FI68041C - PROCEDURE FOR THE FRAMSTATION OF ORTHOS SUBSTITUTES FENOXY-ALKYLAMINODERIVAT - Google Patents

Description

1 -.....__ π Γβ1 „advertisement publication. λ λ Β 11 UTLÄGGNINGSSKRIFT 6 8041 (45) ['; c n f i.r. - J: -. t / 51) Kvlk * / lntCl4 C 07 C 93 / ° 6 'U9 / 32' (51) Kv.k. /lnt.CI. c 07 D 295/08 FINLAND —FINLAND (21) Patenttlhememu * - Patentansdknlng 763324 (22) Filing date - Ansdkningsdag 19.11.76 (EN) (23) Starting date - Giltighetsdag 19.11.76 (41) Published public - Blivlt offentlig 20.05.78

National Board of Patents and Registration / 44) Date of display and publication. - 07 Rq

Patent-och registerstyrelsen 'Ansökan utlagd och utl.skrlften publicerad D' -> (32) (33) (31) Privilege requested — Begärd priority (71) Mitsubishi Chemical Industries Limited, 5-2, Marunouchi 2-chome, Chiyoda-ku , Tokyo, Japan-Japan (JP) (72) Ryoji Kikumoto, Tokyo, Akihiro Tobe, Kanagawa,

Shinji Tonomura, Tokyo, Hidenobu Ikoma, Kanagawa,

Kazuo Honda, Kanagawa, Japan-Japan (JP) (74) Oy Kolster Ab (54) Method for the preparation of ortho-substituted phenoxyalkylamino derivatives - Förfarande för framstälIning av ortosubstitue-Rade phenoxyalkylamino derivatives L. C. Cheney et al. in J. Am. Chem. Soc.,

Bd 71 (1949), pages 60-64, describes various diphenylmethane derivatives having a substituent in the o-position, for example 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 2-morpholinoethoxy, 2- (1-piperidyl) -ethoxy, 2-isopropylaminoethoxy, 3- (1-piperidyl) propoxy, 3-dimethylaminopropoxy and 3-dibutylaminopropoxy. This publication further describes that 2- (2-aminoethoxy) diphenylmethane and 2- (3-aminopropoxy) diphenylmethane have antihistaminic and local anesthetic activity in animal experiments.

It was experimentally found that 2- (3-dimethylaminopropoxy) -diphenylmethane described in the publication has no antidepressant effect.

68041

The invention relates to a process for the preparation of therapeutically active orthosubstituted and phenoxyalkylamino derivatives of the general formula (I), or of their pharmaceutically acceptable acid addition salts, in the formula where benzyl and n are * 4 or 5, is C 1 -C 4 alkylamino or 1-piperidyl; when R 2 is benzyl and n is 3, it is C 1 -C 1 alkylamino; when there is phenoxy, R 1 is amino, C 1 -C 4 alkylamino or dialkylamino, where the sum of carbon atoms is 3-6 and n is 4 or 5; when there is phenylthio and n is 3, R 1 is C 1 -C 4 alkyl-amino; when R 1 is phenylthio and n is 4, R 1 is amino, C 1 -C 4 alkylamino, dialkylamino wherein the sum of carbon atoms is 2-6, or morpho-Lino; when R 2 is phenylthio and n is 5, R 1 is a dialkylamino wherein the sum of carbon atoms is 2-6, or morpholino; when R 2 is 1-phenylethyl and n is 4, is amino, C 1 -C 4 alkylamino or dialkylamino wherein the sum of carbon atoms is 2-6; when R 1 is 1-phenylethyl and n is 3, R 2 is dimethylamino; and when R 1 is phenyl, R 1 is amino, alkylamino or dialkylamino wherein the sum of carbon atoms is 2-6, and n is 4.

The process according to the invention is characterized in that 2-substituted-1- (omega-haloalkoxy) of the general formula (II) is administered.

0- (CH0) X

2 n 2 et 1) • ky wherein X is a halogen atom and R 1 and n are as defined above, react with an amine of general formula (III), R - H (111) wherein R 1 is as defined above, and optionally converting the resulting compound to a salt by reacting it with an acid.

