using 4 - (4-methoxyphenyl) benzamide in place of 4- (4-methoxy f eni l) p ir idina , 4 - (3-bromo-4-methoxy-enyl) -benzamide is produced as a beige crystalline solid, e.g. f. 246-250 ° C.
f) 4'-methoxy-3 '- (benzofurazan-5-yl) -f, 1'-biphenyl] -4-carboxamide Using the procedure of Example 5b), but employing 4- (3-bromo-4-methoxyphenyl) ) benzamide instead of 4- (3-bromo-4-methoxyphenyl) pyridine, a crude product is produced, which is purified by chromatography (silica gel, ethyl acetate), and recrystallized from ethanol-acetate. ethyl, to give the title compound as a beige crystalline solid, mp 235-255 ° C.
EXAMPLE 13: 4'-Methoxy-3 '- (3-nitrofenyl) - [1,1"-biphenyl] -4-carboxylic acid ethyl ester A stirred mixture of 3'-bromo-4'-methoxy acid ethyl ester - [1, 1'-biphenyl] -4-carboxylic acid (26.6 grams, 79.3 mmol), 3-nitrophenylboronic acid (21.2 grams, 127 mmol), tri-o-tolylphosphine (2.51 grams, 8.26 mmol), palladium acetate ( II) (0.91 grams, 4.05 mmol), potassium carbonate (21.9 grams, 159 mmol) and water (100 milliliters) in dimethyl formamide (400 milliliters), heated at 60 ° C for 2 hours, then the mixture is treated with water (1000 milliliters), and extracted with ethyl acetate (3 x 200 milliliters) .The combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purify by chromatography (silica gel, 10 percent ethyl acetate in cyclohexane) to give 4'-methoxy-3 '- (3-nitrophenyl) - [1,1' -bifeni] ethyl ester 1) -carboxylic acid as a colorless crystalline solid, m.p. 106-108 ° C.
The following compounds are prepared in an analogous manner, using the bromobenzoic acid esters and the appropriate arylboronic acids:
EXAMPLE 14: Ethyl ester of 4'-methoxy-3 '- (3-nitrophenyl) - fl, l' -biphenyl-3-carboxylic acid, m.p. 87-89 ° C.
EXAMPLE 15: 4'-Methoxy-3-methyl-3 '- (3-nitrophenyl) -lfl.l'-biphenyl-4-carboxylic acid ethyl ester. p.f. 88-90 ° C.
EXAMPLE 16: 3 '- (5-Benzofurazanyl-4'-methoxy-fl.l' -biphenyl-4-carboxylic acid ethyl ester, mp 166-168 ° C.
EXAMPLE 17: Ester 2,2-di-ethylpropyl 3'- (5-benzo-furazanyl) -4'-methoxy-fl, l '-biphenyl-carboxylic acid, mp 131-136 ° C.
EXAMPLE 18: Acid 3 * - (5-benzofurazanil) -4 * -methoxy- [1, 1'-biphenyl] -4-carboxylic acid A stirred mixture of 4'-methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid ethyl ester (1.88 grams, 5 mmol ) and aqueous sodium hydroxide (20 milliliters of 2M) in ethanol (30 milliliters), heated at 90 ° C for 3 hours. The cooled mixture is then acidified with hydrochloric acid (100 milliliters of 1.0 M), and the resulting precipitate is filtered and dried to give 4'-methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] acid. ] -4-carboxylic acid as a colorless crystalline solid, mp 270-274 ° C.
The following compounds are prepared in an analogous manner, using the appropriate esters:
EXAMPLE 19: 4'-Methoxy-3 '- (3-nitrophenyl) -fl' '-biphenyl] -3-carboxylic acid. p.f. 223-228 ° C.
EXAMPLE 20: 4 '-methoxy-3-methyl-3' - (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid. p.f. 278-281 ° C.
EXAMPLE 21: 3 '- (5-Benzofurazanyl) -4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid, m.p. > 300 ° C.
EXAMPLE 22: 4 '-methoxy-3' - (3-chlorophenyl) - [1,1'-biphenyl-4-carboxylic acid. p.f. 250-252 ° C.
EXAMPLE 23: Acid 4 '-methoxy-3' - (3-cyanophenyl) - [1,1'-bifenyl] -4-carboxylic acid. p.f. 280-285 ° C.
EXAMPLE 24: 4-methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide A solution of trimethyl aluminum in toluene (10 milliliters of 2.0 M) is added for 30 minutes, to a stirred suspension of ammonium chloride (1.07 grams, 20 mmol) in toluene (20 milliliters) at 5 ° C under an argon atmosphere. The mixture is stirred at 20 ° C for 2 hours, treated with a solution of 4'-methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid ethyl ester (1.65 grams, 4.3 mmol) in toluene (40 milliliters), and stirred at 60 ° C for 18 hours. The cooled mixture is washed with hydrochloric acid (50 milliliters of 0.5 M), followed by saturated aqueous sodium chloride (50 milliliters), dried (Na 2 SO 4), filtered, and the solvent is evaporated under reduced pressure, to give the product crude, which is purified by crystallization from ethyl acetate-tertiary butyl ethyl ether, to give 4'-methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide as a colorless crystalline solid, mp 201-205 ° C.
