IE54136B1 - Diphosphonic acid derivatives, process for their preparation and pharmaceutical preparations containing them - Google Patents
Diphosphonic acid derivatives, process for their preparation and pharmaceutical preparations containing themInfo
- Publication number
- IE54136B1 IE54136B1 IE148/83A IE14883A IE54136B1 IE 54136 B1 IE54136 B1 IE 54136B1 IE 148/83 A IE148/83 A IE 148/83A IE 14883 A IE14883 A IE 14883A IE 54136 B1 IE54136 B1 IE 54136B1
- Authority
- IE
- Ireland
- Prior art keywords
- group
- chlorophenyl
- diphosphonic acid
- bis
- phenyl
- Prior art date
Links
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical class OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 34
- YLFBFPXKTIQSSY-UHFFFAOYSA-N dimethoxy(oxo)phosphanium Chemical compound CO[P+](=O)OC YLFBFPXKTIQSSY-UHFFFAOYSA-N 0.000 claims description 16
- -1 1-pyrrolinyl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- MJUJXFBTEFXVKU-UHFFFAOYSA-N diethyl phosphonate Chemical compound CCOP(=O)OCC MJUJXFBTEFXVKU-UHFFFAOYSA-N 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 3
- 229910014033 C-OH Inorganic materials 0.000 claims description 3
- 229910014570 C—OH Inorganic materials 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229960004230 oxidronic acid Drugs 0.000 claims description 2
- 150000003007 phosphonic acid derivatives Chemical class 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- VCZPNVRGBOBTFF-UHFFFAOYSA-N [6-chloro-5-(cyclopentylmethyl)-2,3-dihydro-1H-inden-1-yl]methanol Chemical compound OCC1CCC2=CC(CC3CCCC3)=C(Cl)C=C12 VCZPNVRGBOBTFF-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract 1
- 229940124346 antiarthritic agent Drugs 0.000 abstract 1
- 239000003435 antirheumatic agent Substances 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- 239000000243 solution Substances 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229950005499 carbon tetrachloride Drugs 0.000 description 6
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 6
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- YAMFWQIVVMITPG-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]acetic acid Chemical compound OC(=O)CC1=NN(C=2C=CC(F)=CC=2)C=C1C1=CC=C(Cl)C=C1 YAMFWQIVVMITPG-UHFFFAOYSA-N 0.000 description 2
- BCLXJQOHLUTWTC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]acetyl chloride Chemical compound C1=CC(F)=CC=C1N1N=C(CC(Cl)=O)C(C=2C=CC(Cl)=CC=2)=C1 BCLXJQOHLUTWTC-UHFFFAOYSA-N 0.000 description 2
- VGUWZCUCNQXGBU-UHFFFAOYSA-N 3-[(4-methylpiperazin-1-yl)methyl]-5-nitro-1h-indole Chemical compound C1CN(C)CCN1CC1=CNC2=CC=C([N+]([O-])=O)C=C12 VGUWZCUCNQXGBU-UHFFFAOYSA-N 0.000 description 2
- YFYVMFUJSMVRCS-UHFFFAOYSA-N 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]propanoic acid Chemical compound OC(=O)CCC1=NN(C=2C=CC(F)=CC=2)C=C1C1=CC=C(Cl)C=C1 YFYVMFUJSMVRCS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002456 anti-arthritic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IVFGIXMLURJXBZ-UHFFFAOYSA-N 1-phosphonopropylphosphonic acid Chemical compound CCC(P(O)(O)=O)P(O)(O)=O IVFGIXMLURJXBZ-UHFFFAOYSA-N 0.000 description 1
- YBPNJBYPFNTZIW-UHFFFAOYSA-N 2-(1,3,5-triphenylpyrazol-4-yl)acetic acid Chemical compound OC(=O)CC=1C(C=2C=CC=CC=2)=NN(C=2C=CC=CC=2)C=1C1=CC=CC=C1 YBPNJBYPFNTZIW-UHFFFAOYSA-N 0.000 description 1
- UODROGXCIVAQDJ-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)propanoyl chloride Chemical compound C1=C(C(C)C(Cl)=O)C=CC2=CC(OC)=CC=C21 UODROGXCIVAQDJ-UHFFFAOYSA-N 0.000 description 1
- LRXFKKPEBXIPMW-UHFFFAOYSA-N 2-(9h-fluoren-2-yl)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C(C(O)=O)C)C=C3CC2=C1 LRXFKKPEBXIPMW-UHFFFAOYSA-N 0.000 description 1