3 68041

Specific examples of compounds of general formula (I) to be prepared according to the invention: 2- (4-methylaminobutoxy) phenylphenane, 2- (4-ethylaminobutoxy) diphenylmethane, 2- (5-methylaminopentyloxy) diphenylmethane, 2- (5-Dimethylaminopentyloxy) -diphenylmethane! , 2-N- (1-piperidyl) -butoxy-diphenylmethane, 2- (4-aminobutoxy) diphenyl ether, 2- (4-methylaminobutoxy) diphenyl ether, 2- (4-dimethylaminobutoxy) diphenyl ether, 2- (5-Methylaminopentyloxy) diphenyl ether, 2- (5-dimethylaminopentyloxy) diphenyl ether, 2- (3-methylaminopropoxy) diphenyl sulfide, 2- (4-aminobutoxy) diphenyl sulfide, 2- (4-methylaminobutoxy) -diphenylsulfide, 2- (4-dimethylaminobutoxy) -diphenylsulfide, 2- (4-morpholinobutoxy) -diphenylsulfide, 2- (5-methylaminopentyloxy) -diphenylsulfide, 2- (5-dimethylaminopentyloxy) -diphenylsulfide , 2- (3-methylaminopropoxy) diphenylmethane, 2- (3-ethylaminopropoxy) diphenylmethane, 2- (3-dimethylaminopropoxy) diphenylmethylmethane, 2- (4-aminobutoxyphenylmethylmethane, 2- (4-methylaminophenethane) 2-methylmethylmethane - (4-dimethylaminobutoxy) -diphenylmethyl methane, 2- (4-aminobutoxy) -diphenyl, 2- (4-methylaminobutoxy) -diphenyl, 2- (4-ethylaminobutyl) oxy) diphenyl, 2- (4-isopropylaminobutoxy) diphenyl, 2- (4-dimethylaminobutoxy) diphenyl, 68041

Salts of the compounds of general formula I may be derived from organic or inorganic acids. Specific examples of acids used in salt formation include acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, malic acid, maleic acid, citric acid, benzoic acid, toluenesulfonic acid, methylsulfonic acid, bromic acid, hydrochloric acid, hydrochloric acid, hydrochloric acid,

Highly preferred compounds of general formula I are: 2- (4-methylaminobutoxy) diphenylmethane, 2- (4-ethylaminobutoxy) diphenylmethane, 2- (5-methylaminopentyloxy) diphenylmethane, 2- (4-methylaminobutoxy) diphenyl 2- (4-dimethylaminobutoxy) diphenyl ether, 2- (5-methylaminopentyloxy) diphenyl ether, 2- (3-methylaminopropoxy) diphenyl sulfide, 2- (4-methylaminobutoxy) diphenyl sulfide, 2- (4-dimethylaminobutoxy) diphenyl sulfide, 2- (5-methylaminopentyloxy) diphenyl sulfide, 2- (3-methylaminopropoxy) diphenylmethane, 2- (4-methylaminobutoxy) diphenylmethylmethane, 2- (4-dimethylaminobutoxy) dimethylmethylmethylmethylmethylmethane -diphenylmethylmethane, 2- (4-methylaminobutoxy) -diphenyl, 2- (4-aminobutoxy) -diphenyl and 2- (4-dimethylaminobutoxy) -diphenyl.

The compounds of general formula II used according to the invention can be prepared in a manner known per se by reacting the corresponding orthosubstituted phenols with 1,3-dihalopropane, 1,4-dihalobutane or 1,5-dihalopentane in the presence of a base.

Specific examples of amines of general formula III used according to the invention include ammonia, primary amines such as methylamine, ethylamine or isopropylamine, secondary amines such as dimethylamine, diethylamine, N-methylethylamine, morpholine and piperidine.

The amount of the amine used is 1 to 100 moles per one mole of the ortho-substituted o> -haloalkoxybenzene derivative. Preferably, an excess of amine is used because it accelerates the reaction. The reaction can be carried out without a solvent. Preferably it is carried out in a homogeneous phase, in a reaction-inert solvent.

Specific examples of the solvents to be used include water, dioxane, tetrahydrofuran, dimethyl sulfoxide, lower aliphatic alcohols and mixtures thereof.