The following compounds are prepared in an analogous manner, using the appropriate esters:
EXAMPLE 25: 4'-methoxy- '- (3-nitro-enyl) -TI'1'-biphenyl-3-carboxamide, m.p. 118-120 ° C.
EXAMPLE 26: 4'-methoxy-methi 1 - '- (-ni rofeni 1) - TI. 1' -biphenyl] -4-carboxamide, m.p. 179-184 ° C.
EXAMPLE 27: N-Methyl-4'-methoxy -3 '- (3-n-trophenyl) -TI-1'-biphenyl] -4-carboxamide Using the procedure described in Example 24, but using methyl amine hydrochloride instead of ammonium chloride, a crude product is produced, which is purified by chromatography (silica gel, 50 percent ethyl acetate in cyclohexane), and recrystallized from tetrahydrofuran-cyclohexane, to give N-methyl- ' -methoxy-3 '- (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide as a pale yellow crystalline solid, mp 171-172 ° C.
A representative imidazopyridine compound is prepared as follows.
EXAMPLE 28: 6- r4-methoxy-3- (5-benzofurazanyl) phenyl imidazo ri.2- to iridine to 5- (2-hydroxyphenyl) benzofurazan A stirred mixture of 5-bromobenzofurazane (11.94 grams, 60 mmol), acid 2 -hydroxyphenylboronic acid (9.10 grams, 66 millimoles), tri-o-tolylphosphine (1.82 grams, 6 millimoles), palladium (II) acetate (0.672 grams, 3 millimoles), potassium carbonate (12.4 grams, 90 millimoles), and water (90 milliliters) in dimethyl formamide (180 milliliters), is heated at 80 ° C under an argon atmosphere for 30 minutes. The mixture is then treated with water (300 milliliters), and extracted with ethyl acetate (3 x 100 milliliters). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by chromatography (silica gel, ethyl acetate of 20%). percent to 100 percent in cyclohexane), and recrystallized from ethyl acetate-hexane, to give 5- (2-hydroxy-phenyl) -benzofurazane as a pale yellow crystalline solid, mp 166-169 ° C.
b) 5- (3-bromo-5-hydroxyphenyl) benzofurazan A stirred mixture of 5- (2-hydroxyphenyl) benzofurazan (11.2 grams, 52.8 mmol), and tetrabutyl ammonium tribromide (25.5 grams, 52.8 mmol) in dichloromethane (530 g) milliliters), is stirred at 18 ° C for 18 hours. The solvent evaporates under reduced pressure, to give a residue, which is treated with water (300 milliliters), and extracted with ethyl acetate (3 x 100 milliliters). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by recrystallization from ethyl acetate-hexane, give 5- (3-bromo-5-hydroxyphenyl) benzofurazane as a pale yellow crystalline solid, mp 179-181 ° C.
c) 5- (3-bromo-5-methoxyphenyl) benzofurazane A stirred mixture of 5- (3-bromo-5-hydroxyphenyl) benzofurazane (8.70 grams, 30 mmol), potassium carbonate (14.42 grams, 90 mmol), and Methyl iodide (2.83 milliliters, 45 mmol) in dimethyl formamide (100 milliliters) is stirred at 18 ° C for 16 hours. The mixture is then treated with water (600 milliliters), and extracted with ethyl acetate
(3 x 150 milliliters). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by recrystallization from methyl tertiary butyl ether-hexane , to give 5- (3-bromo-5-methoxyphenyl) benzofurazane as a beige crystalline solid, m.p. 135-137 ° C.
d) 6- (Trimethylstannyl) imidazo [1,2-a] pyridine A stirred mixture of 6-bromoimidazo [1,2-a] pyridine
(2.36 grams, 12 mmol), hexamethyl acetate (5.0 grams,
. 3 millimoles), triphenylphosphine (496 milligrams, 1.89 millimoles), and bis (dibenzylidene ketone) palladium (0) (270 milligrams, 0.47 millimoles) in toluene (120 milliliters), is heated at 118 ° C under an argon atmosphere for 6 hours . The mixture is then treated with an aqueous solution of potassium fluoride (300 milliliters of 0.50 M), and extracted in toluene (3 x 50 milliliters). The combined extracts are dried (Na 2 SO 4), filtered, and the solvent is evaporated under reduced pressure, to give the crude product, which is purified by chromatography (silica gel, 50 percent ethyl acetate in cyclohexane), give 6- (trimethylstannyl) imidazo [1,2-a] pyridine as a colorless oil.
e) 6- [4-methoxy-3- (5-benzofurazanyl) phenylimidazo [1,2-pyridine] A stirred mixture of 5- (3-bromo-5-methoxyphenyl) benzofurazane (2.44 grams, 8 mmol), - (trimethylstanil) imidazo [1,2-a] pyridine (2.2 grams, 7.9 millimoles), triphenylphosphine (336 milligrams, 1.28 millimoles), and bis (dibenzylidene ketone) palladium (0) (186 milligrams, 0.32 millimoles) in dimethyl formamide ( 60 milliliters), is heated at 125 ° C under an argon atmosphere for 36 hours. The solvent is evaporated under reduced pressure, to give a crude product, which is purified by chromatography (silica gel, 95 percent ethyl acetate / 4.5 percent ethanol / 0.5 percent aqueous NH3 (25 percent) ), and recrystallized from ethyl acetate-tertiary butyl methyl ether, to give 6- [4-methoxy-3- (5-benzofurazanyl) phenyl] imidazo [1,2-a] pyridine as a yellow crystalline solid pale, mp 190-196 ° C.
