NO790648L - PROCEDURE FOR THE PREPARATION OF CYCLOALKYL-ALKYLBENZAMIDES - Google Patents
PROCEDURE FOR THE PREPARATION OF CYCLOALKYL-ALKYLBENZAMIDESInfo
- Publication number
- NO790648L NO790648L NO790648A NO790648A NO790648L NO 790648 L NO790648 L NO 790648L NO 790648 A NO790648 A NO 790648A NO 790648 A NO790648 A NO 790648A NO 790648 L NO790648 L NO 790648L
- Authority
- NO
- Norway
- Prior art keywords
- mol
- methoxy
- acetone
- formula
- benzoic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- -1 2-methoxy-5-substituted benzoic acid Chemical class 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- QFIYFROFRTUSPW-UHFFFAOYSA-N [1-(cyclopropylmethyl)pyrrolidin-2-yl]methanamine Chemical compound NCC1CCCN1CC1CC1 QFIYFROFRTUSPW-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IUTPSVNWIWQIDX-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)pyrazol-4-yl]ethanone Chemical compound C1=C(C(=O)C)C=NN1C1=CC=C(Cl)C=C1 IUTPSVNWIWQIDX-UHFFFAOYSA-N 0.000 description 2
- NAKZCKOHULJEID-UHFFFAOYSA-N 2-methoxy-5-(trifluoromethyl)benzoic acid Chemical compound COC1=CC=C(C(F)(F)F)C=C1C(O)=O NAKZCKOHULJEID-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VOQPCMLSRLWUEQ-UHFFFAOYSA-N 2-methoxy-3-(trifluoromethyl)benzoyl chloride Chemical compound COC1=C(C(Cl)=O)C=CC=C1C(F)(F)F VOQPCMLSRLWUEQ-UHFFFAOYSA-N 0.000 description 1
- KZZUPJSYJCNYMW-UHFFFAOYSA-N 2-methoxy-5-methylbenzenecarbothioyl chloride Chemical compound COC1=CC=C(C)C=C1C(Cl)=S KZZUPJSYJCNYMW-UHFFFAOYSA-N 0.000 description 1
- MNWSGMTUGXNYHJ-UHFFFAOYSA-N 2-methoxybenzamide Chemical class COC1=CC=CC=C1C(N)=O MNWSGMTUGXNYHJ-UHFFFAOYSA-N 0.000 description 1
- OUBZCDOQEMLMAB-UHFFFAOYSA-N 5-chlorosulfonyl-2-methoxybenzoic acid Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1C(O)=O OUBZCDOQEMLMAB-UHFFFAOYSA-N 0.000 description 1
- WBRILLISQMMNMD-UHFFFAOYSA-N 5-ethyl-2-methoxybenzenecarbothioyl chloride Chemical compound COC1=C(C(=S)Cl)C=C(C=C1)CC WBRILLISQMMNMD-UHFFFAOYSA-N 0.000 description 1
- BOLLTSUCKRNILK-UHFFFAOYSA-N COC1=C(C(=S)O)C=C(C=C1)CC Chemical compound COC1=C(C(=S)O)C=C(C=C1)CC BOLLTSUCKRNILK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- BZKGHSWMKGRQMK-UHFFFAOYSA-N N-[[1-(cyclopropylmethyl)pyrrolidin-2-yl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide Chemical compound C1(CC1)CN1C(CCC1)CNC(C1=C(C=CC(=C1)C(F)(F)F)OC)=O BZKGHSWMKGRQMK-UHFFFAOYSA-N 0.000 description 1
- 208000012545 Psychophysiologic disease Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-M ethyl sulfate Chemical compound CCOS([O-])(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-M 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- AQZWYQHLYWDFEO-UHFFFAOYSA-N n-[[1-(cyclopropylmethyl)pyrrolidin-2-yl]methyl]-2-methoxy-5-methylbenzenecarbothioamide Chemical compound COC1=CC=C(C)C=C1C(=S)NCC1N(CC2CC2)CCC1 AQZWYQHLYWDFEO-UHFFFAOYSA-N 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
Description
Fremgangsmåte for fremstilling av cykloalkyl-alkylbenzamider. Process for the preparation of cycloalkyl-alkylbenzamides.
