CA1088554A - Preparation of 5-substituted indane-2 carboxylic acid and derivatives - Google Patents
Preparation of 5-substituted indane-2 carboxylic acid and derivativesInfo
- Publication number
- CA1088554A CA1088554A CA293,076A CA293076A CA1088554A CA 1088554 A CA1088554 A CA 1088554A CA 293076 A CA293076 A CA 293076A CA 1088554 A CA1088554 A CA 1088554A
- Authority
- CA
- Canada
- Prior art keywords
- indane
- radical
- acid
- benzoyl
- formula
- 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.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- -1 5-substituted indane-2 carboxylic acid Chemical class 0.000 title claims description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract 3
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims abstract 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 46
- 239000002253 acid Substances 0.000 claims description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 44
- XUDCMQBOWOLYCF-UHFFFAOYSA-N 2,3-dihydro-1h-indene-2-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)CC2=C1 XUDCMQBOWOLYCF-UHFFFAOYSA-N 0.000 claims description 37
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 27
- 230000008569 process Effects 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 10
- 150000003857 carboxamides Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- LDUHQKWPUVJJPU-UHFFFAOYSA-N 2,3-dihydro-1h-indene-2-carboxamide Chemical compound C1=CC=C2CC(C(=O)N)CC2=C1 LDUHQKWPUVJJPU-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 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 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 7
- RMOPJLIMRSAIMD-UHFFFAOYSA-N methyl 2,3-dihydro-1h-indene-2-carboxylate Chemical compound C1=CC=C2CC(C(=O)OC)CC2=C1 RMOPJLIMRSAIMD-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 150000002468 indanes Chemical class 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- QDLFVXRWLQSBTF-UHFFFAOYSA-N 1,1,2-triethylhydrazine Chemical compound CCNN(CC)CC QDLFVXRWLQSBTF-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 238000006193 diazotization reaction Methods 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 150000001879 copper Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 19
- MCMQEARTOUMJPK-UHFFFAOYSA-N 2,3-dihydro-1h-indene;propanoic acid Chemical compound CCC(O)=O.C1=CC=C2CCCC2=C1 MCMQEARTOUMJPK-UHFFFAOYSA-N 0.000 claims 2
- JTTVFOGHBRSFQM-UHFFFAOYSA-N C(C)NCC.ClCCCl Chemical compound C(C)NCC.ClCCCl JTTVFOGHBRSFQM-UHFFFAOYSA-N 0.000 claims 2
- 230000001476 alcoholic effect Effects 0.000 claims 2
- 150000001768 cations Chemical class 0.000 claims 2
- 230000007062 hydrolysis Effects 0.000 claims 2
- 238000006460 hydrolysis reaction Methods 0.000 claims 2
- LGTZRESQDNRCAZ-UHFFFAOYSA-N 1-benzoyl-2,3-dihydro-1H-indene-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)(=O)C1C(CC2=CC=CC=C12)C(=O)O LGTZRESQDNRCAZ-UHFFFAOYSA-N 0.000 claims 1
- DZGMFITYAJIDHR-UHFFFAOYSA-N 2,3-dihydro-1h-indene-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)CCC2=C1 DZGMFITYAJIDHR-UHFFFAOYSA-N 0.000 claims 1
- AJSVPEVDFBYRCH-UHFFFAOYSA-N 3-methylthiophene-2-carbonyl chloride Chemical compound CC=1C=CSC=1C(Cl)=O AJSVPEVDFBYRCH-UHFFFAOYSA-N 0.000 claims 1
- OVOCLWJUABOAPL-UHFFFAOYSA-N 5-methylfuran-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)O1 OVOCLWJUABOAPL-UHFFFAOYSA-N 0.000 claims 1
- YDUOFRZUFBNVOO-UHFFFAOYSA-N 6-sulfonylcyclohexa-2,4-diene-1-carbonyl chloride Chemical compound S(=O)(=O)=C1C(C(=O)Cl)C=CC=C1 YDUOFRZUFBNVOO-UHFFFAOYSA-N 0.000 claims 1
- 241001331845 Equus asinus x caballus Species 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 230000001760 anti-analgesic effect Effects 0.000 abstract description 2
- 230000000702 anti-platelet effect Effects 0.000 abstract description 2
- 239000003146 anticoagulant agent Substances 0.000 abstract description 2
- 231100000926 not very toxic Toxicity 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 238000002329 infrared spectrum Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 10
- 150000003254 radicals Chemical group 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 229940039748 oxalate Drugs 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 230000007704 transition Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 101100020663 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) ppm-1 gene Proteins 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229940072033 potash Drugs 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000002744 anti-aggregatory effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 235000010269 sulphur dioxide Nutrition 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- RTRZIWZZYGDMFE-UHFFFAOYSA-N 1-chloro-n,n-diethylethanamine;hydron;chloride Chemical compound Cl.CCN(CC)C(C)Cl RTRZIWZZYGDMFE-UHFFFAOYSA-N 0.000 description 1
- KTUOJDXAHZOFCA-UHFFFAOYSA-N 3-(diethylamino)propanamide Chemical compound CCN(CC)CCC(N)=O KTUOJDXAHZOFCA-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241001338801 Chlorus Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- BUVKILSTJGGJJN-UHFFFAOYSA-N acetic acid;2,3-dihydro-1h-indene Chemical compound CC(O)=O.C1=CC=C2CCCC2=C1 BUVKILSTJGGJJN-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- DXHPZXWIPWDXHJ-UHFFFAOYSA-N carbon monosulfide Chemical compound [S+]#[C-] DXHPZXWIPWDXHJ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 description 1
- XLSMFKSTNGKWQX-UHFFFAOYSA-N hydroxyacetone Chemical compound CC(=O)CO XLSMFKSTNGKWQX-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- HCTVWSOKIJULET-LQDWTQKMSA-M phenoxymethylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1 HCTVWSOKIJULET-LQDWTQKMSA-M 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
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Abstract
Composé représentés par la formule générale: (I) dans laquelle R est un radical phényle substitué par au moins un substituant choisi parmi les halogènes et les radicaux acétamido, dialkylamino, alkylsulfonyl, dialkylaminosulfonyl et sulfamido: un radical thiényle substitué par au moins un substituant choisi parmi les halogènes et un radical alkyle inférieur; ou un radical furyle substitué par un radical alkyle inférieur. Ces composés possèdent une activité pharmacologique anti-inflammatoi-re, analgésique et antigrégante plaquettaire et sont en général peu toxiques. Procédés de préparation ainsi que compositions pharmaceutiques.Compound represented by the general formula: (I) in which R is a phenyl radical substituted by at least one substituent chosen from halogens and the acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfonyl and sulfamido radicals: a thienyl radical substituted by at least one chosen substituent from halogens and a lower alkyl radical; or a furyl radical substituted by a lower alkyl radical. These compounds have anti-inflammatory, analgesic and anti-platelet pharmacological activity and are generally not very toxic. Preparation methods as well as pharmaceutical compositions.
Description
La présente invention concerne de nouveaux dérivés de l~indane, leurs procédés de préparation, leurs applications notamment comme médicaments.
La demande de brevet numéro 269.02~ déposée au Canada le 31 décembre 1976, par la demanderesse décrit les composés représentés par la formule générale:
R - CO ~ ~ (I) ~ ~ COOH .
dans laquelle R est un groupe aryle ou hétéroaryle. En parti-culier, R peut 8tre choisi parmi les radicaux phényle et furyle.
Quant R est un radical phényle il est éventuellement substitué
par un ou plusieurs radicaux alkyles inférieurs, alkoxy in~é- .
rieurs ou le radical nitro.
Cette demande de brevet numéro 269.025 concerne é~a- . :
lement les composés ci-dessus sous forme de sels, esters, ~nino- ,:`
esters et amides~ ~`;; .
Les composés objets de la présente invention sous forme dtacide ou dtesters sont représentés par la mame formule .
générale dans]aquelle R est un radical phényle substitue par au moins un substituant choisi parmi les halo~ènes et les radi- ;`
caux ac~tamido, dial]cylamino, alkylsulfollyl, dia:Lkylclm.inosulfo-nyl et sulfamido; un radical thi~nyle substitué par au moins un ~
substituant choisi parmi les halogènes et un radical alkyle in- i:
.f~rieur; ou un radical furyle substitué par un radical alkyle in~érieur. .
En particulier, quand R est un radical phényle il est . :
substitué par au moins un substituant choisi parmi le chlore et les radicaux acétamido, diméthylamino, méthylsulfonyl, diméthyl- -:
sulfonyl et sulfamido~ Quand R est un radical thiényle substitué ~
".': ' ' i ' -- 1 -- . .
: ., . : .. , . , . , -; . . : , .
554 ~` :
il est substitué par au moins un substituant choisi, parmi le chlore et le radical méthyleu Quand R est un radical furyle, il est substitué par un radical méthyle.
Les nouveaux acides sont notamment les acides p-(dimé-thylamino) benzoyl-5 indane-2 carboxylique, p-(méthyl sulfonyl) benzoyl-5 indane-2 carboxylique, (parasulfamido benzoyl)-3 indane-2 carboxylique, (para diméthylamino sulfonyl) benzoyl-5 indane-2 carboxylique, (acétamido-4' chloro-3') benzoyl-5 indane- The present invention relates to new derivatives of indane, their preparation processes, their applications especially as medicines.
Patent application number 269.02 ~ filed in Canada on December 31, 1976, by the plaintiff describes the compounds represented by the general formula:
R - CO ~ ~ (I) ~ ~ COOH.
wherein R is an aryl or heteroaryl group. In part-particular, R can be chosen from phenyl and furyl radicals.
When R is a phenyl radical it is optionally substituted by one or more lower alkyl radicals, alkoxy in ~ é-.
laughers or the nitro radical.
This patent application number 269.025 relates to ~ a-. :
the above compounds in the form of salts, esters, ~ nino-,:
esters and amides ~ ~ `;; .
The compounds which are the subject of the present invention under form of acid or testers are represented by the same formula.
general in] aquelle R is a phenyl radical substituted by at least one substituent chosen from halo ~ enes and radi-; `
caux ac ~ tamido, dial] cylamino, alkylsulfollyl, dia: Lkylclm.inosulfo-nyl and sulfamido; a thi ~ nyle radical substituted by at least one ~
substituent chosen from halogens and an alkyl radical i:
.f ~ laughing; or a furyl radical substituted by an alkyl radical in ~ er. .
In particular, when R is a phenyl radical it is. :
substituted by at least one substituent chosen from chlorine and acetamido, dimethylamino, methylsulfonyl, dimethyl- - radicals:
sulfonyl and sulfamido ~ When R is a substituted thienyl radical ~
". ':'' i ' - 1 -. .
:.,. : ..,. ,. , -; . . :,.
554 ~ `:
it is substituted by at least one substituent chosen from chlorine and the methyleu radical When R is a furyl radical, it is substituted by a methyl radical.
The new acids are in particular p- (dimed-thylamino) benzoyl-5 indane-2 carboxylic, p- (methyl sulfonyl) benzoyl-5 indane-2 carboxylic, (parasulfamido benzoyl) -3 indan-2 carboxylic, (para dimethylamino sulfonyl) benzoyl-5 indane-2 carboxylic, (acetamido-4 'chloro-3') benzoyl-5 indane-
2 carboxylique, [(méthyl-3' thénoyl)-2']-5 indane-2 carboxylique, [(dichloro-4,5~ thénoyl)-2t]-5 indane-2 carboxylique, [(méthyl-5' furoyl)-21]-5 indane-2 carboxylique. ``~
Les dérivés de ces acides sous forme de sels théra-peutiquement acceptables, d'esters tels les esters aliphatiques inférieurs font parti~ de l'invention. ;
La présente invention a aussi pour objet les amino-esters tels les esters dial]~yl inférieurs aminoalkyl inférieurs.
Ces aminoesters sont dérivés des acides carboxyliques représen-tés par la formule générale I dans laquelle R est un radical thiényleou furyle. Les aminoesters sont notamment les (thénoyl-2')-5 indane-2 carboxylate de N,N-diéthylamino-2' éthyle, (furoyl-2')-S indane-2 carboxylate de N,N diéthylamino-2t éthyle.
La présente invention a pour autre objet les ~mides tels les amides al~yl inférieurs amlno al]iyl inférieurs dérivés des acides carboxyliques, représentés par la formule générale I
dans laquelle ~ est un radical phényle éventuellement substitue par deux halogènes ou un radical thiényle. Les carboxamides sont notamment les diéthylaminoéthylcarboxamide, tels les benzoyl-5 N(N',N'-diéthylamino-2' éthyl) indane-2 carboxamlde, (thénoyl-2')-5N (N',N' diéthylamino-2' éthyl) indane-2 carboxamide et (dichlo-ro-2', 5' benzoyl)-5 N(NI,Nl diéthylamino-2' éthyl) indane-2 'r ~ ~.