The AGENTS OF THE INVENTION, as defined above, for example, of the formula la or Ib, particularly as exemplified, in free form or pharmaceutically acceptable acid addition salt, exhibit pharmacological activity, and are useful as pharmaceuticals, for example, for therapy, in the treatment of diseases and conditions as described hereinabove. In particular, the AGENTS OF THE INVENTION exhibit inhibitory activity of the cyclic nucleotide isoenzyme phosphodiesterase (PDE), selective for the type 4 isoenzyme. The AGENTS OF THE INVENTION possess anti-inflammatory, anti-hyperreactivity properties of the airways, and bronchodilators. They also possess immunosuppressive activities, inhibitors of the secretion of tumor necrosis factor-a, and other pharmacological activities, as can be demonstrated in conventional test methods, for example, as follows:
A. Inhibition of PDE4: Recombinant isoenzyme inhibition assays PDE4A, PDE4B. PDE4C and PDE4D. Cloning and expression: The PDE4 cDNA encoding the four isoenzymes, human PDE4A (as described by Sullivan et al., Cell Signal 1994; 6: 793-812), rat PDE4B (as described by Colicelli et al., Proc. Nati, Acad. Sci. USA 1989; 86: 3599-3903), human PDE4C (as described by Engels et al., FEBS Lett.; 358: 305-310), and human PDE4D (as described by Baecker et al., Gene 1994; 138: 253-256), either cloned into an extrachromosomal yeast expression vector (PDE4C, PDE4D), or integrated (PDE4A, PDE4B; a single copy) in the pep4 site of a strain of Saccaromyces cerevisiae lacking the wild-type yeast phosphodiesterase genes. The yeast strains expressing the PDE4 isoenzymes are cultured in 1 liter cultures at 30 ° C, granulated, and frozen until homogenization.
Homogenization: the granulated yeast (5 milliliters) is suspended in 50 milliliters of pH regulator (10 mM tris-hydroxymethylaminomethane, lmM ethylenediaminetetraacetic acid, 1 milligram / milliliter of each of leupeptin and pepstatin A, 175 milligrams / milliliter of fluoride of phenylmethylsulfonyl, 1 mM dithioerythritol, pH 7.4 with HCl). After the centrifugation, 15 grams of glass beads (from 425 to 600 millimeters, washed with acid, Sigma Chemical Co.) are added, washed with pH regulator, to the granule. To this slurry, 1 milliliter of pH regulator and 60 milligrams of colamidopropanesulfonic acid are added, and the slurry is stirred vigorously for 4 hours at 4 ° C. The yeast cells disintegrate, as seen microscopically (phase contrast optics) as dark cells, and are > 30 percent (usually 50 percent). The slurry is transferred to a thick glass funnel, and the homogenate is collected by suction, and the glass beads are washed with a total of 15 milliliters of pH regulator. The cell fragments are prepared from cytosol by centrifugation (2000 xg, 10 minutes, 4 ° C). The granule is resuspended in 15 milliliters of pH regulator, and assayed for phosphodiesterase activity together with the cytosol. Phosphodiesterase assay: the assay protocol is based on the two-step method described by Thompson et al. (Adv. Second Messenger Phosphoprotein Res. 1979; 10: 69-92), modified for 96-well microtiter plates. Briefly stated, the enzyme is diluted with homogenization buffer (see above), in order to obtain a hydrolysis of the total substrate between 10 percent and 30 percent during the assay. To start the reaction, add 25 milliliters of diluted enzyme to 25 milliliters of substrate ([3H] -cAMP, 1.25 mM, 740 Bq) and 75 milliliters of inhibitor solution (see below). After 30 minutes at 37 ° C, the reaction is stopped in a hot water bath (65 ° C, 5 minutes). The plates are cooled on ice, and incubated for 10 minutes at 37 ° C with 25 milliliters of 5'-nucleotidase (snake venom, oiophaghus hannah, Sigma Chemical Co, 0.1 milligrams / milliliter in water). The unreacted substrate is separated from [3 H] -adenosine by sequential addition of aliquots (100 + 50 + 50 milliliters, at 5 minute intervals) of Dowex 1 x 2 30% (volume / volume) slurry ( acetate form) in 0.2 percent (volume / volume) acetic acid. The Dowex is granulated by centrifugation (150 xg, 5 minutes). The aliquots of the supernatants are transferred to 96-well solid phase scintillation plates (LumaPlate, Canberra Packard) using an automated pipetting device (Hamilton MicroLab 2200), dried (at least 4 hours at 50 ° C), and makes the count (Canberra Packard TopCount). Inhibitors: Inhibitory delivery solutions are prepared in dimethyl sulfoxide (DMSO), and diluted with water / dimethyl sulfoxide, to reach 7 concentrations selected to cover the inhibition range of 30 percent to 70 percent. The concentration of dimethyl sulfoxide is kept constant at 50 milliliters / milliliter throughout the entire assay. Determination of the inhibition parameters: the concentration at which the mean-maximum inhibition (ICS0) occurs, and the inclination of the dose response curve (Hill coefficient), are determined from the concentration- inhibition by adjusting nonlinear least squares to the logistic equation of two parameters. The results are expressed as the negative decimal logarithm of the inhibitor concentration where the mean-maximum inhibition (ICS0) is observed (in moles / liter, pIQ0). Confidence intervals of 95 percent were estimated, and were expressed as pL and pU (negative decimal logarithms of the lower and upper confidence limits, respectively). The concentrations that cause a visible precipitation in the test are excluded from the analysis. In this test method, the AGENTS OF THE INVENTION predominantly inhibit phosphodiesterase isozymes of type 4 which have relatively little effect in relation to types 1, 2, 3, and 7. Within the group of phosphodiesterase type 4 isoenzymes (is say, phosphodiesterase type 4A to D), the AGENTS OF THE INVENTION generally exhibit selectivity for the inhibition of the phosphodiesterase type 4D isoenzyme compared to the phosphodiesterase isoenzymes types 4A, 4B, and 4C.