- SZFHZSLOCLOCAW-UHFFFAOYSA-N 2-[2-(n-acetyl-2,6-dichloroanilino)phenyl]acetic acid Chemical compound ClC=1C=CC=C(Cl)C=1N(C(=O)C)C1=CC=CC=C1CC(O)=O SZFHZSLOCLOCAW-UHFFFAOYSA-N 0.000 description 1
- OEOBIFMQBXSTEK-UHFFFAOYSA-N 2-[3-(4-chlorophenyl)-1-phenylpyrazol-4-yl]-1-dimethoxyphosphorylethenol Chemical compound COP(OC)(=O)C(=CC=1C(=NN(C1)C1=CC=CC=C1)C1=CC=C(C=C1)Cl)O OEOBIFMQBXSTEK-UHFFFAOYSA-N 0.000 description 1
- YSQLFGQECCZYNG-UHFFFAOYSA-N 2-[3-(4-chlorophenyl)-1-phenylpyrazol-4-yl]acetyl chloride Chemical compound ClC(=O)CC1=CN(C=2C=CC=CC=2)N=C1C1=CC=C(Cl)C=C1 YSQLFGQECCZYNG-UHFFFAOYSA-N 0.000 description 1
- QXVRLFIKHYCFJS-UHFFFAOYSA-N 2-[4-(2-methylpropyl)phenyl]propanoyl chloride Chemical compound CC(C)CC1=CC=C(C(C)C(Cl)=O)C=C1 QXVRLFIKHYCFJS-UHFFFAOYSA-N 0.000 description 1
- AARQGXJHRQOCAU-UHFFFAOYSA-N 2-[[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]methyl]propanedioic acid Chemical compound OC(=O)C(C(O)=O)CC1=NN(C=2C=CC(F)=CC=2)C=C1C1=CC=C(Cl)C=C1 AARQGXJHRQOCAU-UHFFFAOYSA-N 0.000 description 1
- YMFDAYPDKZIZSE-UHFFFAOYSA-N 3-(bromomethyl)-4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazole Chemical compound C1=CC(F)=CC=C1N1N=C(CBr)C(C=2C=CC(Cl)=CC=2)=C1 YMFDAYPDKZIZSE-UHFFFAOYSA-N 0.000 description 1
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- DNBHXYIAEMHCFY-UHFFFAOYSA-N 6-chloro-5-(cyclopentylmethyl)-2,3-dihydro-1h-indene-1-carbonyl chloride Chemical compound ClC=1C=C2C(C(=O)Cl)CCC2=CC=1CC1CCCC1 DNBHXYIAEMHCFY-UHFFFAOYSA-N 0.000 description 1
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- YPWCDZHNMLYAEW-UHFFFAOYSA-N [1-hydroxy-2-(6-methoxynaphthalen-2-yl)-1-phosphonopropyl]phosphonic acid Chemical compound C1=C(C(C)C(O)(P(O)(O)=O)P(O)(O)=O)C=CC2=CC(OC)=CC=C21 YPWCDZHNMLYAEW-UHFFFAOYSA-N 0.000 description 1
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- KAZRLJCDXRMZTJ-UHFFFAOYSA-N [2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]-1-hydroxy-1-phosphonoethyl]phosphonic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=NN(C=2C=CC(F)=CC=2)C=C1C1=CC=C(Cl)C=C1 KAZRLJCDXRMZTJ-UHFFFAOYSA-N 0.000 description 1
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- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
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- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
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- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229950002545 cicloprofen Drugs 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960003768 lonazolac Drugs 0.000 description 1
- XVUQHFRQHBLHQD-UHFFFAOYSA-N lonazolac Chemical compound OC(=O)CC1=CN(C=2C=CC=CC=2)N=C1C1=CC=C(Cl)C=C1 XVUQHFRQHBLHQD-UHFFFAOYSA-N 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229950001411 trifezolac Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3882—Arylalkanephosphonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/404—Esters of poly(thio)phosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
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- General Health & Medical Sciences (AREA)
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- Molecular Biology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
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Abstract
Diphosphonic acid derivatives of the general formula in which R is hydrogen or (C1-4) alkyl and A is the radical of an anti- inflammatorily and anti-phlogistically active carboxylic acid, ACOOH, which contains an aryl or heteroaryl group, processes for their preparation and their use as anti-inflammatory and anti- arthritic agents.