:, carbo~amide.
On peut accéder ~ de nouveaux dérivés de la présente invention par hydrolyse alcaline d'un ester de formule (II) dans laquelle R7 est de préférence un groupe alkyl inférieur:
~ /~ \ / L COOR' (II) On fait réagir sur ce dernier selon les conditions de la réaction de Friedel et Crafts un halogène d'aroyle de formule (III): ~ ;
R - COX (III) dans laquelle R a la signification précédemment citée et X re- -présente un halogène.
La réaction peut ~tre conduite avec ou sans solvant, `
mais de pré~érence avec un solvant convenable comme le chlo-rure de méthylène, le sulfure de carbone, etc... à des tempéra-tures s'échelonnant de 0C à la température d'ébullition du ~-solvant, de préférence à la température de reflux du solvant~
Parmi les acides de Lewis utilisables, on préfère le chlorure ~;
d'aluminium. Les différents réactifs pourront être présents en quantité stoechiométriques ou en excès, de préference en excès ;~
en ce qui concerne llhalogénure d~aroyle et le chlarure d~alumi-nium, cet exc~s pouvant aller ju3qu~ à ~00 %~
En ce qui concerne les composés dans lesquels R est un groupe phényle substitué par un radical sulfamido ou dimé-thylsulfamido, on part d'un ester de formule (~V)~
R - CO _ ~ (IV) ~ COORI
dans lequel Rl est un groupe alkyle inférieur et R un groupe phényle substitué par un radical amino.
":
_ 3 _ ~
~g?813554 Le composé (IV) dans lequel R et Rt ont les signi~ica-tions précédemment citées est sournis à une diazotation selon les techniques connues en soi, puis le sel d'aryldiazonium obtenu est traité par une solution d t anhydride sulfureux dans l'acide acétique en présence d t un sel de cuivre, de préférence le chloru~
re cuivrique de façon à obtenir un composé de formule (IV):
R - CO ~ ' ~ ~ - I (IV) ~1~ COORt dans laquelle R' a la même signification que précédemment et R est un radical phényle convenablement substitué par un radical chlorosul~onyle.
En traitant ce dernier par 1 t ammoniac gazeux ou en solution dans l'eau ou dans un alkanol inférieur, on obtient le composé de formule (IV), dans lequel R est un radical phényle ~`
substitué par un radical sulfamido. Si on remplace l'ammoniac par la diméthylamine, on obtient un composé de formule (IV) dans lequel R est un radical phényle substitué par un radical diméthylsulfamido.
En ce qui concerne les composés dans lesquels R est un radical phényle substitué par un radical diméthylamino, on traite un compos~ de formule (lV) dans :lequel Rl est un groupe alkyle inférieur et R un radical phényle substitué par un ra-dical amino, par le formaldéhyde sous sa forme monomère, pur ou ;
en solution dans l'eau, en présence d'hydrogène et dlun cataly-seur d'hydrogénation, de préférence le palladium sur carbone et à une température appropriée. On peut aussi traiter le com-posé de formule (IV) par un halogénure d'alkyle, de préférence l~iodure de méthyle, en présence dlun solvant tel que le dimé-thylformamide.
,.
_ ~ _ ~ ,....
.
85i5~
On obtient ainsi les composés de formule (I~) pour lesquels R est un groupe phényle substitué par un radical dimé-thylamino, Rt ayant la siynification précé~emment citée.
Enfin, quand R est un radical substitué par au moins .
un halogène, on obtient ces composés en traitant un composé de .
formule (IV) dans lequel R est un radical phényle, thiényle ou . ~ :
furyle monosubstitué et Rt a la signification précédemment citée, .-~
par une solution de l'halogène dans ltacide acétique, cette solution pouvant etre saturée ou non et la réaction ayant lieu ;~
10 à des températures stéchelonnant de la température ambiante à
celle du reflux.
Il est donné ci-après à titre illustratif mais non limitatif des exemples de préparation de composés qui illustrent la présente invention~ ;.:
Exemple n 1 Acide [(méthyl-3' thénoyl)-2'~-5 indane~2 carboxylique P.M. = 286,33 S CO
a) ~(Méthyl-3' thénoyl)-2'~-5 indane-2 carboxvlate de méthyle:
Dans un réacteur de 250 cm équlpe cllune ag:ltation, . .
cl'un ré~rigérant muni dtune garde à chlorure de calcium, d'une : ampoule à brome et dtun thermomètre~ on introduit:
- 18,5 g (0,139 mole) de chlorure d'aluminium - 14,1 g (0,08 mole) d'indane-2 carboxylate de méthyle .~.. -; goutte à goutte par l'ampoule à brome.
L,a température atteint 35C en fin d'addition. On chauffe légèrement pour homogénéiser. Puis à une température voi-sine de 20C on additionne goutte à goutte: `~`
~ ~ 5 ~ ~ -.
: ' ... . ... , . . . ~ . , . . . . . ~ - , - 12,8 g (0,08 mole) de chlorure dlacide méthyl-3 thiophène-2 carboxylique.
On chauffe ensuite progressivement jusque vers 70-80C. On maintient cette température pendant 30 minutes puis .
laisse revenir vers 40C. On additionne, à ce moment-là, du chlorure de méthylène puis verse la solution obtenue dans l'eau glacée additionnée dlacide chlorhydrique. La phase organique est décantée, lavée à l'eau sodée puis à lleau. On sèche sur :. -sulfate de sodium, filtre, concentre le filtrat et distille le résidu. On recueille une fraction huileuse épaisse Ebo 7 torr 180-200C. ~:
~ Spectre infra-rouqe:
- ~CO: 1740 cm~
- ~CO: 1640 cm~
Spectre R.M.N.:
- massif de 5 protons aromatiques centré vers 7,4 ppm - pic de 3 protons OCH3 à 3,4 ppm - pic de 5 protons indane à 3,33 ppm - pic de 3 protons CH3 à 2,4 ppm.
b) Passage à llacide r~méthyl-3' thenoy~)-2tl-5 indane~2 carbo-xylique Dans un réacteur de 250 cm3 équipé d t une agitation et d~un ré~.rig~rant, on introduit successivement:
- 6,7 g (0,0223 mole) d~ester obtenu à a) en solution dans 30cm3 de méthanol - 2,8 g (0,05 mole) de potasse en solution dans 30 cm de méthanol.
on chauffe à reflux une heure. On concentre ~ sec, reprend par l'eau, fait un lavage à ltéther en milieu alcalin.
La phase aqueuse est acidifiée à froid par 1 t acide chlorhydrique :~
un solide précipite. On ltessore, le lave à lteau, le sèche~
554 :~:
Par recristallisation dans 1 t acétate d'éthyle, on ..
obtient un solide fondant ~ 136 - 138C (tube capillaire). ~.~
Spectre infra-rouge: ;.
- ~CO: 1700 cm~l - ~CO: 1635 cm 1 . -Spectre R.M~
- massif de 5 protons aromatiques centré vers 7,32 ppm :~::
- pic de 5 protons indane vers 3,4 ppm .
- pic de 3 protons méthyle à 2,47 ppm - pic de 1 proton OH vers 10,7 ppm. `:
Indice d'acidité: :
Trouvé: 195 . .
Calculé: 190 Analyse_centésimale:
C/O ~P/O S% ' ~
Cal.culé 67,13 4,93 11,20 . .
Trouvé 67,06 4,99 11,24 . :', Exemple n2 .
Acide [(méthyl-5' furoyl)-2t~ 5 indane-2 carboxylique .:;, .
~ C16~1~
CH3 CO ,~ ..
P~M. = 270,27 ~ "_~"`COOH
a) [(méthyl-5' ~ yl)-2'~-5 indane-2 carboxylate de mé-thyle:
C17H1604 ` ' ' ' Dans un reacteur de 250 cm3, équipé dtun agitateur, d'un réfrigérant muni d'une garde à chlorure de calcium, d'une -ampoule à brome et d'un thermomètre, on introduit: :
- 11,4 g (0,086 mole) de chlorure dlaluminium en sus-pension dans 30 cm de chlorure de méthylène ~ , '." '.
5S~ :
..
5,5 g (0,0382 mole) de chlorure d1acide méthyl-5 furane carboxylique-2 en solution dans 30 cm de chlorure de méthylène. ;
On amène le mélange à une température de 20C puis additionne goutte à goutte une solution de~
- 5,6 (0,0318 mole~ d t indane-2 carboxylate de méthyle ; dans 50 cm3 de chlorure de méthylène~
On laisse sous agitation deux heures à température ambiante puis chauffe trois heures à reflux. On laisse une nuit au repos puis verse dans un bain d'eau glacée acidulée. On extrait au chlorure de méthylène, lave l'extrait à l t eau sodée, à l'eau, le sèche sur sulfate de sodium, filtre, concentre le filtrat et distille le résidu. On recueille une fraction Ebltorr : 195 - 205 C. ~ i Spectre infra-rouge:
- ~CO: 1740 cm~
- ~CO: 1640 cm~
Spectre R.M.N.:
- massif de 4 protons aromatiques vers 7,33 ppm - l proton aromatique vers 6,2 ppm - pic de 5 protons indane à 3,3 ppm - pic de 3 protons OCH3 ~ 3,7 ppm - pic de 3 protons CH3 ~ 2,47 ppm b) Passa~e à l~acide r(méthyl-5'_furoyl)-2'1-5 indane-2 ~: '.
Dans un réacteur de 50 cm3, on introduit successive-ment:
- 2,7 g (0,0095 mole) d'ester obtenu ~ a) en solution dans 16,5 cm de méthanol - l,16 g (0,0208 mole) de potasse en solution dans 16,5 cm d'eau.
" .,,. :~
~l0~ S15~4 On laisse à température ambiante pendant 48 heures.
On concentre à sec, reprend par l'eau, fait un lavage à l'éther en milieu alcalin puis acidifie la phase aqueuse. On extrait `
à l'éther, sèche sur sulfate de sodium, filtre et concentre le filtrat. Le résidu obtenu après recristallisation dans un mé-lange acétate d'éthyle-hexane fond ~ 128-130C (tube capillaire).
Spectre infra-rouge: `
- ~CO: 1700 cm 1 ~
- ~CO: 1635 cm 1 -Spectre R.M.N.:
- 1 proton OH vers 10,6 ppm - massif de 4 protons aromatiques centré vers 7,5 ppm - 1 proton aromatique vers 6,8 ppm - 5 protons indane à 3,36 ppm 2 carboxylic, [(3-methyl 'thenoyl) -2'] - 5 indane-2 carboxylic, [(4,5-dichloro ~ thénoyl) -2t] -5 indan-2 carboxylic, [(methyl-5 ' furoyl) -21] -5 indan-2 carboxylic. `` ~
The derivatives of these acids in the form of therapeutic salts may be acceptable, esters such as aliphatic esters lower are part ~ of the invention. ;
The present invention also relates to the amino-esters such as dial] ~ yl lower aminoalkyl lower esters.
These amino esters are derived from the carboxylic acids represented ted by the general formula I in which R is a radical thienyleou furyle. The aminoesters are in particular the (2-thénoyl-2 ') - 2 indane-2, N, N-diethylamino-2' carboxylate ethyl, (furoyl-2 ') - S indane-2 carboxylate of N, N diethylamino-2t ethyl.
Another subject of the present invention is ~ mides such amides al ~ yl lower amlno al] iyl lower derivatives carboxylic acids, represented by the general formula I
in which ~ is an optionally substituted phenyl radical by two halogens or a thienyl radical. Carboxamides are in particular diethylaminoethylcarboxamide, such as benzoyl-5 N (N ', N'-diethylamino-2' ethyl) indane-2 carboxamlde, (thénoyl-2 ') -5N (N ', N' diethylamino-2 'ethyl) indan-2 carboxamide and (dichlo-ro-2 ', 5' benzoyl) -5 N (NI, Nl diethylamino-2 'ethyl) indane-2' r ~ ~.
:, carbo ~ amide.
We can access ~ new derivatives of this invention by alkaline hydrolysis of an ester of formula (II) in which R7 is preferably a lower alkyl group:
~ / ~ \ / L COOR '(II) We react on the latter according to the reaction conditions from Friedel and Crafts an aroyl halogen of formula (III): ~;
R - COX (III) in which R has the aforementioned meaning and X re- -has a halogen.
The reaction can be carried out with or without solvent, but pre ~ erence with a suitable solvent such as chlo-methylene ride, carbon sulfide, etc ... at temperatures tures ranging from 0C to the boiling point of ~ -solvent, preferably at the reflux temperature of the solvent ~
Among the Lewis acids which can be used, chloride ~ is preferred;
aluminum. The different reagents may be present in stoichiometric or excess amount, preferably excess; ~
as regards the aroyl halide and the aluminum chlaride nium, this exc ~ s can range from ju3qu ~ to ~ 00% ~
As regards the compounds in which R is a phenyl group substituted by a sulfamido or dimer radical thylsulfamido, we start from an ester of formula (~ V) ~
R - CO _ ~ (IV) ~ COORI
wherein Rl is a lower alkyl group and R is a group phenyl substituted with an amino radical.
