NO120190B - - Google Patents
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- Publication number
- NO120190B NO120190B NO2254/68A NO225468A NO120190B NO 120190 B NO120190 B NO 120190B NO 2254/68 A NO2254/68 A NO 2254/68A NO 225468 A NO225468 A NO 225468A NO 120190 B NO120190 B NO 120190B
- Authority
- NO
- Norway
- Prior art keywords
- propargyloxy
- acid
- pharmacologically acceptable
- alkynyloxy
- diethylaminoethyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 17
- -1 aminoalkyl amine Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000003589 local anesthetic agent Substances 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 3
- 229940054066 benzamide antipsychotics Drugs 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229960005015 local anesthetics Drugs 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 7
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 6
- 231100000862 numbness Toxicity 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- SJVUVVMGPMNICD-UHFFFAOYSA-N 3,5-dibromo-N-[2-(diethylamino)ethyl]-2-prop-2-ynoxybenzamide Chemical compound CCN(CC)CCNC(=O)C1=C(OCC#C)C(Br)=CC(Br)=C1 SJVUVVMGPMNICD-UHFFFAOYSA-N 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000004087 cornea Anatomy 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940102396 methyl bromide Drugs 0.000 description 3
- 229960004919 procaine Drugs 0.000 description 3
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 3
- 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 2
- LKXOMRBOYHVXQA-UHFFFAOYSA-N 3,5-dichloro-N-[2-(diethylamino)ethyl]-2-prop-2-ynoxybenzamide Chemical compound C(C#C)OC1=C(C(=O)NCCN(CC)CC)C=C(C=C1Cl)Cl LKXOMRBOYHVXQA-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- YPLIFKZBNCNJJN-UHFFFAOYSA-N n,n-bis(ethylamino)ethanamine Chemical compound CCNN(CC)NCC YPLIFKZBNCNJJN-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- NTQZEHOPDXFQDM-UHFFFAOYSA-N 3,5-dibromo-2-prop-2-ynoxybenzamide Chemical compound C(C#C)OC1=C(C(=O)N)C=C(C=C1Br)Br NTQZEHOPDXFQDM-UHFFFAOYSA-N 0.000 description 1
- SWKGOTXIMPKBFY-UHFFFAOYSA-N 3,5-dichloro-2-prop-2-ynoxybenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Cl)=C1OCC#C SWKGOTXIMPKBFY-UHFFFAOYSA-N 0.000 description 1
- QHIJYCOWZBXENW-UHFFFAOYSA-N 3,5-dichloro-2-prop-2-ynoxybenzoyl chloride Chemical compound ClC(=O)C1=CC(Cl)=CC(Cl)=C1OCC#C QHIJYCOWZBXENW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- PIQVDUKEQYOJNR-VZXSFKIWSA-N cocaine hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@H]2CC[C@@H]([NH+]2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 PIQVDUKEQYOJNR-VZXSFKIWSA-N 0.000 description 1
- 229960003771 cocaine hydrochloride Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940072358 xylocaine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
Description
Analogifremgangsmåte ved fremstilling av farmakologisk aktive N-(tert.aminoalkyl)-2-alkynyloxybenzamider. Analogous method for the production of pharmacologically active N-(tert.aminoalkyl)-2-alkynyloxybenzamides.
Denne oppfinnelse angår en analogifremgangsmåte ved fremstilling av farmakologisk aktive N-(tert.aminoalkyl)-2-alkynyloxybenzamider og deres i farmakologisk henseende -aksepterbare salter. This invention relates to an analogous process for the preparation of pharmacologically active N-(tert.aminoalkyl)-2-alkynyloxybenzamides and their pharmacologically acceptable salts.
De nye benzamider svarer til den folgende generelle formel: The new benzamides correspond to the following general formula:
hvor A er et lavere alkynylradikal, X og Y er like eller forskjellige halogenatomer, og R^, R2 er lavere alkylradikaler. where A is a lower alkynyl radical, X and Y are the same or different halogen atoms, and R 1 , R 2 are lower alkyl radicals.