Description
The present invention provides a diphosphonic acid derivative of the general formula P0(0R)2 A-C-OH (I) I P0(0R)2 wherein R is hydrogen, an alkali-metal, an alkaline earth metal 15 or an alkyl group of 1 to 4 carbon atoms and A is i) the group Ϊ B-CH wherei n X is hydrogen, methyl or ethyl, and B is phenyl substituted in the para position by an isobutyl, cyclohexyl, or 1-pyrrolinyl group, and optionally, additionally substituted in the -3meta position by fluorine or chlorine, or is phenyl substituted in the meta position by a benzoyl or a phenoxy group or is phenyl substituted in the ortho position by a 2,4-dichlorophenoxy or a 2,6-dichloropheny5 lamino group, R where R^ is a cyclohexyl or cyclopentylmethyl group and Y is hydrogen or chlorine, IO OHwherein X has the meaning given above, and is the group Cl or Ό· 6 iv) W wherein n is the integer 1,2 or 3, W and W are the same or different and are hydrogen, chlorine or fluorine, and one of the groups V or V is nitrogen and the other is a methine group, optionally substituted by phenyl, or R wherei n is a p-chlorobenzoyl or a cinnamoyl group.
Diphosphonic acid derivatives having an anti-atherogenic activity are already known from European Patent Specification 0 015 370.
The novel phosphonic acid derivatives are derived from 15 carboxylic acids which have an anti-inflammatory and an anti-phlogistical action and which are of the general :· -5formula II ACOOH (II) wherein A is defined as above. Such carboxylic acids are for example the substances described in the Encyclopeadia by M. Windholz et al. The Merck Index'1, 10th edition 1976, Merck and Co. Inc., Rahway N.J., USA: known for their anti-inflammatory action, for example, ibuprofen (index no. 4797), butibufen (index no. 1496), pirprofen (index no. 7380), ketoprofen (index no. 5142), fenoprofen (index no. 3913), fenclofenac (index no. 3900), diclofenac (Index no. 3066), clindonac (index no. 2319), benoxaprofen (index no. 1044), naproxen (index no. 6269), lonazolac (index no. 5392) or indomethacin (index no. 4852).
Further carboxylic acids are for example 6-chloro-515 cyclopentylmethyl-l-indanecarboxylic acid, 1-(2-98fluorenyl)-propionic acid (Cicloprofen), 1,3, -tripheny1-pyrazo1-4-yl-acetic acid(Trifezolac) or 4-(4chlorophenyl)-l-(4-fluorophenyl) 3-pyrazolyl-acetic acid.
The compounds according to the invention have a -6pronounced anti-inflammatory and anti-arthritic action, just like the carboxylic acids of formula (II): A-COOH (II) They are distinguished from these substances by the fact that they are capable, inter alia, of influencing the synthesis and degaradation activity of bone cells (osteoblasts/osteoclasts) in such a manner that curative effects can clearly be detected in rats with induced arthritis.
This anti-arthritic activity of the compounds according to the invention constitutes the basis for a therapy for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other related disorders, especially those of the collagen and of the skeletal system (osteoporosis, Paget's disease). In addition, as good complex formers for calcium, the phosphonates may be used in therapeutically effective manner wherever a disturbed calcium-metabolism has been found to be the cause of a disorder, for example in the case of cardiovascular disorders, ectopic calcification, etc.
The compounds may be employed in the form of their esters or semiesters, but are preferably employed in the form of the free phosphonic acids or of their physiologically tolerable salts with alkali metal hydroxides or alkaline earth metal hydroxides or tolerable organic bases, like sodium hydroxide, potassium hydroxide, calcium hydroxide, piperazine, or n-methylglucamine. 541 -6aSuitable galenical formulations are capsules, tablets, dragees and suppositories, also injection and infusion solutions and dermal preparations. Local application for treating dermal or systemic disorders is also possible.
The phosphonates may be prepared according to methods which are well known to a person skilled in the art (Houben-Weyl, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 4th edition, 1963 Volume XII/1,453 ff) for example as shown in the following reaction scheme.
Reaction Scheme P(OR), a) AC0C1 - HPOgRj Base PO3*2 e present in an enolized ΡΟ,Ηf Ester cleavage AC-OH -\ PO3H2 (The compounds of formula A-COPO-jR? ar< form, when A represents an arylmethyl radical) There may be mentioned as examples of bases suitable for carrying out a process according to the invention, secondary amines, for example diethylamine, dipropylamine, diisopropylamine, morpholine and piperidine. The reaction may be carried out in an inert organic solvent, e.g. ether (for example diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran and chlorinated hydrocarbon (for example dichloromethane, tetrachloroethane, chloroform and carbon tetrachloride).
The optional subsequent hydrolysis of an ester may be carried out using a mineral acid (for example semiconcentrated hydrochloric acid or sulphuric acid). The cleavage may be achieved especially gently in an inert solvent (for example one of the above-mentioned chlorinated hydrocarbons) with trimethylsilyl iodide. ΰό ί -8Το form a salt, a free acid may be reacted in customary manner with a corresponding base.
