DK154070B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2-SUBSTITUTED 1- (OMEGA-AMINOAL COXY) BENZENER DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF 2-SUBSTITUTED 1- (OMEGA-AMINOAL COXY) BENZENER DERIVATIVES Download PDFInfo
- Publication number
- DK154070B DK154070B DK276276A DK276276A DK154070B DK 154070 B DK154070 B DK 154070B DK 276276 A DK276276 A DK 276276A DK 276276 A DK276276 A DK 276276A DK 154070 B DK154070 B DK 154070B
- Authority
- DK
- Denmark
- Prior art keywords
- process according
- prepared
- carbon atoms
- diphenyl
- alkylamino
- Prior art date
Links
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
- C07D295/08—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 bound oxygen or sulfur atoms
- C07D295/084—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 154070 BDK 154070 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af 2-substituerede 1- (w-aminoalkoxy)benzenderivater, hvilke forbindelser er farmakologisk aktive og virker antidepressivt.The present invention relates to an analogous process for the preparation of 2-substituted 1- (w-aminoalkoxy) benzene derivatives which are pharmacologically active and act antidepressantly.
L.C. Cheney et al. har i J.Am.Chem.Soc., bind 71, 60-64 (1949) 5 beskrevet adskillige diphenylmethaner indeholdende en substituent i 2-stillingen, herunder 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-morpholinoethoxy, 2-(1-piperidyl)ethoxy, 2-isopropylaminoethoxy, 3-(l-piperidyl)propoxy, 3-dimethylaminopropoxy og 3-dibutylami-nopropoxy.L. C. Cheney et al. J. Am.Chem.Soc., Vol. 71, 60-64 (1949) 5 have described several diphenylmethanes containing a substituent at the 2-position, including 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-morpholinoethoxy, 2- (1- piperidyl) ethoxy, 2-isopropylaminoethoxy, 3- (1-piperidyl) propoxy, 3-dimethylaminopropoxy and 3-dibutylaminopropoxy.
10 I denne artikel er det også anført, at 2-(2-aminoethoxy)diphenylmethaner og 2-(3-aminopropoxy)diphenylmethaner har antihistaminaktivitet og lokal anæstetisk aktivitet i dyr.10 This article also states that 2- (2-aminoethoxy) diphenylmethanes and 2- (3-aminopropoxy) diphenylmethanes have antihistamine activity and local anesthetic activity in animals.
Det skal imidlertid bemærkes, at de 2-(4-aminobutoxy)diphenylmethaner og 2-(5-aminopentyloxy)diphenylmethaner, som er omhandlet i nærværen-15 de beskrivelse, ikke er nævnt i den omtalte artikel.However, it should be noted that the 2- (4-aminobutoxy) diphenylmethanes and 2- (5-aminopentyloxy) diphenylmethanes referred to in the present description are not mentioned in the said article.
Det skal også bemærkes, at der i den nævnte artikel ingen antydning er af, at 2-ω-aminoalkoxydiphenylmethaner skulle have antidepressiv virkning.It should also be noted that in the said article there is no indication that 2-ω-aminoalkoxydiphenylmethanes should have antidepressant effect.
Den i den nævnte artikel omtalte 2-(3-dimethylaminopropoxy)diphenyl-20 me than har ifølge farmakologisk afprøvning faktisk ingen antide-pressiv virkning.Indeed, the 2- (3-dimethylaminopropoxy) diphenylmethane mentioned in the said article has, according to pharmacological testing, no antidepressant effect.
Den foreliggende opfindelse bygger på denne erkendelse og angår en analogifremgangsmåde til fremstilling af hidtil ukendte forbindelser med den almene formel I 25 O-(CH-) r1The present invention is based on this disclosure and relates to an analogous process for the preparation of novel compounds of the general formula I O (CH-) r
iViV
DK 154070 BDK 154070 B
2 hvor R^· betegner alkylamino med 1-5 carbonatomer, når R^ betegner benzyl, og n betegner 3, 4 eller 5; R^ betegner alkylamino med 1-5 carbonatomer eller dialkylamino med 2-6 carbonatomer, og n betegner 4 eller 5, når R^ betegner phenoxy; betegner alkylamino med 1-5 5 carbonatomer, når R^ betegner phenylthio, og n betegner 3; R^ betegner alkylamino med 1-5 carbonatomer eller dialkylamino med 2-6 carbonatomer, når R^ betegner phenylthio, og n betegner 4; R^-betegner alkylamino med 1-5 carbonatomer eller dialkylamino med 2-6 carbonatomer, når R^ betegner 1-phenylethyl, og n betegner 4; R^2 wherein R ^ represents alkylamino of 1 to 5 carbon atoms when R R represents benzyl and n represents 3, 4 or 5; R 1 represents alkylamino of 1-5 carbon atoms or dialkylamino of 2-6 carbon atoms, and n represents 4 or 5 when R 2 represents phenoxy; represents alkylamino having 1 to 5 carbon atoms when R 1 represents phenylthio and n represents 3; R ^ represents alkylamino of 1-5 carbon atoms or dialkylamino of 2-6 carbon atoms when R når represents phenylthio and n represents 4; R 1 represents alkylamino of 1-5 carbon atoms or dialkylamino of 2-6 carbon atoms when R 2 represents 1-phenylethyl and n represents 4; R ^
10 betegner dimethylamino, når R^ betegner 1-phenylethyl, og n betegner 3; og R^- betegner amino, alkylamino med 1-5 carbonatomer eller dialkylamino med 2-6 carbonatomer, og n betegner 4, når betegner phenyl, eller farmaceutisk tolerable syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved, at en 2-substitueret 1-(ω-15 halogenalkoxy)benzen med den almene formel II10 represents dimethylamino when R 1 represents 1-phenylethyl and n represents 3; and R 3 - represents amino, alkylamino of 1 to 5 carbon atoms or dialkylamino of 2-6 carbon atoms, and n represents 4 when represents phenyl, or pharmaceutically tolerable acid addition salts thereof, characterized in that a 2-substituted 1- ( ω-haloalkoxy) benzene of the general formula II
0-(CH2)nX0- (CH 2) n -X
Αγί2 ilΑγί2 il
hvor X betegner halogen, og R^ og n har den ovenfor angivne betyd-20 ning, omsættes med en amin med den almene formel IIIwhere X represents halogen and R 1 and n have the meaning given above, are reacted with an amine of the general formula III
R1-H IIIR1-H III
hvor r1 har den ovenfor anførte betydning.where r1 has the meaning given above.
De farmaceutisk tolerable syreadditionssalte af de ovenfor anførte forbindelser er naturligvis også omfattet af nærværende opfindelses 25 omfang.Of course, the pharmaceutically tolerable acid addition salts of the above compounds are also within the scope of the present invention.