De i farmakologisk henseende aksepterbare salter av de ovenfor beskrevne baser kan være syreaddisjonssalter med mineralsyrer eller organiske syrer, såsom saltsyre, hydrobromsyre, hydrojodsyre, fosfor-syre, svovelsyre, sitronsyre, vinsyre, melkesyre, eddiksyre, ethan-sulfonsyre, osv., eller kvartære ammoniumsalter erholdt ved omsetning The pharmacologically acceptable salts of the above-described bases can be acid addition salts with mineral acids or organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid, lactic acid, acetic acid, ethanesulfonic acid, etc., or quaternary ammonium salts obtained by conversion
av de ovenfor beskrevne baser med et alifatisk eller aromatisk alkyleringsmiddel såsom methylklorid, methylbromid, methyljodid, di-methylsulfat, methylbenzensulfonat, methyl-p-toluensulfonat, ethyl-bromid, propylbromid, benzylklorid, osv. of the above-described bases with an aliphatic or aromatic alkylating agent such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl bromide, propyl bromide, benzyl chloride, etc.
De nye forbindelser har interessante farmakologiske egenskaper The new compounds have interesting pharmacological properties
og egner seg spesielt for anvendelse som lokalt virkende anaesthetika. and is particularly suitable for use as a locally acting anaesthetic.
Ved analogifremgangsmåten for fremstilling av de nye forbindelser starter man med et 2-alkynyloxybenzoylklorid og behandler dette med et tertiært aminoalkylamin. Derved fåes det tilsvarende N-(tert.~ aminoalkyl)-2-alkynyloxybenzamid. In the analogous method for preparing the new compounds, one starts with a 2-alkynyloxybenzoyl chloride and treats this with a tertiary aminoalkylamine. Thereby the corresponding N-(tert.~aminoalkyl)-2-alkynyloxybenzamide is obtained.
De nye forbindelser er blitt gjort til gjenstand for farmakologiske og kliniske undersøkelser for å bestemme deres toksisitet og aktivi-tet. The new compounds have been subjected to pharmacological and clinical investigations to determine their toxicity and activity.
Den akutte grad av toksisitet, som ble undersokt på mus, viste at de nye forbindelsers toksisitet fullt ut er forlikelig med terapeutisk anvendelse. Som eksempel er graden av toksisitet av den nye forbindelse N-(diethylaminoethyl)-2-propargyloxy-3,5-dibrombenzamid (b) gitt i den nedenstående tabell til sammenligning med toksisiteten av procain, tetracain, xylocain og den nær beslektede kjente forbindelse N-(di-ethylaminoethyl).-2-allyloxy-3,5-dibrombenzamid (A). The acute degree of toxicity, which was investigated in mice, showed that the toxicity of the new compounds is fully compatible with therapeutic use. As an example, the degree of toxicity of the new compound N-(diethylaminoethyl)-2-propargyloxy-3,5-dibromobenzamide (b) is given in the table below for comparison with the toxicity of procaine, tetracaine, xylocaine and the closely related known compound N -(di-ethylaminoethyl).-2-allyloxy-3,5-dibromobenzamide (A).
De lokale anaesthetiske egenskaper av de nye forbindelser gikk frem av de forskjellige tester som er beskrevet nedenfor. The local anesthetic properties of the new compounds were determined by the various tests described below.
Lokal overflatefolelsesloshet ble bestemt etter Regnier-metoden, som går ut på å studere hemningen av den oculopalpebrale refleks på oyets hornhinne hos kaniner. Local surface numbness was determined according to the Regnier method, which involves studying the inhibition of the oculopalpebral reflex on the cornea of the eye in rabbits.
Idet en gruppe a 10 kaniner underkastes testen, måles graden av folelsesloshet av oyets hornhinne etter drypping i oyet av to dråper av en vandig opplosning av produktet som skal undersokes, ved sammenligning med den grad av folelsesloshet som fremkalles med to vandige oppløsninger av cocainhydroklorid i forskjellige konsentrasjoner. Eksperimentet utfores som krysstester med en ukes intervaller. When a group of 10 rabbits is subjected to the test, the degree of numbness of the cornea of the eye is measured after instillation into the eye of two drops of an aqueous solution of the product to be examined, by comparison with the degree of numbness induced by two aqueous solutions of cocaine hydrochloride in different concentrations. The experiment is carried out as cross-tests at one-week intervals.
