JPH04275271A - Indomethacin derivative - Google Patents
Indomethacin derivativeInfo
- Publication number
- JPH04275271A JPH04275271A JP6257391A JP6257391A JPH04275271A JP H04275271 A JPH04275271 A JP H04275271A JP 6257391 A JP6257391 A JP 6257391A JP 6257391 A JP6257391 A JP 6257391A JP H04275271 A JPH04275271 A JP H04275271A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- indomethacin
- compound
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical class CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 title abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 6
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- -1 ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3- indolylacetate hydrobromide Chemical compound 0.000 abstract description 44
- 229960000905 indomethacin Drugs 0.000 abstract description 24
- 229940002612 prodrug Drugs 0.000 abstract description 9
- 239000000651 prodrug Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 150000001298 alcohols Chemical class 0.000 abstract description 6
- 230000006378 damage Effects 0.000 abstract description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract description 3
- 239000003435 antirheumatic agent Substances 0.000 abstract description 2
- 208000027418 Wounds and injury Diseases 0.000 abstract 1
- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 208000014674 injury Diseases 0.000 abstract 1
- 210000004877 mucosa Anatomy 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000000254 damaging effect Effects 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 125000003277 amino group Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010061164 Gastric mucosal lesion Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
【０００１】本発明は新規なインドメタシン誘導体に関
し、さらに詳しくは、下記一般式[0001] The present invention relates to a novel indomethacin derivative, more specifically, it has the following general formula:
【０００２】0002
【化６】[C6]
【０００３】式中、Ｌ１は低級アルキレン基又はフェニ
レン基を表わし；ＡはIn the formula, L1 represents a lower alkylene group or a phenylene group; A is
【０００４】0004
【化７】―Ｘ―Ｌ２―ＣＯＮＲ１Ｒ２ 又は[Chemical 7]-X-L2-CONR1R2 or
【０００５】[0005]
【化８】―Ｌ２―ＮＲ１Ｒ２
で示される基を表わす（ここで、Ｌ２は低級アルキレン
基又はフェニレン基を表わし、Ｒ１及びＲ２は各々独立
に水素原子、低級アルキル基、低級アルコキシアルキル
基、若しくは低級アルキル基で置換されてもよい複素環
基を表わすか、又はＲ１とＲ２とが結合する窒素原子と
一緒になって複素環基を表わし、Ｘは酸素原子又は硫黄
原子を表わす）、で示されるインドメタシンのエステル
誘導体及びその塩に関する。[Chemical 8] -L2-NR1R2 (where L2 represents a lower alkylene group or phenylene group, and R1 and R2 each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, or a lower represents a heterocyclic group which may be substituted with an alkyl group, or represents a heterocyclic group together with the nitrogen atom to which R1 and R2 are bonded, and X represents an oxygen atom or a sulfur atom). This invention relates to ester derivatives of indomethacin and salts thereof.
【０００６】上記式（Ｉ）の化合物およびその塩は、イ
ンドメタシンの胃粘膜障害作用を抑えたプロドラッグと
して、臨床上優れた経口抗炎症、抗リウマチ薬となるこ
とが期待される。The compound of formula (I) and its salts are expected to be clinically excellent oral anti-inflammatory and anti-rheumatic drugs as prodrugs that suppress the gastric mucosal damaging effects of indomethacin.
【０００７】インドメタシン（ＩＮＮ；Ｉｎｄｏｍｅｔ
ａｃｉｎ）は非ステロイド系抗炎症剤の中でも薬理作用
が特に強いことが知られている。また、近年では、リウ
マチ治療剤としても用いられ、臨床上極めて有用性の高
い化合物である。[0007] Indomethacin (INN; Indomet
acin) is known to have particularly strong pharmacological effects among non-steroidal anti-inflammatory drugs. In recent years, it has also been used as a therapeutic agent for rheumatism, making it an extremely useful compound clinically.