":
_ 3 _ ~
~ g? 813554 The compound (IV) in which R and Rt have the signi ~ ica-previously mentioned is returned to a diazotization according to the techniques known per se, then the aryldiazonium salt obtained is treated with a solution of sulfur dioxide in acid acetic in the presence of a copper salt, preferably chloru ~
cupric so as to obtain a compound of formula (IV):
R - CO ~ '~ ~ - I (IV) ~ 1 ~ COORt in which R 'has the same meaning as above and R is a phenyl radical suitably substituted by a radical chlorosul ~ onyle.
By treating the latter with 1 t ammonia gas or by solution in water or in a lower alkanol, we obtain the compound of formula (IV), in which R is a phenyl radical ~ `
substituted by a sulfamido radical. If we replace ammonia with dimethylamine, a compound of formula (IV) is obtained in which R is a phenyl radical substituted by a radical dimethylsulfamido.
As regards the compounds in which R is a phenyl radical substituted by a dimethylamino radical, we processes a compound of formula (IV) in which Rl is a group lower alkyl and R a phenyl radical substituted by a ra-dical amino, with formaldehyde in its monomeric form, pure or;
in solution in water, in the presence of hydrogen and a cataly-hydrogenation sor, preferably palladium on carbon and at an appropriate temperature. We can also treat the laid of formula (IV) with an alkyl halide, preferably ~ methyl iodide in the presence of a solvent such as dimed thylformamide.
,.
_ ~ _ ~, ....
.
85i5 ~
The compounds of formula (I ~) are thus obtained for in which R is a phenyl group substituted by a dimeric radical thylamino, Rt having the above siynification ~ emment cited.
Finally, when R is a radical substituted by at least.
a halogen, these compounds are obtained by treating a compound of.
formula (IV) in which R is a phenyl, thienyl or. ~:
monosubstituted furyl and Rt has the meaning mentioned above, .- ~
by a solution of the halogen in acetic acid, this solution may or may not be saturated and the reaction taking place; ~
10 at temperatures ranging from room temperature to that of reflux.
It is given below by way of illustration but not limiting examples of preparation of compounds which illustrate the present invention ~;.:
Example 1 Carboxylic acid [(methyl-3 'thenoyl) -2' ~ -5 indane ~ 2 PM = 286.33 S CO
a) ~ (Methyl-3 'thénoyl) -2' ~ -5 indane-2 methyl carboxvlate:
5:16 PM
In a 250 cm reactor equipped with an ag: lation,. .
cl'a re ~ rigorous provided with a calcium chloride guard, a : bulb with bromine and a thermometer ~ we introduce:
- 18.5 g (0.139 mole) of aluminum chloride - 14.1 g (0.08 mole) of methyl indan-2 carboxylate. ~ .. -; drip through the bromine bulb.
The temperature reaches 35C at the end of the addition. We slightly heats to homogenize. Then at a temperature around sine of 20C we add drop by drop: `~`
~ ~ 5 ~ ~ -.
: '.... ...,. . . ~. ,. . . . . ~ -, - 12.8 g (0.08 mole) of 3-methyl acid chloride thiophene-2 carboxylic.
Then gradually heated to around 70-80C. This temperature is maintained for 30 minutes then.
let come back to 40C. We add, at that time, methylene chloride then pour the solution obtained into water ice-cold with hydrochloric acid. The organic phase is decanted, washed with soda water and then with water. We dry on:. -sodium sulfate, filter, concentrate the filtrate and distill it residue. We collect a thick oily fraction Ebo 7 torr 180-200C. ~:
~ Infrared spectrum:
- ~ CO: 1740 cm ~
- ~ CO: 1640 cm ~
NMR spectrum:
- massif of 5 aromatic protons centered around 7.4 ppm - peak of 3 protons OCH3 at 3.4 ppm - peak of 5 indane protons at 3.33 ppm - peak of 3 protons CH3 at 2.4 ppm.
b) Transition to the acid r ~ methyl-3 'thenoy ~) -2tl-5 indane ~ 2 carbo-xylic In a 250 cc reactor equipped with agitation and of a re. rig, we successively introduce:
- 6.7 g (0.0223 mole) of ester obtained in a) in solution in 30cm3 of methanol - 2.8 g (0.05 mole) of potassium hydroxide solution in 30 cm methanol.
heated at reflux for one hour. We concentrate ~ dry, taken up in water, washed with ether in an alkaline medium.
The aqueous phase is acidified cold with 1 t hydrochloric acid: ~
a solid precipitates. We wash it, wash it with water, dry it ~
554: ~:
By recrystallization from 1 t ethyl acetate, we ..
obtains a melting solid ~ 136 - 138C (capillary tube). ~. ~
Infrared spectrum:;.
- ~ CO: 1700 cm ~ l - ~ CO: 1635 cm 1. -RM spectrum ~
- massif of 5 aromatic protons centered around 7.32 ppm: ~ ::
- peak of 5 indane protons around 3.4 ppm.
- peak of 3 methyl protons at 2.47 ppm - peak of 1 OH proton around 10.7 ppm. `:
Acidity index::
Found: 195. .
Calculated: 190 Percentage_Analysis:
C / O ~ P / OS% '~
Calculation code 67.13 4.93 11.20. .
Found 67.06 4.99 11.24 . : ', Example n2.
[(5 'methyl furoyl) -2t ~ 5 indan-2 carboxylic acid .:;,.
~ C16 ~ 1 ~
CH3 CO, ~ ..
P ~ M. = 270.27 ~ "_ ~" `COOH
a) [(methyl-5 '~ yl) -2' ~ -5 indane-2 methyl carboxylate:
C17H1604 `` ''' In a 250 cc reactor, equipped with an agitator, a refrigerant fitted with a calcium chloride guard, a -bulb with bromine and a thermometer, we introduce:
- 11.4 g (0.086 mol) of aluminum chloride in addition-board in 30 cm methylene chloride ~, '. "'.
5S ~:
..
5.5 g (0.0382 mole) 5-methyl acid chloride carboxylic furan-2 dissolved in 30 cm of methylene chloride. ;
The mixture is brought to a temperature of 20C then add a solution of ~ drop by drop - 5.6 (0.0318 mole ~ dt indane-2 methyl carboxylate ; in 50 cm3 of methylene chloride ~
The mixture is left stirring for two hours at temperature ambient then heats for three hours at reflux. We leave one night at rest then poured into a bath of tart ice water. We extract with methylene chloride, wash the extract with soda water, with water, dry it over sodium sulfate, filter, concentrate the filtrate and distill the residue. We collect a fraction Ebltorr: 195 - 205 C. ~ i Infrared spectrum:
- ~ CO: 1740 cm ~
- ~ CO: 1640 cm ~
NMR spectrum:
- massif of 4 aromatic protons around 7.33 ppm - the aromatic proton around 6.2 ppm - peak of 5 indane protons at 3.3 ppm - peak of 3 protons OCH3 ~ 3.7 ppm - peak of 3 protons CH3 ~ 2.47 ppm b) Passa ~ e to r (methyl-5'_furoyl) -2'1-5 indane-2 acid ~: '.
In a 50 cm3 reactor, successively-is lying:
- 2.7 g (0.0095 mole) of ester obtained ~ a) in solution in 16.5 cm of methanol - 1.16 g (0.0208 mole) of potassium hydroxide solution in 16.5 cm of water.
". ,,.: ~
~ l0 ~ S15 ~ 4 The mixture is left at room temperature for 48 hours.
Concentrate to dryness, take up in water, wash with ether in an alkaline medium then acidifies the aqueous phase. We extract `
with ether, dry over sodium sulfate, filter and concentrate the filtrate. The residue obtained after recrystallization from a metal ethyl acetate-hexane mixture background ~ 128-130C (capillary tube).
Infrared spectrum: `
- ~ CO: 1700 cm 1 ~
- ~ CO: 1635 cm 1 -NMR spectrum:
- 1 OH proton around 10.6 ppm - mass of 4 aromatic protons centered around 7.5 ppm - 1 aromatic proton around 6.8 ppm - 5 indane protons at 3.36 ppm
- 3 protons OEI3 à 2,47 ppm Analyse centésimale:
... ..
~/0 ` ~:
Calculé 71,10 5,22 Trouvé 70,99 5,16 'i :
Exemple n 3 .
Acide (diméthylamino-4' benzoyl)-S indane-2 carboxyli-que:
CH3 Cl9H19N3 N~CO - ~ - C00H P.M.= 309,35 a) (diméthylamino 4' :~n-ovl~-5 indane-2 carboxylate de méthyle On peut procéder selon:
a) dans un autoclave de 250 cm , on introduit: 5 g _ g _ ~ ''''.: ~''' !3855~
(0,017 mole) d'(amino-4' benzoyl)-5 indane-2 carboxylate de :~ -méthyle, 100 cm3 d'éthanol, 26 cm3 d'aldéhyde formique à 36%
dans l'eau, en présence de 2g de Pd/C à 5%. On chauffe à
environ 40C avec ayitation après avoir chargé 1 t autoclave avec de l'hydrogène. Après absorption de la quantité théori- .
que, on filtre pour éliminer le catalyseur. On concentre l'éthanol sous vide, reprend par de l'eau et extrait à l'étherO .
on sèche sur sulfate de sodium, filtre et concentre le filtrat.
Le résidu après recristallisation dans un mélange acétate d'é-thyle - diisopropyléther fond à 87~ - 89C (tube capillaire).
Spectre infra-rouge:
- ~CO: 1740 cm 1 --~CO: 1640 cm~l - disparition des bandes NH2 Spectre_R.M.N.:
- doublet 2 protons aromatiques: 7,85 ppm - multiplet 2 protons aromatiques: 7,55 ppm - multiplet 1 proton aromatique: 7,25 ppm - doublet 2 protons aromatiques: 6,7 ppm - pic 3 protons CH3: 3,8 ppm - massif 5 protons indane: 3,35 ppm - pic 6 protons C~I3: 3,1 ppm ~na~se centésimale:
C/O ~P/O ~/0 Calculé 74,29 6,55 4,33 Trouvé 74,41 6,60 4,42 b) dans un autoclave de 125 cm3, on introduit: 9,6 g (0,068 mole) d'iodure de méthyle, 4,9 g (0,034 mole -~ 5%) de -K2CO3, 30 cm de diméthylformamide et 5 g (0,017 mole) d'(amino-- 3 OEI3 protons at 2.47 ppm Centesimal analysis:
... ..
~ / 0 `~:
Calculated 71.10 5.22 Found 70.99 5.16 'i:
Example No. 3 .
4-dimethylamino-benzoyl acid -S indane-2 carboxyli-than:
CH3 Cl9H19N3 N ~ CO - ~ - C00H PM = 309.35 a) (4 'dimethylamino: ~ n-ovl ~ -5 methyl indane-2 carboxylate We can proceed according to:
a) in a 250 cm autoclave, the following is introduced: 5 g _ g _ ~ ''''.: ~ ''' ! 3855 ~
(0.017 mole) of (4-amino 'benzoyl) -5 indane-2 carboxylate of: ~ -methyl, 100 cm3 of ethanol, 26 cm3 of 36% formaldehyde in water, in the presence of 2g of Pd / C at 5%. We heat to about 40C with ayitation after loading 1 t autoclave with hydrogen. After absorption of the theoretical quantity.
that is filtered to remove the catalyst. We concentrate ethanol under vacuum, taken up in water and extracted with etherO.
dried over sodium sulfate, filtered and concentrated the filtrate.
The residue after recrystallization from an acetate mixture of thyle - diisopropylether melts at 87 ~ - 89C (capillary tube).
Infrared spectrum:
- ~ CO: 1740 cm 1 - ~ CO: 1640 cm ~ l - disappearance of NH2 bands Specter_R.MN:
- doublet 2 aromatic protons: 7.85 ppm - multiplet 2 aromatic protons: 7.55 ppm - multiplet 1 aromatic proton: 7.25 ppm - doublet of 2 aromatic protons: 6.7 ppm - 3 proton CH3 peak: 3.8 ppm - massive 5 protons indane: 3.35 ppm - peak 6 protons C ~ I3: 3.1 ppm ~ na ~ centesimal:
C / O ~ P / O ~ / 0 Calculated 74.29 6.55 4.33 Found 74.41 6.60 4.42 b) into a 125 cm3 autoclave, 9.6 g are introduced (0.068 mole) methyl iodide, 4.9 g (0.034 mole - ~ 5%) of -K2CO3, 30 cm of dimethylformamide and 5 g (0.017 mole) of (amino-
4' benzoyl)-5 indane-2 carboxylate de méthyle. On laisse sous agitation 24 heures.
q~ ' .