The ways of synthesis in the reaction scheme are illustrated in the following typical and representative Examples.
Example 1 A suspension of 3.70 g of 2-fl-(4-chlorobenzoyl)5-methoxy-2-methyl-3-indolyl]-1-hydroxyethenephosphonic acid dimethyl ester (US Patent Specification No. 4 014 997) in 20 ml of tetrahydrofuran is added at -7°C to a solution of 1.08 g of dimethylphosphite and 0.63 g of diethylamine and the mixture is left to stand for 3 hours at -7°C and then for 16 hours at -15°C The precipitate is then suction-filtered and in this manner 3.2 g of 2-£l-(4-chlorobenzoyl)-5-methoxy-2methy1-3-indolylj-l-bydroxyethane-1,1-bis(phosphonic acid dimethyl ester) are obtained having a melting point of 163°C.
I » '» Example 2 16.6 g of 2-(6-methoxy-2-naphthyl)-propionic acid in 200 ml of diethyl ether are stirred for 60 minutes at 20'C with 16.2 g of phosphorus pentachloride. The mixture is then concentrated, the residue is triturated with benzine and in this manner 18 g of 2-(6-methoxy-2naphthyl)-propionyl chloride are obtained having a melting point of 95°C. 3.99 g of trimethyl phosphite are added at 20°C to 6.66 g of that acid chloride in 100 ml of diethyl ether and the mixture is left for 16 hours. The mixture is then concentrated, the residue is crystallised from diisopropyl ether and 3.63 g of 2-(6-methoxy-2-naphthyl)-propionyl15 phosphonic acid dimethyl ester are obtained having a melting point of 59°C. 1.42 g of dimethyl phosphite and, at -10cC, 0.26 g of dibutylamine in 10 ml of diethyl ether are added to a suspension of 5.0 g of that phosphonic acid ester in TO ml of diethyl ether. The mixture is cooled for 2 hours at -5eC, the product of crystallisation is suction-filtered and 4.46 g of 2-(6-methoxy-2-naphthyl)-1-hydroxypropane1, 1-bis (phosphonic acid dimethyl ester) are obtained having a melting point of 140°C. -10Example 3 4.66 g of 2-(4-isobutylphenyl )-propionic acid in 150 ml of diethyl ether are stirred at 20°C for an hour with 5.04 g of phosphorus pentachloride. The mixture is then concentrated in vacuo and 5.02 g of 2-(4-isobutylphenyl)-propionyl chloride are obtained. This is reacted as described in Example 2 with trimethyl phosphite and 2-(4-isobutylphenyl)-propiony1phosphonic acid dimethyl ester is obtained. The dimethyl ester is reacted under the conditions described in Example 2 with dimethyl phosphite and 2-(4-isobutylphenyl)-l-hydroxypropane-l ,1bis (phosphonic acid dimethyl ester) is obtained. - 11 Example 4 3.22 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid are refluxed for one hour together with .5 ml of thionyl chloride, the mixture is concentrated and 3.45 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid chloride are obtained in the form of an oil.
The acid chloride is reacted as described in Example 2 with triethyl phosphite and 3 g of (6-chloro-5-cyclopentylmethyl-1-indanylidene)-hydroxymethanephosphonic acid IO diethyl ester are obtained having a melting point of 126°C. The compound obtained is reacted under the conditions mentioned in Example 2 with diethyl phosphite and (6-chloro-5-cyclopentylmethyl-1-indanyl)-hydroxymethane-bis(phosphonic acid diethyl ester) is obtained. j 5 Example 5 2-[N-acetyl-N-(2,6-dichlorophenyl)-amino)phenylacetic acid is reacted with phosphorus pentachloride in diethyl ether to form 2-iN-acetyl-N-(2,6-dichlorophenyl )amino]-phenylacetic acid chloride. The acid chloride is then reacted under the conditions described in Example 2 with trimethyl phosphite to form 2-{ 2-[N-acetyl-N-(2,6dichlorophenyl)-amino]-phenylj'-l-hydroxyethene-l-phosphonic acid dimethyl ester which is converted under the conditions of Example 1 into 2-[2-(2,6-dichlorophenylamino) -pher.yl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) with dimethyl phosphite. - 12 Example 6 2-12-(2,6-dichlorophenylamino)-phenyl ] -1-hydroxyethane-1 ,1-bis(phosphonic acid dimethyl ester) is heated with concentrated hydrochloric acid on a steam bath for 4 hours and then the mixture is diluted with water, left to cool and the precipitated product is suction-filtered. In this manner 2-[2-(2,6-dichlorophenylamino) -phenyl]-1-hydroxyethane-1,1-diphosphonic acid is obtained.