Det er klart, at udtrykket "farmaceutisk tolerable syreadditions-salte" skal omfatte ikke-toxiske salte af de omhandlede forbindelser med en anion. Repræsentative eksempler på sådanne salte er hydrochlorider, hydrobromider, sulfater, phosphater, nitrater,It is to be understood that the term "pharmaceutically tolerable acid addition salts" is intended to include non-toxic salts of the subject compounds with an anion. Representative examples of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrates,
DK 154070 BDK 154070 B
3 acetater, succinater, adipater, propionater, tartrater, maleater, citrater, benzoater, toluensulfonater og methansulfonater.3 acetates, succinates, adipates, propionates, tartrates, maleates, citrates, benzoates, toluene sulfonates and methanesulfonates.
Hed de omhandlede forbindelser kan depressionstilstande hos varmblodede dyr lindres ved til dyret at administrere en antidepressivt 5 virksom mængde af en forbindelse med formlen I.In the present compounds, depressive states in warm-blooded animals can be alleviated by administering to the animal an antidepressant effective amount of a compound of formula I.
På grund af deres høje antidepressive virkningsniveau og deres lave toxicitetsniveau foretrækkes nedenstående forbindelser: 2 - ( 4 -me thy laminobutoxy ) dipheny lme than, 2 - (4 - ethy laminobutoxy ) dipheny lme than, 10 2 - ( 5 -me thylaminopentyloxy) dipheny lme than, 2 - (4-methylaminobutoxy) diphenylether, 2 - (4 - dimethylaminobutoxy) diphenylether, 2 - ( 5 -me thylaminopentyloxy) diphenylether, 2 - ( 3 -me thylaminopropoxy ) diphenylsulf id, 15 2 - (3 -me thylaminopropoxy) dipheny lme than, 2 - (4-methylaminobutoxy) dipheny lme thy lme than, 2- (4-dimethylaminobutoxy) dipheny lme thy lme than, 2-(3-dimethylaminopropoxy)diphenylmethylmethan, 2-(4-methylaminobutoxy)diphenyl, 20 2-(4-aminobutoxy)diphenyl og 2- (4-dimethylaminobutoxy) diphenyl.Due to their high level of antidepressant activity and their low toxicity level, the following compounds are preferred: 2- (4- methyl thylamino butoxy) diphenylamine, 2- (4- Ethylaminamin butoxy) diphenylamine, 2- (5- methyl thylaminopentyloxy) diphenyl lme than, 2- (4-methylaminobutoxy) diphenyl ether, 2- (4-dimethylaminobutoxy) diphenyl ether, 2- (5-methyl thylaminopentyloxy) diphenyl ether, 2- (3- methyl thylaminopropoxy) diphenyl sulfide, 2- (3- methyl thylaminopropoxy) 2- (4-methylaminobutoxy) diphenylme thyme than, 2- (4-dimethylaminobutoxy) diphenylme thyme than, 2- (3-dimethylaminopropoxy) diphenylmethylmethane, 2- (4-methylaminobutoxy) diphenyl, 20 2- (4-aminobutoxy) diphenyl and 2- (4-dimethylaminobutoxy) diphenyl.
De omhandlede forbindelser fremstilles ved omsætning af en 2-sub-stitueret 1-(w-halogenalkoxy)benzen med en amin. De 2-substituerede 1-(c<>-halogenalkoxy)benzen-udgangsmaterialer, som er illustreret med 25 formlen II, kan fremstilles ved omsætning af en 2-substitueret phenol med en 1,3-dihalogenpropan, 1,4-dihalogenbutan eller 1,5-dihalogenpentan i nærværelse af en base.The present compounds are prepared by reacting a 2-substituted 1- (w-haloalkoxy) benzene with an amine. The 2-substituted 1- (c <halogenalkoxy) benzene starting materials illustrated by Formula II can be prepared by reacting a 2-substituted phenol with a 1,3-dihalo-propane, 1,4-dihalo-butane or 1 , 5-dihalogen pentane in the presence of a base.
De aminudgangsmaterialer, som er illustreret med formlen III, omfatter ammoniak, primære aminer såsom methylamin, ethylamin og 30 isopropylamin, sekundære aminer såsom dimethylamin, diethylamin og lime thylethylamin.The amine starting materials illustrated by formula III include ammonia, primary amines such as methylamine, ethylamine and isopropylamine, secondary amines such as dimethylamine, diethylamine and lime thylethylamine.
DK 154070 BDK 154070 B
44
Aminen reagerer med en ækvimolær mængde af den 2-substituerede 1-(ω-halogenalkoxy)benzen. Et overskud af aminen fremskynder dog omsætningen. Normalt ligger den mængde amin, som skal anvendes, i området mellem 1 og 100 mol pr. mol af den 2-substituerede 1-(ω-5 halogenalkoxy)benzen.The amine reacts with an equimolar amount of the 2-substituted 1- (ω-haloalkoxy) benzene. However, an excess of the amine speeds up the turnover. Usually, the amount of amine to be used is in the range of 1 to 100 moles per ml. moles of the 2-substituted 1- (ω-5 haloalkoxy) benzene.
Reaktionen kan udføres uden tilsætning af et opløsningsmiddel. Det er imidlertid muligt at udføre en homogen reaktion ved anvendelse af et opløsningsmiddel, som er inert i forhold til reaktionen. Eksempler på sådanne opløsningsmidler er vand, dioxan, tetrahydrofuran, 10 dimethylsulfoxid, lavere aliphatiske alkoholer og blandinger deraf.The reaction can be carried out without the addition of a solvent. However, it is possible to perform a homogeneous reaction using a solvent which is inert to the reaction. Examples of such solvents are water, dioxane, tetrahydrofuran, dimethyl sulfoxide, lower aliphatic alcohols and mixtures thereof.
Reaktions temper aturen er ikke kritisk, men den ligger normalt i området mellem stuetemperatur og 150°C.The reaction temperature is not critical, but it is usually in the range between room temperature and 150 ° C.
Reaktionstiden varierer i vid udstrækning med reaktions temperaturen og udgangsmaterialernes reaktivitet, men den ligger normalt i området 15 mellem 10 minutter og 40 timer.The reaction time varies widely with the reaction temperature and the reactivity of the starting materials, but it is usually in the range of 15 between 10 minutes and 40 hours.
Nærværelse af baser, som neutraliserer det hydrogerihalogenid, som dannes under reaktionen, fremskynder reaktionen. Eksempler på sådanne baser er uorganiske baser såsom kaliumhydroxid, natriumhydroxid, kaliumcarbonat og natriumcarbonat samt tertiære aminer såsom pyridin 20 og triethylamin. Den mængde base, som skal anvendes, ligger normalt i området mellem 1 og 5 mol pr. mol af den 2-substituerede 1-(ω-halogenalkoxy)benzen. Når der ikke forekommer base, reagerer de 2-substituerede 1-(cø-aminoalkoxy)benzener med det under reaktionen dannede hydrogerihalogenid og omdannes til syreadditionssalte deraf.The presence of bases which neutralize the hydroxy halide formed during the reaction speeds up the reaction. Examples of such bases are inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, as well as tertiary amines such as pyridine 20 and triethylamine. The amount of base to be used is usually in the range of 1 to 5 moles per ml. moles of the 2-substituted 1- (ω-haloalkoxy) benzene. When no base is present, the 2-substituted 1- (co-aminoalkoxy) benzenes react with the hydrogeric halide formed during the reaction and are converted to acid addition salts thereof.