The reaction is carried out satisfactorily over a relatively wide temperature range. In general, the reaction is carried out between room temperature and 150 ° C. The reaction time depends on the reaction temperature and the reactivity of the starting compounds; usually it is from 10 minutes to 40 hours. The reaction is preferably also carried out in the presence of a hydrogen halide acceptor because it increases the reaction rate.

Examples of hydrogen halide acceptors that can be used include inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate, and tertiary amines such as pyridine and triethylamine. The amount of the base used is preferably 1 to 5 moles per mole of the ortho-substituted (Cu-haloalkoxy) benzene derivative.

In the absence of a hydrogen halide acceptor, the ortho-substituted (C 1-8 aminoalkoxy) benzene derivative reacts with the hydrogen halide formed during the reaction to give the corresponding salt.

Salts of ortho-substituted (C 0 -aminoalkoxy) benzene derivatives are prepared by reacting the compounds with an acid.

Orthosubstituted (N-aminoalkoxy) benzene derivatives and their salts are purified by recrystallization from a solvent such as a mixture of ethanol and diethyl ether.

The compounds of general formula I are valuable drugs which have a thymoleptic and anticonvulsant effect. This has been shown by animal experiments.

The compounds of general formula I were tested in mice for their antidepressant, sedative, anticonvulsant and anticholinergic activity. For this purpose, the compounds were injected intraperitoneally (intraperitoneally) into mice, using 3- (3-dimethylaminopropylidene) -1,2,4-dibenzocyclohepta-1,4-diene (amitriptyline) as a reference compound.

68041 6

The antidepressant effect was studied by antagonism of hypothermia (hypothermia) induced by reserpine (5 mg / kg intraperitoneally); cf.. P.S.J. Spencer, "Antidepressants Drugs," S. Garattini und M.M.G. Duhes, Exeerpta Medica Foundation, Amsterdam, 1967, pp. 194-204. The antireserpine effect was expressed as a relative effect (Amitriptyline has an effect of 1.).

Acute toxicity was calculated according to the Licht f ield-VJilcoxon method.

The CNS depressant effect was studied on the ability of the compounds to induce catalepsy (stress stiffness state) by measuring by means of a tensile test (cf. S. Courvoisier, R. Ducrot, L. Julou, "Psychotropic Drugs", published by S. Garattini, V. Ghetti (1957), page 373) , and their ability to affect spontaneous motility. Spontaneous motility was measured using an Animex device.

The seizure-triggering effect was determined by antagonism of tonic extension spasms induced by electroshock; compare L. S. Goodman, M. Singh Greval, W. C. Brown and E. A.

Swinyard, J. Pharmacolo, Exptl. Therap., Bd. 108 (1953), page 168.

The central anticholinergic effect was determined by Tremorine-induced tremor in mice; cf.. G. M. Everett, L. E. Bloucus and J, M. Sheppard, Science 124, (1956), page 79.

The results are summarized in Tables IA and II7 where EDj.q represents the dosage of test compound that reduces the corresponding reaction to 50%.

Table IB shows the anti-reserpine activity of the compounds of formula I compared to the compounds known from the prior art.

6 8 0 41

Table 1A

Antireserpiini-effect

Compound Relative! ΤΓ (^ activities Li, ,, ', (mg / kg in Ira -! ·'.: · -; T tone.ii.! - __________________ ii) ______ 2- (4-methylaminobutoxy) -djphenyl-2 .73,173 Methane hydrochloride i.

2- (4-Ethylaminobutoxy) -diphenyl-0.53,120 methane hydrochloride 2- (5-methylaminopentyloxy) -dis-0,54,160 phenylmethanehydrochloride 2- (4-methylaminobutoxy) -diphenyl-1,10 100 ether hydrochloride 2- (5-methylaminopentyloxy) -di- 0.57 85 phenyl ether hydrochloride 2- (4-methylaminobutoxy) -diphenyl-0.90 120 sulfide hydrochloride 2- (4-dimethylaminobutoxy) -di-, 70 130 Phenyl sulfide hydrochloride 2- (3-methylaminopropoxy) diphenyl 0.60 135 sulfide hydrochloride 2- (3-methylaminopropoxy) diphenyl-0.56 160 methane hydrochloride 2- (3-dimethylaminopropoxy) diphenyl .00 methane hydrochloride (known compound) 2- (2-dimethylaminoethoxy) diphenyl-0.00 methane hydrochloride (known compound) 2- (2-methylaminoethoxy) diphenyl-0.00 methane hydrochloride (known compound) 2 - (4-methylaminobutoxy) -diphenyl-0.66 14ϋ methylmethane hydrochloride 2- (4-dimethylaminobutoxy) -di- 0.36 110 phenylphenylmethane hydroxide chloride 2- (3-dimethylaminopropoxy) -diphenyl-O , 34,155 methyl methane hydrochloride.