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av 2-metoksy-benzamider i form av racemater eller enantiomerer samt farmasoytisk tålbare syreaddisjonssalter derav, med den generelle formel (I) The present invention relates to a process for the production of 2-methoxybenzamides in the form of racemates or enantiomers as well as pharmaceutically acceptable acid addition salts thereof, with the general formula (I)
hvori in which
n og m uavhengig av hverandre hver er et tall enten 1, 2, 3 eller 4, og n and m independently each is a number either 1, 2, 3 or 4, and
R er CF-j eller alkyltio hvor alkyl er rett eller forgrenet medR is CF-j or alkylthio where alkyl is straight or branched with
1 til 6 karbonatomer, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at en 2-metoksy-5-substituert benzosyre (II) eller et av dens funksjonelle derivater (halogenid, ester) kondenseres med db pyrrolidin i form av racemat eller enantiomer, med formel (III) 1 to 6 carbon atoms, and the peculiarity of the method according to the invention is that a 2-methoxy-5-substituted benzoic acid (II) or one of its functional derivatives (halide, ester) is condensed with db pyrrolidine in the form of a racemate or enantiomer, with formula (III)
og forbindelser med formel (I) overfores eventuelt i sine syreaddisj onssalter. and compounds of formula (I) are optionally transferred in their acid addition salts.
Forbindelsene har en innvirkning på sentralnervesystemet. The compounds have an impact on the central nervous system.
2-metoksy-5-trifluormetyl-benzosyren er tidligere beskrevet i litteraturen. The 2-methoxy-5-trifluoromethyl-benzoic acid has previously been described in the literature.
2-metoksy-5-alkyltio-benzosyrene (II) og deres klorider fremstilles ved hjelp av det folgende reaksjonsskjema: The 2-methoxy-5-alkylthio-benzoic acids (II) and their chlorides are prepared using the following reaction scheme:
Cykloalkylalkyl-pyrrolidinene (III) er kjente forbindelser og kan fremstilles ved hjelp av kjente metoder. The cycloalkylalkylpyrrolidines (III) are known compounds and can be prepared using known methods.
Kondensasjonen ved fremgangsmåten i henhold til oppfinnelsen gjennomfores fordelaktig ved en temperatur på 0 til 30°C i et løsningsmiddel som aceton. The condensation in the method according to the invention is advantageously carried out at a temperature of 0 to 30°C in a solvent such as acetone.
De etterfolgende eksempler illustrerer oppfinnelsen. Analyser og spektra IR og RMN bekrefter strukturen av forbindelsene. The following examples illustrate the invention. Analyzes and spectra IR and RMN confirm the structure of the compounds.
Eksempel 1 N-/"(l-cyklopropylmetyl-2-pyrrolidinyl )metyl/-2-metoksy-5-metyltio-benzamid og dets hydroklorid. Example 1 N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylthiobenzamide and its hydrochloride.
1. 2- metoksy- 5- klorsulfonyl^- benzosyre.1. 2- methoxy- 5- chlorosulfonyl^- benzoic acid.
I en trehalskolbe med roreverk og kjoleoppsats innfores 44 ml (0,506 mol) klorsulfonsyre og blandingen avkjoles til 5°C. 44 ml (0.506 mol) of chlorosulfonic acid are introduced into a wooden-necked flask with a stirrer and a neck attachment and the mixture is cooled to 5°C.
Det tilsettes så i små porsjoner 20 g 2-metoksy-5-benzosyre med en hastighet slik at temperaturen holdes mellom 10 og 15°C. Etter avsluttet tilsetning får reaksjonsblandingen anta romtemperatur som holdes i 1 time. Temperaturen bringes deretter gradvis til 60 - 70°C og holdes der i 1 time tilsvarende avsluttet gassutvikling. Blandingen avkjoles og den brune væske helles ut i en blanding av 60 ml vann og 2 50 g is. Det dannes et faststoff som frafiltreres og vaskes flere ganger med isblandet vann og torkes deretter under vakuum ved 80°C. 20 g of 2-methoxy-5-benzoic acid are then added in small portions at a rate such that the temperature is kept between 10 and 15°C. After the addition is complete, the reaction mixture is allowed to reach room temperature, which is maintained for 1 hour. The temperature is then gradually brought to 60 - 70°C and held there for 1 hour corresponding to the end of gas development. The mixture is cooled and the brown liquid is poured into a mixture of 60 ml of water and 250 g of ice. A solid is formed which is filtered off and washed several times with ice-cold water and then dried under vacuum at 80°C.