B. Anti-inflammatory activity: Inhibition of eosinophil activation by formyl-MetLeuPhe (fMLP) Purified human eosinophils (104 / cavity in 0.2 milliliters of HBSS) are stimulated with fMLP (1 μM) in the presence of lucigenin (25 μM) . Inhibition of the oxidative burst (measured as changes in chemiluminescence) is determined from the dose response curves, using the logistic equation. The AGENTS OF THE INVENTION are active in test methods A and B, in concentrations of the order of 0.001 to 5 μM, generally in the low range of nM.
c. Influence on allergen-induced pulmonary eosinophilia Exposure of Brown Norway rats to inhaled antigen (Ovalbum ina) causes pulmonary eosinophilia that is maximal 48 hours later. In addition to the numbers of eosinophils, the activation status of these cells can be assessed by the enzymatic activity of eosinophil peroxidase (EPO) of the eosinophil granule enzyme. In the present experiments, the inhibition of accumulation of pulmonary eosinophils by the AGENTS OF THE INVENTION is evaluated. Ovalbumin (10 micrograms / milliliter) is mixed (1 hour on ice) in a mixer with aluminum hydroxide (10 milligrams / milliliter), and injected subcutaneously in a coincidental manner with a B. pertussis vaccine (0.25 milliliters / rat, intraperitoneally ) in Brown Norway male rats (approximately 200 grams). The ovalbumin injection, together with the auxiliary, is repeated 15 and 21 days later. On day 28, sensitized animals are restricted in plastic tubes, and exposed for 1 hour to an ovalbumin aerosol (3.2 milligrams / milliliter) using an exposure system? only to the nose. The animals are sacrificed 48 hours after c o n f e noba rb i t a l (2 5 0 mi 1 g branch s / i 1 g, intraperitoneally). The lungs are washed using three aliquots (4 milliliters) of Hank's solution (HBSS x 10, 100 milliliters, 100 mM EDTA, 100 milliliters, 1 M HEPES, 10 milliliters, 1 liter of water); the recovered cells are grouped, air-dried, and stained to differentiate cell types. The cells are identified and counted under immersion in oil (x 1000). A minimum of 500 cells per spot is counted, and the total population of each cell type is calculated. The test substance is administered intratracheally 1 hour before, and 24 hours after, the stimulation with ovalbumin. In untreated animals, the stimulation with ovalbumin induces an increase of all cell types in the BAL fluid 24 hours after the stimulus. Before administration of the AGENTS OF THE INVENTION, in dosages of the order of 0.01 to 10 milligrams / kilogram, reduces the eosinophil count in BAL in a dose-dependent manner, compared to untreated controls. Cell counts are also reduced for other leukocytes (macrophages, neutrophils). Considering its anti-inflammatory activity, its influence on the airway hyperreactivity, and its profile in relation to the inhibition of the phosphodiesterase isoenzyme, in particular as selective inhibitors of type IV, the AGENTS OF THE INVENTION are useful for the treatment , in particular the prophylactic treatment, of the obstructive or inflammatory disease of the airways. Accordingly, by continuous and regular administration for prolonged periods of time, the AGENTS OF THE INVENTION are useful to provide early protection against the recurrence of bronchoconstrictor or other symptomatic attack as a result of obstructive or inflammatory airway disease, or for control, reduce, or reverse the basal state of that disease. Considering its bronchodilator activity, the AGENTS
OF THE INVENTION are useful as bronchodilators, for example, for the treatment of chronic or acute bronchoconstriction, for example, for the symptomatic treatment of obstructive or inflammatory airway disease. The words "treatment" and "treating", as used throughout the present specification and in the claims in relation to the obstructive or inflammatory disease of the airways, should be understood in accordance with the same, to encompass both the prophylactic mode as the symptomatic mode of therapy. In accordance with the above, the present invention further provides: A. A method: a) for the treatment of airway hyperreactivity, b) for bronchodilation, or in particular, c) for treating obstructive or inflammatory disease of the airways, in a subject that needs it, said method comprises administering to this subject an effective amount of an AGENT OF THE INVENTION. Obstructive or inflammatory diseases of the airways to which the present invention applies include asthma, pneumoconiosis, chronic or obstructive airway disease or lung disease (COAD or COPD), and adult respiratory distress syndrome (ARDS). , as well as the exacerbation of airway hyperreactivity as a consequence of another drug therapy, for example aspirin or ß-agonist therapy. The present invention is applicable to the treatment of asthma of any type or genesis, including intrinsic asthma, and especially extrinsic asthma. It is applicable to the treatment of allergic asthma (atopic / IgE mediated). It is also applicable to the treatment of non-atopic asthma, including, for example, bronchitic, exercise-induced, and occupational asthma, asthma induced at once by bacterial infection and other non-allergic asthma. It is also applicable to the treatment of panting baby syndrome (infant asthma). The invention is applicable to the treatment of pneumoconiosis of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tabacosis, and byssinosis.
