IE43284B1

IE43284B1 - Benzyloxyalkyl derivatives

Info

Publication number: IE43284B1
Application number: IE1746/76A
Authority: IE
Original assignee: Warner Lambert Co
Priority date: 1975-09-09
Filing date: 1976-08-06
Publication date: 1981-01-28
Also published as: AU1736176A; NL7610040A; BE845964A; DK403576A; NL186238C; AU502573B2; GB1488646A; NL186238B; JPS5233639A; DE2539941A1; LU75735A1; CH628613A5; AT346306B; IE43284L; ES451158A1; ATA668876A; SE430056B; JPS6121940B2; FR2323377A1; DE2539941C2

Abstract

Aminoalkoxyphenylalkyl benzyl ethers of the formula I are prepared by reacting a compound of the formula II with one of the formula III. The symbols in the formulae have the meaning stated in Claim 1. The compounds of the formula I and their pharmacologically compatible salts display lower toxicity, and pronounced antiinflammatory and good analgesic effects.

Description

The present invention is concerned with benzyloxy-alkyl derivatives and with the preparation thereof. o-Aminoalkoxy-substituted dibenzyl ethers having analgesic and antiphlogistic properties are known from, for example, German Patent Specification No. 1,518,453. The compounds described in this German Patent Specification contain two optionally substituted benzyl radicals attached via an oxygen or sulphur atom.

Unexpectedly, we have now found that the pharmacological properties of certain compounds of this class can be substantially improved when the methylene group of one of the benzyl radicals is substituted with a lower alkyl radical.

Thus, according to the present invention, there are provided compounds of the general formula:2 wherein X is a hydrogen or halogen atom, R1 is an alkyl radical 2 3 containing up to 4 carbon atoms; R and R , which can be the same or different, are alkyl radicals containing up to 4 2 3 carbon atoms or R and R , together with the nitrogen atom to which they are attached, is a heterocyclic ring; and n is 2 or 3; as well as the pharmacologically compatible salts of these compounds.

The halogen atoms in the above compounds (I) can be fluo10 rine, chlorine or bromine atoms. 3 The alkyl radicals R and R can be straight-chain, for example, ethyl, n-propyl or n-butyl radicals. However, insofar as steric hindrance does not prevent it, they can also be branched radicals, for example, isopropyl or isobutyi radicals. 2 3 Furthermore, R and R , together with the amino nitrogen atom to which they are attached, can also form a heterocyclic ring containing 4 to 6 carbon atoms, for example, a pyrrolidine or piperidine ring. The alkyl radical R1 can also be straight or branched chain, for example, a methyl, ethyl, n-propyl, isopropyl or n-butyl radical.

Compounds of general formula (I) are preferred in which X is a hydrogen, fluorine or chlorine atom, R'L is a methyl or a μ ra α <4 ethyl radical, R and R , which can be the same or different, are methyl or ethyl radicals, and n is 2 or 3, as well as the pharmacologically compatible salts thereof.

Compounds of general formula (I) can be prepared, for example, by reacting a compound of the general formula:wherein R1, R2 a compound of , R and n have the same the general formula:meanings as (II) above, with Y - ch2 (XIX) wherein X has the same meaning as above and Y is a reactive ester group. If desired, the compound so obtained can be reac ted with an inorganic or organic acid to give a corresponding pharmacologically compatible salt.

Compounds of general formula (II) can be prepared by reac ting a known aldehyde of the general formula:- (IV) 3 wherein R , R and n have the same meanings as above, with a Grignard compound of the general formula:- 4 R1—Mg—Hal wherein has the same meaning as above and Hal is a halogen atom, preferably a bromine or iodine atom.

The reaction of compounds (IV) is carried out in a solvent which is conventional for Grignard reactions, preferably in an aliphatic ether, such as diethyl ether or tetrahydrofuran, at a temperature of from 30 to 60°C. and preferably at about 40°C.

The compounds of general formula (II) obtained after removal of the solvent and conventional purification are then reacted with known compounds of general formula (III) at a temperature of from 30 to 80°C. and preferably of about 60°C. in the presence of a basic, condensation agent, for example, sodium hydride or sodamide, with a conventional solvent for such reactions, for example, benzene, toluene, dimethyl formamide, dimethyl sulphoxide or mixtures thereof, dimethyl formamide being preferred.