' ~L0~3~559L
On évapore le diméthyl-formamide SOU5 vide, reprend par de lteau9 ;
extrait à l'éther. On sèche sur sulfate, filtre et concentre le filtrat. Le résidu obtenu est recristallisé dans un mélange ~ ;
acétate d'éthyle ~ diisopropyléther. On obtient un produit dont les caractéristiques physiques et spectrales sont identiques à
celles du produit obtenu selon a).
b) Le passage à l'acide stobtient selon l'exemple nl, b) à -partir de: ; 4 'benzoyl) -5 methyl indane-2 carboxylate. We leave under 24 hour agitation.
q ~ '.
'' ~ L0 ~ 3 ~ 559L
The empty dimethylformamide SOU5 is evaporated, taken up with lteau9;
ether extract. Dried on sulfate, filtered and concentrated the filtrate. The residue obtained is recrystallized from a mixture ~;
ethyl acetate ~ diisopropyl ether. We obtain a product whose the physical and spectral characteristics are identical to those of the product obtained according to a).
b) The transition to acid is obtained according to example nl, b) to -from: ;
- 5,6 g (0,0174 mole) de (diméthylamino-4' benzoyl)-5 indane carboxylate de méthyle - 1,95 g (0,0348 mole) de potasse dans 60 cm3 de métha-nole. `
Par recristallisation dans 11acétate dléthyle, on obtient un solide fondant à 164-165C (tube capillaire).
Spectre infra-rouqe:
~ ~)CO: 1730 cm~
- ~CO: 1620 cm~
Spectre R.M~N.:
- massif de 7 protons aromatiques centré vers 7,23 ppm - pic de 5 protons indane ca 3,3 ppm - pic de 6 protons CH3 à 3,1 ppm.
Analyse centésimale: ~
C% ~/o N% ,,; ~., Calculé 73,776,19 4,53 Trouvé 73,906,05 4,53 Exemple n 4 :. .
Acide (paraméthyl sulfonyl) benzoyl-5 indane-2 carboxy-lique:
~ ' .
` ' 1~8~SS~ `
Co ~ 18H165S
~ ~ P.M. = 34~,37 a) Selon llexemple nl, a) on prépare le (paraméthyl sulfonyl) benzoyl-5 indane carboxylake de méthyle a partir de:
- 14 9 5 g (0,107 mole) de chlorure d'aluminium - 11 g (0,0475 mole) de chlorure d'acide paraméthyl sulfonyl benzo~que. -Le tout dans 60 cm3 de chlorure de méthylène.
- 7 g (0,0397 mole) d'indane-2 carboxylate de méthyle dans 30 cm3 de chlorure de méthylène.
Après concentration et reprise du résidu par l'hexane, on obtient un solide que llon utilise brut.
b) Selon l'exemple n 1, b) on prépare ltacide a partir de:
- 3 g ~0,008~ mole) d~ester obtenu à a) - 1,1 g (0,02 mole) de potasse - 50 cm3 de méthanol.
Par recristallisation dans l'éthanol, on obtient un so-lide fondant à 187 - 190C (tube capillaire).
Spectre infra-rou~e:
- ~CO: 1710 cm~
- ~CO: 1670 cm 1 Spectre R.M.N.:
. . _ _ _ - massif de 7 protons aromatiques centré vers 7,8 ppm - pic de 5 protons indane à 3,33 ppm - pic de 3 pro~ons Cl-I3 à 3,17 ppm.
Indice d'acidité:
.. .. _ ................................................ .
Calculé: 163 Trouvé: 155 ~ . ;
108~3SS4 ' Analyse centésimale: ~
C% I-l"/o S%
Calculé 62,78 4,68 9,31 Trouvé 62,90 5,01 9,17 Exem~_e n 5: , Acide (parasulfamido benzoyl)-5 indane-2 carboxylique:
H2N-502 ~ ~ CO r C17H15N0 COO~I P.M. = 345,36 - a) (Parachloro sulfonyl benz_~1)-5 indane-2 carboxylate de _é-thyle Dans un réacteur de 250 cm3 avec agitation, thermomètre et ampou-le à brome, on introduit:
- 14,7 g (0,05 mole) d'(amino-4' benzoyl)-5 indane-2 carboxylate de méthyle. `
A température comprise entre 0~ et 10C, on additionne:
- 40 cm3 d'acide chlorhydrique à 24/c puis, entre 0 et 5C, une solution de:
- 3,8 g de nitrite de sodium dans 10 cm3 d'eau.
Le sel de diazonium ainsi forme est ajouté ensulte vers 15C à un mélange aglté de:
- 80 cm3 d'acide acetique saturé d'anhydride suleureux et, - 2,8 y de chlorure cuivrique dissout dans 5 cm3 d'eau. ;
On laisse revenir à température ambiante, tiédit vers 40~C pour finir la reaction~ laisse au repos une nuit. Le lende-main, on reprend par l'eau glacée, essore le solide qui précipite.
On s'assure du produit obtenu par spectrographie R.M.N. et infra- ` -,.; , rouge.
b) Passage au (parasulfamido benzoyl)-5 indane-2 carboxylate de méthyle:
:' ~ - 13 -55~ ~
I~2N-S02 / \~ CO C18H17N5S
_ P.M. = 359,40 ~\~/ \COOCM
Dans un réacteur de 500 cm3 avec agitation, réfrigérant, arnpoule à brome, on introduit:
- 15,6 g (0,041 mole) du dérivé obtenu à a) - 150 cm de chloroforme.
Puis, avec une bonne agitation, on additionne:
- 100 cm d'a~noniaque à 15%.
On laisse agiter une heure et demie à température am-biante. On reprend par l'eau et le chloroforme. La phase chloro-formique est décantée, séchée sur sulfate de sodium, filtrée et concentree.
Par recristallisation du r~sidue dans un melange acéta-te d'éthyle-éther diisopropylique, on obtient un solide ondant a 147 - 149C (tube capillalre).
Spectre infra-rouqe:
- ~ NH: 3400 - 3320 cm - ~1CO: 1745 cm~l `
- ~ CO: 1660 cm~
Spectre R.M.N.:
- massif de 7 protons aromatiques vers 7,~6 ppm - pic de 2 protons NM2 a 6~1 ppm - pic de 3 protons OCM3 à 3,7 ppm - pic de 5 protons indane à 3,3 ppm.
c) Passage à l'acide:
en opérant selon l'exemple nl, b) à partir de:
- 11 g (0,0306 mole) d'ester obtenu à b) en solution dans 100 cm3 d'éthanol 30 - 3,4 g (0,06 mole) de potasse en solution dans 100 cm3 d'eau. ~;
On obtient, après recristallisation du produit ob-tenu ~ .. ..
8~S9L
dans un mélange acide acétique - eau, un solide fondant à 157 - ~
158C (tube capillaire). .
Spectre in-fra-rouqe: .-- ~ NH: 3320 cm - ~CO: 1720 cm 1 - ~CO: 1650 cm 1 Spectre R.M.N.:
- massif de 7 protons aromatiques vers 7,6 ppm ~.
- pic de 2 protons NH2 vers ~,o ppm - 1 proton OH vers 10,5 ppm - 5 protons indane à 3,4 ppm. `
Analyse centésimale: ; :
.
C% H~)/o N% S%
Calculé 59,12 4,38 4,06 9,28 Trouvé 59,38 4,14 4,09 9,24 Exemple n6: .
Acide (paradiméthylamino sulfonyl) benzoyl-5 indane-2 ~`
carboxylique: .
H3 ~
\N SO ~_CO ClgHlgNO5S ~:
¦ P.M.- 373,41 , ~ ~ COOII ;~
a) (Paradiméthylamino_sul:Eonyl) benæoyl-5 indane-2 carboxylate de :.
méthyl~e: C20~I21N5S
On le prepclre selon l'exemple n 5, h) à partir de:
- 28 g (0.074 mole) de (parachlorosulfonyl benzoyl)-5 indane-2 carboxylate de méthyle dans 90 cm3 de ch:Loroforme - 34 cm3 (0,148 mole) d'une solu-tion de dimé-thylamine à 40% dans l'eau. ;
30 b) Passa~e à l'acide: ;-:, Selon l'exemple n 5, c) à partir de: -- 21 g (C,0545 mole) d'ester brut obtenu à a) dans 200 cm3 d'eau - ]~ -- 5.6 g (0.0174 mole) of (4'-dimethylamino benzoyl) -5 indane methyl carboxylate - 1.95 g (0.0348 mole) of potash in 60 cm3 of metha-nole. ``
By recrystallization from ethyl acetate, obtains a solid melting at 164-165C (capillary tube).
Infrared spectrum:
~ ~) CO: 1730 cm ~
- ~ CO: 1620 cm ~
RM ~ N spectrum:
- massif of 7 aromatic protons centered around 7.23 ppm - peak of 5 indan protons ca 3.3 ppm - peak of 6 protons CH3 at 3.1 ppm.
Centesimal analysis: ~
C% ~ / o N% ,,; ~., Calculated 73,776.19 4.53 Found 73.906.05 4.53 Example No. 4 :. .
Benzoyl-5 indane-2 carboxy- (paramethyl sulfonyl) acid-lique:
~ '.
`` 1 ~ 8 ~ SS ~ `
Co ~ 18H165S
~ ~ PM = 34 ~, 37 a) According to example nl, a) preparing (paramethyl sulfonyl) 5-benzoyl indane methyl carboxylake from:
- 14 9 5 g (0.107 mole) of aluminum chloride - 11 g (0.0475 mole) of paramethyl acid chloride sulfonyl benzo ~ that. -All in 60 cm3 of methylene chloride.
- 7 g (0.0397 mole) of methyl indan-2 carboxylate in 30 cm3 of methylene chloride.
After concentration and recovery of the residue with hexane, a solid is obtained which is used raw.
b) According to example n 1, b) the acid is prepared from:
- 3 g ~ 0.008 ~ mole) d ~ ester obtained in a) - 1.1 g (0.02 mole) of potash - 50 cm3 of methanol.
By recrystallization from ethanol, a lide melting at 187 - 190C (capillary tube).
Infrared spectrum:
- ~ CO: 1710 cm ~
- ~ CO: 1670 cm 1 NMR spectrum:
. . _ _ _ - massif of 7 aromatic protons centered around 7.8 ppm - peak of 5 indane protons at 3.33 ppm - peak of 3 pro ~ ons Cl-I3 at 3.17 ppm.
Acidity index:
.. .. _ ............................................. ...
Calculated: 163 Found: 155 ~. ;
108 ~ 3SS4 '' Centesimal analysis: ~
C% Il "/ o S%
Calculated 62.78 4.68 9.31 Found 62.90 5.01 9.17 Example ~ _e n 5:, Carboxylic acid (parasulfamido benzoyl) -5 indan-2:
H2N-502 ~ ~ CO r C17H15N0 COO ~ I PM = 345.36 - a) (Parachloro sulfonyl benz_ ~ 1) -5 indane-2 carboxylate _-thyle In a 250 cc reactor with agitation, thermometer and ampoule the bromine, we introduce:
- 14.7 g (0.05 mole) of (4-amino-benzoyl) -5 indane-2 carboxylate methyl. ``
At a temperature between 0 ~ and 10C, we add:
- 40 cm3 of hydrochloric acid at 24 / c then, between 0 and 5C, a solution of:
- 3.8 g of sodium nitrite in 10 cm3 of water.
The diazonium salt thus formed is then added around 15C to a blend of:
- 80 cm3 of acetic acid saturated with sulphurous anhydride and, - 2.8 y of cupric chloride dissolved in 5 cm3 of water. ;
Leave to return to room temperature, warm to 40 ~ C to finish the reaction ~ left to stand overnight. The lende-hand, take up in ice water, wring out the solid which precipitates.
We make sure of the product obtained by NMR spectrography and infra- `-,.; , red.
b) Transition to (parasulfamido benzoyl) -5 indane-2 carboxylate methyl:
: ' ~ - 13 -55 ~ ~
I ~ 2N-S02 / \ ~ CO C18H17N5S
_ PM = 359.40 ~ \ ~ / \ COOCM
In a 500 cm3 reactor with stirring, coolant, arnpoule to bromine, we introduce:
- 15.6 g (0.041 mole) of the derivative obtained in a) - 150 cm of chloroform.
Then, with good agitation, we add:
- 100 cm a ~ noniac at 15%.
Leave to stir for an hour and a half at room temperature.
biante. It is taken up in water and chloroform. The chloro- phase formic is decanted, dried over sodium sulfate, filtered and concentrated.
By recrystallization of the residue in an acetate mixture te ethyl diisopropyl ether, an undulating solid is obtained a 147 - 149C (capillary tube).