【０００８】しかしながら、インドメタシンを経口投与
した場合には副作用として胃粘膜障害が発現し、長期間
連続投与が必要なリウマチ等の慢性疾患の治療に用いる
場合にはこの副作用が特に大きな問題となる。インドメ
タシンのかかる問題点を克服するため、いくつかのプロ
ドラッグの開発が行なわれてきた（たとえばＪ．Ｍｅｄ
．Ｃｈｅｍ．２３ｐ９〜１２（１９８０）又は特開昭５
８−１５９４０号公報参照）。しかしながら、これらは
インドメタシンの上記副作用を十分には軽減できず、あ
るいはプロドラッグである化合物自体の安定性が低いた
めに消化管から吸収される以前に分解してしまう等の欠
点を残しており、未だ臨床上満足し得るプロドラッグの
開発はなされていない。[0008] However, when indomethacin is orally administered, gastric mucosal damage occurs as a side effect, and this side effect becomes a particularly serious problem when used for the treatment of chronic diseases such as rheumatism that require long-term continuous administration. In order to overcome these problems of indomethacin, several prodrugs have been developed (for example, J.Med
．． Chem. 23p9-12 (1980) or JP-A-5
8-15940). However, these drugs still have disadvantages, such as not being able to sufficiently alleviate the side effects of indomethacin, or the prodrug compound itself having low stability, resulting in decomposition before being absorbed from the gastrointestinal tract. A clinically satisfactory prodrug has not yet been developed.
【０００９】本発明者らは、かかる状況に鑑み、インド
メタシンの優れた抗炎症作用を損なうことなく副作用を
軽減し、臨床上使用し得るプロドラッグを開発すべく検
討を重ねた結果、前記式（Ｉ）で示されるインドメタシ
ンのエステル誘導体の胃粘膜障害作用がインドメタシン
に比べて極めて弱く、かつ、消化管内でも十分に安定で
あることとを見出し、本発明を完成した。In view of this situation, the present inventors have conducted repeated studies to develop a clinically usable prodrug that reduces the side effects of indomethacin without impairing its excellent anti-inflammatory effect. The inventors have completed the present invention by discovering that the ester derivative of indomethacin represented by I) has an extremely weak gastric mucosal damaging effect compared to indomethacin, and is sufficiently stable in the gastrointestinal tract.
【００１０】すなわち本発明は、インドメタシンの副作
用を大幅に軽減するとともに、インドメタシンの優れた
作用を発揮できるようにしたインドメタシンのプロドラ
ッグを提供するものである。That is, the present invention provides a prodrug of indomethacin that can significantly reduce the side effects of indomethacin and exhibit the excellent effects of indomethacin.
【００１１】以下に、本発明について詳細に説明する。The present invention will be explained in detail below.
【００１２】本明細書において「低級」なる語は、この
語が付された基又は化合物の炭素原子数が１〜７個、好
ましくは１〜４個であることを意味する。As used herein, the term "lower" means that the group or compound to which this term is attached has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms.
【００１３】「低級アルキル基」は直鎖状または分岐鎖
状のいずれであってもよく、たとえばメチル、エチル、
ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル
、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、
イソペンチル、ｎ−ヘキシル、イソヘキシル基等が挙げ
られる。The "lower alkyl group" may be linear or branched, such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
Examples include isopentyl, n-hexyl, and isohexyl groups.
【００１４】「低級アルコキシアルキル基」は、アルキ
ル部分が上記の低級アルキル基であるアルキルオキシア
ルキル基であり、メトキシメチル、メトキシエチル、エ
トキシエチル、ｎ−プロポキシエチル、イソプロポキシ
エチル、メトキシプロピル、エトキシプロピル、ｎ−プ
ロポキシプロピル、イソプロポキシプロピル、メトキシ
ブチル、エトキシブチル、ｎ−プロポキシブチル、イソ
プロポキシブチル基等が挙げられる。"Lower alkoxyalkyl group" is an alkyloxyalkyl group in which the alkyl moiety is the above lower alkyl group, and includes methoxymethyl, methoxyethyl, ethoxyethyl, n-propoxyethyl, isopropoxyethyl, methoxypropyl, ethoxy Examples include propyl, n-propoxypropyl, isopropoxypropyl, methoxybutyl, ethoxybutyl, n-propoxybutyl, and isopropoxybutyl groups.