The invention is applicable to the treatment of chronic obstructive airway or pulmonary disease, including chronic bronchitis, pulmonary emphysema, or dyspnea associated therewith. The invention is also applicable to the treatment of bronchitis of any type or genesis, including, for example, acute, arachidic, catarrhal, chronic, or croupy, or phthinoid bronchitis, etcetera. Considering their activity as selective inhibitors of tumor necrosis factor-release, the AGENTS OF THE INVENTION are also useful for downregulating or inhibiting the release of tumor necrosis factor-a, for example, for the treatment of diseases or conditions in where it is involved the release of tumor necrosis factor, or have a mediating role, for example, diseases or conditions having an aetiology involving or comprising releasing factor, tumor-necrosis morbid, for example undesirable, excessive, or unregulated, in particular for the treatment of cachexia or endotoxin shock, and in the treatment of AIDS [cf. Sharief et al., Mediators of Inflammation, 1 323-338 (1992)]. The method of the invention is applicable to the treatment of cachexia associated with morbid factor release tumor-necrosis or blood serum levels of factor ce tumor-necrosis of any origin, including cachexia resulting from, for example, infection bacterial, viral, or parasitic, or to the deprivation or deterioration of humoral function or other organic function, for example renal. For example, it is applicable to the treatment of cancerous cachexia, malaria, and vermal cachexia resulting from dysfunction of the pituitary, thyroid, or thymus glands, as well as uraemic cachexia. It is in particular applicable to the treatment of AIDS-related cachexia, ie, cachexia as a result of, or associated with, HIV infection. The method of the invention is also applicable to the treatment of septic shock, for example, shock conditions resulting from bacterial infection, for example, toxic or endotoxic shock. In this regard, it should be noted that the present invention provides a method for the treatment of septic shock, as well as conditions resulting from, or symptomatic of, septic shock, for example ARDS (adult respiratory distress syndrome). The method of the invention is also applicable to other severe acute inflammatory conditions, for example severe burns, meningitis, and pneumonia. The method of the invention is also applicable to the treatment of disease as a result of HIV infection, for example AIDS, for example to reduce or control the progression of that disease. Considering their profile in relation to inhibition of isoenzymes of phosphodiesterase and / or inhibition of factor release tumor-HEARD necrosis, as well as their immunosuppressive activity, AGENTS OF THE INVENTION are also useful as immunosuppressive agents, e.g. , for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases where the inflammatory processes are involved, or which have an inflammatory component or etiology, or as anti-inflammatory agents for the treatment of inflammatory disease, in particular for the treatment of inflammatory disease where autoimmune reactions are involved, or that has an autoimmune component or etiology. Examples of this disease that can apply the present invention include, autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, granulomatosis Egener , dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic pruritus, inflammatory autoimmune bowel disease (eg, ulcerative colitis and Crohn's disease), ophthalmic opathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), ubeitis (anterior and posterior), keratoconjunctivitis, and vernal keratoconjunctivitis, lung fibrosis interstitial, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome, for example including idiopathic nephrotic syndrome or minimal-change nephropathy), as well as inflammatory and / or hyperproliferative skin diseases, such as atopic psoriasis dermatitis, pemfigus, and particular, contact dermatitis, for example allergic contact dermatitis. The AGENTS OF THE INVENTION are in particular useful for the treatment of arthritis, and another rheumatic or inflammatory disease, especially for the treatment of rheumatoid arthritis. As immunosuppressants, the AGENTS OF THE INVENTION are further indicated for use in the prevention of graft rejection, for example for the maintenance of transplants of halogenic organs, or the like, for example in relation to transplantation of kidney, liver, lung, heart, heart-lung, intestine, bone marrow, skin, or cornea. Considering their anti-inflammatory activity, in particular in relation to the inhibition of eosinophil activation, the AGENTS OF THE INVENTION are also useful for the treatment of disorders related to eosinophils, for example eosinophilia, in particular disorders related to eosinophils of the airways (for example, involving morbid eosinophilic infiltration of lung tissues), including hypereosinophilia as it affects the airways