The reactive ester groups Y are to be understood to be groups suitable for nucleophilic exchange. The halides, methane-sulphonates, benzene-sulphones and £-toluene-sulphonates are especially preferred.

The conversion of the free bases of general formula (I) into pharmacologically compatible salts takes place in the usual manner by neutralisation with an organic or inorganic acid which, in the dosages administered, is non-toxic, for example, hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid, a naphthalene-sulphonic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid or ascorbic acid. This neutralisation is preferably carried out in an 43iJDa aqueous, aqueous/alcoholic or alcoholic solution.

The new compounds of the present invention have an unusually low toxicity and outstanding and valuable anti-phlogistic properties, as well as analgesic properties. They are > useful for the steroid-free therapy of inflammatory and degenerative diseases of the skeleto-muscular system for counteracting pain and inhibiting inflammation.

Because of their valuable activity profile, 1-p-chlorobenzyloxy-1-(ο-β-diethylaminoethoxyphenyl)-ethane and ΙΌ benzyloxy-I-(ο,-β-diethylaminoethoxyphenyl)ethane are particularly preferred.

Compounds of general formula (I) and the salts thereof can be administered enterally or parenteraily in liquid or solid form. Thus, the present invention also provides pharma5 ceutical compositions containing at least one of the new compounds according to the present invention in admixture with a solid or liquid pharmaceutical diluent or carrier. For injection solutions, water containing the usual additives for injection solutions, such as stabilising agents, solubilising agents and buffers, is preferred. Additives of this kind include, for example, tartrate and citrate buffers, ethanol, complexforming agents (such as ethylenediamine-tetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight - 6 4 3 2 8 4 polymers (such as polyethylene glycol); compositions suitable for oral administration nay contain flavouring and/or sweetening agents.

Compounds of general formula (I) and the salts thereof can be administered enterally or parenterally one or more times daily in a dosage of 100 to 300 mg.

The following Examples 2, 3, 5, 6, 8 and 9 are given for the purpose of illustrating the present invention. Examples 1, 4 and 7 illustrating the preparation of intermediates:Example 1. 1-(ο-β-diethylaminoethoxypheny1)-ethanol.

A Grignard solution is prepared in anhydrous diethyl ether from 2.43 g. (0.1 mol) magnesium filings and 14.2 g. (0.1 mol) methyl iodide. A solution of 22.1 g. (0.1 mol) odiethylaminoethoxybenzaldehyde in 70 ml. anhydrous diethyl ether is added dropwise to this Grignard solution at reflux temperature within the course of an hour. Subsequently, the reaction mixture is boiled for 1 hour. The adduct is broken down by the dropwise addition of 20% aqueous ammonium chloride solution. The ethereal phase is separated off, dried over anhydrous sodium sulphate and filtered. The ethereal phase is evaporated and the residue is distilled in a high vacuum.

There is obtained 21.1 g. (89% of theory) l-(o-p-diethylaminoethoxyphenyl)-ethanol; b.p. 130—131°C/0.3 mm.Hg. The corresponding hydrochloride, prepared for characterisation, melts, after recrystallisation from isopropanol, at 166°C.

Analysis; C..H_.C1NO_ (M.W. 273.81) £4 24 Z calc.: C 61.40%; H, 8.84%; N 5.12%; Cl 12.95% found: C 61.34%; H 8.69%; N 4.94%; Cl 12.50% όύΟ 'Λ Example 2. l-£-Chlorobenzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-ethane. g. 1-(ο-β-diethylaminoethoxyphenyl)-ethanol are dissolved in 25 ml. dry dimethyl formamide. This is added drop5 wise at 60°C. to a suspension of 4.2 g. 50% sodium hydride in 40 ml. anhydrous dimethyl formamide. Subsequently, a solution of 13.7 g. £-chlorobenzyl chloride in 15 ml. dimethyl formamide is added and the reaction mixture stirred for 1 hour at 60°C. After filtration, the solvent is removed in a vacuum and the residue distilled in a high vacuum (174—177°C./ 0.1 mm.Hg). The oil obtained is taken up in isopropanol and precipitated with an isopropanolic solution of naphthalene1, 5-disulphonic acid. The crystals are recrystallised from ethanol. There are obtained 22.3 g. (52% of theory) l-£15 chlorobenzyloxy-1- (<3-fi-diethylaminoethoxyphenyl) -ethane naphthalene-1,5-disulphonate; m.p. 179—181°C.