【００１５】「低級アルキレン基」としては、たとえば
メチレン、エチレン、トリメチレン、テトラメチレン基
等が挙げられる。Examples of the "lower alkylene group" include methylene, ethylene, trimethylene, and tetramethylene groups.
【００１６】「フェニレン基」とは、ｏ−フェニレン、
ｍ−フェニレン又はｐ−フェニレン基である。"Phenylene group" means o-phenylene,
m-phenylene or p-phenylene group.
【００１７】「複素環基」とは、環原子として窒素原子
を少なくとも１個以上有する４〜７員環の脂環式複素環
基を意味し、たとえば１−アゼチジニル、２−アゼチジ
ニル、３−アゼチジニル、１−ピロリジニル、２−ピロ
リジニル、３−ピロリジニル、１−ピペリジニル、２−
ピペリジニル、３−ピペリジニル、４−ピペリジニル、
１−イミダゾリジニル、２−イミダゾリジニル、４−イ
ミダゾリジニル、１−ピペラジニル、２−ピペラジニル
基等が挙げられ、好ましくは１−ピロリジニル、２−ピ
ロリジニル、１−ピペリジニル、２−ピペリジニル、３
−ピペリジニル基であることができる。さらに、これら
「ヘテロシクリル基」の環窒素原子は、メチル基又はエ
チル基等の低級アルキル基で置換されていてもよい。"Heterocyclic group" means a 4- to 7-membered alicyclic heterocyclic group having at least one nitrogen atom as a ring atom, such as 1-azetidinyl, 2-azetidinyl, 3-azetidinyl. , 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperidinyl, 2-
piperidinyl, 3-piperidinyl, 4-piperidinyl,
Examples include 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-piperazinyl, 2-piperazinyl groups, and preferably 1-pyrrolidinyl, 2-pyrrolidinyl, 1-piperidinyl, 2-piperidinyl, 3
- can be a piperidinyl group. Furthermore, the ring nitrogen atom of these "heterocyclyl groups" may be substituted with a lower alkyl group such as a methyl group or an ethyl group.
【００１８】しかして、前記式（Ｉ）における基−ＮＲ
１Ｒ２として好ましいものとしては、メチルアミノ、ジ
メチルアミノ、メトキシエチルアミノ、メトキシプロピ
ルアミノ等のモノ−若しくはジ−アルキル置換アミノ基
、１−ピロリジニル、１−ピペリジニル、１−イミダゾ
リジニル等のヘテロシクリル基、３−ピペリジニルアミ
ノ、１−メチルピペリジン−３−イル−アミノ等のヘテ
ロシクリル基によって置換されたアミノ基が挙げられる
。[0018] Therefore, the group -NR in the above formula (I)
Preferred examples of 1R2 include mono- or dialkyl-substituted amino groups such as methylamino, dimethylamino, methoxyethylamino, and methoxypropylamino, heterocyclyl groups such as 1-pyrrolidinyl, 1-piperidinyl, and 1-imidazolidinyl, and 3- Examples include amino groups substituted with heterocyclyl groups such as piperidinylamino and 1-methylpiperidin-3-yl-amino.
【００１９】本発明により提供される前記式（Ｉ）の化
合物の代表例を示せば下記第１表及び第２表のとおりで
ある。Representative examples of the compounds of formula (I) provided by the present invention are shown in Tables 1 and 2 below.