De resultater som er oppfort i de nedenstående tabeller er gitt som eksempler. Det midlere antall slag pr. time med et grovt hår på oyets hornhinne som ikke gir noen reaksjon, gir uttrykk for graden av folelsesloshet. Et antall av 1300 svarer til fullstendig folelsesloshet i 60 minutter. Et antall av 13 viser at ingen folelsesloshet er fremkalt. The results listed in the tables below are given as examples. The average number of strokes per hour with a coarse hair on the eye's cornea that gives no reaction, expresses the degree of numbness. A number of 1300 corresponds to complete numbness for 60 minutes. A number of 13 shows that no numbness has been induced.
En annen test som tilkjennegir den lokalbedovende virkning består i å stikke marsvin i mavehuden med en nål og notere antall stikk som medforer en reaksjon etter at marsvinet på forhånd er blitt påfort lokalt en opplosning av forbindelsen som skal testes. Resultatene er i den nedenstående tabell gitt for den ovennevnte nye forbindelse B, Another test which indicates the local anesthetic effect consists in pricking the guinea pig in the abdominal skin with a needle and noting the number of pricks which cause a reaction after the guinea pig has previously been locally administered a solution of the compound to be tested. The results are given in the table below for the above-mentioned new compound B,
for den kjente forbindelse A og for procain. for the known compound A and for procaine.
Resultatene viser at begge forbindelser A og B er meget mer aktive som lokalbedovelsesmidler enn procain, og at den nye forbindelse B er mer virksom enn den kjente forbindelse A. The results show that both compounds A and B are much more active as local anesthetics than procaine, and that the new compound B is more effective than the known compound A.
For å undersoke den nekrotiske virkning på vevceller ved hud-injeksjon ble trypariblått-testen benyttet. De to forbindelser A og B ble injisert 5 minutter forut for en intravenos injeksjon av trypan-blått. De folgende resultater ble oppnådd: To investigate the necrotic effect on tissue cells by skin injection, the trypari blue test was used. The two compounds A and B were injected 5 minutes before an intravenous injection of trypan blue. The following results were obtained:
Det sees at forbindelsen B tåles adskillig bedre enn forbindelsen It can be seen that the compound B is tolerated much better than the compound
A. A.
De eksperimentelle resultater er bekreftet ved kliniske under-søkelser, hvor de nye forbindelser, i form av farmakologisk aksepterbare salter, ble administrert som aktiv komponent av tabletter, kaps-ler, salver eller aerosoler. The experimental results have been confirmed by clinical investigations, where the new compounds, in the form of pharmacologically acceptable salts, were administered as active components of tablets, capsules, ointments or aerosols.
De folgende eksempler illustrerer fremstillingen av de nye forbindelser. The following examples illustrate the production of the new compounds.
Eksempel 1 N-( diethylaminoethyl)- 2- propargyloxy- 3« 5- dibrombenzamid Example 1 N-(diethylaminoethyl)-2-propargyloxy-3,5-dibromobenzamide
28,6 g thioriylklorid og 13,5 g 2-propargyloxy-3,5-dibrombenzoesyre anbringes i en 250 ml rundkolbe som er forsynt med en tilbakelopskjoler. Blandingen oppvarmes på vannbad ved h0% inntil reagensene er fullstendig opplost (2 timer). Etter avkjoling .tilsettes resten av syren (13,5 g ). Blandingen oppvarmes forst ved <1>+0°C og deretter til 70°C for å opplose reagensene fullstendig (1,5 timer). Overskuddet av thionylklorid fjernes deretter under vakuum. Der erholdes 28 g 2-propargyloxy-3,5-dibrombenzoylklorid. 28.6 g of thioriyl chloride and 13.5 g of 2-propargyloxy-3,5-dibromobenzoic acid are placed in a 250 ml round bottom flask fitted with a reflux condenser. The mixture is heated in a water bath at h0% until the reagents are completely dissolved (2 hours). After cooling, the rest of the acid (13.5 g) is added. The mixture is heated first at <1>+0°C and then to 70°C to completely dissolve the reagents (1.5 hours). The excess thionyl chloride is then removed under vacuum. 28 g of 2-propargyloxy-3,5-dibromobenzoyl chloride are obtained.