Smp. = 143 - 145°C. Temp. = 143 - 145°C.
2. Ditio- bis-( 4- metoksy- 3- benzosyre).2. Dithio-bis-(4-methoxy-3-benzoic acid).
I en reaktor utstyrt med mekanisk roreverk innfores 100 g100 g are introduced into a reactor equipped with mechanical stirring
(0,4 mol) 2-metoksy-5-klorsulfonyl-benzosyre, 750 ml etanol og 500 ml konsentrert 12N saltsyre. (0.4 mol) 2-methoxy-5-chlorosulfonyl-benzoic acid, 750 ml of ethanol and 500 ml of concentrated 12N hydrochloric acid.
Til suspensjonen som omrores kraftig tilsettes i porsjoner 130,8 g zinkpulver (2 mol) i lopet av omtrent 2 timer slik at temperaturen holdes ved 15 - 20°C og reaksjonsblandingen avkjoles om nodVendig med et isblandet vannbad. To the suspension, which is stirred vigorously, 130.8 g of zinc powder (2 mol) are added in portions over the course of approximately 2 hours so that the temperature is maintained at 15 - 20°C and the reaction mixture is cooled if necessary with an ice-mixed water bath.
Etter denne operasjon filtreres blandingen. Til filtratet tilsettes vann og under omroring 70 g ferriklorid. Omroringen fortsettes i 1 time hvoretter det utfelte produkt frafiltreres og vaskes tre ganger med vann. Produktet renses ved opplosning i en opplosning av natriumbikarbonat i nærvær av aktivkull, uopploselig substans fjernes ved filtrering og filtratet surgjores ved hjelp av saltsyre i overskudd, og det resulterende bunnfall filtreres og vaskes tre ganger med vann og torkes deretter. After this operation, the mixture is filtered. Water and, with stirring, 70 g of ferric chloride are added to the filtrate. Stirring is continued for 1 hour, after which the precipitated product is filtered off and washed three times with water. The product is purified by dissolving in a solution of sodium bicarbonate in the presence of activated carbon, insoluble matter is removed by filtration and the filtrate is acidified with excess hydrochloric acid, and the resulting precipitate is filtered and washed three times with water and then dried.
Etter omkrystallisering fra eddiksyre, vasksing med eter og torking i 8 timer ved 80°C under vakuum oppnås den ovennevnte forbindelse. After recrystallization from acetic acid, washing with ether and drying for 8 hours at 80°C under vacuum, the above-mentioned compound is obtained.
Smp. = 212 - 212,5°C. Temp. = 212 - 212.5°C.
3. 2- metoksy- 5- metyltio- benzosyre og dets klorid.3. 2-Methoxy-5-methylthio-benzoic acid and its chloride.
I en reaktor innfores 50 g (0,136 mol) ditio-bis-(4-metoksy-3-banzosyre) og det tilsettes en losning av 27,3 g (0,682 mol) av NaOH i lal vann. 50 g (0.136 mol) of dithio-bis-(4-methoxy-3-benzoic acid) are introduced into a reactor and a solution of 27.3 g (0.682 mol) of NaOH in pale water is added.
Til den resulterende opplosning tilsettes dråpevis 34,8 g (0,275 mol) metylsulfat. Det omrores i 4 timer hvoretter det ekstraheres med eter. Den vandige fase isoleres og surgjores og den resulterende olje ekstraheres med eter, torkes over magnesiumsulfat og inndampes. Det oppnås et faststoff som behandles på filteret med cykloheksan. 34.8 g (0.275 mol) methyl sulfate is added dropwise to the resulting solution. It is stirred for 4 hours, after which it is extracted with ether. The aqueous phase is isolated and acidified and the resulting oil is extracted with ether, dried over magnesium sulfate and evaporated. A solid is obtained which is treated on the filter with cyclohexane.