【００２０】[0020]
【表１】[Table 1]
【００２１】[0021]
【表２】[Table 2]
【００２２】また、本発明の式（Ｉ）で示される化合物
は酸付加塩の形態で存在することができ、そのような塩
としては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、燐
酸塩などの無機酸塩、およびシュウ酸塩、酢酸塩、クエ
ン酸塩、コハク酸塩、酒石酸塩、メタンスルホン酸塩、
マレイン酸塩、フマル酸塩等の有機酸塩を例示すること
ができ、特に薬理学的に許容しうる塩が好ましい。Further, the compound of formula (I) of the present invention can exist in the form of an acid addition salt, and such salts include, for example, hydrochloride, hydrobromide, sulfate, Inorganic acid salts such as phosphates, and oxalates, acetates, citrates, succinates, tartrates, methanesulfonates,
Examples include organic acid salts such as maleate and fumarate, and pharmacologically acceptable salts are particularly preferred.
【００２３】前記式（Ｉ）で示される化合物は、たとえ
ば下記反応式に従って合成することができる。The compound represented by the above formula (I) can be synthesized, for example, according to the following reaction formula.
【００２４】反応式（Ａ）Reaction formula (A)
【００２５】[0025]
【化９】[Chemical formula 9]
【００２６】式中、Ｌ１及びＡは前記定義のとおりであ
る。In the formula, L1 and A are as defined above.
【００２７】すなわち、本願化合物（Ｉ）は、式（ＩＩ
）で示されるインドメタシンと式（ＩＩＩ）で示される
アルコール誘導体とを縮合させ、エステル化合物とする
ことによって合成することができる。That is, the compound (I) of the present application has the formula (II
) can be synthesized by condensing indomethacin represented by formula (III) with an alcohol derivative represented by formula (III) to form an ester compound.
【００２８】反応は、式（ＩＩ）のインドメタシンに、
クロロホルム、ジクロルメタン等の不活性溶媒中で塩基
存在下にカルボン酸活性化試薬及び式（ＩＩＩ）のアル
コール誘導体を加えて撹拌することによって行なうこと
ができる。The reaction is carried out to indomethacin of formula (II),
This can be carried out by adding a carboxylic acid activating reagent and the alcohol derivative of formula (III) in the presence of a base in an inert solvent such as chloroform or dichloromethane, and stirring the mixture.
【００２９】本反応で使用される塩基としては、ジメチ
ルアミノピリジン、ピリジン、キノリン、ルチジン、ト
リエチルアミン、水素化ナトリウム等を例示することが
でき、その使用量は、塩基の種類によっても異なるが、
一般には原料であるカルボン酸１モルに対して約０．０
１モルないし約０．１モルの範囲内が好ましい。Examples of the base used in this reaction include dimethylaminopyridine, pyridine, quinoline, lutidine, triethylamine, and sodium hydride, and the amount used varies depending on the type of base.
Generally, about 0.0 per mole of carboxylic acid as a raw material
A range of 1 mol to about 0.1 mol is preferred.
【００３０】上記カルボン酸活性化試薬としては、塩酸
１−エチル−３−（３−ジメチルアミノプロピル）カル
ボジイミド、ジシクロヘキシルカルボジイミド等を例示
することができる。Examples of the carboxylic acid activating reagent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and dicyclohexylcarbodiimide.
【００３１】反応は、特に限定されないが、通常、約０
℃ないし約４０℃、好ましくは室温程度の温度で約１時
間ないし約２４時間行うことができる。The reaction is not particularly limited, but usually about 0
C. to about 40.degree. C., preferably about room temperature, for about 1 hour to about 24 hours.
【００３２】また、式（ＩＩ）のインドメタシンを予め
反応性誘導体となし、次いで式（ＩＩＩ）で示されるア
ルコール誘導体と反応させることによっても式（Ｉ）で
示される本願化合物（Ｉ）を製造することができる。[0032] The compound (I) of the present invention represented by the formula (I) can also be produced by previously converting indomethacin of the formula (II) into a reactive derivative and then reacting it with an alcohol derivative represented by the formula (III). be able to.