Example 7 2.29 ml of iodotrimethylsilane are added at -5°C to 2-11-(4-chlorobenzoyl)-5-nethoxy-2-methyl-3indclyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) (2.18 g) in 15 ml of tetrachloromethane and the mixture is left at OeC for 4 hours. The mixture is then concentrated in vacuo and ice-water is added. The precipitate is triturated with acetonitrile, suction-filtered and 1.92 g of 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl3-indolyl]-1-hydroxyethane-1,1-diphosphonic acid are obtained having a melting point of 202°C.
Example 8 2- (6-methoxy-2-naphthyl)-1-hydroxypropane-1,1bis ( phosphonic acid dimethyl ester) is hydrolysed under tbe conditions of Example 6 and 2-(6-methoxy-2-naphthyl)1-hydroxypropane-1,1-diphosphonic acid is obtained having a melting point of 205°C. -13Example 9 2-(4-1sobutylphenyl )-1-hydroxypropane-1,1-bis(phosphonic acid dimethyl ester) is hydrolysed under the conditions of Example 6 and 2-(4-isobutylphenyl)-1-hydroxy5 propane-1,1-diphosphonic acid is obtained.
Example 10 (6-chi or0-5-cyclopentylmethy1-1-indanyl)-hydroxymethane-bis(phosphonic acid diethyl ester) is reacted under the conditions of Example 6 and (6-chloro-5-cyclopentyl10 methyl-l-indanyl)-hydroxymethanediphosphonic acid is obtained.
Example 11 a) 16.5 g of 4-(4-chlorophenyl)-l-(4-fluorophenyl) 3-pyrazoleacetic acid in 400 ml of diethyl ether are cooled to -15°C and 14.6 g of phosphorus pentachloride are added in portions. The mixture is stirred for 2.5 hours at -15°C and for a further 2.5 hours at 0°C. The clear solution is then concentrated in vacuo to a condiserable extent, the oily residue is stirred with benzine (boiling range 40-60‘C) and 16 g of 4-(4-chlorophenyl)-1-(4-fluorophenyl) 3-pyrazoleacetic acid chloride are obtained having a melting point of 93-95'C.
A solution of 17.5 g of 4-(4-chlorophenyl)-1(4-fluorophenyl)-3-pyrazoleacetic acid chloride in 100 ml of tetrahydrofuran is cooled to 10°C and 9.8 ml of triethyl phosphite are added. The solution is stirred for 3 hours at 10-15°C, concentrated in vacuo and the oily residue is crystallised from diisopropyl ether. 18.8 g (83.4 %) of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylJ-1hydrcxyethenephosphonic acid diethyl ester are obtained having a melting point of 96-98°C. b) A solution of 18 g of 2-(4-(4-chlorophenyl)-1-(4fluorophenyl)-3-pyrazolyl]-1-hydroxyethenephosphonic acid diethyl ester in 40 ml of tetrahydrofuran is added dropwise at 0°C to a solution of 5.7 g of diethyl phosphite and 4.6 ml of diethylamine in 30 ml of tetrahydrofuran and the mixture is stirred for 5 hours at 0-5°C. The mixture is concentrated in vacuo, the residue is crystallised from diethyl ether ana then recrysrallisec from carbon tetrachloride and 15.2 g (64.4 %) o: 2-[4-(4-chlorophenyl)1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-bis (phosphonic acid diethyl ester) are obtained having a melting point of 141-142°C.
Example 12 Π.8 g of 2-l4-(4-chlorophenyl)-1-(4-fluorophenyl) -3-pyrazolyll~1-hydroxyethane-1,1-bis(phosphonic acid diethyl ester) are stirred for 1 hour at room tempe5 rature under nitrogen with 5 equivalents of iodotrimethylsilane in 50 ml of carbon tetrachloride. The mixture is concentrated in vacuo, water and acetone are added to the residue, the mixture is stirred for 30 minutes and the precipitated product is recrystallised from ethanol. In this manner, 8.0 g (84 %) of 2—[4—(4-chlorophenyl)-1-(4fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonii acid are obtained having a melting point of 202-204°C.
Example 13 ml of 63 % hydrobromic acid are added to 0.59 n of 2-l4-(4-chlorophenyl)-1-l4-fluorophenyl)-3-pyrazolyl] 1 -hydroxyethane-1,1-bis(phosphonic acid diethyl ester) and the mixture is heated at 100eC for two hours. The mixture is then diluted with water and left to cool. The resulting crude product is comminuted, recrystallised from ethanol and 0.37 g (77 %) of 2-[4-(4-chlorophenyl)-1(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid is obtained having a melting point of 201203°C.