9,2 g N,N-diethylaminoethylamin i 30 ml vannfritt methylethylketon anbringes i en 1 liters rundkolbe som er forsynt med rorer, termometer og dråpetrakt. 28 g av syrekloridet opplost i 80 ml methylethylketon tilsettes deretter dråpevis, idet temperaturen holdes i området fra 5° til 10°C. Blandingen holdes under omroring i en halv time ved 10°C og tillates deretter å stå ved omgivelsenes temperatur 12-3 timer. Oppløsningen opploses deretter i 200 ml vann. Methyl-ethylketonet fjernes under vakuum. Opplosningen behandles med benkull og filtreres, hvoretter basen utfelles ved en beregnet mengde natron-lut. Den f raf Utreres, vaskes med vann og torres ved <1>+0°C. Der erholdes 15 g N-(diethylaminoethyl)-2-propargyloxy-3,5-dibrombenzamid. 9.2 g of N,N-diethylaminoethylamine in 30 ml of anhydrous methyl ethyl ketone are placed in a 1 liter round-bottomed flask which is fitted with a stirrer, thermometer and dropping funnel. 28 g of the acid chloride dissolved in 80 ml of methyl ethyl ketone are then added dropwise, keeping the temperature in the range from 5° to 10°C. The mixture is kept under stirring for half an hour at 10°C and is then allowed to stand at ambient temperature for 12-3 hours. The solution is then dissolved in 200 ml of water. The methyl ethyl ketone is removed under vacuum. The solution is treated with bone charcoal and filtered, after which the base is precipitated by a calculated amount of caustic soda. It is drained, washed with water and dried at <1>+0°C. 15 g of N-(diethylaminoethyl)-2-propargyloxy-3,5-dibromobenzamide are obtained.
Utbytte: <>>+3,5 %. Smeltepunkt 5^ - 55°C Dividend: <>>+3.5%. Melting point 5^ - 55°C
Eksempel 2 N-( diethylaminoethyl)- 2- propargyloxyd- 3<5- diklorbenzamid Example 2 N-(diethylaminoethyl)-2-propargyloxyd-3<5-dichlorobenzamide
195 g 2-propargyloxy-3,5-diklorbenzoesyre, g thionylklorid og noen få dråper dimethylformamid anbringes i en 2 liters rundkolbe som er forsynt med rorer, termometer og tilbakelopskjoler. Blandingen oppvarmes forsiktig på et vannbad av <1>+0°C inntil reagensene er fullstendig opplost. Etter 1,5 timer er reaksjonen fullfort, og thionylkloridet avdestilleres fullstendig under vakuum. Der erholdes 210 g 2-propargyloxy-3,5-diklorbenzoylklorid (utbytte: 100 %), som opploses i 500 ml methylethylketon. 195 g of 2-propargyloxy-3,5-dichlorobenzoic acid, g of thionyl chloride and a few drops of dimethylformamide are placed in a 2 liter round bottom flask fitted with stirrups, thermometer and reflux skirts. The mixture is gently heated in a water bath of <1>+0°C until the reagents are completely dissolved. After 1.5 hours, the reaction is complete, and the thionyl chloride is completely distilled off under vacuum. 210 g of 2-propargyloxy-3,5-dichlorobenzoyl chloride are obtained (yield: 100%), which are dissolved in 500 ml of methyl ethyl ketone.
92,3 g N,N-diethylaminoethylamin opplost i 200 methylethylketon anbringes i en 2 liters rundkolbe som er forsynt med rorer, termometer og dråpetrakt. Den ovenfor beskrevne syrekloridopplosning tilsettes så, idet temperaturen holdes i området fra 0° til 5°C. Blandingen holdes deretter ved en temperatur mellom 5° °g 10°G under fort-satt omroring i 30 minutter og deretter ved omgivelsenes temperatur i 1 time. De erholdte krystaller frafUtreres, vaskes gjentatte ganger med methylethylketon og torres deretter ved 50°C. Det erholdte produkt opploses i kokende aceton, hvoretter opplosningen behandles med ben- 92.3 g of N,N-diethylaminoethylamine dissolved in 200 methyl ethyl ketone is placed in a 2 liter round bottom flask which is fitted with stirrers, thermometer and dropping funnel. The acid chloride solution described above is then added, keeping the temperature in the range from 0° to 5°C. The mixture is then kept at a temperature between 5°C and 10°C with continued stirring for 30 minutes and then at ambient temperature for 1 hour. The crystals obtained are filtered off, washed repeatedly with methyl ethyl ketone and then dried at 50°C. The product obtained is dissolved in boiling acetone, after which the solution is treated with ben-
kull og filtreres varm,, Opplosningen kjoles til 0°C. Etter 2 timer frafUtreres de dannede krystaller, hvoretter de vaskes i iskoldt aceton og torres ved 50"'C. Der erholdes 170 g N-(diethylaminoethyl)-2-propargyloxy-3?5-diklorbenzamid. Utbytte: % g. Smeltepunkt 110° - charcoal and filtered hot,, The solution is cooled to 0°C. After 2 hours, the formed crystals are filtered off, after which they are washed in ice-cold acetone and dried at 50°C. 170 g of N-(diethylaminoethyl)-2-propargyloxy-3?5-dichlorobenzamide are obtained. Yield: % g. Melting point 110° -
111°C. 111°C.
Eksempel 3 N-(diethylaminoethyl)-2-propargyloxy-3,5-dibrombenzamid- Example 3 N-(diethylaminoethyl)-2-propargyloxy-3,5-dibromobenzamide-
brommethylat bromomethylate
15,5 g 2-propargyloxy-3,5-dibrombenzamid opploses i 15 ml aceton. Dissolve 15.5 g of 2-propargyloxy-3,5-dibromobenzamide in 15 ml of acetone.
Der tilsettes 10 g methylbromid opplost i 20 ml aceton. Blandingen 10 g of methyl bromide dissolved in 20 ml of acetone is added there. The mixture
holdes i ro i 2\ timer. Krystallisering finner sted i sterk grad. kept still for 2\ hours. Crystallization takes place to a great extent.
Krystallene frafUtreres, vaskes på filteret med iskoldt aceton og The crystals are filtered off, washed on the filter with ice-cold acetone and
torres ved romtemperatur. Der erholdes 16 g N-(diethylaminoethyl)-2-propargyloxy-3,5-dibrombenzamid. Smeltepunkt: 110°C. dried at room temperature. 16 g of N-(diethylaminoethyl)-2-propargyloxy-3,5-dibromobenzamide are obtained. Melting point: 110°C.
Eksempel h N-(diethylaminoethyl)-2-propargyloxy-3,5-diklorbenzamid- Example h N-(diethylaminoethyl)-2-propargyloxy-3,5-dichlorobenzamide-
brommethylat bromomethylate
2^,5 g 2-propargyloxy-3,5-diklorbenzamid opploses i 50 ml aceton. Dissolve 2.5 g of 2-propargyloxy-3,5-dichlorobenzamide in 50 ml of acetone.
Der tilsettes 16 g methylbromid opplost i 32 ml aceton. Dette forer 16 g of methyl bromide dissolved in 32 ml of acetone are added there. This leads
til umiddelbar utkrystallisering av N-(diethylaminoethyl)-2-propargyloxy-3,5-d.iklorbenzamid-brommethylat. Blandingen tillates å stå i ro i 2h timer. Produktet frafUtreres, vaskes på filteret med iskoldt aceton og torres ved romtemperatur. Smeltepunkt: 155°C. for immediate crystallization of N-(diethylaminoethyl)-2-propargyloxy-3,5-dichlorobenzamide bromomethylate. The mixture is allowed to stand for 2 hours. The product is filtered off, washed on the filter with ice-cold acetone and dried at room temperature. Melting point: 155°C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR111225A FR6557M (en) | 1967-06-20 | 1967-06-20 | |
| FR120062A FR1542708A (en) | 1967-06-20 | 1967-09-05 | New n- (tertiary-aminoalkyl) -2-alkylene (or alkinyl) oxybenzamides and their preparation process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO120190B true NO120190B (en) | 1970-09-14 |
Family
ID=26177493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO2254/68A NO120190B (en) | 1967-06-20 | 1968-06-10 |
Country Status (20)
| Country | Link |
|---|---|
| AT (1) | AT284821B (en) |
| BE (1) | BE716315A (en) |
| BG (1) | BG15553A3 (en) |
| CA (1) | CA935161A (en) |
| CH (1) | CH489472A (en) |
| CS (1) | CS172300B2 (en) |
| DE (1) | DE1768671C3 (en) |
| DK (1) | DK144063C (en) |
| ES (1) | ES355189A1 (en) |
| FI (1) | FI49710C (en) |
| FR (2) | FR6557M (en) |
| GB (1) | GB1201221A (en) |
| IE (1) | IE32154B1 (en) |
| IL (1) | IL30185A (en) |
| MC (1) | MC720A1 (en) |
| NL (1) | NL160806C (en) |
| NO (1) | NO120190B (en) |
| OA (1) | OA03878A (en) |
| SE (2) | SE391333B (en) |
| YU (1) | YU32928B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH653670A5 (en) * | 1983-03-03 | 1986-01-15 | Hoffmann La Roche | BENZAMIDE DERIVATIVES. |
| JP3933244B2 (en) * | 1997-04-04 | 2007-06-20 | 株式会社資生堂 | Alkylenediamine derivatives and anti-ulcer agents, antibacterial agents |
-
1967
- 1967-06-20 FR FR111225A patent/FR6557M/fr not_active Expired
- 1967-09-05 FR FR120062A patent/FR1542708A/en not_active Expired
-
1968
- 1968-06-10 NO NO2254/68A patent/NO120190B/no unknown
- 1968-06-10 BE BE716315D patent/BE716315A/xx not_active IP Right Cessation
- 1968-06-14 DE DE1768671A patent/DE1768671C3/en not_active Expired
- 1968-06-16 IL IL30185A patent/IL30185A/en unknown
- 1968-06-17 CH CH898068A patent/CH489472A/en not_active IP Right Cessation
- 1968-06-18 SE SE7410567A patent/SE391333B/en unknown
- 1968-06-18 SE SE6808239A patent/SE372261B/xx unknown
- 1968-06-19 ES ES355189A patent/ES355189A1/en not_active Expired
- 1968-06-19 FI FI681715A patent/FI49710C/en active
- 1968-06-19 YU YU1408/68A patent/YU32928B/en unknown
- 1968-06-19 CA CA022982A patent/CA935161A/en not_active Expired
- 1968-06-19 AT AT589168A patent/AT284821B/en not_active IP Right Cessation
- 1968-06-19 CS CS4532A patent/CS172300B2/cs unknown
- 1968-06-19 DK DK288968A patent/DK144063C/en not_active IP Right Cessation
- 1968-06-19 MC MC762A patent/MC720A1/en unknown
- 1968-06-20 GB GB29497/68A patent/GB1201221A/en not_active Expired
- 1968-06-20 IE IE736/68A patent/IE32154B1/en unknown
- 1968-06-20 NL NL6808703.A patent/NL160806C/en not_active IP Right Cessation
- 1968-06-20 OA OA53299A patent/OA03878A/en unknown
- 1968-07-18 BG BG010153A patent/BG15553A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE7410567L (en) | 1974-08-20 |
| GB1201221A (en) | 1970-08-05 |
| BE716315A (en) | 1968-12-10 |
| CS172300B2 (en) | 1976-12-29 |
| AT284821B (en) | 1970-09-25 |
| FR6557M (en) | 1968-12-23 |
| CH489472A (en) | 1970-04-30 |
| SE372261B (en) | 1974-12-16 |
| NL160806B (en) | 1979-07-16 |
| DE1768671C3 (en) | 1974-03-14 |
| SE391333B (en) | 1977-02-14 |
| FI49710C (en) | 1975-09-10 |
| OA03878A (en) | 1975-08-14 |
| YU32928B (en) | 1975-12-31 |
| NL6808703A (en) | 1968-12-23 |
| IL30185A (en) | 1972-11-28 |
| DE1768671A1 (en) | 1972-08-10 |
| ES355189A1 (en) | 1970-03-16 |
| NL160806C (en) | 1979-12-17 |
| FI49710B (en) | 1975-06-02 |
| BG15553A3 (en) | 1972-05-20 |
| IL30185A0 (en) | 1968-08-22 |
| DE1768671B2 (en) | 1973-08-02 |
| YU140868A (en) | 1975-06-30 |
| DK144063B (en) | 1981-11-30 |
| CA935161A (en) | 1973-10-09 |
| FR1542708A (en) | 1968-10-18 |
| IE32154L (en) | 1968-12-20 |
| MC720A1 (en) | 1969-04-01 |
| IE32154B1 (en) | 1973-05-02 |
| DK144063C (en) | 1982-04-19 |
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