Analysis: C_-H „ClNOrS (M. W. 506.08) 32 3 calc.: C 61.07%; H 6.37%; N 2.77%; Cl 7.01%; S 6.34% found: C 61.84%; H 6.25%; N 3.03%; Cl 6.41%; S 6.68%.

Example 3. 1-Benzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-ethane. g. of the 1-(ο,-β-diethylaminoethoxyphenyl)-ethanol, prepared in the manner described in Example 1, are reacted in !5 a suspension o f sodium hydride and anhydrous dimethyl formamide with 7.9 g. benzyl chloride. There is obtained 1benzyloxy-1-(ο-β-diethylaminoethoxyphenyl)-ethane in the form of an oil; b.p. 160—162°C./0.05 mm Hg. The free base is converted into the 1/2 naphthalene-1,5-disulphonate in a manner analogous to that described in Example 2. The yield is 10 g. (35% of theory). After reerystallisation from isopropanol, the salt has a melting point of 157—158°C.

Analysis; C26H33NO5S (M-W· 471·63) calc.; C 66.21%; H, 7.05%; N 2.97%; S 6.80% found: C 66.16%; H 6.90%; N 3.17%; S 6.83%.

Example 4. 1-(o-p-diethylaminoethoxyphenyl)-propanol.

A Grignard solution is prepared from 2.43 g. (0.1 mol) magnesium filings and 15.6 g. (0.1 mol) ethyl iodide in anhydrous diethyl ether and reacted with 22.1 g, (0.1 mol) odiethylaminoethoxybenzaldehyde in a manner analogous to that described in Example 1. There are obtained 20 g. (80% of theory) 1-(o-p-diethylaminoethoxyphenyl)-propanol; b.p. 112°C./0.1 mm.Hg. The acidic oxalate thereof, prepared for characterisation, melts at 105°C., after reerystallisation from methyl ethyl ketone.

Analysis; C1_H._NOc (M.W. 341.41) 27 6 calc.: C 59.80%; H 7.97%; N 4.11% found: C 59.67%; H 7,69%; N 3.99% Example 5. l-p-chlorobenzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-propane. 20 g. 1-(o-p-diethylaminoethoxyphenyl)-propanol are dissolved in 25 ml. anhydrous dimethyl formamide. The solution so obtained is added dropwise at 60°C. to a suspension of 4.2 g. 50% sodium hydride in 40 ml. anhydrous dimethyl formamide. Subsequently, a solution of 13.7 g. p-chlorobenzyl chloride - 9 4 3 2 8 4 is added and the reaction mixture stirred for 1 hour at 60°C. After filtration, the solvent is removed at 20 mm.Hg. and the residue distilled under a high vacuum. There is first obtained l-£-chlorobenzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-propane in the form of an oily base which distils at 190—200°C./0.1 mm.Hg. The base is dissolved in ethanol and an ethanolic solution of citric acid is added thereto. The citrate which precipitates out is recrystallised from water. The yield is 8 g. and the product melts at 128—129°C.

Analysis: C28H38Clli°9 (M’W· 568-05) calc.: C 59.20%; H 6.74%; N 2.47%; Cl 6.24% found: C 59.25%; H 6.81%; N 2.73%; Cl 5.83% Example 6. 1-Benzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-propane In a manner analogous to that described in Example 5, by the reaction of 25 g. 1-(ο-β-diethylaminoethoxyphenyl)-propanol with 12.7 g. benzyl chloride and subsequent neutralisation with hydrochloric acid, there are obtained 8.5 g. 1-benzyloxy1-(ο-β-diethylaminoethoxyphenyl)-propane hydrochloride which, after recrystallisation from isopropanol, melts at 126°C. Analysis: C22H 2C1NO2 (M.W. 377.96) calc.: C 69.91%; H 8.53%; N 3.71%; Cl 9.38% found: C 69.75%; H 8.46%; N 3.89%; Cl 9.15%.