and / or the lungs, as well as, for example, disorders related to airway eosinophils as a result of , or in a manner concomitant with, Lóffler syndrome, eosinophilic pneumonia, parasitic (particularly metazoal) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarthritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and disorders related to eosinophils that affect the airways, caused by reaction to drugs. Considering their profile in relation to the inhibition of phosphodiesterase isoenzymes, in particular their profile as selective inhibitors of type IV, the AGENTS OF THE INVENTION are furthermore useful as inhibitors of phosphodiesterase type IV, for example, for the treatment of the disease that involves the depletion of calcium from the tissue, in particular degenerative diseases of bone and joints that involve calcium depletion, especially osteoporosis. In this regard, they are also useful for the treatment of allergic inflammatory diseases, such as rhinitis, conjunctivitis, atopic dermatitis, urticaria, and gastrointestinal allergies.; as vasodilators, for example, for the treatment of angina, hypertension, congestive heart failure, and dementia due to multiple infarcts; and for the treatment of other conditions where the inhibition of phosphodiesterase IV is indicated, for example, depression, conditions and diseases characterized by impaired cognitive function, including Alzheimer's disease, Parkinson's disease, and embolism. Considering their ability to interact synergistically with the substances of immunosuppressive and / or anti-inflammatory drugs, the AGENTS OF THE INVENTION are also useful as co-therapeutic agents to be used in conjunction with these drugs, for example, as enhancers of therapeutic activity of those drugs, or as means to reduce the required dosage or the potential side effects of those drugs. Drug substances with which the AGENTS OF THE INVENTION can be co-administered properly include, for example, substances of immunosuppressive or anti-inflammatory drugs of cyclopeptide, cyclopeptolide, or macrolide, for example, drugs belonging to the class of cyclosporin, for example cyclosporins A or G, tacrolimus drug substances (also known as FK 506), asmicin and rapamycin and their different congeners and known derivatives, as well as glucocorticosteroid drugs. The diseases to which this co-therapy can be applied include, for example, any disease or condition requiring therapy with immunosuppressive or anti-inflammatory drugs, for example, as described hereinabove. In particular, the AGENTS OF THE INVENTION are suitable for use in the co-therapy mentioned above, for example, for the purposes of an immunosuppressive, anti-inflammatory, or anti-attic treatment, for example, to achieve the dispersing effect of cyclosporin, for example cyclosporin A, macrolide, or steroid. According to the foregoing, the present invention also provides: B. A method: a) to down-regulate or inhibit the release of tumor necrosis factor-a, b) to inhibit the activity of phosphodiesterase IV isoenzyme, c) to perform immunosuppression, d) for the treatment of inflammatory disease, or e) for the treatment of any particular condition or disease as described hereinabove, in a subject in need thereof, which method comprises administering to this subject an effective amount of a AGENT OF THE INVENTION. The present invention also provides: C. AN AGENT OF THE INVENTION for use as a pharmaceutical product, for example, for use in any method or in the treatment of any disease or condition as described hereinabove, for example, as define low A or B above. The dosages employed in the practice of the present invention, of course, will vary, depending, for example, on the particular disease or condition to be treated, the particular AGENT OF THE INVENTION used, the mode of administration, and the therapy desired. However, it is generally indicated that satisfactory results are obtained, for example, for the treatment of diseases as described hereinabove, with oral administration in dosages of the order of about 0.01 to 2.0 milligrams / kilogram. In larger mammals, for example humans, a daily dosage indicated for oral administration, according to the above, will be on the scale of approximately 0.75 to 150 milligrams, conveniently administered once or in divided doses of 2 to 4 times a day, or in a sustained release form. The unit dosage forms for oral administration, accordingly, suitably comprise from about 0.2 to 75 or 150, for example from about 0.2 or 2.0 to 50, 75, or 100 milligrams of the AGENT OF THE INVENTION, together with a pharmaceutically acceptable diluent or vehicle therefor. For use in the treatment of chronic or obstructive airway disease, for example, asthma, the AGENTS OF THE INVENTION may also be administered via the inhaled route. Again, the dosages employed will vary, for example, depending on the particular disease or conditions, of the particular agent employed, of