【００３３】インドメタシンの反応性誘導体は、クロロ
ホルム、ジクロルメタン等の不活性溶媒中で、ジメチル
アミノピリジン、ピリジン、トリエチルアミン等の塩基
存在下にクロル炭酸エチル、塩化チオニル等の活性化試
薬を反応させることによって容易に得ることができる。
この場合に使用される塩基の使用量は、一般には原料で
あるインドメタシン１モルに対して、約１モルないし約
２モルの範囲が好ましい。これによって得られる反応性
誘導体は、上記と同様の条件で式（ＩＩＩ）で示される
アルコール誘導体と反応させ、式（Ｉ）で示される本願
化合物を製造することができる。A reactive derivative of indomethacin can be obtained by reacting an activating reagent such as ethyl chlorocarbonate or thionyl chloride in an inert solvent such as chloroform or dichloromethane in the presence of a base such as dimethylaminopyridine, pyridine, or triethylamine. can be obtained easily. In general, the amount of the base used in this case is preferably in the range of about 1 mol to about 2 mol per 1 mol of indomethacin, which is the raw material. The reactive derivative obtained thereby can be reacted with an alcohol derivative represented by formula (III) under the same conditions as above to produce the compound of the present invention represented by formula (I).
【００３４】式（ＩＩＩ）で示されるアルコール誘導体
が一級又は二級アミノ基を有する場合には、上記反応処
理中、このアミノ基を通常用いられるアミノ保護基、た
とえばｔｅｒｔ−ブチルオキシカルボニル、ベンジルオ
キシカルボニル、ｐ−ニトロベンジルオキシカルボニル
基等によって保護することができる（後述する実施例１
及び２参照）。When the alcohol derivative represented by formula (III) has a primary or secondary amino group, this amino group is protected by a commonly used amino protecting group such as tert-butyloxycarbonyl, benzyloxy It can be protected by carbonyl, p-nitrobenzyloxycarbonyl group, etc. (Example 1 described below)
and 2).
【００３５】かかる方法によって得られる式（Ｉ）で示
される化合物は、常法に従って酸と反応させることによ
って、酸付加塩に変えることができる。ここで用いられ
る酸としては、例えば、塩酸、臭化水素酸、硫酸、リン
酸などの無機酸、またはシュウ酸、酢酸、クエン酸、コ
ハク酸、酒石酸、メタンスルホン酸、マレイン酸、フマ
ル酸などの有機酸を例示することができ、特に薬理学的
に許容し得る塩が好ましい。The compound represented by formula (I) obtained by such a method can be converted into an acid addition salt by reacting it with an acid according to a conventional method. Examples of acids used here include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, or oxalic acid, acetic acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, and fumaric acid. Examples include organic acids, and pharmacologically acceptable salts are particularly preferred.
【００３６】前記反応式（Ａ）において合成原料として
用いられる式（ＩＩＩ）の化合物は既知化合物であり、
あるいは該既知化合物と同様にして製造することができ
る。本発明により提供される式（Ｉ）の化合物は、酸性
条件下で安定であり、インドメタシンに比較して経口投
与時の胃粘膜障害が極めて少ないという特徴を有する。
本酸化合物のかかる特徴は以下の実験により明らかであ
る。The compound of formula (III) used as a synthetic raw material in the reaction formula (A) is a known compound,
Alternatively, it can be produced in the same manner as the known compound. The compound of formula (I) provided by the present invention is stable under acidic conditions and is characterized by extremely less gastric mucosal damage upon oral administration compared to indomethacin. Such characteristics of the present acid compound are clarified by the following experiments.
【００３７】１．化学的安定
本発明の化合物の化学的安定性を確認するため、後記実
施例で合成された化合物（５）、（６）及び（７）の酸
性条件下での経時的残存量を測定した。1. Chemical Stability In order to confirm the chemical stability of the compounds of the present invention, the residual amounts of compounds (5), (6), and (7) synthesized in Examples described later under acidic conditions were measured over time.