2- (4-methylaminobutoxy) -diphenyl-0.99 78 hydrochloride 2- (4-aminobutoxy) -diphenyl-0.59,37 hydrochloride 2- (4-dimethylaminobutoxy) -diphenyl-0.45 100 hydrochloride

Amitriptyline 1.00 65 8 68041

Table IB

Antireserpine activity in mice ~ Compound Relative potency 2- (2-methylaminoethoxy) diphenylmethane hydrochloride O 2- (2-isopropylaminoethoxy) diphenylmethane-hydrochloride 9 2 * 2- (2-dimethylarinoethoxy) diphenylmethane hydrochloride 2- ( 3-methylaminopropoxy) diphenylmethane hydrochloride 5 * 2- (3-dimethylaminopropoxy) diphenylmethane hydrochloride —— ............................ ..... ............— ...... ........

2- (4-Methylaminobutoxy) diphenylmethane hydrochloride 2- (4-ethylaminobutoxy) diphenyl iodine hydrochloride 0.53 ............... - -------- ------- - ......- M.- ..... - - g * 2- (4-dimethylaminobutoxy) diphenylmethane hydrochloride 2- / 3 - (1-piperidyl) butoxy] diphenylmethane-9 ** hydrochloride 0.41 2- (5-methylaminopentyloxy) diphenylmethane-10 ** hydrochloride 0.54 2- (5-dimethylaminopentyloxy) diphenylmethane-H * hydrochloride 0.23 1 11 1 11 -I p ····· »· '. .................... im "MM -....... ........ j-, 2- (2-dimethylaminoethoxy) diphenyl ether - hydrochloride, 2 * 2- (3-dimethylaminopropoxy) diphenyl ether hydrochloride 9 68041

relative

Well. Compound activity 2- (4-aminobutoxy) diphenyl ether O # 28 hydrochloride 2- (4-ethylethylaminobutoxy) diphenyl ether iodide hydrochloride Ig ** 2- (4-dimethylaminobutoxy) diphenyl ether 0.58 hydrochloride 17 ** I 2- ( 5-methylaminopentyloxy) diphenyl ether 0.57 hydrochloride X8 ** 2- (5-dimethylaminopentyloxy) diphenyl ether 0.24 hydrochloride 19 * 2- (2-dimethylaminoethoxy) diphenyl sulfide hydrochloride —— '"' ... ........... »· ι .............. -" —......

20 ** 2- (3-methylaminopropoxy) diphenyl sulfide-0.60 hydrochloride 21 * 2- (3-dimethylaminopropoxy) diphenyl sulfide-O-hydrochloride 22 ** 2- (4-aminobutoxy) diphenyl sulfide-0.36 hydrochloride ... 1 - ........ 1 - .. 1-. ............... ........ '1' "» 'm 1111 I111 * ·' · 1 - 2- (4-methylaminobutoxy) diphenyl sulfide-23 ** hydrochloride 0.90 24 ** 2- (4-dimethylaminobutoxy) diphenylsulfide-0.70 hydrochloride 2- (4-morpholinobutoxy) diphenylsulfide-25 ** hydrochloride 2- (5-dimethylaminopentyloxy) diphenylsulfide-26 ** hydrochloride ° ' 15 2- (2-Dimethylaminoethoxy) diphenylmethylmethane-27 * hydrochloride 0 2- (3-dimethylaminopropoxy) diphenylmethylmethane-28 ** hydrochloride 0.14 2- (4-methylaminoobutoxy) diphenylethylmethane-29 ** hydrochloride ° '66 10 68041

Well. relative

Compound potency -3D ** 2- (4-dimethylaminobutoxy) diphenylmethylmethane hydrochloride 31 '2- (2-aminoethoxy) diphenyl hydrochloride 32 * 2- (2-methylaminoethoxy) diphenyl hydrochloride 33 ** 2- (4-amindbutoxy) diphenyl-, q hydrochloride