Smp. = 68,5 - 69°C. Temp. = 68.5 - 69°C.
I en erlenmeyer-kcGbe innfores 14,4 ml (0,2 mol) tionylklorid og 19,8 g (0,1 mol) syre. Det omrores ved romtemperatur og oppvarmes deretter til tilbakelop i 4 timer. Det inndampes til torrhet og den resterende olje destilleres gjennom kuleror. 14.4 ml (0.2 mol) of thionyl chloride and 19.8 g (0.1 mol) of acid are introduced into an Erlenmeyer flask. It is stirred at room temperature and then heated to reflux for 4 hours. It is evaporated to dryness and the remaining oil is distilled through carbon tubes.
Kp.Q 1 = 180°C.Kp. Q 1 = 180°C.
4 . N- i;f( l- cvklopropylmetvl- 2- pvrrolidinyl)- metyl/- 2- metyl- 5-me tyltio- benzamid. 4. N-i;f(1-cyclopropylmethyl-2-pyrrolidinyl)-methyl/-2-methyl-5-methylthiobenzamide.
I en erlenmeyer-kolbe innfores 10,7 g (0,069 mol) 1-cyklo-propylmetyl-2-aminometyl-pyrrolidin, 9,6 g (0,069 mol) kaliumkarbonat og aceton. Under avkjSling med isbad og under nitrogenstrom tilsettes dråpevis 15 g (0,069 mol) 2-metpksy-5-metyltio-benzosyre. Det omrores i 2 timer ved vanlig temperatur og inndampes til torrhet ved en temperatur under eller lik 30°C og resten opptas i vann og kloroform. Den organiske fase fraskilles og ekstraheres i surt miljo, den vandige fase gjores alkalisk og ekstraheres med kloroform. Det torkes over magnesiun-sulfat og inndampes og oppnås en olje som fores gjennom en silikakolonne under eluering med aceton. 10.7 g (0.069 mol) of 1-cyclopropylmethyl-2-aminomethyl-pyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and acetone are introduced into an Erlenmeyer flask. While cooling with an ice bath and under a stream of nitrogen, 15 g (0.069 mol) of 2-methoxy-5-methylthio-benzoic acid are added dropwise. It is stirred for 2 hours at ordinary temperature and evaporated to dryness at a temperature below or equal to 30°C and the residue is taken up in water and chloroform. The organic phase is separated and extracted in an acidic environment, the aqueous phase is made alkaline and extracted with chloroform. It is dried over magnesium sulfate and evaporated to obtain an oil which is passed through a silica column while eluting with acetone.
KP'0,05= 240°C-KP'0.05= 240°C-
5. Hydroklorid.5. Hydrochloride.
I 100 ml eter innfores 6,68 g (0,02 mol) N-^d-cyklopropyl-metyl-2-pyrrolidinyl)metyl/-2-metoksy-5-metyltio-benzamid. 6.68 g (0.02 mol) of N-[d-cyclopropyl-methyl-2-pyrrolidinyl)methyl]-2-methoxy-5-methylthio-benzamide are introduced into 100 ml of ether.
Det tilsettes dråpevis en ekvimolekylær mengde saltsur eter og oljen separeres, opptas i 100 ml eter og omrores og inndampes deretter til torrhet. Den resterande olje behandles i 100 ml etylacetat og etter 1 time oppnås et hvitt faststcbff som filtreres og torkes. An equimolecular amount of hydrochloric ether is added dropwise and the oil is separated, taken up in 100 ml of ether and stirred and then evaporated to dryness. The remaining oil is treated in 100 ml of ethyl acetate and after 1 hour a white solid is obtained which is filtered and dried.
Smp. 111,5 - 112°C. Temp. 111.5 - 112°C.
Eksempel 2 (S) (-) av N-/"(l-cyklopropylmetyl-2-pyrrolidinyl )-me tyl7-2-me toksy-5-me tylti o-ben zamid. Example 2 (S) (-) of N-[(1-cyclopropylmethyl-2-pyrrolidinyl)-methyl7-2-methylthoxy-5-methylthio-benzamide.