the particular mode of administration (eg, whether by inhalation of dry powder or otherwise), and of the desired effect. However, in general, an inhaled daily dosage indicated will be of the order of from about 2.5 to about 130.0 micrograms / kilogram / day, for example, from about 13.0 to about 60.0 micrograms / kilogram / day. For larger mammals, for example humans, a daily dosage indicated for administration by inhalation, for example, in the treatment of asthma, will be on the scale of from about 0.2 to about 10.0 milligrams, for example, from about 1 to about 5 milligrams, given conveniently in a single administration, or in two or three separate administrations throughout the day. An appropriate dosage per administration, therefore, will be of the order of about 200 micrograms to about 3.3 milligrams, with administration up to 3 times a day, suitably administered from an application device by inhalation of dry powder in a series of 2 to 8 aspirations. in each administration. The AGENTS OF THE INVENTION can also be administered by any other appropriate route, for example, by infusion, for example for the treatment of endotoxin shock.; nasally, for example for the treatment of rhinitis; ocularly, for example for the treatment of autoimmune diseases of the eye; dermally, that is, locally to the skin, for example for the treatment of dermatosis or psoriasis; or rectally, for example by means of enema or suppository, for example for the treatment of inflammatory bowel disease. The dosages suitable for application by these routes will generally be of the order of 10 to 100 times lower than those required for oral administration. Pharmaceutical compositions comprising the AGENTS OF THE INVENTION can be prepared using conventional diluents or excipients, and techniques known in the galenic field. Accordingly, oral dosage forms may include tablets, capsules, and the like. Formulations for dermal administration may take the form of creams, ointments, gels, or transdermal application systems, for example patches, and in addition to diluents or inert carriers, may adequately contain skin penetration enhancing agents, again as It is known in the field. Compositions for inhalation may comprise aerosol formulations or other sprayable formulations, as well as inhalable dry powder formulations, with and without diluent, to be administered by any suitable dry powder inhalation system, as is known in the art. For the preparation of dry powder forms for inhalation, the AGENTS OF THE INVENTION are suitably employed in a pharmaceutically acceptable acid addition salt form. The salt form is suitably milled, for example, using an air jet or ceramic mill, to provide a finely divided inhalable powder, for example, having an average particle diameter of about 2 to 3 microns. Suitably, at least 90 percent of the material will have an average particle diameter of less than 7.8 microns, more preferably less than 4.8 microns. In order to ensure obtaining an appropriate and consistent particulate product suitable for administration by inhalation in a dry powder form, it may be preferable to effect grinding of the active ingredient previously mixed with an appropriate inhalable carrier medium, for example lactose, under conditions of reduced temperature. In accordance with the foregoing, the present invention also provides: a pharmaceutical composition comprising an AGENT OF THE INVENTION, together with a pharmaceutically acceptable diluent or carrier therefor, for example, for use in any method as defined hereinbefore .
Claims (12)
1. A compound of (4-oxy-3- (aryl) phenyl) -azaryl or -arylcarbonyloxy, in free or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical product.
2. A pharmaceutical composition comprising a compound of (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt.
3. The use of a compound of (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy, in free form or pharmaceutically acceptable acid addition salt, for the preparation of a medicament for the treatment or prophylaxis of inflammation.
4. A method for the treatment or prophylaxis of inflammation, which comprises administering an effective amount of a compound of (4-oxy-3- (aryl) phenyl) -aryl or -arylcarbonyloxy, in free or addition salt form of pharmaceutically acceptable acid, to a subject in need of this therapy.
5. A compound of (4-oxi-3- (aryl) phenyl-azarylc or -arylcarbonyloxy, in free form or of pharmaceutically acceptable acid addition salt, with the understanding that: the 3-aryl fraction is not phenyl unsubstituted, when: the arylcarbonyloxyl fraction is phenyl-4-carboxylic acid or phenyl-methyl-carboxylate, or the randomly selected fraction is 5-methylthiazol-2-yl, or the 3-aryl fraction is unsubstituted phenyl or 2-methoxyphen-1-yl when the fraction of azaryl is 2-quinoline unsubstituted, or 2-quinoline substituted by methyl or phenyl in the 3-position, and / or by carboxy in the 4-position.