25 Syreadditionssalte af de 2-substituerede 1-(c«>-aminoalkoxy)benzener kan bekvemt fremstilles ved at bringe forbindelserne i kontakt med en passende syre.Acid addition salts of the 2-substituted 1- (C 1-4 aminoalkoxy) benzenes can be conveniently prepared by contacting the compounds with an appropriate acid.
De 2-substituerede 1-(ω-aminoalkoxy)benzener og syreadditionssaltene deraf kan renses ved omkrystallisation under anvendelse af et 30 passende opløsningsmiddel såsom alkohol-ether.The 2-substituted 1- (ω-aminoalkoxy) benzenes and their acid addition salts can be purified by recrystallization using a suitable solvent such as alcohol ether.
Farmakologisk afprøvning af de 2-substituerede l-(w-aminoalkoxy)-benzener har vist, at de er værdifulde som antidepressive midler, hvilket vises ved deres evne til at modvirke reserpin-hypotermi iPharmacological testing of the 2-substituted 1- (w-aminoalkoxy) benzenes has shown to be valuable as antidepressants, evidenced by their ability to counteract reserpine hypothermia in
DK 154070 BDK 154070 B
5 mus. Der er også fundet antikonvulsiv virkning hos de omhandlede forbindelser.5 mice. Anticonvulsant effects have also been found in the compounds of the present invention.
Forbindelserne er blevet afprøvet i mus for antidepressiv, sedativ, antikonvulsiv og anticholinerg virkning. Forbindelserne blev 5 administreret intraperitonealt, og forbindelsernes virkning blev sammenlignet med virkningen af amitriptylin.The compounds have been tested in mice for antidepressant, sedative, anticonvulsant and anticholinergic activity. The compounds were administered intraperitoneally, and the effect of the compounds was compared with that of amitriptyline.
Den antidepressive virkning blev vurderet ved antagonisme af re-serpininduceret (5 mg/kg intraperitonealt) hypotermi (P.S.J. Spencer i "Antidepressant Drugs", S. Garattini og M.N.G. Duhes, udgivere 10 Excerpta Medica Foundation, Amsterdam, side 194 -204 (1967)), og antireserpinvirkningen blev udtrykt som den relative styrke (amitriptylin = 1).The antidepressant effect was assessed by antagonism of re-serpin-induced (5 mg / kg intraperitoneal) hypothermia (PSJ Spencer in "Antidepressant Drugs", S. Garattini and MNG Duhes, publishers 10 Excerpta Medica Foundation, Amsterdam, pages 194-204 (1967) ) and the antireserpine effect was expressed as the relative potency (amitriptyline = 1).
LD50-Værdien blev beregnet efter Litchfield-Wilcoxon-metoden. Den CNS-depressive virkning blev bestemt efter forbindelsernes evne til 15 at forårsage neurologisk balance, hvilket blev målt ved muskelkontraktionsforsøg (S. Courvoisier, R. Duerot, L. Julou; "Psychotropic Drugs", S. Garattini og V. Ghetti, side 373, (1957)) og ved spontan motorisk aktivitet (den spontane motoriske aktivitet blev målt ved hjælp af et "ANIMEX"-apparatur).The LD50 value was calculated by the Litchfield-Wilcoxon method. The CNS depressant effect was determined by the ability of the compounds to cause neurological balance, as measured by muscle contraction experiments (S. Courvoisier, R. Duerot, L. Julou; "Psychotropic Drugs", S. Garattini and V. Ghetti, page 373 , (1957)) and by spontaneous motor activity (the spontaneous motor activity was measured by an "ANIMEX" apparatus).
20 Den antikonvulsive aktivitet blev bestemt Ved antagonisme af elektrochok-induceret tonikum-extensor (L.S. Goodman, M. Singh Grewal, W.C. Brown og E.A. Swinyard, J. Pharmacol, Exptal. Therap., 108, 168 (1953)).The anticonvulsant activity was determined by electro-shock tonic extensor antagonism (L.S. Goodman, M. Singh Grewal, W.C. Brown, and E.A. Swinyard, J. Pharmacol, Exptal. Therap., 108, 168 (1953)).
Den central-anticholinerge virkning blev målt ved at afprøve 25 tremorin-induceret tremor på mus (G.M. Everett, L.E. Bloucus og J.M.The central anticholinergic effect was measured by testing 25 tremorine-induced tremors in mice (G.M. Everett, L.E. Bloucus and J.M.
Sheppard, Science 124 79 (1956)).Sheppard, Science 124 79 (1956)).
Resultaterne er sammenfattet i nedenstående tabel I og II, hvor ED50-værdien er defineret som den dosis af forsøgsforbindelsen, som forhindrer 50% af det pågældende respons.The results are summarized in Tables I and II below, where the ED50 value is defined as the dose of the test compound that prevents 50% of the response in question.
DK 154070 BDK 154070 B
66
Tabel 1Table 1
Antireserpin-aktivitet i mus.Antireserpine activity in mice.