Infrared spectrum:
- ~ NH: 3400 - 3320 cm - ~ 1CO: 1745 cm ~ l `
- ~ CO: 1660 cm ~
NMR spectrum:
- range of 7 aromatic protons around 7, ~ 6 ppm - peak of 2 NM2 protons at 6 ~ 1 ppm - peak of 3 OCM3 protons at 3.7 ppm - peak of 5 indane protons at 3.3 ppm.
c) Transition to acid:
by operating according to example nl, b) from:
- 11 g (0.0306 mole) of ester obtained in b) in solution in 100 cm3 ethanol 30 - 3.4 g (0.06 mole) of potassium hydroxide dissolved in 100 cm3 of water. ~;
After recrystallization of the obtained product, ~ .. ..
8 ~ S9L
in a mixture of acetic acid and water, a solid melting at 157 - ~
158C (capillary tube). .
In-fra-rouqe spectrum: .-- ~ NH: 3320 cm - ~ CO: 1720 cm 1 - ~ CO: 1650 cm 1 NMR spectrum:
- range of 7 aromatic protons around 7.6 ppm ~.
- peak of 2 NH2 protons towards ~, o ppm - 1 OH proton around 10.5 ppm - 5 indane protons at 3.4 ppm. ``
Centesimal analysis:; :
.
C% H ~) / o N% S%
Calculated 59.12 4.38 4.06 9.28 Found 59.38 4.14 4.09 9.24 Example n6:.
Acid (paradimethylamino sulfonyl) benzoyl-5 indane-2 ~ `
carboxylic:.
H3 ~
\ N SO ~ _CO ClgHlgNO5S ~:
¦ PM- 373.41 , ~ ~ COOII; ~
a) (Paradimethylamino_sul: Eonyl) benæoyl-5 indane-2 carboxylate of:.
methyl ~ e: C20 ~ I21N5S
We preprepare it according to example n 5, h) from:
- 28 g (0.074 mole) of (parachlorosulfonyl benzoyl) -5 indane-2 methyl carboxylate in 90 cm3 of ch: Loroform - 34 cm3 (0.148 mole) of a 40% dime-thylamine solution in the water. ;
B) Passa ~ e to acid:; -:, According to Example 5, c) from: -- 21 g (C, 0545 mole) of crude ester obtained in a) in 200 cm3 of water -] ~ -
- 6,15 g (0,11 mole) de potasse dans 200 cm3 d'éth~nol.
Après recristallisa-tion dans un mélange acétate cl'éthy-le - hexane, on obtient un solide fondant à 144 - 145''C (tube capillaire).
Spectre infra-rouqe:
- ~ CO: 1700 cm 1 - ~CO: 1~60 cm 1 Spectre R.M.~.:
- pic de 4 protons aromatiques à 7,97 ppm - massif de 3 protons aromatiques à 7,53 ppm - pic de 5 protons indane à 3,3 ppm - pic de 6 protons CH3 à 2,8 ppm.
nalyse centesimale:
C% H~/o N~/o S%
Calculé 61,11 5,13 3,75 ~"57 Trouvé 61,09 5,19 3,71 8,64 Exemple n~ 7:
~(acé-tamido-4' chloro-3') benzoyl~-5 indane-2 carboxy-late d'é-thyle:
/~===~\ 21 20ClNO~
CH3-CO-NII ~\ ~ '`~ P.M. = 385,8 Cl C2lI5 Dans un réacteur de 250 cm3 avec acJitatlon, reErlgérant, ampoule à brome et thermomètre, on introdu:it:
- 8,8 g (0,025 mole) de (para-acétamido benzoyl)-5 indane-2 carbo-xylate d'éthyle - 30 cm3 cl'acicle acetlque~
A une temperature voisine de 10~C, on rajoute goutte à goutte:
- 40 cm3 d'acide acétique saturé de chlore.
La suspension initiale disparaît progressivement. On laisse revenir une heure à température ambiante, puis concentre l'acide acétique sous vide. On obtient une huile qui par recris-1 ~
a~85~
tallisation dans un mélange acétate d'éthyle - hexane donne un solide fondant à 126 - 127C (-tube capillaire). ;`
S,Pectre infra-r~: :
- ~ NI-I: 3350 cm - ~ CO: 1740 cm 1 :
- ~CO: 1690 cm~
- ~CO:- 1650 cm 1 ~
Spectre R.M.N.: :
- 1 proton aromatique vers 8,6 ppm - massif de 6 protons aromatiques centre vers 7,5 ppm - quadruplet 2 protons CH2 vers 4,2 ppm - 5 protons indane à 3,33 ppm - pic de 3 protons CH3 à 2,23 ppm ; - pic de 3 protons C~I3 à 1,3 ppm. :
Analyse centésimale:
., . ~
C% E1% C1% ~,% ~`
Calculé 65,37 5,23 9,19 3,63 ~.:
Trouve 65,50 5,22 9,15 3,63 Exernple n 3: .`
Acide ~ dichloro-4',5' thénoyl)-2'~-5 incdane-2 carboxy-lique:
Cl~ -, I
Cl ~ S ~ ~ CO C15I-I10CI23S
P.M. = 341,20 COOH
Dans un réacteur de 250 cm3 équipé d'une agitation, cl'un réfrigé-rant, d'une ampoule à brome et d'un tube permettant un barbotage gazeux au sein du mélange réactionnel, on introduit:
- 5,2 g (0,017 mole) d'acide ~(chloro-5' thénoyl)-2'~-5 indane-2 carboxylique On y ajoute vers 15C:
- ].7 --- ~088~4 - 27 cm3 d'acide ~cétique saturé de chlore.
On chauffe ensuite au bain-marie vers 75C tout en fai-sant barboter du chlore au sein du mélange réac-tionnel. Après re-~roidissement, on isole un solide par essorage. Ce dernier, re-cristallisé dans l'acétage d'éthyle, voit son point de fusion se stabiliser à 190 - 192"C (tube capillaire).
Spectre in~ra-rouqe:
- ~ CO: 1720 cm 1 - ~CO: 1650 cm 1 Spectre R.M.N._:
- massif de 3 protons indane plus 1 proton thiophène centré vers 7,5 ppm - pic de 5 protons indane à 3,33 ppm.
Analyse centésimale:
C% ~% Cl% S%
Calculé 52,80 2,95 20,78 9,~0 Trouvé 52,86 2,98 20,82 9,48 Exemple nu 9-(Thénoyl-2')-S indane-2 carboxylate de N,N diéthylamino- ~
20 2' éthyle `
\ S CO P.M. - 371,~
\ ~ .
1 COOCM2-CM2-N ~
C2H5 ., a) Dans un réacteur de 500 cm3 equipé d'une agitation, d'un ré~ri-~rant, d'une arnpoule à brome, on introduit successivement:
- 27,1 g (0,1 mole) d'acide (thénoyl-2')-5 indane-2 carboxylique s - 200 cm3 d'isopropanol, - lo, 6 g (0,1 mole ~ 20%) de carbonate de potassium - 17,2 g ~0,1 mole) de chlorhydrate de chloro-éthyl diéthylamine - 150 cm3 d'isopropanol.
~"'' ' ~ - 18 -1 (~8B554 On chauf~e 15 heures à reflux. On concentre à sec, re-prend par l'eau et l'acide chlorhydrique dilué, fait un lavaqe à ~
l'éther en milieu acide. On passe en rnilieu alcalin sur la phase ;
aqueuse e-t extrait à l'éther. On sèche sur sulfate de sodium, filtre et concentre le filtrat.
On distille le résidue et recueille une fraction 0,7-0,8 torr 230-240C
Spectre infra-rouqe~
- ~ CO: 1740 cm 1 ~-- ~ CO: 1650 cm 1 Spectre R.M.N.:
- massif de 6 protons aromatiques vers 7,47 ppm - triplet de 2 protons CH2 vers 4,2 ppm - pic de 5 protons indane à 3,33 ppm - masslf de 6 protons CH2 vers 2,7 ppm - triplet de 6 protons C~I3 vers 1,07 ppm.
b) Passage au chlorhydrate: C21H26ClN03S P.M. = 407,94 Selon les techniques connues, on obtient après recris-tallisation dans l'éthanol un solide fondant à 157 - 158~C ~tube ~-capillaire).
Indice d'acldité:
Trouvé: 132 Calculé: 137 Spectr~ infra--rouqe:
- ~ CO: 1745 cm ]
- ~ CO: 1630 cm 1 ;
Analyse centésimale (chlorhydrate):
C% EI% Cl% ~/0 S%
Calculé 61,83 6,43 8,69 3,43 7,86 Trouvé 61,86 6,57 8,56 3,40 7,89 Exemple n 10:
(Furoyl-2'-5 indane-2 carboxylate de N,N diéthylamino- ~;
2' éthyle g ' ! ' ~ ' ' ' ' ' ' ' ' : . .
iO8BS54 0 ~ C0~ P.M. = 355,~2 OOC~I2-CII2-Préparé selon l'exemple n 9 à partir de:
- 21,4 g (0,0835 mole) d'acide (furoyl-2')-5 indane-2 carboxyli-que - 14,2 g (0.0835 mole) + 20%) de carbonate de potassium - 14,4 g (0,0835 mole) de chlorhydrate de chloro-éthyl diéthyl- :;~
amine.
Par distillation, on recueille une fraction Ebo 5 0 4 torr 200 - 220C
Spectre infra-rouqe~
- '~ C0: 1740 cm 1 ~.
- ~ C0: 1650 cm Spectre R.M.N.:
- massif de 3 protons aromatiques vers 7,83 ppm - massif de 2 protons aromatiques vers 7,3 ppm - 1 proton aromatique vers 6,53 ppm - massif de 2 protons CH2 vers 4,1 ppm - pic de 5 protons indane à 3,33 ppm ~ .
- massif cle 6 protons CM2 vers 2,7 ppm - massi~ de 6 proton9 CM3 vers 1,07 ppm.
Passaqe au chlorhydrate: C21M2~ClN04 ... ..
Après recristallisation dans un rnélange acétate d'éthy~
.
le - ethanol, on obtlent un solide fondant à 165 - 166,5C (tube capillaire) `
Indice d'acidité:
Calculé: 143 ..
Trouvé: 142 :.
:'. ' .
, , - 20 - ;
35~4 : -Analyse_centésimale (chlorhvdrate):
C% H% Cl% ~/O
Calculé 64,36 6,69 9,05 3,57 `
Trouvé 64,44 6,49 8,98 3,53 ;.
Exemple _u 11 , ~
senzoyl-5 N(N',N' diéthylamino-2' éthyl) indane-2 carboxamide /'=\ C 2 3H 2 4N 2 2 < ~ CO ~ ,~ P.M. = 364,47 ~ / CH2 CI12 N\
C 2H5,~, .
Dans un réacteur de 250 cm3 équipé d'une agitation, d'un réfrigérant, d'une ampoule à brome et d'un thermomètre, on introduit:
- 25,5 g (0,2 mole ~ 10%) de (N',N' diéthylami.no)-2 éthylamine .. . .
- 50 cmJ de dioxane.
A une température comprise entre 10~ et 20C, on addi-tionne une solution de:
- 30,2 g (0,1 mole) de chlorure d'acide benzoyl-5 indane-2 carbo- -xylique dans ; .;
- 50 cm3 de dioxane On laisse ensuite revenir à temperature ambian-te puis tourner une heure à cette température. On concentre le dioxane sous vide, reprend par de l'eau glac~e et extrait à l'ether en ~ .:
milieu alcalin. L'extrait éthéré est séché sur sulfate, filtré
et le filtrat concentré. On obtient une huile sur laquelle on fait un oxalate. ~ :
Après recristallisation dans un mélange acétone - alcool, on obtient un point de fusion de 153 - 154C (tube capillaire).
Indice d'acidité: ~-Calculé: 246 ~rouvé: 226 ', , . ~ - 21 -~LC31~85iS~
Spectre infra-rouge:
- - ~ C0: 1660 cm 1 Analyse centésimale: (C25H30N206) C% I-I% N~/o Calculé 66,07 6,65 6,17 Trouvé 66,10 6,50 6,18 Exemple n 12: -(Thénoyl-2')-5 N(N',N' diéthylamino-2' éthyl) indane-2 ~
carboxamide ..
~ C21H26N22 C0 P.M. - 370,51 ~C 2H5 Co-NEI-cH2-cII2 N\ C H ~. ~
Préparé selon l'exemple n~ 11 à partir de: ~ .
- 9,4 g (0.03 mole) de chlorure d'acide (thénoyl-2')-5 indane-2 .~
carboxylique . - 6.15 g (0.11 mole) of potash in 200 cm3 of eth ~ nol.
After recrystallization from an ethyl acetate mixture - hexane, we obtain a solid melting at 144 - 145''C (tube capillary).