Example 7. 1-(£-dimethylaminopropoxyphenyl)-ethanol is prepared in a manner analogous to that described in Example 1 by reacting a 0.1 molar Grignard solution of methyl magnesium iodide with dimethylaminopropoxybenzaldehyde in tetrahydrofuran, 19.5 g. of the free base is obtained; b.p. 122—125°C./O,1 mm Hg.

Example 8, 1-(jo-Chlorobenzyloxy)-1-(o-Y-dimethylaminopropoxyphenyl)ethane g. 1-(o-dimethyIaminopropoxyphenyl)-ethanol are reacted with 11 g. p-chlorobenzyl chloride in a manner analogous to that described in Example 2. After filtering and tripping off the solvent at 20 mm.Hg., the base is distilled in a high vacuum. There are obtained 16 g. (68.5% of theory) l-(pchlorobenzyloxy)-1-(o-Y-dimethylaminopropoxyphenyl)-ethane; b.p. 173—176°C./O.l mm.Hg. The corresponding oxalate prepared from the base has a melting point of 152—153°C.

Analysis; C22H28C1NO6 (M-W· 437-9) calc.: C 60.30%; H 6.44%; N 3.20%; Cl 8.10% found: C 60.37%; H 6.51%; N 3.33%; Cl 7.68%.

Example 9.

I-(p-Fluorobenzyloxy-1-(ρ-β-diethylaminoethoxyphenyl)-ethane g. of the 1-(ρ-β-diethylaminoethoxyphenyl)-ethanol obtained in the manner described in Example 1 are dissolved in anhydrous dimethyl sulphoxide and reacted at 60°C., in a suspension of sodium hydride, with a solution of 26.8 g, £.fluorobenzyl chloride in dimethyl sulphoxide. After working up the reaction mixture, there are obtained 52 g. (81% of theory) 1-(p-fluorobenzyloxy)-1-(ο-β-diethylaminoethoxyphenyl)ethane in the form af an oily base (b.p. 175—181°C./0.1 mmHg, which is precipitated out from ethanolic solution with naphthalene-1,5-disulphonic acid as the 1/2 naphthalene-1,5disulphonate for characterisation; m.p. 169—170°C, Analysis; CO£.Ho-FN0cS (M.W. 489.7) ZD 0 calc.; C 63.76%; H 6.58%; N 2.86%; S 6.54% found: C 63.74%; H 6.57%; N 3.11%; S 6.58%.

Pharmacological comparative investigations with aminophenazone meperidine, phenylbutazone and tilidin. 1. Acute toxicity.

Determination of the acute toxicity was carried out on male mice (NMRX) with a body weight of 19 to 25 g. All the animals fasted for 16 to 18 hours before the experiment; water was freely available. Each dosage group contained 4 animals. The dosage sequence was logarithmic. Volume of liquid adminis tered was, in the case of subcutaneous administration (s.c.), ml./100 g. body weight and, in the case of intragastral administration (i.g.), 2 ml./100 g. body weight.

TABLE I Acute toxicity in mice test compound route of administration LD50 mg/kg. Example 3 i.g. 1200 Example 3 S-C. >1000 Example 4 s-c. 1000 Example 2 i.g. 1000 Example 1 i.g. > 2000 Example 5 i.g. 1600 Aminophena zone i.g. 475 Aminophenazone S.C. 300 - 12 43284 TABLE I (Continued) test compound route of administration LD5Q mg/kg. Meperidine i.g. 252 Meperidine S.C. 154 Phenylbutazone i.g. 714 Tilidin i.g. 437 It can be seen from Table I that the new compounds according to the present invention have a remarkably low toxicity in comparison with the known compounds. 2. Analgesic action.

Conventional methods, such as the phenyl-n-quinone and the hot plate tests, were used to characterise the analgesic action of the compounds. 2.1. Phenyl-q-quinone test.

Method: Pasting male mice (NMRI) of 19 to 27 g. were employed, minutes after subcutaneous administration of the test substances or 30 minutes after intragastral administration thereof, 0.25 ml./20 g. body weight of a 0.02% solution of phenyl-q15 quinone in 5% ethanol was administered intraperitoneally.

The animals were observed for 20 minutes in order to ascertain how many of the 12 animals per dosage group showed typical pain reactions with administration of phenyl-q-quinone.