Forbindelse Relativ LD^q-værdi styrke (mg/kg 5 intra- peritonealt 2 - (4-methylaminobutoxy) diphenylme than- hydrochlorid 0,73 173 10 2 - (4-ethylaminobutoxy) diphenylme than- -hydrochlorid 0,53 120 2-(5-methylaminopentyloxy)diphenyl-15 methan-hydrochlorid 0,54 160 2 - ( 3 - dime thylaminopropoxy) diphenyl - methan-hydrochlorid 0,00 20 2- (4-methylaminobutoxy) diphenylether- -hydrochlorid 1,10 100 2 - (4- dimethylaminobutoxy) diphenylether- hydrochlorid 0,58 92 25 2-(5-methylaminopentyloxy)diphenylether- hydrochlorid 0,57 85 2- (4-methylaminobutoxy) diphenylsulfid-30 hydrochlorid 0,90 120 2 - (4- dimethylaminobutoxy) diphenylsulfid- hydrochlorid 0,70 130 35 2 - ( 3 -me thylaminopropoxy) diphenylsulfid- hydrochlorid 0,60 135 2 - ( 3 -me thylaminopropoxy) diphenylmethan- hydrochlorid 0,56 160 40 2 - ( 3 - dime thylaminopropoxy) diphenylmethan-hydrochlorid 0,00 2 - ( 2 - dimethylaminoethoxy) diphenylmethan-45 hydrochlorid 0,00 2 - ( 2 -me thylaminoethoxy ) diphenylmethan-hydrochlorid 0,00 50 2- (4-methylaminobutoxy) diphenylmethylmethan- hydrochlorid 0,66 140 2 - (4- dimethylaminobutoxy) diphenylme thylme - than-hydrochlorid 0,36 110 55Compound Relative LD₂ value (mg / kg 5 intraperitoneally 2- (4-methylaminobutoxy) diphenylme than hydrochloride 0.73 173 10 2- (4-ethylaminobutoxy) diphenylme than- hydrochloride 0.53 120 2- (5-methylaminopentyloxy) diphenylmethane hydrochloride 0.54 160 2- (3-dime thylaminopropoxy) diphenylmethane hydrochloride 0.00 20 2- (4-methylaminobutoxy) diphenyl ether hydrochloride 1.10 100 2 - ( 4- (dimethylaminobutoxy) diphenyl ether hydrochloride 0.58 92 25 2- (5-methylaminopentyloxy) diphenyl ether hydrochloride 0.57 85 2- (4-methylaminobutoxy) diphenylsulfide hydrochloride 0.90 120 2- (4-dimethylaminobutoxy) diphenylsulfide 2 - (3-thylaminopropoxy) diphenylsulfide hydrochloride 0.60 135 2 - (3-thylaminopropoxy) diphenylmethane hydrochloride 0.56 160 40 2- (3-dime thylaminopropoxy) diphenylmethane hydrochloride 0, 00 2- (2-Dimethylaminoethoxy) diphenylmethane hydrochloride 0.00 2- (2-Methylaminoethoxy) diphenylmethane hydrochloride 0.00 2- (4-methylaminobutoxy) diphenylmethylmethane hydrochloride 0.66 140 2- (4-dimethylaminobutoxy) diphenylmethylene than hydrochloride 0.36 110 55
DK 154070 BDK 154070 B
7 2-(3-dimethylaminopropoxy)diphenylmethyl- methan-hydrochlorid 0,34 155 2 - (4 -methylaminobutoxy ) diphenyl -hydro -5 chlorid 0,99 78 2-(4-aminobutoxy)diphenyl-hydrochlorid 0,59 137 2-(4- dimethylaminobutoxy) diphenyl -hydro -10 chlorid 0,45 100 amitriptylin 1,00 652- (3-dimethylaminopropoxy) diphenylmethyl methane hydrochloride 0.34 155 2- (4-methylaminobutoxy) diphenyl hydrochloride 0.99 78 2- (4-aminobutoxy) diphenyl hydrochloride 0.59 137 2- (4-dimethylaminobutoxy) diphenyl hydro-chloride 0.45 100 amitriptyline 1.00 65
15 Tabel IITable II
CNS-depressiv, antikonvulsiv og central-anticholinerg virkning i mus.CNS depressant, anticonvulsant, and central anticholinergic action in mice.
Antikonvul- Muskelre- Spontan mo- Antitremor 20 Forbindelse siv virk- laxerende torisk akti- in-ef- ning virkning vitetsunder- fekt trykkelse ED50-værdi ED50-værdi ED50-værdi ED50-værdi 25 (mg/kg (mg/kg (mg/kg (mg/kg intraperi- intraperi- intraperi- intraperi- tonealt) tonealt) tonealt) tonealt) 2-(4-methylaminobu-3 0 toxy)diphenylmethan- -hydrochlorid 45 80 70 »60 2-(4-methylaminobutoxy ) diphenylether- 35 -hydrochlorid 32 60 60 30 2- (4-me thylaminobutoxy ) diphenylsulfid- -hydrochlorid >60 50 >60 30 40 2-(3-methylaminopro-poxy)diphenylmethan- -hydrochlorid 40 65 90 42 45 2-(4-methylaminobu- toxy) diphenylmethyl- methan-hydrochlorid 25 >60 32 20 2 - (4-methylaminobu-50 toxy)diphenyl-hydrochlorid 14 40 30 20Anti-convulsant Muscle re- Spontaneous mo- Antitremor 20 Compound antiviral activating toric actin action effect underfed pressure ED50 value ED50 value ED50 value ED50 value 25 (mg / kg (mg / kg (mg) / kg (mg / kg intraperi-intraperi-intraperi-intraperitoneal) toneal) toneal) toneal) 2- (4-methylaminobutoxyl) diphenylmethane hydrochloride 45 80 70 60 2- (4-methylaminobutoxy) diphenyl ether 35 hydrochloride 32 60 60 30 2- (4-methylethylobutoxy) diphenylsulfide hydrochloride> 60 50> 60 30 40 2- (3-methylaminopropoxy) diphenylmethane hydrochloride 40 65 90 42 45 2- (4- methyl aminobutoxy) diphenylmethyl methane hydrochloride 25> 60 32 20 2- (4-methylaminobutoxy) diphenyl hydrochloride 14 40 30 20
DK 154070 BDK 154070 B
8 2-( 4 -aminobutoxy)di- phenyl-hydrochlorid 14 50 40 60 amitriptylin 16 15 18 4 58 2- (4-Aminobutoxy) diphenyl hydrochloride 14 50 40 60 amitriptyline 16 15 18 4 5
Det fremgår af tabelerne I og II, at de 2-substituerede l-(cd-amino-alkoxy)benzener har antireserpin-virkning, som kan sammenlignes med virkningen af amitriptylin, medens de har lav toxicitet og svag CNS-depressiv og anticholinerg virkning.Tables I and II show that the 2-substituted 1- (cd-amino-alkoxy) benzenes have antireserpine activity comparable to that of amitriptyline while having low toxicity and weak CNS depressant and anticholinergic activity.
10 De omhandlede forbindelser kan administreres på en hvilken som helst måde, som bevirker lindring af depressionstilstande hos varmblodede dyr. F.eks. kan administrationen foretages parenteralt, subcutant, intravenøst, intramuskulært eller intraperitonealt. Alternativt eller samtidig kan administrationen foretages ad oral vej. Den ad-15 ministrerede dosis afhænger af patientens alder, helbredstilstand og vægt, depressionens grad, arten af eventuel samtidig behandling, behandlingshyppigheden og arten af den ønskede virkning. En daglig dosis af den aktive forbindelse vil almindeligvis ligge mellem ca.The compounds of the present invention may be administered in any manner which relieves depression conditions in warm-blooded animals. Eg. the administration may be performed parenterally, subcutaneously, intravenously, intramuscularly or intraperitoneally. Alternatively or at the same time, administration may be performed by oral route. The administered dose depends on the patient's age, health condition and weight, the degree of depression, the nature of any concomitant treatment, the frequency of treatment and the nature of the desired effect. A daily dose of the active compound will generally be between about
0,5 og 50 mg/kg legemsvægt. Normalt er 1-30 mg/kg/dag i én eller 20 flere daglige doser i stand til at medføre det ønskede resultat.0.5 and 50 mg / kg body weight. Usually, 1-30 mg / kg / day in one or 20 multiple daily doses is capable of achieving the desired result.