I en erlenmeyer-kolbe innfores 10,7 g (0,069 mol) 2-aminometyl-1-cyklopropylmetyl-pyrrolidin (S), 9,6 g (0,069 mol) kalkum-karbonat og aceton. Under avkjoling med et isbad og under nitrogenstrom innfores dråpevis 15 g (0,069 mol) 2-metoksy-5-metyltio-benzosyreklorid i en losning i aceton. 10.7 g (0.069 mol) of 2-aminomethyl-1-cyclopropylmethyl-pyrrolidine (S), 9.6 g (0.069 mol) of calcium carbonate and acetone are introduced into an Erlenmeyer flask. While cooling with an ice bath and under a stream of nitrogen, 15 g (0.069 mol) of 2-methoxy-5-methylthiobenzoic acid chloride are introduced dropwise in a solution in acetone.
Blandingen får anta romtemperatur og omrores i 2 timer. Den inndampes til torrhet og den resterende olje behandles med vann og eter. Den organiske fase isoleres og ekstraheres i surt miljo, gjores alkalisk med natriumkarbonat og ekstraheres med eter. Det torkes over magnesiumsulfat og inndampes og oppnås en olje som fores gjennom en silikakolonne under eluering med etylacetat og deretter med aceton. Den oppnådde olje destilleres. The mixture is allowed to reach room temperature and stirred for 2 hours. It is evaporated to dryness and the remaining oil is treated with water and ether. The organic phase is isolated and extracted in an acidic environment, made alkaline with sodium carbonate and extracted with ether. It is dried over magnesium sulfate and evaporated, and an oil is obtained which is passed through a silica column while eluting with ethyl acetate and then with acetone. The obtained oil is distilled.
<Kp>'0,05<=>220°C/^d20="83° (c=1'DMF) <Kp>'0.05<=>220°C/^d20="83° (c=1'DMF)
Hydrokloridet oppnås i saltsur eter.The hydrochloride is obtained in hydrochloric ether.
Smp. = 116 - 116,5°C Temp. = 116 - 116.5°C
/c27d° + 21° (c-1'DMF)/c27d° + 21° (c-1'DMF)
Eksempel 3 N-/~(l-cyklopropylmetyl-2-pyrrolidinyl )metyl7-2-metoksy-5-etyltio-benzamid. Example 3 N-(1-cyclopropylmethyl-2-pyrrolidinyl)methyl 7-2-methoxy-5-ethylthiobenzamide.
1. 2- metoksy- 5- etyltio- benzosyre ogdets klorid.1. 2- methoxy- 5- ethylthio- benzoic acid and its chloride.
Man går frem som i eksempel 1 og erstatter metylsulfatet med etylsulfat. Smp. = 58 - 59°C for syren. Proceed as in example 1 and replace the methyl sulphate with ethyl sulphate. Temp. = 58 - 59°C for the acid.
Kp.Q Q5 = 160°C for syrekloridet.Kp.Q Q5 = 160°C for the acid chloride.
2. N-/"(l-cyklopropylmetyl-2-pyrrolidinyl)-metyl/-2-metoksy-5-etyltio- benzamid 1 en erlenmeyer-kolbe innfores 9,4 g (0,0611 mol) 1-cyklopropyl-metyl-2-aminometyl-pyrrolidin, 8,5 g (0,0611 mol) kaliumkarbonat og aceton. Ved en temperatur lavere enn eller lik 10°C og under nitrogenstrom tilsettes dråpevis 14,1 g (0,0611 mol) av 2-metoksy-5-etyltio-benzosyreklorid i aceton. Det omrores i 2 timer ved vanlig temperatur, inndampes til torrhet, resten opptas i vann og kloroform, den organiske fase fraskilles, ekstraheres i surt miljo, gjores alkalisk og ekstraheres med kloroform, og torkes over magnesiumsulfat og inndampes. Det oppnås en olje som fores gjennom en silikakolonne og elueres med aceton. Det oppnås en olje som destilleres. 2. N-/(1-cyclopropylmethyl-2-pyrrolidinyl)-methyl/-2-methoxy-5-ethylthiobenzamide 1 an Erlenmeyer flask is introduced with 9.4 g (0.0611 mol) 1-cyclopropyl-methyl- 2-aminomethyl-pyrrolidine, 8.5 g (0.0611 mol) potassium carbonate and acetone At a temperature lower than or equal to 10°C and under a stream of nitrogen, 14.1 g (0.0611 mol) of 2-methoxy- 5-ethylthio-benzoic acid chloride in acetone. It is stirred for 2 hours at room temperature, evaporated to dryness, the residue is taken up in water and chloroform, the organic phase is separated, extracted in an acidic medium, made alkaline and extracted with chloroform, and dried over magnesium sulfate and evaporated.An oil is obtained which is passed through a silica column and eluted with acetone.An oil is obtained which is distilled.