The results obtained are set out in Table II: * 3 2 8 4 TABLE IX LD 50 therapeutically effective dosage 20.5 10.0 co O 1 · . kD o rd kD co 1 . sj* in r-l kD CO 1 . sf co H number of animals with positive pain reaction CN If) H cn st in f—1 r-l CO Sf rl CN CN CN rH number of animals used CN CN CN r-l r-i rH CN CN CN W H rH CN CN CN r4 r—1 rH CN CN CN r-l rl r-l route of administration 0 0 0 ui ui m tP &» •rl -rl *rl to to to •rl *rl -rl 6 6 to •rl *rl *rl Φ tn id ra · 0 O' Ό g 7.5 1OO. O 40.0 200.0 30.0 300.0 30.0 150.0 test compound control Meperidine Example 4 control Meperidine Example 1 control Tilidin Example 5 control Tilidin Example 6 3 2 8 4 It can be seen from Table II that all compounds investigated possessed an analgesic action which is comparable with commercially available compounds. The compound of Example 1 has an especially great difference between the therapeuti5 cally effective dose and the LD_- value and, even with regard 50 to the analgesic action, is clearly superior to the comparison compound meperidine. 2.2 Hot plate test.

Method: Pasting male mice (NMRI) of 20 to 26 g. were used as experimental animals. The animals were placed on a copper plate kept at a constant temperature of 55°C. and the time measured until they started to lick their front paws. After three initial measurements, the test substances were adminis15 tered. The volume administered was 1 ml./100 g. in the case of subcutaneous administration and 2 ml./100 g. body weight in the case of intragastral administration. The measurements after the administration of test substances took place after 30, 60, 90 and 120 minutes. 10 animals were used per dosage.

From the reaction times of the pre-measurements, there was determined the average reaction time and the average time after the administration of the test substance was calculated as a percentage thereof.

The results obtained are given in Table III: TABLE III Hot plate test on mice test compound dosage mg/kg. route of administration initial value in % change of the reaction in % after minutes 30 60 90 120 control - i.g. 100 + 1 + 2 + 23 + 35 ASA 200 i.g. 100 + 19 + 5 + 11 + 23 Example 1 100 i.g. 100 + 92 + 48 + 82 + 82 control - i.g. 100 + 27 + 14 + 26 + 51 Meperidine 40 i.g. 100 + 81 + 49 + 71 + 72 Example 2 150 i.g. 100 +123 + 94 + 79 + 89 in the hot plate test, the compound of Example 2 is, at a dosage level of 150 mg./kg. i.g., with about the same relationship of the LD^q value to the therapeutic dosage employed, clearly more analgesically effective than 40 mg./kg. i.g. meperidine. The compound of Example 1 shows a good action after a dosage of 100 mg./kg. i.g. The compound acetylsalicylic acid (ASA) used as comparison substance is, on the other hand, ineffective at a dosage of 200 mg./kg. i.g. 3. Antiphlogistic action.

Rat paw oedema, using egg albumin and formalin as phlogistic substances, was used for investigating the antiphlogistic effect.

Method: Rats (SIV 50 strain) with a body weight of 120 to 160 g., which had fasted for 16 hours, were used as experimental animals. After the determination of the initial value of the paw volume of the right rear extremity, the test substance was administered subcutaneously or intragastrally, 10 animals were used per dosage. The volume administered was 1 ml./lOOg. body weight in the case of subcutaneous administration and 2 ml./100 g. body weight in the case of intragastral administration. The paw volume was determined by means of mercury displacement. minutes after the administration of the test substances, the phlogistic substance was injected subplanatarily into the right rear paw (0.1 ml. egg albumin or 0.1 ml. of a 3% formalin solution). Two further measurements were made of the paw volume of the right rear extremity 60 and 120 minutes after the injection of the egg albumin or of the formalin. The average increase of the paw volume of the treated and of the control animals 60 and 120 minutes after injection of the phlogistic substance was calculated as a percen15 tage of the average value of the initial measurements. The average value from the percentage increase of the paw volume of the control group after 60 and 120 minutes was taken as being 100% and the corresponding values for the treated groups calculated as a percentage thereof. The difference of these values from 100% of the control group gives the relative inhibition of the paw oedema brought about by the test substance.