34 ** QQ for 2- (4-methylaminobutoxy) diphenyl

hydrochloride u, yy i „2- (4-dimethylaminobutoxy) diphenyl-, hydrochloride 36 ** Amitriptyline 1 _J__ __ * Known compounds ** Compounds of formula I *** Reference compound

It can be seen from Table IB that the antireserpine activity of the compounds of formula I is in most cases considerably higher than that of the compounds known from the prior art. In general, the relative potency of compounds containing a 2-aminoethoxy or 3-aminopropoxy group is zero. On the other hand, the relative potency of compounds containing a 4-aminobutoxy group, e.g. 4-alkylaminobutoxy group, or a 5-aminopentoxy group, e.g. 5-alkylaminopentyloxy group, is high.

11 68041

Table II

Central nervous system depressant} anticonvulsant and centrally anticholinergic effect.

----------------- 1 ---

Kouristuk-1 · Litesjänni-. Spontaneous Antitrust trigger accounts.in ^ itre _

Compound odorous attenuation ^ effect I __ ^ - ^ 50 ^ 50 ED50 ^ * 50 sm- ^ i. · __: ...... facade I 2- (4-methylamino-1-butoxy) -diphenyl--k methane hydrochloride 2- (4-methylaminobutoxy) diphenyl 32 60 60 30 ether hydrochloride 2- (H-methylaminobutoxy) diphenyl-> g050 > 60 30 s ufide hydrochloride 2- (3-methylaminopropoxy) diphenyl-40 65 90 ^ 2; methane hydrochloride 2- (U-methylamino-!

butoxy) -diphenyl-> 6o, 2 20 L

methylmethylhydroxy-5'-chloride '2- (H-methylaminobutoxy) -diphenyl-11'; hydrochloride 2- (4-aminobutoxy) -. , .1 diphenyl hydrochloride,

Amitriptyline 16 15 lö ^! ^ ^ ^ t 68041

Tables I and II show that ortho-substituted phenoxyalkylamino derivatives of general formula II have an antireserpine activity comparable to amitriptyline with low toxicity and weak central nervous system depressant and anticholinergic activity.

The compounds of general formula I can be administered orally, subcutaneously (subcutaneously), intravenously (intravenously), intramuscularly (intramuscularly) or intraperitoneally (intraperitoneally). The dosage is adjusted e.g. according to the age, state of health and weight of the patient, depending on the severity of the depression, the frequency of treatment and the nature of the desired effect. In general, the dosage of the drug is 0.5 to 50 mg / kg, preferably 1 to 30 mg / kg of body weight and day.

The form of administration of the drugs is not limited. Examples are tablets, capsules, powders, solutions or suspensions for oral or parenteral use. The dosage units have a drug content of 0.5 to 90% of the total weight.

In addition to the drug, the drug products may contain a solid or liquid carrier. Examples of liquid carriers to be used include water, peanut oil, soybean oil, mineral oil and sesame oil. Examples of carriers for parenteral use are saline or sugar solution and glycols such as ethylene glycol, propylene glycol and polyethylene glycol. The saline solution contains 0.5-20, preferably 1-10% by weight of drug.

The examples illustrate the invention.

Example 1

A solution of 5.0 g of 2- (α-bromobutoxy) diphenyl ether and 30 ml of a 10% aqueous solution of dimethylamine in 100 ml of ethanol is allowed to stand for 8 hours at room temperature. Ethanol and excess dimethylamine are then distilled off under reduced pressure. To the residue is added 2N NaOH and extracted with diethyl ether. The ether extract is evaporated, 2N hydrochloric acid is added to the residue and the solution is evaporated to dryness. The residue is recrystallized from a mixture of ethanol and diethyl ether. Yield * 4.6 g of 2- (α-dimethylaminobutoxy) diphenyl ether hydrochloride, m.p. 131-135 ° C.