【００３８】その結果、ｐＨ４の水溶液中では被験化合
物のいずれも、１０時間経過後でもほとんど加水分解さ
れなかった。ｐＨ１．２およびｐＨ７．４では徐々に分
解されたが、最も分解の速い化合物（７）の半減期はｐ
Ｈ１．２で５時間ｐＨ７．４で７時間であった。As a result, none of the test compounds were substantially hydrolyzed in the pH 4 aqueous solution even after 10 hours. It was gradually degraded at pH 1.2 and pH 7.4, but the half-life of the fastest-degrading compound (7) was p
H1.2 for 5 hours and pH 7.4 for 7 hours.
【００３９】以上の結果から、本願化合物は、経口投与
された場合、胃内でも直ちには分解されず、プロドラッ
グのまま消化管から吸収されることが予想される。From the above results, it is predicted that when the compound of the present invention is orally administered, it will not be immediately degraded even in the stomach and will be absorbed from the gastrointestinal tract as a prodrug.
【００４０】２．胃粘膜障害作用
本願化合物（５）、（６）及び（７）の胃粘膜障害作用
をインドメタシンと比較するため、以下の実験を行なっ
た。2. Gastric mucosal damaging effect The following experiment was conducted to compare the gastric mucosal damaging effect of Compounds (5), (6) and (7) of the present application with that of indomethacin.
【００４１】体重１８０〜２００ｇのｗｉｓｔｅｒ系雄
性ラットを摂水下で２４時間絶食させ、５％アラビアゴ
ム溶液に懸濁させた被験化合物の、インドメタシンに換
算して２０ｍｇ／ｋｇ相当量を経口投与した。経口投与
の３．５時間後に２％エバンスブルーの生理食塩水を０
．８ｍｌ血管内投与してその３０分後に瀉血致死させた
。開腹して胃を取り出し、５％ホルマリンで胃を膨満さ
せて固定した後、大湾に沿って胃を開き剖検した。各被
験化合物について６匹のラットに投与して胃粘膜障害部
分の長径を測定し、１匹当りの障害部分の長さの緩和を
潰瘍係数とした。[0041] Wister male rats weighing 180 to 200 g were fasted with water for 24 hours, and a test compound suspended in a 5% gum arabic solution was orally administered in an amount equivalent to 20 mg/kg in terms of indomethacin. . 3.5 hours after oral administration, 2% Evans blue in saline was administered.
．． 8 ml was administered intravascularly, and 30 minutes later, the animals were killed by bloodletting. The abdomen was opened, the stomach was removed, the stomach was inflated with 5% formalin and fixed, and then the stomach was opened along the greater bay and autopsy was performed. Each test compound was administered to 6 rats, the long axis of the gastric mucosal lesion was measured, and the relaxation of the length of the lesion per animal was defined as the ulcer coefficient.
【００４２】コントロールとしてインドメタシンを開い
た。Indomethacin was used as a control.
【００４３】結果を次表に示した。The results are shown in the following table.
【００４４】[0044]
【表３】[Table 3]
【００４５】潰瘍係数の値は、平均値±標準偏差を示す
。[0045] The values of the ulcer index represent the mean value ± standard deviation.
【００４６】第３表の結果をみれば、被験化合物（５）
、（６）及び（７）の潰瘍係数は、インドメタシンに比
較して著しく低下していることが判る。Looking at the results in Table 3, test compound (5)
, (6) and (7) are found to be significantly lower than that of indomethacin.
【００４７】したがって、本願化合物の胃粘膜障害作用
は、インドメタシンに比べて著しく軽減されていること
が明らかである。Therefore, it is clear that the gastric mucosal damaging effect of the compound of the present application is significantly reduced compared to indomethacin.
【００４８】以上の実験結果から、本発明の化合物（Ｉ
）はインドメタシンの副作用が軽減されたプロドラッグ
として、臨床上使用されることが期待されるものである
。From the above experimental results, it was found that the compound of the present invention (I
) is expected to be used clinically as a prodrug with reduced side effects of indomethacin.
【００４９】以下、実施例によって本発明をさらに具体
的に説明するが、本発明の範囲はこれらの記載によって
何ら限定されるものではない。[0049] The present invention will be explained in more detail with reference to Examples below, but the scope of the present invention is not limited in any way by these descriptions.