KP'0,05= 240°C-KP'0.05= 240°C-
Eksempel 4 N-/*(l-cyklopropylmetyl-2-pyrrolidinyl )metyl7-2-metoksy-5-trifluormetyl-benzamid og dets hydroklorid. Example 4 N-(1-cyclopropylmethyl-2-pyrrolidinyl)methyl-7-2-methoxy-5-trifluoromethyl-benzamide and its hydrochloride.
I en erlenmeyer-kolbe innfores 6,37 g (0,0413 mol) 2-aminometyl-1-cyklopropylmetyl-pyrrolidin, 5,7 g (0,0413 mol) kaliumkarbonat og 125 ml aceton hvoretter det avkjoles til omtrent 5°C og tilfores dråpevis sakte (T< 8°C) 9,85 g (0,0413 mol) 2-metoksy-5-trifluormetyl-benzosyre i 50 ml aceton, under nitrogenstrom. Etter tilsetningen omrores i 2 timer i smeltende is og 1 time ved vanlig temperatur hvoretter det inndampes til torrhet. Resten opptas i vann og eter, dekanteres, moderlutene ekstraheres to ganger og de organiske ekstrakter vaskes for de torkes over magnesiumsulfat. Det filtreres, inndampes til torrhet og oppnås en gul olje. 6.37 g (0.0413 mol) 2-aminomethyl-1-cyclopropylmethyl-pyrrolidine, 5.7 g (0.0413 mol) potassium carbonate and 125 ml acetone are introduced into an Erlenmeyer flask, after which it is cooled to approximately 5°C and 9.85 g (0.0413 mol) of 2-methoxy-5-trifluoromethyl-benzoic acid in 50 ml of acetone are added dropwise slowly (T< 8°C), under a stream of nitrogen. After the addition, it is stirred for 2 hours in melting ice and 1 hour at ordinary temperature, after which it is evaporated to dryness. The residue is taken up in water and ether, decanted, the mother liquors are extracted twice and the organic extracts are washed before they are dried over magnesium sulphate. It is filtered, evaporated to dryness and a yellow oil is obtained.
Hydrokloridet av benzamidet oppnås ved omroring i torr eter ved hjelp av HC1 i eter. Faststoffet avsuges på filter, vaskes og torkes , omkrystalleres to ganger fra aceton og det oppnås et fint hvitt pulver. The hydrochloride of the benzamide is obtained by stirring in dry ether with the aid of HC1 in ether. The solid is filtered off, washed and dried, recrystallized twice from acetone and a fine white powder is obtained.
Smp. = 149,5 - 150°C. Temp. = 149.5 - 150°C.
Eksempel 5 Isomer (S) (-) av N-/~(l-cyklopropylmetyl-2-pyrrolidinyl)metyl/-2-metoksy-5-trifluormetyl-benzamid. Example 5 Isomer (S) (-) of N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-trifluoromethyl-benzamide.