13 68041

Example 2

A solution of 5.0 g of 2- (5-bromopentyloxy) diphenyl ether and 6 g of methylamine in 100 ml of ethanol is heated in a bomb for 2 hours at 50 ° C. Ethanol and excess methylamine are then distilled off under reduced pressure. To the residue is added 2N sodium hydroxide solution and extracted with diethyl ether. Dry hydrogen chloride gas is introduced into the ether extract and the precipitate formed is filtered off. The crude product is recrystallized from a mixture of ethanol and diethyl ether. Yield: 4.2 g of 2- (5-methylaminopentyloxy) -diphenyl ether hydrochloride, m.p. 88-90 ° C.

Example 3

A solution of 5.0 g of 2- (4-bromobutoxy) diphenyl in 10 g of isopropylamine is allowed to stand for 5 hours at room temperature. The excess isopropylamine is then distilled off under reduced pressure, and 2N sodium hydroxide solution is added to the residue and extracted with diethyl ether. The ether extract is evaporated, 2N hydrochloric acid solution is added to the residue and the mixture is evaporated to dryness. The residue is recrystallized from a mixture of ethanol and diethyl ether. Yield 4.5 g of 2- (4-isopropylaminobutoxy) -diphenyl hydrochloride, m.p. 172-177 ° C.

Examples 4-26

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Claims (1)

A process for the preparation of therapeutically active orthosubstituted phenoxyalkylamino derivatives of the general formula (I), or pharmaceutically acceptable acid addition salts thereof,? is C 1 -C 4 alkylamino or 1-piperidyl; when R 2 is benzyl and n is 3, it is C 1 -C 3 alkylamino; when R 1 is phenoxy, R 1 is amino, C 1 -C 6 alkylamino or dialkylamino, where the sum of carbon atoms is 2-6 and n is 4 or 5; when R 1 is phenylthio and n is 3, R 1 is C 1 -C 6 alkylamino; when R 2 is phenylthio and n is 4, R 1 is amino, C 1 -C 6 alkylamino, dialkylamino where the sum of carbon atoms is 2-6, or morpho-Lino · when R 2 is phenylthio and n is 5, is a dialkylamino wherein the sum of carbon atoms is 2-6, or morpholino; when R 2 is 1-phenylethyl and n is 4, R 1 is amino, C 1 -C 6 alkylamino or dialkylamino in which the sum of carbon atoms is 2-6; when R 2 is 1-phenylethyl and n is 3, is dimethylamino; and when R 2 is phenyl, R 1 is amino, C 1 -C 6 alkylamino or dialkylamino in which the sum of the carbon atoms is 2-6 and n is 4, characterized in that a 2-substituted-1- (omega-haloalkoxy) benzene is administered which is a general formula (II), O- (CHO) X 2 n (II) wherein X is a halogen atom and R 2 and n are as defined above, react with an amine of general formula (III), R to H (III) wherein R 1 is as defined above, and optionally the resulting compound is converted into a salt by reacting it with an acid. 21 68041 The present invention provides a therapeutically active ortho-substituted phenoxyalkylamino derivative with all of the formulas (I) or a pharmacologically active compound of the formula, N-alkylamino or 1-piperidyl, benzyl and 3-C 1-4 alkylamino, phenoxy, amino, C 1-4 alkylamino or dialkylamino, the sum of the alkyl atom 2-6, and from 4 to 5 or 5; from R 1 to phenylthio and 3 from 3 to R 1 -C 4 -C 4 -alkylamino; from 4 to 4-phenylthio and 4, from R 4 amino, C 1 -C 4 -alkylamino, dialkylamino, from XXO the sum of the cholatom is 2-6 or morpholino; R2 is phenylthio and 5 is R1 dialkylamino, the sum of cholatom is 2-6 or morpholino; R1 is 1-phenylethyl and 4 , R 1 is amino, C 1 -C 2 alkylamino or dialkylamino, the sum of the cholatom is 2-6, R 1 is 1-phenylethyl and 3, R 2 is dimethylamino, and R 2 is phenyl, R 2 is amino, C 1 -C 4 -alkylamino or dialkylamino, the sum of the chapters being 2-6, oc h när4, kännetecknat därav, att man omsätter 2-substituerad-l (omegahaloalkoxyi) benzen med den allmänna formuleln (II) Q- (CH0) X 2 n (II) Ky * där X är en halogenatom och R2 och n har samma betydelse In this case, the amine in the form of (III) Ra - H (III) may be used as such, and may be used in the form of an account for the presence of the genome.