Infrared spectrum:
- ~ CO: 1700 cm 1 - ~ CO: 1 ~ 60 cm 1 RM spectrum ~ .:
- peak of 4 aromatic protons at 7.97 ppm - massif of 3 aromatic protons at 7.53 ppm - peak of 5 indane protons at 3.3 ppm - peak of 6 CH3 protons at 2.8 ppm.
centesimal analysis:
C% H ~ / o N ~ / o S%
Calculated 61.11 5.13 3.75 ~ "57 Found 61.09 5.19 3.71 8.64 Example n ~ 7:
~ (acé-tamido-4 'chloro-3') benzoyl ~ -5 indane-2 carboxy-late ethyl:
/ ~ === ~ \ 21 20ClNO ~
CH3-CO-NII ~ \ ~ '' ~ PM = 385.8 Cl C2lI5 In a 250 cm3 reactor with acJitatlon, reErlgérant, bulb with bromine and thermometer, we introduce: it:
- 8.8 g (0.025 mole) of (para-acetamido benzoyl) -5 indane-2 carbo-ethyl xylate - 30 cm3 of the acetlque article ~
At a temperature close to 10 ~ C, we add drop by drop:
- 40 cm3 of acetic acid saturated with chlorine.
The initial suspension gradually disappears. We leave to return to room temperature for one hour, then concentrate acetic acid under vacuum. An oil is obtained which by recreating 1 ~
a ~ 85 ~
tallization in an ethyl acetate-hexane mixture gives a solid melting at 126 - 127C (capillary tube). ; `
S, Pectre infra-r ~::
- ~ NI-I: 3350 cm - ~ CO: 1740 cm 1:
- ~ CO: 1690 cm ~
- ~ CO: - 1650 cm 1 ~
NMR spectrum::
- 1 aromatic proton around 8.6 ppm - mass of 6 aromatic protons center around 7.5 ppm - quadruple 2 protons CH2 around 4.2 ppm - 5 indane protons at 3.33 ppm - peak of 3 CH3 protons at 2.23 ppm ; - peak of 3 protons C ~ I3 at 1.3 ppm. :
Centesimal analysis:
.,. ~
C% E1% C1% ~,% ~ `
Calculated 65.37 5.23 9.19 3.63 ~ .:
Found 65.50 5.22 9.15 3.63 Example 3: .`
Acid ~ dichloro-4 ', 5' thenoyl) -2 '~ -5 incdane-2 carboxy-lique:
Cl ~ -, I
Cl ~ S ~ ~ CO C15I-I10CI23S
PM = 341.20 COOH
In a 250 cc reactor equipped with stirring, a refrigerator rant, a bulb with bromine and a tube for bubbling gaseous within the reaction mixture, the following are introduced:
- 5.2 g (0.017 mole) of acid (chloro-5 'thenoyl) -2' ~ -5 indane-2 carboxylic We add around 15C:
-] .7 -- ~ 088 ~ 4 - 27 cm3 of acetic acid saturated with chlorine.
Then heat in a water bath around 75C while health bubbling chlorine into the reaction mixture. After re-~ stiffening, a solid is isolated by wringing. The latter, re-crystallized in ethyl acetate, sees its melting point stabilize at 190 - 192 "C (capillary tube).
In ~ ra-rouqe spectrum:
- ~ CO: 1720 cm 1 - ~ CO: 1650 cm 1 NMR spectrum:
- mass of 3 indan protons plus 1 thiophene proton centered around 7.5 ppm - peak of 5 indane protons at 3.33 ppm.
Centesimal analysis:
C% ~% Cl% S%
Calculated 52.80 2.95 20.78 9, ~ 0 Found 52.86 2.98 20.82 9.48 Naked example 9-(Thénoyl-2 ') - S indane-2 carboxylate of N, N diethylamino- ~
20 2 'ethyl `
\ S CO PM - 371, ~
.
1 COOCM2-CM2-N ~
C2H5., a) In a 500 cm3 reactor equipped with agitation, a re ~ ri-~ rant, from a bromine arnpoule, we successively introduce:
- 27.1 g (0.1 mole) of 2-thénoyl-acid - 5 indane-2 carboxylic s - 200 cm3 of isopropanol, - lo, 6 g (0.1 mole ~ 20%) of potassium carbonate - 17.2 g ~ 0.1 mole) of chloro-ethyl diethylamine hydrochloride - 150 cm3 of isopropanol.
~ "''' ~ - 18 -1 (~ 8B554 We heat ~ e 15 hours at reflux. Concentrate dry, re-take with water and dilute hydrochloric acid, wash at ~
ether in an acid medium. We pass in an alkaline medium on the phase;
aqueous and extracted with ether. It is dried over sodium sulfate, filters and concentrates the filtrate.
The residue is distilled and a fraction is collected 0.7-0.8 torr 230-240C
Infrared spectrum ~
- ~ CO: 1740 cm 1 ~ -- ~ CO: 1650 cm 1 NMR spectrum:
- range of 6 aromatic protons around 7.47 ppm - triplet of 2 CH2 protons around 4.2 ppm - peak of 5 indane protons at 3.33 ppm - masslf of 6 CH2 protons around 2.7 ppm - triplet of 6 C ~ I3 protons around 1.07 ppm.
b) Transition to the hydrochloride: C21H26ClN03S PM = 407.94 According to known techniques, after recrystallization, tallization in ethanol a solid melting at 157 - 158 ~ C ~ tube ~ -capillary).
Acidity index:
Found: 132 Calculated: 137 Infrared spectrum:
- ~ CO: 1745 cm]
- ~ CO: 1630 cm 1;
Centesimal analysis (hydrochloride):
C% EI% Cl% ~ / 0 S%
Calculated 61.83 6.43 8.69 3.43 7.86 Found 61.86 6.57 8.56 3.40 7.89 Example 10:
(Furoyl-2'-5 indane-2 carboxylate of N, N diethylamino- ~;
2 'ethyl g '! '~'''''''':. .
iO8BS54 0 ~ C0 ~ PM = 355, ~ 2 OOC ~ I2-CII2-Prepared according to Example No. 9 from:
- 21.4 g (0.0835 mole) of (furoyl-2 ') - 5 indane-2-carboxylic acid than - 14.2 g (0.0835 mole) + 20%) of potassium carbonate - 14.4 g (0.0835 mole) of chloro-ethyl diethyl hydrochloride:;
amine.
By distillation, an Ebo 5 0 4 fraction is collected torr 200 - 220C
Infrared spectrum ~
- '~ C0: 1740 cm 1 ~.
- ~ C0: 1650 cm NMR spectrum:
- mass of 3 aromatic protons around 7.83 ppm - massif of 2 aromatic protons around 7.3 ppm - 1 aromatic proton around 6.53 ppm - mass of 2 CH2 protons around 4.1 ppm - peak of 5 indane protons at 3.33 ppm ~.
- massive 6 CM2 protons around 2.7 ppm - massi ~ of 6 proton9 CM3 around 1.07 ppm.
Passage to hydrochloride: C21M2 ~ ClN04 ... ..
After recrystallization from a mixture of ethyl acetate ~
.
- ethanol, we obtain a solid melting at 165 - 166.5C (tube capillary) `
Acidity index:
Calculated: 143 ..
Found: 142:.
: '. '.
,, - 20 -;
35 ~ 4: -Percentage_Analysis (chlorhvdrate):
C% H% Cl% ~ / O
Calculated 64.36 6.69 9.05 3.57 `
Found 64.44 6.49 8.98 3.53;.
Example _u 11 , ~
senzoyl-5 N (N ', N' diethylamino-2 'ethyl) indane-2 carboxamide / '= \ C 2 3H 2 4N 2 2 <~ CO ~, ~ PM = 364.47 ~ / CH2 CI12 N \
C 2H5, ~,.
In a 250 cc reactor equipped with agitation, a coolant, a dropping funnel and a thermometer, we introduced:
- 25.5 g (0.2 mole ~ 10%) of (N ', N' diethylami.no) -2 ethylamine ... .
- 50 cmJ of dioxane.
At a temperature between 10 ~ and 20C, addi-tion a solution of:
- 30.2 g (0.1 mol) of 5-benzoyl-indane-2 carbohydrate chloride - -xylic in; .
- 50 cm3 of dioxane Then let it return to ambient temperature and then turn one hour at this temperature. Concentrate dioxane under vacuum, taken up in ice water ~ e and extracted with ether in ~.:
alkaline medium. The ethereal extract is dried over sulphate, filtered.
and the concentrated filtrate. We get an oil on which we makes an oxalate. ~:
After recrystallization from an acetone-alcohol mixture, we obtain a melting point of 153 - 154C (capillary tube).
Acidity index: ~ -Calculated: 246 ~ found: 226 ',, . ~ - 21 -~ LC31 ~ 85iS ~
Infrared spectrum:
- - ~ C0: 1660 cm 1 Centesimal analysis: (C25H30N206) C% II% N ~ / o Calculated 66.07 6.65 6.17 Found 66.10 6.50 6.18 Example 12: -(2'-Thénoyl) - 5 N (N ', N' 2-diethylamino-ethyl) indane-2 ~
carboxamide ..
~ C21H26N22 C0 PM - 370.51 ~ C 2H5 Co-NEI-cH2-cII2 N \ CH ~. ~
Prepared according to example n ~ 11 from: ~.
- 9.4 g (0.03 mole) of acid chloride (2-thénoyl-2) - 5 indane-2. ~
carboxylic.
- 7,7 g ~0,066 mole) de (Nl ,N' diéthylamino)-2 éthylamine .
- 120 cm3 de dioxane.
Par passage à l'oxalate, on obtient, après recristalli- ;;~
sation dans l'acétone, un solide fondant à 110'`5 - 112"C (tube .
capillaire) .
Indice d'acidité: ~ ;
Calculé: 243 Trouvé: 2~7 :: :
Spectre infra-rouqe: :
- ~ C0: 1630 cm~l :~
Spectre R M.N.:
- massif de 6 protons aromatique vers 7,4 ppm - massif de 5 protons indane ~ 8 protons CH2 vers 3,33 ppm ......
~ _ )~) . ' '' ' . : . ' : , ' : ~
~ 3554 - triplet de 6 protons CH3 vers 1,27 ppm.
Analyse centésimale: (C23H28N2O6S) C% I-1% N~/o S%
Calcule 59,98 6,13 6,09 6,96 Trouvé 59,95 6,2O 5,9O 7,06 Exemple n~ 13 ~ y/
(Dichloro-2',5')~5 N(N',N' diéthylamino-2' éthyl) inda-ne-2 carboxamide 10Cl c23~26Cl2N2o2 ;
)~\ P.M. = 433,38 c o~/, = CO-NH- CF1 2 - C~1 2 -~
C2H5 .
Préparé selon l'exemple n 11 à partir de: ;
- 17,6 g (0,048 mole) de chlorure d'acide (dichloro-2',-5') ben-zoyl-5 indane-2 carboxyl:Lque - 13,9 g (0,12 mole) de (N',N' diéthylamino)-2 éthylamine .
20 - 80 cm3 de dioxane. .
Par passage à l'oxalate et après recristallisation dans l'acétone, on obtient un solide :Eondant à 103 - 104'-'C (tube capillaire) Inclice d'ac:Ldité:
Calcul~: 216 Trouvé: 206 Spectre infra-rouqe:
- ~ C0: 1670 cm~l ;
Spectre R.M.N.:
- massi:f de 6 protons aromatiques centré vers 7,46 ppm .
- massif de 5 protons indane + 8 protons CH2 vers 3,43 ppm : .
- triplet de 6 protons CH3 vers 1,33 ppm :'~
-2.3-5S9~
- 1 proton N~I vers 8,3 ppm AnalYse centésimale: (C 5H 8Cl N 6) C% ~1% MD/o C1%
Calcul~ 57,37 5,39 5,35 13,55 Trouvé 57,38 5,48 5,39 13,56 L'activité pharmacologique anti-inflammatoire, analgé-sique et antigrégante plaquettaire des ~omposés selon l'invention a été démontrée sur l'animal.
A. Les produits sont en général peu toxiques, la DL S0 est déterminée chez la souris.
B. L'activité analgésique a été déterminée chez la souris par la méthode de KOSTER et Col. (Fed. Proc. 1959, 18, 412)~ On cherche la dose active 50 du produit qui administré PO
diminue de 50% les contractions douloureuses provoquées par l'in-jection intrapéritonéale d'une solution d'acide acétique.
C. L'activité anti-inflammatoire a été montrée par le test à l'oed~me à la carragénine selon WINTER et Col. (Proc. ~xp.
Biol. Med. 111, 544-47). On recherche la protection que confère le traitement par le produit administré PO au rat, vis à vis d'un oedeme déclenché par injection sous la voûte plantaire d'une sus-pen~ion de carragénine. La dose active DA 30 e~t celle qui inhi-be 30% de l'oedème.
D~ L'activit~ protectrice Vi9 ~ ViS de l'inflammation pr~coce a ~té determinée sur le cobaye albinos selon la méthode de WINTER et Col. (Arch. Inv. Pharmacodyn. 1958. 116 261). On recherche la DA 50 du produit qui, administré PO à l'animal, di-minue de 50% l'érythème produit par l'exposition à un rayonne-ment ultra-violet de la surface dorsale épilée du cobaye.