【００５０】但し、以下の記載においては、下記略号を
用いるものとする。However, in the following description, the following abbreviations will be used.
【００５１】ＷＳＣ；塩酸１−エチル−３−（３−ジメ
チルアミノプロピル）カルボジイミド
Ｚ；ベンジルオキシカルボニルWSC; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Z; benzyloxycarbonyl
【００５２】[0052]
【実施例】実施例 １[Example] Example 1
【００５３】[0053]
【化１０】[Chemical formula 10]
【００５４】インドメタシン（１）３４７．３ｍｇ、Ｎ
−（１−ベンジルオキシカルボニルピペリジン−３−イ
ル）−４−ヒドロキシエチルオキシベンズアミド（２）
３８６．６ｍｇ、ＷＳＣ２７８ｍｇ及びジメチルアミノ
ピリジン１１ｍｇをジクロルメタン２５ｍｌに溶解し、
この溶液を室温で１時間撹拌する。反応液を１規定塩酸
水溶液、飽和重ソウ水及び飽和食塩水で順次洗浄し、無
水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去す
る。得られた残渣をシリカゲルクロマトグラフィーに付
して、式（３）の化合物を無晶形の微黄色固体として７
１６．４ｍｇを得た（収率定量的）。Indomethacin (1) 347.3 mg, N
-(1-benzyloxycarbonylpiperidin-3-yl)-4-hydroxyethyloxybenzamide (2)
386.6 mg, WSC 278 mg and dimethylaminopyridine 11 mg were dissolved in 25 ml of dichloromethane,
The solution is stirred at room temperature for 1 hour. The reaction solution is washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen chloride solution, and a saturated brine solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain the compound of formula (3) as an amorphous slightly yellow solid.
16.4 mg was obtained (yield quantitative).
【００５５】
ＩＲ（ＣＨＣｌ３）；１６８０ｃｍ−１、１７３５ｃｍ
−１実施例 ２IR (CHCl3); 1680 cm-1, 1735 cm
-1 Example 2
【００５６】[0056]
【化１１】[Chemical formula 11]
【００５７】上記実施例１で得られた２−［４−［Ｎ−
（１−ベンジル−オキシカルボニルピペリジン−３−イ
ル）カルバモイル］フェノキシ］エチル１−（ｐ−クロ
ロベンゾイル）−５−メトキシ−２−メチル−３−イン
ドリルアセテート（３）７１６．４ｍｇ及びアニソール
０．１５ｍｌに２５％臭化水素酸・酢酸溶液４．２ｍｌ
を加えて、室温で１時間撹拌する。得られた反応液にエ
ーテルを加えて析出する固体を窒素気流中で濾取する。
得られた固体をエーテルで洗浄した後真空下で乾燥させ
て、２−［４−（３−ピペリジノカルバモイル）フェノ
キシ］エチル１−（ｐ−クロロベンゾイル）−５−メト
キシ−２−メチル−３−インドリルアセテート臭化水素
酸塩（４）を微黄色固体として６６４ｍｇ得た（収率定
量的）。
ＩＲ（ＫＢｒ）；１６７５ｃｍ−１、１７３０ｃｍ−１
実施例 ３
前記実施例１及び２に記載された方法に準じて、下記第
４表に示される化合物を得た。2-[4-[N-] obtained in Example 1 above
(1-Benzyl-oxycarbonylpiperidin-3-yl)carbamoyl]phenoxy]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetate (3) 716.4 mg and anisole 0. 4.2ml of 25% hydrobromic acid/acetic acid solution in 15ml
and stir at room temperature for 1 hour. Ether is added to the resulting reaction solution, and the precipitated solid is collected by filtration in a nitrogen stream. The resulting solid was washed with ether and dried under vacuum to give 2-[4-(3-piperidinocarbamoyl)phenoxy]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl- 664 mg of 3-indolyl acetate hydrobromide (4) was obtained as a slightly yellow solid (quantitative yield). IR (KBr); 1675 cm-1, 1730 cm-1
Example 3 According to the methods described in Examples 1 and 2 above, the compounds shown in Table 4 below were obtained.