6. A compound of ( -oxi-3- (aryl) phenyl) -azaryl according to claim 1 or 5.
7. A (4-oxy-3- (aryl) phenyl) -arylcarbonyloxy compound according to claim 1 or 5. 8 A compound according to claim 1, 5, 6, or 7 of the formula la or formula Ib: wherein: in the formula la, W is N or C-CO-R, wherein R is OH, O-alkyl (of 1 to 6 carbon atoms), or NR3R4, wherein R3 and R, which may be equal or different, are H or alkyl (of 1 to 6 carbon atoms), or in formula Ib, Az is a randomyl group containing one or more nitrogen atoms, such as quinoline, isoquinoline, indole, imidazopyridine, for example imidazo [1,2-a] pyridine, and both in the formula la and Ib: Rx is alkyl (of 1 to 4 carbon atoms), preferably methyl; and R2 is a phenyl moiety, for example of the formula II: where R5 and < R are independently H, nitro, halogen (e.g., chloro), trifluoromethyl, alkoxy (1 to 4 carbon atoms), cyano, or phenoxy; or R5 and R together form a bridge of 3 to 5 atoms in length, wherein the bridge atoms are selected from S, 0, N, and C, for example -0CH20-, or propylene; or R2 is a fraction of 2,5-cyclohexadien-3,4-ylidene-1-yl, for example of the formula III: III wherein R7 and RB together form an aromatic bridge of 3 to 5 carbon atoms in length, wherein the bridge atoms are selected from S, O, N, and C, for example = N-0-N =; in free form or pharmaceutically acceptable acid addition salt. 9. A compound selected from the group consisting of: 4- [2- (methoxy-biphenyl-5-yl] pyridine, 4- [2- (methoxy -3- (nitro) biphenyl-5-yl] pyridine, 4- [2- (methoxy -3- (trifluoromethyl) biphenyl-5-yl] pyridine, 4- [2- (methoxy-3,4 '- (propylene) biphenyl] pyridine, 4- [4- (methoxy -3 - (benzofurazan-5-yl) phenyl] pyridine, 4- [2- (methoxy-3 '- (cyano) biphenyl-5-yl] pyridine, 4- [2- (methoxy-3' - (chloro) biphenyl- 5-yl] pyridine, 4- [2- (methoxy -3 ', 4' - (methylenedioxy) biphenyl-5-yl] pyridine 4- [2- (methoxy-3 '- (phenoxy) biphenyl-5-yl] pyridine, 4- [2- (methoxy -4 '- (phenoxy) biphenyl-5-yl] pyridine, 4- [2- (methoxy-3' - (chloro) -4 '- (fluoro) biphenyl-5-yl ] pyridine, 4'-methoxy-3 '- (benzofurazan-5-yl) - [1,1'-biphenyl] - -carboxamide, 4'-methoxy-3' - (3-nitrophenyl) - [1, 1] ethyl ester '-biphenyl] -4-carboxylic acid, ethyl ester of 4 '-methoxy-3' - (3-nitrophenyl) - [1,1 '-biphenyl] -3-carboxylic acid ester, ethyl ester of' -methoxy-3-methyl-3 '- (3-) nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid, 3 '- (5-benzofurazanyl) -4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid ethyl ester, ester 2, 3 '- (5-Benzofurazanyl) -4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid 2-dimethylpropyl, 3' - (5-benzofurazanyl) -4'-methoxy- [1, 1 '-biphenyl] -4-carboxylic acid, 4'-methoxy-3' - (3-nitrophenyl) - [1,1'-biphenyl] -3-carboxylic acid, 4'-methoxy-3-methyl-3 'acid - (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxylic acid, 3 '- (5-benzofurazanyl) -4'-methoxy- [1,1'-biphenyl] -4-carboxylic acid '-methoxy-3' - (3-chlorophenyl) - [1,1'-biphenyl] -4-carboxylic acid, 4 '-methoxy-3' - (3-cyanophenyl) - [1,1'-biphenyl] - 4-carboxylic acid, 4 '-methoxy-3' - (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide, 4 '-methoxy-3' - (3-nitrophenyl) - [1,1 '] -biphenyl] -3-carboxamide, 4 '-methoxy-3-methyl-3' - (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide, N-methyl-4 '-methoxy-3' - (3-nitrophenyl) - [1,1'-biphenyl] -4-carboxamide, 6- [4-methoxy-3- (5-benzofurazanyl) phenyl] imidazo [1,2-a] pyridine. in free form or pharmaceutically acceptable acid addition salt. 10. A process for the preparation of a compound according to any of claims 1 or 5-9, which comprises reacting a compound of the formula I 'a or I'b: wherein X is halogen or an leaving group, and Rx, W, and Az are as defined in claim 8, with an activated aryl compound of the formula lia or Illa: wherein Y is halogen (preferably bromine) or an exit group, such as a group containing tin or boron (preferably -B (0H) 2), and the R groups are as defined in claim 8; and recovering the resulting compound, in free form or from pharmaceutically acceptable acid addition salt. 11. A compound of the formula I 'a or of the formula wherein X is halogen (preferably bromine) or an exit group, such as a group containing tin or boron (preferably -B (0H) 2), and R_,, and Az are as defined in claim 8 , on the understanding that: when X is bromine R ^ is methyl, is different from C- C00CH3, when X is chlorine or bromine, and Rx is methyl, ethyl, propyl or butyl, it is different from C-COOH, when X is chlorine and Rx is methyl, is different from C-COOCH2CH3 C-COOCH2CH2CH3, and when R2 is methyl and Az is a substituted quinoline or an unsubstituted or substituted indole group, X is different from fluorine. 12. One method: a) to down-regulate or inhibit the release of tumor necrosis factor-, b) to inhibit the activity of phosphodiesterase IV isoenzyme, c) to effect immunosuppression, d) to treat inflammatory disease, oe) for the treatment of any particular disease condition as described hereinabove, in a subject in need thereof, said method comprises administering to this subject an effective amount of an AGENT OF THE INVENTION.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9604926.7 | 1996-03-08 | ||
GBGB9604926.7A GB9604926D0 (en) | 1996-03-08 | 1996-03-08 | Organic compounds |
Publications (2)
Publication Number | Publication Date |
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MX9807247A MX9807247A (en) | 1998-12-31 |
MXPA98007247A true MXPA98007247A (en) | 1999-02-01 |
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