The results obtained are given in Table IV: Anti-phlogistic action in rat paw 28 4 relative value % O « m O cm tn O D V Ot^io Or-'tf O id id t-4 »—1 r—t O ro co O o- in ι—1 average swelling after VI C •rl H O OJ H σι ro r- σι oa co ο- ^ί» h in si* ro id in ro % σ\ m io in ro xo O'- fi •rl s o ID O in 00 ro r- ro 0\ 0- Γιο co co in ro id <4* *4* O in ro ω ro phlogistic substance fi •rl a nJ = = = = = = = = tp tP Φ fi 0 •rl •P : ni 0 fi φ oi •Ρ -H g.5 fi 5 nJ ό ο ο ooo tr> tr> ώ • · · «> «· m ra οι οι ω ra ·η -η ·η 6 □ ϋ ra ra ra dosage mg/kg. o o o o o o 1 Ο Ο 1 O tn ι ra o r-l r-4 r-4 r-| r4 rl 1OO 1OO test compound control Aminophenazone Example 3 control Aminophenazone Example 3 control Aminophenazone Example 3 control Aminophenazone Example 4 18•33284 TABLE IV (Continued) relative value % O V V oot- O O CO oootn O m in Ο ι- ώ H r~1 H O Is· O O O co O CO H H lling after G Ή ε ο d Η ο σ. m* oot^ <φ η o cn p- in ψ d •sf n co O cn ooh cn > M* 10 CM 0) ω φ Cn «J Im G •rl ε o Odd r- vo h cn o r· in vf m* ro d d O d p- r- io r*- d phlogistic substance egg albumin II II tl formalin IS 1» £ •rl ε £ rd = = = * - tn tn φ route of administration tn tn tn tn tn tn tn tn tn -rl Η -Η -rl «rl *r| *rl -rl -rl tn Cn tn tn tn tn •rl *r| *r| -rl *rl Ή Φ · tn Cn to X to \ 0 tn ό e Ο O OQ Ο O ι in d ι m Ο ι in in i—l r—l f—l r—1 ι—1 o o o o ι m O l in O Η Η Η N test compound control Aminophenazone Example 2 control Aminophenazone Example 2 control Aminophenazone Example 2 control Aminophenazone Example 1 control Aminophenazone Example 1 a·)*» relative value .% O co cm o cm ω ο η φ O r- o O cn xh Ο σι co Oom Ooo i-l ι-l —I i—l average swelling after 5% b •rl e o ol r-l ι-i r' co m cm sh cd σι m Tf cn cd co m cm m in Tf Tf cn cm in tt cn 60 min. % cvd > in co (n n ri > η σ» vo id r- cm r-- io id in ro n phlogistic substance egg albumin II ί II II II formalin tt II fl II route of administration CniPtP tP CP tP tP tP tP tP fr tP · ·♦ »*« ♦·« «·· •rl Ή Ή »rl ·Η ·Η ·γ! ·γ! ·γΙ ·Η ·γ! ·γ1 Φ . tP tP Iff X ω \ 0 & TO S οο οο ο ο ο ο ι ιη Ο ι ιη ιη ι ιη Ο ι ιη Ο 1—1 ι—1 rHrH γ»1 ι—Ι ι—Ι «—1 test compound control Aminophenazone Example 6 control Aminophenazone Example 6 control Aminophenazone Example 6 control Aminophenazone Example 6 P 43 0 1 0 0 •rl G •rl £ •rl P & g Φ nJ a rH CJ 0 ω Φ 44 I—1 TO 9» P G 0 (0 nJ •rl κ P Φ H Φ rH CU ,0 MH G nJ 0 to X P τί Sh G rH Pj G P Φ 0 nJ p 9* Φ g rH (0 0 a υ 0) >< > φ rH • nJ 43 G >1 Λ •P 0 +1 •rl Μ 44 υ φ 0 0 •rl +> ΨΙ G X nJ 0 tP TO to 44 •rl G •rl 44 G s 10 0 * 0 Φ tp 44 rH > (0 £ί Φ Φ >1 •rl P 44 P Φ Φ UJ S gj > TO S G to Φ nJ ΰ a TO 0 *rl Φ >1 o< 43 0 Λ 6 to 0 G G TO a 0 •rl Φ •rl g to φ 44 G Ή nJ P 3 • rH rH Φ Ul Φ nJ Ρ 1“l UJ P a rH Φ φ ft nJ G Φ 43 P Φ rH 44 nJ 4J > £ rG nJ •rl nJ G U •P P •rl 3 u G 0 Φ 0 to to ω MH > to rH £ MH nJ Φ nJ 0 Φ MH G 43 Φ to uj U >i > ri •rl ι—I •rl > 44 rH 44 44 H to nJ 0 G •H •rl Φ 43 Φ 5* 0 MH rH 0 Φ MH Φ Λ H Qt Φ G JO 43 01 0 £ Gt w CO N I 44 nJ •rl •«H G •P Φ G G 43 nJ •rl Oi Thus, the new compounds according to the present invention are valuable pharmaceuticals with an outstanding antiphlogistic and, at the same time, good analgesic action. Because of their low toxicity and of the great therapeutic breadth associated therewith, they represent a considerable technical advance.