Forbindelsen med formlen I kan anvendes i dosisformer såsom tabletter, kapsler, pulvere, flydende opløsninger, suspensioner eller eliksirer til oral administration eller sterile flydende præparater såsom opløsninger eller suspensioner til parenteral anvendelse. I 25 sådanne præparater forekommer den aktive bestanddel almindeligvis i en mængde på mindst 0,5 vægtprocent, baseret på præparatets totalvægt, og ikke mere end 90 vægtprocent.The compound of formula I can be used in dosage forms such as tablets, capsules, powders, liquid solutions, suspensions or elixirs for oral administration or sterile liquid preparations such as solutions or suspensions for parenteral use. In 25 such compositions, the active ingredient is generally present in an amount of at least 0.5% by weight, based on the total weight of the composition, and not more than 90% by weight.
Foruden det aktive stof vil præparatet indeholde et fast eller flydende, ikke-toxisk farmaceutisk bærestof for aktivstoffet. I en 30 udførelsesform for præparatet kan det faste bærestof være en kapsel af den almindelige gelatinetype. I kapslen kan der være ca. 30-60 vægtprocent af en forbindelse med formlen I og 70-40 vægtprocent af et bærestof. I en anden udførelsesform kan den aktive bestanddel tabletteres med eller uden adjuvanser eller fyldes i pulverpakker.In addition to the active substance, the composition will contain a solid or liquid, non-toxic pharmaceutical carrier for the active substance. In one embodiment of the composition, the solid carrier may be a capsule of the ordinary gelatin type. The capsule may contain approx. 30-60% by weight of a compound of formula I and 70-40% by weight of a carrier. In another embodiment, the active ingredient may be tableted with or without adjuvants or filled into powder packs.
35 Disse kapsler, tabletter og pulvere består almindeligvis af ca. 5 -These capsules, tablets and powders usually consist of approx. 5 -
DK'154070 BDK'154070 B
9 ca. 95, fortrinsvis 25-90, vægtprocent af det aktive stof. Disse dosisformer indeholder fortrinsvis ca. 5 - ca. 500 mg aktivstof, især ca. 25 - ca. 250 mg.9 approx. 95, preferably 25-90, weight percent of the active substance. These dosage forms preferably contain approx. 5 - approx. 500 mg of active substance, in particular approx. 25 - approx. 250 mg.
Det farmaceutiske bærestof kam være en steril væske såsom vand og 5 olier, herunder sådanne af jordolieoprindelse eller af animalsk, vegetabilsk eller syntetisk oprindelse, f.eks. jordnøddeolie,, sojabønneolie, mineralolie og sesamolie.The pharmaceutical carrier comb is a sterile liquid such as water and oils, including those of petroleum origin or of animal, vegetable or synthetic origin, e.g. peanut oil ,, soybean oil, mineral oil and sesame oil.
Almindeligvis er vandig saltopløsning, vandig dextrose og beslægtede sukkeropløsninger og glycoler såsom ethylenglycol, propylenglycol og 10 polyethylenglycol foretrukne flydende bærestoffer. Især til injicerbare opløsninger såsom saltvand ligger indholdet mellem ca.Generally, aqueous saline, aqueous dextrose and related sugar solutions and glycols such as ethylene glycol, propylene glycol and polyethylene glycol are preferred liquid carriers. Especially for injectable solutions such as saline, the content is between approx.
0,5 og 20 vægtprocent, fortrinsvis mellem ca. 1 og 10 vægt-procent, beregnet på den aktive bestanddel.0.5 to 20% by weight, preferably between ca. 1 and 10% by weight, based on the active ingredient.
Som ovenfor anført kan midler til oral administration foreligge som 15 en passende suspension eller sirup, i hvilken aktivstoffet .normalt udgør ca. 0,5 -10 vægtprocent- Det farmaceutiske bærestof i sådanne præparater kan være et vandigt bærestof såsom et aromatiseret vand, en sirup eller en farmaceutisk slimart.As noted above, agents for oral administration may be present as a suitable suspension or syrup in which the active ingredient normally constitutes approx. The pharmaceutical carrier in such compositions may be an aqueous carrier such as an aromatized water, a syrup or a pharmaceutical mucus.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående 20 eksempler:The process according to the invention is further illustrated by the following examples:
Eksempel 1.Example 1.
En opløsning af 5,0 g 2-(4-br©mbutoxy)diphenylether i 30 ml 40%'s dimethylamin-vandig opløsning og 100 ml ethanol lades henstå ved stuetemperatur i 8 timer. Ethanolet og overskydende dimethylamin 25 afdestilleres i vakuum, der tilsættes 2N vandig natriumhydroxid opløsning, og reaktionsproduktet ekstraheres med ether. Den etheriske opløsning destilleres, der tilsættes 2N HCl-opløsning, og opløsningen inddampes til tørhed.A solution of 5.0 g of 2- (4-bromobutoxy) diphenyl ether in 30 ml of 40% dimethylamine aqueous solution and 100 ml of ethanol is left at room temperature for 8 hours. The ethanol and excess dimethylamine 25 are distilled off in vacuo, 2N aqueous sodium hydroxide solution is added and the reaction product is extracted with ether. The ethereal solution is distilled, 2N HCl solution is added and the solution is evaporated to dryness.
Remanensen omkrystalliseres af ethanol-ether, hvorved der fås 4,6 g 30 (89% af det teoretiske) 2-(4-dimethylaminobutoxy)diphenylether-hy- drochlorid, smeltepunkt 131 -135°C.The residue is recrystallized from ethanol-ether to give 4.6 g of 30 (89% of theory) 2- (4-dimethylaminobutoxy) diphenyl ether hydrochloride, mp 131-135 ° C.
DK 154070 BDK 154070 B
1010
Analyse:Analysis:
Beregnet for C18H23N02.HC1: C 67,17 H 7,52 N 4,35Calcd. For C18 H23 NO2. HCl: C, 67.17; H, 7.52; N, 4.35
Fundet : C 67,35 H 7,46 N 4,25.Found: C, 67.35; H, 7.46; N, 4.25.
Eksempel 2.Example 2.
5 En opløsning af 5,0 g 2-(5-brompentyloxy)diphenylether og 6 g methylamin i 100 ml ethanol opvarmes til en temperatur på 50°C i 2 timer i et lukket rør. Ethanolet og overskydende methylamin destilleres i vakuum, der tilsættes 2N vandig natriumhydroxidopløsning, og reaktionsproduktet ekstraheres med ether. Der ledes tør 10 hydrogenchloridgas ind i den etheriske opløsning, og bundfaldet isoleres ved filtrering. Ved omkrystallisation af ethanol-ether fås 4,2 g (88% af det teoretiske) 2-(5-methylaminopentyloxy)diphe-nylether-hydrochlorid, smeltepunkt 88 -90°C.A solution of 5.0 g of 2- (5-bromopentyloxy) diphenyl ether and 6 g of methylamine in 100 ml of ethanol is heated to a temperature of 50 ° C for 2 hours in a closed tube. The ethanol and excess methylamine are distilled in vacuo, 2N aqueous sodium hydroxide solution is added and the reaction product is extracted with ether. Dry 10 hydrogen chloride gas is fed into the ethereal solution and the precipitate is isolated by filtration. Recrystallization from ethanol-ether gives 4.2 g (88% of theory) of 2- (5-methylaminopentyloxy) diphenyl ether hydrochloride, mp 88 -90 ° C.