E. L'efficacité anti-agrégante plaquettaire est déter-minée "in vitro" par agrégation provoquée au collagène selon laméthode de BOR~.
Les résultats sont consignés dans le tableau suivant.
~(~885~i~
.
Les doses actives sont exprimées en mg/kg, à l'exception de l'a-grégation plaquettaire où il s'agit de la concentration minima -active en ~/ml.
. _ -- - --- :, Acide Carragé- U.V.Agrégation DL 50 Acétique nine DA. 50 au DA. 50DA. 30 collagène -~
__ _ :, Acide ~(mé-thyl-3' thénoyl)-2'~-5 in- 1200 37 26 25 10 ,-dane-2 carboxylique -... _ .. _ , _ . . ---10 Acide ~méthyl-5' furoyl)-2'7-5 in- 2400 8 10 16 1 ;
dane-2 carboxy-que .. ... ____ . . ... ~ :' "
Acide ,~para dimé- -thylamino benzoy~,7- 960 3 14 20 O,5 5 indane carboxyli-que _ ._ . ._ . . .
Acide (para méthyl sulfonyl benzoyl)- 2800 1 35 40 10 ¦ 1 5 indane-2 carbo- l 20 xyllque ' ~;
Acide (para sul-famido benzoyl)-~ 3200 25 43 90 ~ 5 5 indane-2 car-boxylique . . _ I . .. .
Acide (paradimé-thylamino sulEo- 2600 80 1~0 ;~300 10 nyl benzoyl)-5 indane-2 carbo-xylique , , _ . ---- :
30 ~tacétamido-4' chloro-3') ben- 3200 35 60 80 5 æoyl,7-S indane-2 carboxylate d'ethyle .... __ .
Acide ~(dichlo-ro-4',5' thénoyl) 180 30 42 90 7,5 -2~7-5 indane-2 carboxylique _ __ - __ '' ' ' :. ' ', :' ,~ ~o~æ5s4 DL 50 ¦Acide Carragé- U.V. IAgrégation Acétique nine DA. 50 au ~;
DA. 50 DA. 30 collagène ~
- ~ :
(Thénoyl-2')-5 lndane-2 carbo- 2160 4 8 101 0,25 xylate de N,N
diéthylamino-2 ¦
éthyle, chlorhy-drate I ~--- ! `
10 ~uroyl-2')-5 in- I ~ -dane-2 carboxy- 1200 8 18 20! 1 ::~
late de N,N dié-thylamino-2 é-thyle, chlorhy-drate - - ..... _ __ _ .
Benzoyl-5 N-(N'N' diéthylamino-2' 1100 30 9 25 ~ 2,5 éthyl) indane-2 i carboxamide, oxa-late _ _ (Thénoyl-2')-5 N-(N'N'-diéthylamino 660 2,5 8 10 ~ 0,25 -2' éthyl) indane-2 carboxamide, oxalate , ~
_ ., _ , :
(Dichloro-2',5' benzoyl)-5N(N'N' 720 15 25 50 2,5 diéthylamino-2' é-thyl) indane-2 ~ ; ;
carboxamide, I i oxalate . ............... __ __ . .. __ ___.~
(Diméthylamino-4' 1450 2,5 12 24 0,25 benzoyl)-5 indane l carboxylate cle mé- !
thyle l _. _ _ . .. .... _ I _.___ . .. -- -- , .
Les compositions thérapeutiques contenant comme princi-pe acti~ au moins un composé selon la présente invention e-t un ~-support ou diluant pharmaceutique solide ou liquide, peuvent être sous forme de comprimés, de solutions injectables, suppositoires et analogues.
.. : .
~ ' "
' . , . . ~ . : ..
~ i gL~8~$S4~
Exemples de formulatlon Principe actif 200 mg Exc_pients Lactose 30 mg Amidon de blé 29 mg Talc 10 mg Gélatine 5 mg Acide alginique 20 mg écule 5 mg ~-Stéarate de magnésium 1 mg Pour un comprimé de 300 mg Les compositions thérapeutiques contenant comme princi~
pe actif, un dérivé de l'indane selon la présente invention, sont efficaces en tant qu'anti-inflammatoires, antalgique et anti-agrégante plaquettaire, à des doses comprises entre 50 et 500 mg par dose unitaire. La posologie pouvant être réglée pour obtenir la réponse =hérapeutique optimale. ~ ;
. ' .' ~ - 27 -, . . ~ - 7.7 g ~ 0.066 mol) of (Nl, N 'diethylamino) -2 ethylamine.
- 120 cm3 of dioxane.
By passage to the oxalate, one obtains, after recrystalli- ;; ~
sation in acetone, a solid melting at 110'5 - 112 "C (tube.
capillary) .
Acidity index: ~;
Calculated: 243 Found: 2 ~ 7 :::
Infrared spectrum::
- ~ C0: 1630 cm ~ l: ~
R MN spectrum:
- range of 6 aromatic protons around 7.4 ppm - mass of 5 indan protons ~ 8 CH2 protons around 3.33 ppm ......
~ _) ~). '''' '. :. ':,': ~
~ 3554 - triplet of 6 CH3 protons around 1.27 ppm.
Centesimal analysis: (C23H28N2O6S) C% I-1% N ~ / o S%
Calculate 59.98 6.13 6.09 6.96 Found 59.95 6.2O 5.9O 7.06 Example n ~ 13 ~ y /
(Dichloro-2 ', 5') ~ 5 N (N ', N' diethylamino-2 'ethyl) inda-ne-2 carboxamide 10Cl c23 ~ 26Cl2N2o2;
) ~ \ PM = 433.38 co ~ /, = CO-NH- CF1 2 - C ~ 1 2 - ~
C2H5.
Prepared according to Example No. 11 from:;
- 17.6 g (0.048 mole) of acid chloride (dichloro-2 ', - 5') ben-zoyl-5 indane-2 carboxyl: Lque - 13.9 g (0.12 mole) of (N ', N' diethylamino) -2 ethylamine.
20 - 80 cm3 of dioxane. .
By switching to oxalate and after recrystallization in acetone, a solid is obtained: Eondant at 103 - 104 '-' C (tube capillary) Inclice of ac: Credit:
Calculation ~: 216 Found: 206 Infrared spectrum:
- ~ C0: 1670 cm ~ l;
NMR spectrum:
- massi: f of 6 aromatic protons centered around 7.46 ppm.
- solid mass of 5 indane protons + 8 CH2 protons around 3.43 ppm:.
- triplet of 6 CH3 protons around 1.33 ppm : '~
-2.3-5S9 ~
- 1 proton N ~ I around 8.3 ppm Centesimal analysis: (C 5H 8Cl N 6) C% ~ 1% MD / o C1%
Calculation ~ 57.37 5.39 5.35 13.55 Found 57.38 5.48 5.39 13.56 Anti-inflammatory, analgesic pharmacological activity sique and anti-aggregation platelet ~ omposés according to the invention has been demonstrated on the animal.
A. The products are generally not very toxic, the DL S0 is determined in mice.
B. The analgesic activity was determined in the mice by the method of KOSTER and Col. (Fed. Proc. 1959, 18, 412) ~ We are looking for the active dose 50 of the product which administered PO
decreases by 50% the painful contractions caused by intraperitoneal injection of an acetic acid solution.
C. Anti-inflammatory activity has been shown by oed ~ me test with carrageenan according to WINTER and Col. (Proc. ~ Xp.
Biol. Med. 111, 544-47). We are looking for the protection that treatment with the product administered PO to the rat, with respect to a edema triggered by injection under the arch of a sus-pen ~ ion of carrageenan. The active dose DA 30 is that which inhi-be 30% of edema.
D ~ Activity ~ protective Vi9 ~ ViS of inflammation pr ~ coce was ~ determined on the albino guinea pig according to the method by WINTER et Col. (Arch. Inv. Pharmacodyn. 1958. 116 261). We looks for the DA 50 of the product which, administered PO to the animal, 50% reduction in erythema produced by exposure to a ultra-violet color of the guinea pig's shaved dorsal surface.
E. The anti-platelet aggregation efficacy is deter-mined "in vitro" by aggregation caused by collagen according to the BOR ~ method.
The results are recorded in the following table.
~ (~ 885 ~ i ~
.
The active doses are expressed in mg / kg, with the exception of the a-platelet aggregation where it is the minimum concentration -active in ~ / ml.
. _ - - ---:, Acid Tile - UV aggregation DL 50 Acetic nine DA. 50 to DA. 50DA. 30 collagen - ~
__ _:, Acid ~ (mes-thyl-3 ' thenoyl) -2 '~ -5 in- 1200 37 26 25 10, -dane-2 carboxylic -... _ .. _, _. . ---10 Acid ~ methyl-5 ' furoyl) -2'7-5 in- 2400 8 10 16 1;
dane-2 carboxy-than .. ... ____. . ... ~: '"
Acid, ~ para dima- -thylamino benzoy ~, 7- 960 3 14 20 O, 5 5 indane carboxyli-than _ ._. ._. . .
Acid (para methyl sulfonyl benzoyl) - 2800 1 35 40 10 ¦ 1 5 indane-2 carbon 20 xyllque '~;
Acid (para sul-famido benzoyl) - ~ 3200 25 43 90 ~ 5 5 indane-2 car-boxylic . . _ I. ...
Acid (paradimi-thylamino sulEo- 2600 80 1 ~ 0; ~ 300 10 nyl benzoyl) -5 indane-2 carbo-xylic,, _. ----:
30 ~ tacetamido-4 ' chloro-3 ') ben- 3200 35 60 80 5 æoyl, 7-S indane-2 carboxylate of ethyl .... __.
Acid ~ (dichlo-ro-4 ', 5' thénoyl) 180 30 42 90 7.5 -2 ~ 7-5 indane-2 carboxylic _ __ - __ '''':.'',:' , ~ ~ o ~ æ5s4 DL 50 agéAcid Tile- UV IAgregation Acetic nine DA. 50 to ~;
DA. 50 DA. 30 collagen ~
- ~:
(Thénoyl-2 ') - 5 lndane-2 carbo- 2160 4 8 101 0.25 N, N xylate diethylamino-2 ¦
ethyl, chlorhy-drate I ~ --! ``
10 ~ uroyl-2 ') - 5 in I ~ -dane-2 carboxy- 1200 8 18 20! 1 :: ~
late de N, N dié-thylamino-2 é-thyle, chlorhy-drate - - ..... _ __ _.
Benzoyl-5 N- (N'N ' diethylamino-2 '1100 30 9 25 ~ 2.5 ethyl) indan-2 i carboxamide, oxa-late _ _ (Thénoyl-2 ') - 5 N-(N'N'-diethylamino 660 2.5 8 10 ~ 0.25 -2 'ethyl) indane-2 carboxamide, oxalate, ~
_., _,:
(Dichloro-2 ', 5' benzoyl) -5N (N'N '720 15 25 50 2.5 diethylamino-2 'é-thyl) indane-2 ~; ;
carboxamide, I i oxalate . ............... __ __. .. __ ___. ~
(Dimethylamino-4 '1450 2.5 12 24 0.25 benzoyl) -5 indane l key carboxylate!
thyle l _. _ _. .. .... _ I _.___. .. - -,.
Therapeutic compositions containing as principal pe acti ~ at least one compound according to the present invention and one ~ -solid or liquid pharmaceutical carrier or diluent, can be in the form of tablets, injectables, suppositories and the like.
..:.
~ '"
'' . ,. . ~. : ..