Claims

I. Compounds of the general formula:R - / sr \ wherein X is a hydrogen or halogen atom, R is an alkyl 2 3 5 radical containing up to 4 carbon atoms, R and R , which can be the same or different, are alkyl radicals containing up to 4 carbon atoms, or, together with the nitrogen atom to which they are attached, represent a heterocyclic ring and n is 2 or 3; and the pharmacologically compatible salts thereof. 10 2. Compound according to claim 1, wherein X is a hydrogen fluorine or chlorine atom, R^ is a methyl or ethyl radical,
2
3 R and R , which may be the same or different, are methyl or ethyl radicals and n is 2 or 3; and the pharmacologically compatible salts thereof. 15 3. 1-q-Chlorobenzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-ethane.
4. 1-Benzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-ethane.
5. l-£-Chlorobenzyloxy-l-(ο-β-diethylaminoethoxyphenyl) -propane. 20
6. 1-Benzyloxy-l-(ο-β-diethylaminoethoxyphenyl)-propane.
7. 1-(js-chlorobenzyloxy)-1-ο-Ύ -dimethylaminopropoxyphenyl)-ethane. 4 3 284
8. 1-(p-Fluorobenzyloxy)-1-(ο-β-diethylaminoethoxyphenyl)-ethane.
9. A process for the preparation of compounds of the general formula given in claim 1, wherein an amino compound of the general formula :- 12 3 in which R , R , R and n have the same meanings as in claim 1, is reacted with a benzyl compound of the general formula:Y - ch 2 // X X 10. In which X has the same meaning as in claim 1 and Y is a reactive ester group.
10. A process according to claim 9, wherein the reaction is carried out at a temperature of from 30 to 80°C.
11. A process according to claim 10, wherein the reac15 tion is carried out at a temperature of about 60°C.
12. A process according to any of claims 9 to 11, wherein the reaction is carried out in the presence of a strongly basic condensation agent.
13. A process according to any of claims 9 to 12, 20 wherein the reaction is carried out in the presence of a solvent.
14. A process according to any of claims 9 to 13, 23 4328 4 wherein the amino compound used as starting material is prepa red by reacting an aldehyde of the general formula:- 2 3 in which R , R and n have the same meanings as in claim 1, with a Grignard compound of the general formula r\ Mg.Hal, in which R^ has the same meanings as in claim 1 and Hal is a halogen atom.
15. A process according to claim 14, wherein the reaction with the Grignard compound is carried out at a temperature of from 30 to 60°C.
16. A process according to claim 15, wherein the reaction with the Grignard compound is carried out at a temperature of about 40°C.
17. A process according to any of claims 14 to 16, wherein the reaction is carried out in a solvent.
18. A process according to any of claims 9 to 17, wherein the compound obtained is neutralised with an organic or inorganic acid to give a pharmacologically compatible salt.
19. 20 19. A process for the preparation of compounds according to claim 1, substantially as hereinbefore described and exemplified in Examples 2, 3, 5, 6, 8 and 9. 20. Compounds according to claim 1, whenever prepared by the process according to any of claims 9 to 19. - 24 43284
20.
21. Pharmaceutical compositions, comprising at least one compound according to claim 1, in admixture with a solid or liquid pharmaceutical diluent or carrier.