Analyse: 15 Beregnet for C18H23N02.HC1: C 67,17 H 7,52 N 4,35Calcd for C 18 H 23 NO 2 .HCl: C 67.17 H 7.52 N 4.35
Fundet : C 67,30 H 7,64 N 4,37.Found: C, 67.30; H, 7.64; N, 4.37.
Eksempel 3.Example 3
En opløsning af 5,0 g 2-(4-brombutoxy)diphenyl i 10 g isopropylamin lades henstå ved stuetemperatur i 5 timer. Isopropy laminen af dampes i 20 vakuum, der tilsættes 2N vandig natriumhydroxidopløsning, og reaktionsproduktet ekstraheres med ether. Den etheriske opløsning destilleres, der tilsættes 2N HCl-opløsning, og opløsningen inddampes til tørhed. Remanensen omkrystalliseres af ethanol-ether, hvorved der fås 4,5 g (88% af det teoretiske) 2-(4-isopropylamino-25 butoxy)diphenyl-hydrochlorid, smeltepunkt 172 -177°C.A solution of 5.0 g of 2- (4-bromobutoxy) diphenyl in 10 g of isopropylamine is left at room temperature for 5 hours. The isopropyl laminate is evaporated in vacuo, 2N aqueous sodium hydroxide solution is added and the reaction product is extracted with ether. The ethereal solution is distilled, 2N HCl solution is added and the solution is evaporated to dryness. The residue is recrystallized from ethanol ether to give 4.5 g (88% of theory) of 2- (4-isopropylamino-butoxy) diphenyl hydrochloride, mp 172 -177 ° C.
Analyse:Analysis:
Beregnet for G19H250N.HC1: G 71,34 H 8,19 N 4,38Calculated for G19H250N.HCl: G 71.34 H 8.19 N 4.38
Fundet : C 70,95 H 7,94 N 4,48.Found: C, 70.95; H, 7.94; N, 4.48.
CM 154070 BCM 154070 B
1111
Analyse:Analysis:
Beregnet for C2oH28NO-HC1· C 71,94 H 8,45 N 4,20Calcd for C 20 H 28 NO-HCl · C 71.94 H 8.45 N 4.20
Fundet : C 71,80 H 8,58 N 4,05.Found: C 71.80 H 8.58 N 4.05.
Eksempel 4-47.Examples 4-47.
5 De forbindelser, som er anførte i den nedenstående tabel, er fremstillet efter den i eksempel 1, 2 eller 3 anførte metode under anvendelse af relevante udgangsmaterialer:The compounds listed in the table below are prepared according to the method of Examples 1, 2 or 3 using relevant starting materials:
DK 154070BDK 154070B
12 +> <D +j oooo cop- oo in com oo in r*· C Φ Z ro H ro m ro r-t in ro N » in tt Q) tyitJ - ^ * » * *· » « * *· « w<UC* τ rr ^ ^ ττ o< «* ro ^ p---— " " ' " III 1-- r-π o m σι i—i σιο om r-t o ιη H ooo12 +> <D + j oooo cop- oo in com oo in r * · C Φ Z ro H ro m ro rt in ro N »in tt Q) tyitJ - ^ *» * * · »« * * · «w <UC * τ rr ^ ^ ττ o <«* ro ^ p ---—" "'" III 1-- r-π about σι i — i σιο about rt o ιη H ooo
fO Λ s H (M H (O H ro O O "9· ^ m HfO Λ s H (M H (O H ro O O „9 · ^ m H
g ·· ^ k ^ ^ ^ ^ ^ h rtj .. 4J 00 00 0000 0000 Γ-'t" oooo Γ" l" -P in ·—----—--- top « co τΐ< rr -o’ o oo ro «9· vo ro o 5η φ U ro iH ro ro rom vo o ooo ro id φ rQ * * » * fcw hk » % ·» *-g ·· ^ k ^ ^ ^ ^ ^ h rtj .. 4J 00 00 0000 0000 Γ-'t "oooo Γ" l "-P in · —--------- top« co τΐ <rr -o 'o oo ro «9 · vo ro o 5η φ U ro iH ro ro rom vo o ooo ro id φ rQ * *» * fcw hk »% ·» * -
£> o) ιΗ ιΗ Η Η Η H O O ri H VOID£> o) ιΗ ιΗ Η Η Η H O O ri H VOID
®2 p* r^rv r~ p~ p~ r~ r*· r" void ___ - , , _-- ______1_ m 00 · vo O vo®2 p * r ^ rv r ~ p ~ p ~ r ~ r * · r "void ___ -,, _-- ______1_ m 00 · vo O vo
i cn 0\ O H H Hi cn 0 \ O H H H
<0 *“ H 00 Η Η O H<0 * “H 00 Η Η O H
1 I I I I I1 I I I I I
’-'•i m m -σ pv cm ^S^cn · O H oo h'-' • i m m -σ pv cm ^ S ^ cn · O H oo h
|δΛϋ H Η Η H| δΛϋ H Η Η H
M ftO 00M ftO 00
I II I
ι—I O I •Η PAι — I O I • Η PA
ω £βφ H CM CM Η H CMω £ βφ H CM CM Η H CM
ε tu λ _ ω era g · >) ·η o> a> u fa Η ϋ 01 C ·______ ω cε tu λ _ ω era g ·>) · η o> a> u fa Η ϋ 01 C · ______ ω c
O Η Η Η Η Η HO Η Η Η Η Η H
•HOJq ϋ U O U O• HOJq ϋ U O U O
^ g* k a a a a a •H Di^ g * k a a a a a • H Di
Ό CΌ C
T3 ·Ρ __<5 tp____;______T3 · Ρ __ <5 tp ____; ______
<D<D
to cn cn *Λ cn cn >-i tea λ ri aa ^ <H o o a w a o o a •o \ / O o o \ / o •Η 25 » a fc 5¾ λ m ^ j· in -a·to cn cn * Λ cn cn> -i tea λ ri aa ^ <H o o a w a o o a • o \ / O o o \ / o • Η 25 »a fc 5¾ λ m ^ j · in -a ·
p c3‘ «Ί CM CM CMp c3 '«Ί CM CM CM
a1 g. g a a a § A-<g> A-<p> A·^ A-^P> ^ A-^> I i i s “ b b bd <b! 6a1 g. g a a a § A- <g> A- <p> A · ^ A- ^ P> ^ A - ^> I i i s “b b bd <b! 6
HH
0 § .σ m vo p- oo σι to · H C ___ 130 § .σ m vo p- oo σι to · H C ___ 13
DK 154070BDK 154070B
r- id m « cn 04 o co oo® «> h ή ή η £ in £ £ ® «« λ «r ™ ^ rr «r ®__tt ^r ^ ^ ^__^ -__* ^r- id m «cn 04 o co oo®«> h ή ή η £ in £ £ ® «« λ «r ™ ^ rr« r ®__tt ^ r ^ ^ ^ __ ^ -__ * ^
SS ' S3 SS 1 s 5 ‘ SS SS SSSS 'S3 SS 1 s 5' SS SS SS
_ ri_ ri......., t-“ Γ-- »» j «*« ri ri ri = . <°_ ri_ ri ......., t- “Γ--» »j« * «ri ri ri =. <°
^ m oo -*r o«! **3· <«r lo ^ £? °°S ®S^ m oo - * r o «! ** 3 · <«r lo ^ £? °° S ® S
mco en oo o ® °1° ® n· r- m m οι H ro rn o i? JT* io id \D iø ®io vor^ r~- ^ ; *" ^ oo vo c\/ r* c\j ® O -d- O -3- >Λ ,Γ» “7mco en oo o ® ° 1 ° ® n · r- m m οι H ro rn o i? JT * io id \ D iø ®io vor ^ r ~ - ^; * "^ oo vo c \ / r * c \ j ® O -d- O -3-> Λ, Γ» "7