I en erlenmeyer-kolbe innfores 2,15 g (0,0139 mol) 2-aminometyl-1-cyklopropylmetyl-pyrrolidin (S), 1,92 g (0,013 9 mol) kaliumkarbonat og 100 ml aceton. Under avkjoling på et isbad under nitrogenstrom tilsettes dråpevis 3,32 g (0,0139 mol) 2-metoksy-trifluormetyl-benzosyreklorid i aceton. Blandingen får anta vanlig temperatur og omrores i 2 timer. 2.15 g (0.0139 mol) of 2-aminomethyl-1-cyclopropylmethyl-pyrrolidine (S), 1.92 g (0.013 9 mol) of potassium carbonate and 100 ml of acetone are introduced into an Erlenmeyer flask. While cooling in an ice bath under a stream of nitrogen, 3.32 g (0.0139 mol) of 2-methoxy-trifluoromethyl-benzoic acid chloride in acetone are added dropwise. The mixture is allowed to reach normal temperature and stirred for 2 hours.
Blandingen inndampes til torrhet, opptas i vann og eter, den organiske fase fraskilles og ekstraheres i surt miljo. Blandingen gjores alkalisk med natriumkarbonat, ekstraheres med eter, torkes over magnesiumsulfat og inndampes. Det oppnås en olje som destilleres. The mixture is evaporated to dryness, taken up in water and ether, the organic phase is separated and extracted in an acidic environment. The mixture is made alkaline with sodium carbonate, extracted with ether, dried over magnesium sulfate and evaporated. An oil is obtained which is distilled.
KP-0.05= 250°C KP-0.05= 250°C
/a/20 _75/5o /a/20 _75/5o
Forbindelsene ble underkastet farmakologisk testing ved innvirkning på det sentrale nervesystem. The compounds were subjected to pharmacological testing for effects on the central nervous system.
Giftigheten ble bestemt i hannmus Swiss CD1 med middelvektToxicity was determined in medium-weight Swiss CD1 male mice
20 g ved tilforsel i.p.20 g when administered i.p.
LD varierer fra 75 til 200 mg/kg.LD varies from 75 to 200 mg/kg.
Den nevroleptiske aktivitet ble bestemt ved antagonisme overfor "klatring" ("climbing")/("redressement") innfort av apomorfin i mus /Gouret C. (1973) J. Pharmacol. (Paris) 4, 3417. The neuroleptic activity was determined by antagonism to "climbing"/("redressement") administration of apomorphine in mice /Gouret C. (1973) J. Pharmacol. (Paris) 4, 3417.
Dose ED varierer mellom 0,03 til 0,08 mg/kg tilfort i.p.Dose ED varies between 0.03 to 0.08 mg/kg administered i.p.
i in
Forbindelsene kan anvendes ved behandling av forskjellige psykosomatiske lidelser og psykiske forstyrrelser (depressive The compounds can be used in the treatment of various psychosomatic disorders and psychological disorders (depressive
tilstander og psykoser).conditions and psychoses).
Forbindelsene kan anvendes som sådan eller i form av deres salter som aktive bestanddeler, eventuelt i forbindelse med vanlige tilsetningsmidler for forskjellige tilfprselsmåter, enten oralt, endorektalt eller parenteralt. The compounds can be used as such or in the form of their salts as active ingredients, possibly in connection with common additives for different methods of administration, either orally, endorectally or parenterally.