Example 14 A solution of 0.8 g of sodium bicarbonate in ml of Water is added to a solution of 1.9 g of 2-(4(4-chlorophenyl)-1-(4-£luorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid in 5 ml of dimethylformamide and the mixture is stirred for two hours at room temperature. The precipitated product is suction-filtered, washed with a little water, dried at 110°C and 1.8 g (76 ») of the disodium salt of 2-(4-(4-chlorophenyl)-1(4—fluorophenyl)-3-pyrazolyl]-1-hycroxyethane diphosphonic acid are obtained having a melting point of above 300°C.
Example 15 [3-(4-chlorophenyl)-1-phenyl-4-pyrazolyl]-acetylchloride is reacted as described in Example 11 with trimethyl phosphite, the mixture is worked up and 2-(3-(4chlorophenyl) -1-phenyl-4-pyrazolyl)-1 -hydroxyethenephosphonic acid dimethyl ester having a melting point of 174 °C (diethyl ether) is obtained in an 80 % yield. 2-[3-(4-chlorophenyl)-l-phenyl-4-pyrazolyl]-1hydrcxyethenephosphonic acid dimethyl ester is reacted as described in Example 12 with dimethyl phosphite, the mixture is worked up and 2-l3-(4-chlorophenyl)-1-phenyl4-pvrazolyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester) having a melting point of 130°C is obtained in a 69 % yield.
Example 16 2-13-(4-chloropheny1)-1-pheny1-4-pyrazoly1)-1 -Ohydroxyethane-1,1-bis(phosphonic acid dimethyl ester) is reacted as described in Example 12, the mixture is worked up and 2-(3-(4-chlorophenyl)-1-phenyl-4-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid having a melting point of 199eC is obtained in a 78 % yield.
Example 17 a) 2.8 g of malonic acid dimethyl ester are added at 20°C to a suspension of 0.7 g of CO % sodium hydride in 40 ml of 1,2-dimethoxyethane and the mixture is stirred for 30 minutes. A solution of 7.3 g of 3-bromomethyl-4-(4-chlorophenyl)-1-(4-fluorophenyl)-pyrazole in 30 ml of 1,2-dimethoxyethane is then added and the mixture is stirred for a further 12 hours. The reaction mixture is worked up in customary manner, the residue is recrystallised from cyclohexane anc 4.2 g of [4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoly Imethyl]-malonic acid dimethyl ester are obtained having a melting point of 123'C. b) 12 ml of 2N aqueous sodium hydroxide solution are added to a solution of 0.9 g of [4-(4-chlorophenyl)-1 -(4-fluorophenyl)-3-pyrazolyImethyl]-malonic acid dimethyl ester in 2.5 ml of ethanol and the mixture is refluxed for hours. The mixture is left to cool, acidified with 2K hydrochloric acid, the precipitate is recrystallised from acetonitrile and 0.8 g of (4-(4-chlorophenyl)-1-(4-fluoro25 phenyl)-3-pyrazolyImethyl]-malonic acid is obtained having a melting point of 188eC. - iB c) A solution of 3 g of (4-(4-chlorophenyl)1-(4-fluorophenyl)-3-pyrazolylmethyl)-malonic acid in 50 ml of chlorobenzene is refluxed until the gas development has finished (approximately 2.5 hours). The mixture is concentrated in vacuo, the residue is reerystallised from carbon tetrachloride and 2.2 g of 3-[4-(4-chlorophenyl)-1(4-fluorophenyl)-3-pyrazolyl]-propionic acid are obtained having a melting point of 131BC. d) 1.3 g of phosphorus pentachloride are added in portions at 0°C to a mixture of 1.9 g of 3-[4-(4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl ]-propionic acid in 60 ml of diethyl ether ana the mixture is stirred for three hours. The mixture is concentrated, the residue is reerystallised from benzine and 1.85 g of 3-[4-(4-chlorophenyl) -1- (4-fluorophenyl)-3-pyrazclyl]-propionic acid chloride are obtained having a melting point of 111"C. e) A solution of 0.7 5 of trimethyl phosphite in 2 ml of diethyl ether is added dropwise at 0cC to a solution of 1.85 g of 3-14-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl ]-propionic acid chloride ir; 1C -.1 of diethyl ether. The mixture is left to stand for three days, concentrated in vacuo and 1.98 g cf 3-[4-(4-ehlorcphenyl)1-(4-fluorophenyl)-3-pyrazolyl]-1-oxopropane-1-phosphonic acid dimethyl ester are obtained in the form of an oil. f) A solution of 1.98 g of 3-(4-(4-chlorophenyl) 1 - (4-fluorophenyl)-3-pyrazolyl]-1-oxopropane-1-phosphonic acid dimethyl ester in 15 ml of diethyl ether and 10 ml of -,9dichloromethane is added dropwise at O’C to a solution of 0.55 g of dimethyl phosphite and 50 mg of diethylamine in 10 ml of diethyl ether. The mixture is then stirred for three days at O’C, the reaction mixture is worked up in customary manner, the residue is recrystallised from ethanol and 1 g of 3-[4-(4-chlorophenyl)-1-(4-fluorophenyl) 3 -pyrazolyl]-1-hydroxypropane-1,1-bis(phosphonic acid dimethyl ester) is obtained having a melting point of 131’C.