~ i gL ~ 8 ~ $ S4 ~
Examples of formulations Active ingredient 200 mg Exc_pients Lactose 30 mg Wheat starch 29 mg Talc 10 mg Gelatin 5 mg Alginic acid 20 mg used up 5 mg ~ -Magnesium stearate 1 mg For one 300 mg tablet Therapeutic compositions containing as princi ~
active pe, an indane derivative according to the present invention, are effective as anti-inflammatory, analgesic and anti aggregating platelet, at doses between 50 and 500 mg per unit dose. The dosage can be adjusted to obtain the answer = optimal therapeutic. ~;
. '' . ' ~ - 27 -, . . ~
Claims (40)
ou substitué par au moins un substituant choisi parmi les halo-gènes et un radical alkyle inférieur ou un radical furyl non substitué ou substitué par un radical alkyl; sous forme libre de sels, d'esters; d'aminoesters ou de carboxamides caractérisé
en ce que:
a) on fait réagir selon la réaction de Friedel et Crafts un composé représenté par la formule:
(II) dans laquelle R1 représente un groupe alkyl inférieur, avec un halogène d'aroyle de formule:
R - COX (III) dans laquelle R a la signification précédemment citée et X
représente un halogène, le composé obtenu étant ensuite soumis à une hydrolyse alcaline: ou b) quand R est un radical phényle substitue par un radical sulfamido ou diméthylsulfamido, l'on soumet un composé de formule dans laquelle R est un radical phényle substitué par un radical amino et R' a la même signification que précédemment à une diazotation, puis on traite le sel d'aryldiazonium obtenu par une solution d'anhydride sulfureux dans l'acide acétique en présence d'un sel de cuivre et l'on soumet le composé obtenu dans la formule duquel R est un radical chlorosulfonylphényle à un traitement par l'ammoniac ou la diméthylamine, suivi d'une hydrolyse alcaline, ou c) quand R est un radical diméthylaminophényle l'on fait réagir le formaldéhyde en présence d'hydrogène et d'un catalyseur d'hydrogénation ou un halogénure d'alkyle dans un solvant, sur un composé de formule dans laquelle R est un radical phényle substitué par un radical amino et R' a la même signification que précédemment, éventuelle-ment suivi. d'une hydrolyse alcaline, ou d) R est un radical substitué par au moins un halogène qu'on traite par un halogène en solution dans l'acide acétique un composé de formule dans laquelle R est un radical phényle, thiényle ou furyle mono-substitué et R' a la même signification que précédemment, ou e) pour la préparation des aminoesters des acides dérivés de l'indane représentés par les esters dialkyl inférieurs aminoalkyl inférieurs, l'on condense à la température du reflux un acide dérivé de l'indane tel que défini ci-dessus dans la formule duquel R est un radical thiényle ou furyle, avec un halogénoalkyl dialkylamine en milieu solvant alcoolique, ou f) pour la préparation des carboxamides des acides carboxyliques dérivés de l'indane représentés par les amides alkyl inférieurs aminoalkyl inférieurs l'on condense à température comprise entre t 10° et + 20°C un chlorure d'acide dérivé de l'in-dane tel que défini ci-dessus, dans la formule duquel R est un radical phényle éventuellement substitué par deux halogènes ou un radical thiényle, avec une dialkylamino alkylamine. 1. Process for the preparation of indane derivatives represented smelled by the formula (I) in which R is an unsubstituted or substituted phenyl radical killed by at least one substituent chosen from halogens and acetamido, dialkylamino, alkylsulfonyl, dialkyl-aminosulfonyl and sulfamido; an unsubstituted thienyl radical or substituted by at least one substituent chosen from halo-genes and a lower alkyl radical or a non furyl radical substituted or substituted by an alkyl radical; in free form salts, esters; amino esters or carboxamides characterized in that:
a) reacting according to the Friedel reaction and Crafts a compound represented by the formula:
(II) in which R1 represents a lower alkyl group, with a aroyl halogen of formula:
R - COX (III) in which R has the aforementioned meaning and X
represents a halogen, the compound obtained then being subjected to alkaline hydrolysis: or b) when R is a phenyl radical substituted by a sulfamido or dimethylsulfamido radical, a compound of formula in which R is a phenyl radical substituted by a radical amino and R 'has the same meaning as before at a diazotization, and then the aryldiazonium salt obtained is treated with a sulfur dioxide solution in acetic acid in the presence of a copper salt and the compound obtained is subjected to the formula of which R is a chlorosulfonylphenyl radical at a treatment with ammonia or dimethylamine, followed by alkaline hydrolysis, or c) when R is a dimethylaminophenyl radical, it is reacts formaldehyde in the presence of hydrogen and a hydrogenation catalyst or an alkyl halide in a solvent, on a compound of formula in which R is a phenyl radical substituted by a radical amino and R 'has the same meaning as before, possibly-ment followed. alkaline hydrolysis, or d) R is a radical substituted by at least one halogen which is treated with a halogen in solution in acetic acid a compound of formula in which R is a phenyl, thienyl or furyl radical mono-substituted and R 'has the same meaning as before, or e) for the preparation of aminoesters of acids indane derivatives represented by lower dialkyl esters lower aminoalkyl, condensed at reflux temperature an acid derived from indane as defined above in the formula of which R is a thienyl or furyl radical, with a haloalkyl dialkylamine in an alcoholic solvent medium, or f) for the preparation of acid carboxamides indane-derived carboxyls represented by alkyl amides lower aminoalkyl lower condensed at temperature between t 10 ° and + 20 ° C an acid chloride derived from in-dane as defined above, in the formula of which R is a phenyl radical optionally substituted by two halogens or a thienyl radical, with a dialkylamino alkylamine.
en ce que l'on soumet un composé de formule dans laquelle R est un radical phényle substitué par un radical amino et R' a la même signification que précédemment à une dia-zotation, puis on traite le sel d'aryldiazonium obtenu par une solution d'anhydride sulfureux dans l'acide acétique en présence d'un sel de cuivre et l'on soumet le composé obtenu dans la for-mule duquel R est un radical chlorosulfonylphényle à un traite-ment par l'ammoniac ou la diméthylamine, suivi d'une hydrolyse alcaline. 3. Process for the preparation of the compounds of formula I se-lon claim 1 when R is a phenyl radical substituted killed by a characterized sulfamido or dimethylsulfamido radical in that we submit a compound of formula in which R is a phenyl radical substituted by a radical amino and R 'has the same meaning as before at a di-zotation, then the aryldiazonium salt obtained is treated with a sulfur dioxide solution in acetic acid in the presence of a copper salt and the compound obtained is subjected in the form mule of which R is a chlorosulfonylphenyl radical with a treatment with ammonia or dimethylamine, followed by hydrolysis alkaline.
de formule dans laquelle R est un radical phényle, thiényle ou furyle mo-nosubstitué et R' a la même signification que précédemment. 5. Process for the preparation of the esters of the compounds of formula I according to claim 1 when R is a subs- radical constituted by at least one halogen, characterized in that one treats by a halogen in solution in acetic acid a compound of formula in which R is a phenyl, thienyl or furyl radical nosubstituted and R 'has the same meaning as before.
la température du reflux un acide dérivé de l'indane, dans la formule duquel R est un radical thiényle ou furyle, avec un halogénoalkyl dialkylamine en milieu solvant alcoolique. 6. Process for the preparation of aminoesters of acids indane-derived carboxylates of formula I according to the res-dication 1, represented by lower dialkyl esters lower aminoalkyl, characterized in that it condenses the reflux temperature an acid derived from indane, in the formula of which R is a thienyl or furyl radical, with a haloalkyl dialkylamine in alcoholic solvent medium.
une hydrolyse alcaline pour donner l'acide [(méthyl-3' thénoyl)-2']-5 indane-2 carboxylique. 8. Method according to claim 2, characterized in that that we react methyl indan-2 carboxylate with 3-methylthiophene-2 carboxylic acid chloride according to the Friedel and Crafts reaction, thus obtaining the [(methyl-3 ' thienyl) -2 '] - 5 indane-2 methyl carboxylate, which is subjected to an alkaline hydrolysis to give the acid [(methyl-3 'thénoyl) -2 '] - 5 indan-2 carboxylic.
ou substitué par au moins un substituant choisi parmi les halo-gènes et un radical alkyle inférieur ou un radical furyl non substitué ou substitué par un radical alkyle sous forme libre, de sels, d'esters, d'aminoesters ou de carboxamides, tels qu'ob-tenus par un procédé selon la revendication 1 ou ses équivalents chimiques manifestes. 22. Indane derivatives represented by the formula in which R is an unsubstituted or subsphenyl radical with at least one substituent chosen from halogens and the radicals acetamido, dialkylamino, alkylsulfonyl, dialkyl-aminosulfonyl and sulfamido, an unsubstituted thienyl radical or substituted by at least one substituent chosen from halo-genes and a lower alkyl radical or a non furyl radical substituted or substituted by an alkyl radical in free form, salts, esters, aminoesters or carboxamides, such as ob-held by a method according to claim 1 or its equivalents manifest chemicals.
selon la revendication 19 ou ses équivalents chimiques manifestss. 38. Benzoyl-5 N (N ', N' diethylamino-2 'ethyl) indane-2 carboxamide and its oxalate as obtained by a process according to claim 19 or its chemical equivalent manifestss.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7637574A FR2374032A2 (en) | 1976-12-14 | 1976-12-14 | NEW CARBOXYLIC ACIDS DERIVED FROM INDANE |
| FR76.37754 | 1976-12-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088554A true CA1088554A (en) | 1980-10-28 |
Family
ID=9181028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA293,076A Expired CA1088554A (en) | 1976-12-14 | 1977-12-14 | Preparation of 5-substituted indane-2 carboxylic acid and derivatives |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5373548A (en) |
| AT (1) | AT355559B (en) |
| AU (1) | AU515268B2 (en) |
| BE (1) | BE861826R (en) |
| CA (1) | CA1088554A (en) |
| CH (1) | CH627728A5 (en) |
| DD (1) | DD133323A6 (en) |
| DE (1) | DE2753315A1 (en) |
| DK (1) | DK144640C (en) |
| ES (1) | ES465056A2 (en) |
| FR (1) | FR2374032A2 (en) |
| GB (1) | GB1584298A (en) |
| HU (1) | HU177226B (en) |
| IE (1) | IE46013B1 (en) |
| IL (2) | IL60599A0 (en) |
| MX (1) | MX4954E (en) |
| NL (1) | NL7713876A (en) |
| NO (1) | NO774285L (en) |
| SE (1) | SE436740B (en) |
| SU (1) | SU799646A3 (en) |
| ZA (1) | ZA777438B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2801182A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4980053A (en) * | 1972-12-05 | 1974-08-02 | ||
| JPS5838416B2 (en) * | 1974-05-31 | 1983-08-23 | 武田薬品工業株式会社 | Kanjiyoukagobutsunoseizouhou |
| JPS5335944B2 (en) * | 1974-05-21 | 1978-09-29 |
-
1976
- 1976-12-14 FR FR7637574A patent/FR2374032A2/en active Granted
-
1977
- 1977-11-30 DE DE19772753315 patent/DE2753315A1/en not_active Ceased
- 1977-12-12 GB GB51699/77A patent/GB1584298A/en not_active Expired
- 1977-12-13 SE SE7714110A patent/SE436740B/en unknown
- 1977-12-13 MX MX776686U patent/MX4954E/en unknown
- 1977-12-13 DD DD7700202588A patent/DD133323A6/en unknown
- 1977-12-13 DK DK554677A patent/DK144640C/en not_active IP Right Cessation
- 1977-12-13 NO NO774285A patent/NO774285L/en unknown
- 1977-12-13 IE IE2520/77A patent/IE46013B1/en unknown
- 1977-12-13 HU HU77LI316A patent/HU177226B/en unknown
- 1977-12-14 AT AT892577A patent/AT355559B/en not_active IP Right Cessation
- 1977-12-14 ZA ZA00777438A patent/ZA777438B/en unknown
- 1977-12-14 CH CH1541077A patent/CH627728A5/en not_active IP Right Cessation
- 1977-12-14 ES ES465056A patent/ES465056A2/en not_active Expired
- 1977-12-14 BE BE183429A patent/BE861826R/en not_active IP Right Cessation
- 1977-12-14 AU AU31530/77A patent/AU515268B2/en not_active Expired
- 1977-12-14 CA CA293,076A patent/CA1088554A/en not_active Expired
- 1977-12-14 JP JP14943377A patent/JPS5373548A/en active Pending
- 1977-12-14 NL NL7713876A patent/NL7713876A/en not_active Application Discontinuation
-
1979
- 1979-04-06 SU SU792746906A patent/SU799646A3/en active
-
1980
- 1980-07-15 IL IL60599A patent/IL60599A0/en unknown
- 1980-07-15 IL IL60598A patent/IL60598A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2753315A1 (en) | 1978-06-15 |
| DK554677A (en) | 1978-06-15 |
| NO774285L (en) | 1978-06-15 |
| AT355559B (en) | 1980-03-10 |
| FR2374032A2 (en) | 1978-07-13 |
| IL60598A0 (en) | 1980-09-16 |
| MX4954E (en) | 1983-01-13 |
| GB1584298A (en) | 1981-02-11 |
| DD133323A6 (en) | 1978-12-27 |
| BE861826R (en) | 1978-06-14 |
| DK144640B (en) | 1982-04-26 |
| IL60599A0 (en) | 1980-09-16 |
| ZA777438B (en) | 1979-05-30 |
| DK144640C (en) | 1982-10-04 |
| JPS5373548A (en) | 1978-06-30 |
| SE7714110L (en) | 1978-06-15 |
| IE46013L (en) | 1978-06-14 |
| SE436740B (en) | 1985-01-21 |
| AU515268B2 (en) | 1981-03-26 |
| SU799646A3 (en) | 1981-01-23 |
| CH627728A5 (en) | 1982-01-29 |
| AU3153077A (en) | 1979-06-21 |
| IE46013B1 (en) | 1983-01-26 |
| NL7713876A (en) | 1978-06-16 |
| HU177226B (en) | 1981-08-28 |
| ATA892577A (en) | 1979-08-15 |
| ES465056A2 (en) | 1979-01-16 |
| FR2374032B2 (en) | 1979-03-30 |
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