【００５８】[0058]
【表４】[Table 4]
【００５９】表中、ＩＮＤは以下に示される基を表わす
。In the table, IND represents the group shown below.
【００６０】[0060]
【化１２】[Chemical formula 12]
Claims (3)
し；Ａは 【化２】―Ｘ―Ｌ２―ＣＯＮＲ１Ｒ２ 又は 【化３】―Ｌ２―ＮＲ１Ｒ２ で示される基を表わす（ここで、Ｌ２は低級アルキレン
基又はフェニレン基を表わし、Ｒ１及びＲ２は各々独立
に水素原子、低級アルキル基、低級アルコキシアルキル
基、若しくは低級アルキル基で置換されてもよい複素環
基を表わすか、又はＲ１とＲ２とが結合する窒素原子と
一緒になって複素環基を表わし、Ｘは酸素原子又は硫黄
原子を表わす）、で示されるインドメタシン誘導体及び
その塩。Claim 1: General formula [Formula 1] In the formula, L1 represents a lower alkylene group or a phenylene group; A is a group represented by [Chemical formula 2]-X-L2-CONR1R2 or [Chemical formula 3]-L2-NR1R2 (Here, L2 represents a lower alkylene group or a phenylene group, and R1 and R2 each independently represent a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, or a heterocyclic group which may be substituted with a lower alkyl group. or R1 and R2 together with the nitrogen atom to which they are bonded represent a heterocyclic group, and X represents an oxygen atom or a sulfur atom) and salts thereof.
した定義のとおりである、で示される請求項１記載の化
合物。2. The compound according to claim 1, represented by the general formula: [Image Omitted] wherein L1, L2, R1, R2 and X are as defined in claim 1.
定義のとおりである、で示される請求項１記載の化合物
。3. The compound according to claim 1, represented by the general formula: [Image Omitted] wherein L1, L2, R1 and R2 are as defined in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6257391A JPH04275271A (en) | 1991-03-04 | 1991-03-04 | Indomethacin derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6257391A JPH04275271A (en) | 1991-03-04 | 1991-03-04 | Indomethacin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04275271A true JPH04275271A (en) | 1992-09-30 |
Family
ID=13204181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6257391A Pending JPH04275271A (en) | 1991-03-04 | 1991-03-04 | Indomethacin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04275271A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747521A (en) * | 1992-09-16 | 1998-05-05 | Samjin Pharm. Co., Ltd. | N-cinnamoyl-2-methyl-5-methoxy-3-indoleacetic acid ester, and pharmaceutical preparation containing the same |
| EP1778229A2 (en) * | 2004-08-10 | 2007-05-02 | Incyte Corporation | Amido compounds and their use as pharmaceuticals |
| US8071624B2 (en) | 2004-06-24 | 2011-12-06 | Incyte Corporation | N-substituted piperidines and their use as pharmaceuticals |
-
1991
- 1991-03-04 JP JP6257391A patent/JPH04275271A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747521A (en) * | 1992-09-16 | 1998-05-05 | Samjin Pharm. Co., Ltd. | N-cinnamoyl-2-methyl-5-methoxy-3-indoleacetic acid ester, and pharmaceutical preparation containing the same |
| US8071624B2 (en) | 2004-06-24 | 2011-12-06 | Incyte Corporation | N-substituted piperidines and their use as pharmaceuticals |
| US8288417B2 (en) | 2004-06-24 | 2012-10-16 | Incyte Corporation | N-substituted piperidines and their use as pharmaceuticals |
| EP1778229A2 (en) * | 2004-08-10 | 2007-05-02 | Incyte Corporation | Amido compounds and their use as pharmaceuticals |
| EP1778229A4 (en) * | 2004-08-10 | 2009-06-17 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
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