Example 18 0.34 g of iodotrimethylsilane is added at O’C to a suspension of 0.22 g of 3-I4-(4-chlorophenyl)-1-(4fluorophenyl)-3-pyrazolyl]-1-hydroxypropane-1,1- bis (phosphonic acid dimethyl ester) in 4 ml of tetrachloromethane and the mixture is stirred for one hour at O’C and for a further two hours at room temperature. The reaction mixture is then concentrated, the residue is recrystallised from ethanol and 130 mg of 3-(4-(4-chlorophenyl)-1(4-fluorophenyl)-3-pyrazolylJ-1-hvdroxypropane-1,1-dipho= phonic acid are obtained having a melting point of 223°C.
Claims (7)
1.CLAIMS 1. Disphosphonic acid derivatives of general formula 1 P0(0R)„ U-»„ P0(0R) 2 (I) wherein 5 R is hydrogen, an alkali metal, an alkaline earth metal or an alkyl group of 1 to 4 carbon atoms, and A is i) the group B-CH wherein 10 X is hydrogen, methyl or ethyl, and B is phenyl substituted in the para position by an isobutyl, cyclohexyl or 1-pyrrolinyl group, and optionally, additionally substituted in the meta position by fluorine or chlorine, or is phenyl substituted in the meta position 15 by a benzoyl or a phenoxy group or is phenyl substituted in the ortho position by a 2, 4-dichlorophenoxy or a 2, 6dichlorophenylamino group, wherein R.| is a cyclohexyl or cyclopentylmethyl group and Y is hydrogen or chlorine, I ·Α 1 -21cxr Ϊηwherein X has the meaning given above, and / ’ 2 )- n 10 wherein n is the integer 1, 2 or 3, W and W are the same or different and are hydrogen -22chlorine or fluorine, and one of the groups V or V is nitrogen and the other is a methine group, optionally substituted by phenyl, or R 2 is a p-chlorobenzoyl or a cinnamoyl group.
2. Diphosphonic acid derivatives of general formula la X PO(OR), I I z B—CH—C—OH (la), I PO(OR ) 2 wherei n 10 R has the meaning given in claim 1, X is hydrogen, methyl or ethyl and B is phenyl substituted in the para position by an isobutyl, cyclohexyl or 1-pyrrolinyl group, and optionally, additionally substituted in the meta position by fluorine 15 or chlorine, or is phenyl substituted in the meta position by a benzoyl or a phenoxy group or is phenyl substituted in the ortho position by a 2, 4-dichlorophenoxy or a 2,6-dichlorophenylamino group. •J W. X J -23
3. Diphosphonic acid derivatives of general formula ib PO(OR) 2 C—OH I PO(OR), (ib wherein R has the same meaning given in claim 1, 5 R 1 is a cyclohexyl or cyclopentylmethyl group and Y is hydrogen or chlorine.