Daglig dose kan utgjore fra 1 til 200 mg. The daily dose can range from 1 to 200 mg.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7805580A FR2418226A1 (en) | 1978-02-27 | 1978-02-27 | METHOXY-2 ALKYLTHIO-5 BENZAMIDES AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO790648L true NO790648L (en) | 1979-08-28 |
Family
ID=9205110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO790648A NO790648L (en) | 1978-02-27 | 1979-02-26 | PROCEDURE FOR THE PREPARATION OF CYCLOALKYL-ALKYLBENZAMIDES |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS54122269A (en) |
| AT (1) | AT373581B (en) |
| AU (1) | AU521854B2 (en) |
| BE (1) | BE874490A (en) |
| CA (1) | CA1105937A (en) |
| CH (1) | CH637378A5 (en) |
| DE (1) | DE2907377A1 (en) |
| DK (1) | DK82379A (en) |
| ES (1) | ES478073A1 (en) |
| FI (1) | FI790658A (en) |
| FR (1) | FR2418226A1 (en) |
| GB (1) | GB2014995B (en) |
| GR (1) | GR66973B (en) |
| IE (1) | IE47897B1 (en) |
| IL (1) | IL56747A0 (en) |
| IT (1) | IT1114210B (en) |
| LU (1) | LU80976A1 (en) |
| NL (1) | NL7901472A (en) |
| NO (1) | NO790648L (en) |
| NZ (1) | NZ189771A (en) |
| PT (1) | PT69290A (en) |
| SE (1) | SE430501B (en) |
| ZA (1) | ZA799808B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02500291A (en) * | 1987-05-25 | 1990-02-01 | フォーショア プロテクション ピーティーワイ リミテッド | seawall mattress |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2245628B1 (en) * | 1973-09-28 | 1977-03-11 | Ile De France |
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1978
- 1978-02-27 FR FR7805580A patent/FR2418226A1/en active Granted
-
1979
- 1979-02-26 CH CH188379A patent/CH637378A5/en not_active IP Right Cessation
- 1979-02-26 ES ES478073A patent/ES478073A1/en not_active Expired
- 1979-02-26 IT IT20542/79A patent/IT1114210B/en active
- 1979-02-26 CA CA322,283A patent/CA1105937A/en not_active Expired
- 1979-02-26 NL NL7901472A patent/NL7901472A/en not_active Application Discontinuation
- 1979-02-26 NZ NZ189771A patent/NZ189771A/en unknown
- 1979-02-26 AU AU44604/79A patent/AU521854B2/en not_active Ceased
- 1979-02-26 NO NO790648A patent/NO790648L/en unknown
- 1979-02-26 DK DK82379A patent/DK82379A/en not_active Application Discontinuation
- 1979-02-26 DE DE19792907377 patent/DE2907377A1/en not_active Withdrawn
- 1979-02-26 SE SE7901708A patent/SE430501B/en unknown
- 1979-02-26 PT PT69290A patent/PT69290A/en unknown
- 1979-02-26 JP JP2247679A patent/JPS54122269A/en active Pending
- 1979-02-26 ZA ZA00799808A patent/ZA799808B/en unknown
- 1979-02-27 IL IL56747A patent/IL56747A0/en unknown
- 1979-02-27 AT AT0149479A patent/AT373581B/en not_active IP Right Cessation
- 1979-02-27 GR GR58492A patent/GR66973B/el unknown
- 1979-02-27 FI FI790658A patent/FI790658A/en not_active Application Discontinuation
- 1979-02-27 BE BE0/193730A patent/BE874490A/en not_active IP Right Cessation
- 1979-02-27 GB GB7906954A patent/GB2014995B/en not_active Expired
- 1979-02-27 LU LU80976A patent/LU80976A1/en unknown
- 1979-08-08 IE IE558/79A patent/IE47897B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH637378A5 (en) | 1983-07-29 |
| LU80976A1 (en) | 1980-09-24 |
| AU4460479A (en) | 1979-09-06 |
| IT7920542A0 (en) | 1979-02-26 |
| CA1105937A (en) | 1981-07-28 |
| FI790658A (en) | 1979-08-28 |
| AT373581B (en) | 1984-02-10 |
| GR66973B (en) | 1981-05-15 |
| IE790558L (en) | 1979-08-27 |
| IE47897B1 (en) | 1984-07-11 |
| ES478073A1 (en) | 1979-05-16 |
| GB2014995A (en) | 1979-09-05 |
| FR2418226B1 (en) | 1980-11-07 |
| FR2418226A1 (en) | 1979-09-21 |
| DE2907377A1 (en) | 1979-09-06 |
| SE7901708L (en) | 1979-08-28 |
| ZA799808B (en) | 1980-06-25 |
| ATA149479A (en) | 1983-06-15 |
| SE430501B (en) | 1983-11-21 |
| DK82379A (en) | 1979-08-28 |
| GB2014995B (en) | 1982-07-28 |
| JPS54122269A (en) | 1979-09-21 |
| NZ189771A (en) | 1980-11-14 |
| NL7901472A (en) | 1979-08-29 |
| PT69290A (en) | 1979-03-01 |
| AU521854B2 (en) | 1982-05-06 |
| IL56747A0 (en) | 1979-05-31 |
| BE874490A (en) | 1979-08-27 |
| IT1114210B (en) | 1986-01-27 |
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