H H Η Η Η Η HH H Η Η Η Η H
I I I I .i 1 i o o\ cn oo cn in O J- ON J· -a- “7 *\I I I I .i 1 i o o \ cn oo cn in O J- ON J · -a- “7 * \
HH Η H H HHH Η H H H
Η . H CM Η H ^ 1-1Η. H CM Η H ^ 1-1
Η Η Η Η Η Η HΗ Η Η Η Η Η H
O O U O O U OO O U O O U O
a s a a a w Ka s a a a w K
in cn cn o cn Jp cn a Jpa cn cn o cn Jp cn a Jp
§s s g «r s f § o“ 1 y y I y b Sn I§S s g «r s f § o“ 1 y y I y b Sn I
!ø 10 iø fy fy fy y I I 1 » £* cv sP a O CO CO (0 S g 0-0 1 b b b ; b b b b! ø 10 iø fy fy fy y I I 1 »£ * cv sP a O CO CO (0 S g 0-0 1 b b b; b b b b b
0 I0 I
m M-----J___—--- 0)m M ----- J ___—--- 0)
HH
0j I0j I
s qj o H m γο·3< in ids qj o H m γο · 3 <in id
Ulc—|c—I c—I HH Η HUlc— | c — I c — I HH Η H
X HX H
DK 154070 BDK 154070 B
14 o m (Din oo co rr in o η oo^r cm o ro cm in ^ oh oo vo mm * ^ ^ ^ * * fe *. *» k 'Τ 'θ' Ό’Ό' m in <f if ·ο< m oo σι oo ·—i vocm οιη h rr m Ho σ»σι cm n io oo <n o oooo oooo r*· t"· t*«· r* r* γ>·οο «t o 5* in oo Si oo <5 F~ o 5 δ m oo mm ο o η ο oh ιοο < η η η H oo σ>σ» o o oh j η Γ» i>» r* r-' r~ lovo lor·« η C\ H -t 00 00 J- 00 H -¾- Η *Λ -Cf -3·14 om (Your oo co rr in o η oo ^ r cm o ro cm in ^ oh oo vo mm * ^ ^ ^ * * fe *. * »K 'Τ' θ 'Ό'Ό' m in <f if · ο <m oo σι oo · —i vocm οιη h rr m Ho σ »σι cm n io oo <no oooo oooo r * · t" · t * «· r * r * γ> · οο« to 5 * in oo Si oo <5 F ~ o 5 δ m oo mm ο o η ο oh ιοο <η η η H oo σ> σ »oo oh j η Γ» i> »r * r- 'r ~ lovo lor ·« η C \ H -t 00 00 J- 00 H -¾- Η * Λ -Cf -3 ·
IH Η Η Η HIH Η Η Η H
1Λ I I I I I1Λ I I I I I I
«. c\i m m cm . vo a- -t h v\ -3· *y Η Η Η Η Η H .'. c \ i m m cm. vo a- -t h v \ -3 · * y Η Η Η Η Η H.
HH
CM .CM Η Η Η HCM .CM Η Η Η H
Η Η Η Η Η HΗ Η Η Η Η H
ου υ υ o o a a a a a aου υ υ o o a a a a a a a
CA CA CA CA CACA CA CA CA CA CA
CpoOjPf <p oCpoOjPf <p o
\ / . \ / ^ O ίϋ B\ /. \ / ^ O ίϋ B
S? > V i? V “ »« »“ J Jf ~ ~ O O. ^ cm « « ~\J/\ xJT\ g S -3 5S? > V i? V “» «» “J Jf ~ ~ O O. ^ cm« «~ \ J / \ xJT \ g S -3 5
* v ;v ϊ/> io x^> tQ* v; v ϊ /> io x ^> tQ
Μ te a a \1 j ' —' i o-υ o-o ϊ b b o o o o u o M---------' d)Μ te a a \ 1 j '-' i o-υ o-o ϊ b b o o o o u o M --------- 'd)
rHrh
! - 3 3 s h «! - 3 3 s h «
MM
H __H __
Claims (16)
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7474175 | 1975-06-19 | ||
| JP50074741A JPS598265B2 (en) | 1975-06-19 | 1975-06-19 | Omega - Aminoalkoxybiphenyl Rui Mataha Sonosanfucaennoseizohou |
| US61200675A | 1975-09-10 | 1975-09-10 | |
| US61200575A | 1975-09-10 | 1975-09-10 | |
| US61200675 | 1975-09-10 | ||
| US61200575 | 1975-09-10 | ||
| US62705975A | 1975-10-30 | 1975-10-30 | |
| US62705975 | 1975-10-30 | ||
| US63514775 | 1975-11-25 | ||
| US05/635,147 US4024282A (en) | 1975-11-25 | 1975-11-25 | Pharmaceutically active 2-(3-alkylaminopropoxy)diphenylmethanes |
| US64652176A | 1976-01-05 | 1976-01-05 | |
| US64652176 | 1976-01-05 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK276276A DK276276A (en) | 1976-12-20 |
| DK154070B true DK154070B (en) | 1988-10-10 |
| DK154070C DK154070C (en) | 1989-02-27 |
Family
ID=27551303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK276276A DK154070C (en) | 1975-06-19 | 1976-06-18 | ANALOGY PROCEDURE FOR THE PREPARATION OF 2-SUBSTITUTED 1- (OMEGA AMINOAL COXY) BENZEN DERIVATIVES |
Country Status (7)
| Country | Link |
|---|---|
| CH (1) | CH623301A5 (en) |
| DE (1) | DE2627227A1 (en) |
| DK (1) | DK154070C (en) |
| FR (1) | FR2315913A1 (en) |
| GB (1) | GB1512880A (en) |
| NL (1) | NL188944C (en) |
| SE (1) | SE430156B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1086733A (en) * | 1976-12-06 | 1980-09-30 | Ryoji Kikumoto | Pharmaceutically active 2-substituted-1-(omega- aminoalkoxy) benzenes |
| US4220603A (en) * | 1977-10-07 | 1980-09-02 | Mitsubishi Chemical Industries, Limited | Pharmaceutically active (omega-aminoalkoxy)bibenzyls |
| DE3233828A1 (en) * | 1982-09-11 | 1984-03-15 | Basf Ag, 6700 Ludwigshafen | ARYLOXYALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR CONTROLLING UNWANTED PLANT GROWTH |
| JPS5955829A (en) * | 1982-09-22 | 1984-03-31 | Eisai Co Ltd | Agent for improvement and remedy of hyponoia caused by cerebral organic disorder |
| JPS61210063A (en) * | 1985-03-14 | 1986-09-18 | Mitsubishi Chem Ind Ltd | Aryl sulfone compound |
| DK368687A (en) * | 1986-11-21 | 1988-05-22 | Cheminova As | AMINOALCYLED HYDROXY COMPOUNDS AND THEIR USE AS FUNGICIDES |
| CA2153605A1 (en) | 1994-07-12 | 1996-01-13 | Akihiro Tobe | Treatment of hyperkinetic disorders |
| EP0982300A3 (en) * | 1998-07-29 | 2000-03-08 | Societe Civile Bioprojet | Non-imidazole alkylamines as histamine H3 - receptor ligands and their therapeutic applications |