4. Diphosphonic acid derivatives of general formula Ic. X PO(OR) ? I I χΆ C - 0 H ’° ιοι,) ζ wherei n 10 R -and X have the meanings given in claim 1 or 2 and (lc) wherei η n is the integrer 1, 2 or 3, R has the meaning given in claim 1, W and W are the same or different and are hydrogen, 10 chlorine or fluorine, and one of the groups V or V is nitrogen and the other is a methine group, optionally substituted by phenyl. J -256. Diphosphonic acid derivatives of general formula le wherein R has the meaning given in claim 1 and 5 Rj, is p-chlorobenzoyl or a cinnamoyl group. 7. 2-0-(4-Chlorobenzoyl)-5-methoxy-2-methyl-3-indolylj1- hydroxyethane-l,l-bis(phosphonic acid dimethyl ester) and 2- £l-{4- chlorobenzoyl )-5-methoxy-2-methyl-3-indolyl3-lhydroxyethane-1,1-diphosphonic acid. 10 8. 2-(6-Methoxy-2-naphthyl)-l-hydroxypropane-l,1-bis(phosphonic acid dimethyl ester) and 2-(6-methoxy-Znaphthyl)-l-hydroxypropane-l,1-diphosphonic acid. 9. (6-Chloro-5-cyclopentylmethyl-1-indanyl)-hydroxymethane bis(phosphonic acid diethyl ester) and (6-chloro-5-cyclop15 entylmethyl-l-indanyl)-hydroxymethanediphosphonic acid. 10. 2-0- (4-Chl orophenyl )-1- (4-fluorophenyl) - 3-pyrazoly lj1- hydroxyethane -1,1-bis(phosphonic acid diethylester), 2- Q-(4-chlorophenyl-1-(4-fluorophenyl)-3-pyrazolyl]-lhydroxyethane-1,1-diphosphonic acid and its sodium salt. -2611. 2-J3-(4-Chlorophenyl)-l-phenyl-4-pyrazolylJ-lhyd-roxyethane -1,l-bis-(phosphonic acid dimethyl ester and 2- ^-(4-chlorophenyl)-1-phenyl-4-pyrazolylJ-l-hydroxyethane-1 ,1-diphosphonicacid. 5 12. 3-{4-(4-Chlorophenyl)-1 -(4-f1uorophenyl)-3-pyrazolyfj1-hydroxypropane-1,l-bis(phosphonic acid dimethyl ester) and 3. - £4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazoly1J-1hydroxypropane-1,1-diphosphonic acid. 13. Pharmaceutical compositions characterised in that they 10 contain a phosphonic acid derivative according to claims 1 to 12. 14. Process for the preparation of diphosphonic acid derivatives of general formula 1 according to claim 1 characterised in that an acylphosphonate of general formula 15 III A-C0P0(0R) 2 (III) wherein A and R have the meaning given in claim 1, is treated, in the presence of a base, with a dialkyl phosphite of general 20 formula IV HPO(OR) 2 (IV) wherein R has the meaning given in claim 1, the ester formed is optionally saponified and acids are optionally con5 ·1 i 3 6 -27verted to their salts. 1
5. A compound of formula I substantially as hereinbefore described with reference to the Examples 1
6. A composition containing a compound of 5 formula I substantially as hereinbefore described with reference to the Examples. 1
7. A process for the preparation of a compound of formula I substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19823203309 DE3203309A1 (en) | 1982-01-27 | 1982-01-27 | DIPHOSPHONIC ACID DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
Publications (2)
Publication Number | Publication Date |
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IE830148L IE830148L (en) | 1983-07-27 |
IE54136B1 true IE54136B1 (en) | 1989-06-21 |
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ID=6154494
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Application Number | Title | Priority Date | Filing Date |
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IE148/83A IE54136B1 (en) | 1982-01-27 | 1983-01-26 | Diphosphonic acid derivatives, process for their preparation and pharmaceutical preparations containing them |
Country Status (5)
Country | Link |
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JP (1) | JPS58174394A (en) |
DE (1) | DE3203309A1 (en) |
GB (1) | GB2113687A (en) |
IE (1) | IE54136B1 (en) |
ZA (1) | ZA83567B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3428524A1 (en) * | 1984-08-02 | 1986-02-13 | Boehringer Mannheim Gmbh, 6800 Mannheim | NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
JPH0377894A (en) * | 1989-08-18 | 1991-04-03 | Toray Ind Inc | Methylene diphosphonic acid compound |
EP0603401B1 (en) * | 1992-07-10 | 2001-04-11 | Toray Industries, Inc. | Methanediphosphonate derivative, production thereof, and pharmaceutical use thereof |
JPH06135976A (en) * | 1992-10-30 | 1994-05-17 | Toray Ind Inc | Methanediphosphonic acid derivative, its production and medicinal use thereof |
EP1219607B1 (en) | 1999-09-02 | 2011-04-06 | Shionogi & Co., Ltd. | Integrase inhibitors containing aromatic heterocycle derivatives |
-
1982
- 1982-01-27 DE DE19823203309 patent/DE3203309A1/en not_active Withdrawn
-
1983
- 1983-01-26 GB GB08302176A patent/GB2113687A/en not_active Withdrawn
- 1983-01-26 IE IE148/83A patent/IE54136B1/en not_active IP Right Cessation
- 1983-01-27 JP JP58010669A patent/JPS58174394A/en active Granted
- 1983-01-27 ZA ZA83567A patent/ZA83567B/en unknown
Also Published As
Publication number | Publication date |
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IE830148L (en) | 1983-07-27 |
JPS58174394A (en) | 1983-10-13 |
GB2113687A (en) | 1983-08-10 |
GB8302176D0 (en) | 1983-03-02 |
ZA83567B (en) | 1983-10-26 |
DE3203309A1 (en) | 1983-07-28 |
JPH0329078B2 (en) | 1991-04-23 |
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