| EP0978512A1 (en) * | 1998-07-29 | 2000-02-09 | Societe Civile Bioprojet | Non-imidazole aryloxy (or arylthio) alkylamines as histamine H3-receptor antagonists and their therapeutic applications |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2703324A (en) * | 1950-08-30 | 1955-03-01 | Bristol Lab Inc | Basic ethers of aralkyl phenols and salts thereof |
| US2768207A (en) * | 1951-02-05 | 1956-10-23 | Bristol Lab Inc | Unitary process for the production of 2-benzylphenyl beta-dimethylaminoethyl ether dihydrogen citrate |
| US2870150A (en) * | 1954-11-29 | 1959-01-20 | Abbott Lab | Morpholine ethers |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1053523B (en) * | 1949-11-14 | 1959-03-26 | Bristol Lab Inc | Process for the preparation of new therapeutically active compounds |
| GB1133334A (en) * | 1965-04-02 | 1968-11-13 | Vantorex Ltd | Stilbene ethers and their preparation |
| CH563336A5 (en) * | 1972-01-28 | 1975-06-30 | Robins Co Inc A H |
-
1976
- 1976-06-18 DE DE19762627227 patent/DE2627227A1/en active Granted
- 1976-06-18 NL NL7606668A patent/NL188944C/en not_active IP Right Cessation
- 1976-06-18 FR FR7618642A patent/FR2315913A1/en active Granted
- 1976-06-18 GB GB2544276A patent/GB1512880A/en not_active Expired
- 1976-06-18 SE SE7607013A patent/SE430156B/en unknown
- 1976-06-18 DK DK276276A patent/DK154070C/en not_active IP Right Cessation
- 1976-06-18 CH CH783376A patent/CH623301A5/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2703324A (en) * | 1950-08-30 | 1955-03-01 | Bristol Lab Inc | Basic ethers of aralkyl phenols and salts thereof |
| US2768207A (en) * | 1951-02-05 | 1956-10-23 | Bristol Lab Inc | Unitary process for the production of 2-benzylphenyl beta-dimethylaminoethyl ether dihydrogen citrate |
| US2870150A (en) * | 1954-11-29 | 1959-01-20 | Abbott Lab | Morpholine ethers |
Also Published As
| Publication number | Publication date |
|---|---|
| CH623301A5 (en) | 1981-05-29 |
| NL7606668A (en) | 1976-12-21 |
| FR2315913A1 (en) | 1977-01-28 |
| DE2627227C2 (en) | 1989-03-30 |
| NL188944B (en) | 1992-06-16 |
| GB1512880A (en) | 1978-06-01 |
| DK154070C (en) | 1989-02-27 |
| DE2627227A1 (en) | 1976-12-30 |
| SE7607013L (en) | 1976-12-20 |
| DK276276A (en) | 1976-12-20 |
| NL188944C (en) | 1992-11-16 |
| SE430156B (en) | 1983-10-24 |
| FR2315913B1 (en) | 1981-12-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS61233654A (en) | N-(2-amino alicyclic)-arylacylamide and manufacture | |
| EP0000896B1 (en) | Propenyl amines, processes for their production and pharmaceutical compositions containing them | |
| DK154070B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF 2-SUBSTITUTED 1- (OMEGA-AMINOAL COXY) BENZENER DERIVATIVES | |
| US3974158A (en) | 2-(Substituted anilino)methylmorpholines | |
| EP0004066B1 (en) | 2-(4-aminobutoxy)stilbenes and pharmaceutical compositions containing these substances | |
| US3752810A (en) | Substituted n aminoalkyl arylamino imidazolines-(2) | |
| FI80448C (en) | Process for the preparation of novel therapeutically useful piperazine zinc arboxamide derivatives | |
| US4024282A (en) | Pharmaceutically active 2-(3-alkylaminopropoxy)diphenylmethanes | |
| US2485550A (en) | Quaternary salts of carbamic acid esters of tertiary-hydroxybenzyl-amines | |
| US3574221A (en) | Derivatives of aminoalkyl pyridines | |
| IE43258B1 (en) | 1-phenoxypenyl-piperazine derivatives, process for their preparation and pharmaceutical compositions containing them | |
| US4071559A (en) | Pharmaceutically active 2-omega-aminoalkoxydiphenyls | |
| DK154071B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF SUBSTITUTED PETROL GIVEN | |
| US4060641A (en) | Pharmaceutically active 2-(3-alkylaminopropoxy)diphenylmethanes | |
| US4091114A (en) | Pharmaceutically active 2-omega-aminoalkoxydiphenylmethanes | |
| JPS606349B2 (en) | 2-(ω-aminoalkoxy)diphenylmethanes | |
| US3957789A (en) | Diaminopropanols | |
| EP0001759B1 (en) | (omega-aminoalkoxy) bibenzyls, processes for their preparation and pharmaceutical compositions containing these substances | |
| FI60006C (en) | PROCEDURE FOR THE PHARMACOLOGICAL PROPERTIES OF VARIABLE N- (1- (3,4-METHYLENDIOXIFENYL) PROPYL (2)) - N '- (SUBSTITUTED PHENYL) PIPERAZINER OCH DERAS SYRAADDITIONSSALTER | |
| CA1088535A (en) | Pharmaceutically active 2-substituted-1-(omega- aminoalkoxy)benzenes | |
| US4061776A (en) | Pharmaceutically active 2-omega-aminoalkoxydiphenyl ethers | |
| FI68041C (en) | PROCEDURE FOR THE FRAMSTATION OF ORTHOS SUBSTITUTES FENOXY-ALKYLAMINODERIVAT | |
| US4100299A (en) | Pharmaceutically active 2-omega-aminoalkoxydiphenylmethylmethanes | |
| DAHLBOM | Substituted 1, 3-Diamino-2-propanols RICHARD DAHLBOM* and ALFONS MISIORNY | |
| US4140779A (en) | Aryloxy propyldiamines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |