CS199656B2 - Process for preparing ortho-substituted phenoxyalkylaminoderivatives - Google Patents

Description

The present invention provides a process for the manufacture of ortho-substituted phenoxyalkylamino derivatives.

In the work of L. C. Cheney et al. in J. Am. Chem. Soc. 71, (0 (1949), various diphenylmethane derivatives having a single substituent in the ortho position are described, for example with

2-dimethylaminoethoxy,

2-diethylaminoethoxy,

2-morpholinoethoxy,

2- (1-piperidyl) ethoxy,

2-isopropylaminoethoxy,

3- (1-plperidyl) propoxyl,

3-dimethylaminopropoxy,

3-dibutylaminopropoxy.

At the same time it is stated that 2- (2-aminoethoxy) diphenylmethane and 2- (3-aminopropoxy) diphenylmethane are characterized by antihistamine effects as well as by local anesthetic action in animal experiments.

Experiments have shown that 2- (3-dimethylaminopropoxy) diphenylmethane, also described in this work, has no antidepressant effects.

Belgian patent 831514 (identical to French patent 2 278 329) discloses only the following 2 compounds

of the novel ortho-substituted phenoxy alkylamino derivatives of formula I which are in relation to the compounds of the invention.

The object of the present invention is a method of 1996656

where

R 2 is benzyl, n is 4 or 5 and R 1 is C 1 -C 5 alkylamino or 1-piperidyl, or

R 2 is benzyl, n is 3 and R 1 is C 1 -C 5 alkylamino;

R 2 is phenoxy, n is 4 or 5 and R 1 is amino, C 1 -C 5 alkylamino or C 2 -C 6 dialkylamino, or

R 2 is phenylthio, n is and R 1 is C 1 -C 5 alkylamino, or

R 2 is phenylthio, n is and R 1 is amino, C 1 -C 5 alkylamino, C 2 -C 6 dialkylamino or morpholino, or

R 2 is phenylthio, n is 5 and R 1 is C 2 -C 6 dialkylamino or morpholino; or

R 2 is 1-phenylethyl, n is 4, and R 1 is amino, C 1 -C 5 alkylamino or C 2 -C 6 dialkylamino;

R 2 is 1-phenylethyl, n is 3 and R 1 is dimethylamino, or

R 2 is phenyl, n is 4 and R 1 is amino, C 1 -C 5 alkylamino or C 2 -C 6 dialkylamino, as well as the corresponding pharmaceutically acceptable acid addition salts.

The process according to the invention is characterized in that the ortho-substituted (ω-haloalkoxy) benzene derivative of the general formula II

wherein X is halogen and R2 and n are as defined above, with an amine of formula III

R 1 - Η, (ΠΙ) wherein R 1 is as defined above, whereupon the compound obtained is optionally converted into an acid addition salt.

Salts of the compounds of formula (I) may be derived from organic or inorganic acids, and special examples of acids suitable for the preparation of salts include acetic, succinic, adipic, propionic, tartaric, malic, maleic, citric, benzoic, toluenesulfonic acids. , methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric and nitric.

Particularly preferred compounds of formula I are:

2- (4-methylaminobutoxy) diphenylmethane,

2- (4-ethylaminobutoxy) diphenylmethane,

2- (5-methylaminopentyloxy) diphenylmethane,

2- (4-methylaminobutoxy) diphenyl ether,

2- (4-dimethylaminobutoxy) diphenyl ether,

2- (5-methylaminopentyloxy) diphenyl ether,

2- (3-methylaminopropoxy) diphenylsulfide,

2- (4-methylaminobutoxy) diphenylsulfide,

2- (4-dimethylaminobutoxy) diphenylsulfide,

2- (5-methylaminopentyloxy) diphenylsulfide,

2- (3-methylaminopropoxy) diphenylmethane,

2- (4-methylaminobutoxy) diphenylmethylmethane,

2- (4-dimethylaminobutoxy) diphenylmethylmethane,

2- (3-dimethylaminopropoxy) diphenylmethylmethane,

2- (4-methylaminobutoxy) diphenyl,

2- (4-aminobutoxy) diphenyl,

2- (4-dimethylaminobutoxy) diphenyl.

The compounds of the formula (II) which are used as starting materials in the process according to the invention can be prepared in a known manner by reacting the correspondingly ortho-substituted phenol with 1,3-dihalopropane, 1,4-dihalobutane or 1,5-dihalopentane in the presence of a base. :

Special examples of amines of formula III which can be used in the process of the present invention are ammonia, primary amines such as methylamine, ethylamine or isopropylamine, secondary amines such as dimethylamine, diethylamine, N-methylethylamine, morpholine, piperidine , 4-methylpiperazine or pyrrolidine.

The amount of amine used is 1 to 100 moles per 1 mol of ortho-substituted ω-haloalkoxybenzene derivative. Preferably, the amine is used in excess, as this speeds up the reaction. The reaction may be carried out without solvent, but is preferably carried out in a homogeneous phase in a solvent environment which behaves as inert under the reaction conditions.

Special examples of useful solvents include water, dioxane, tetrahydrofuran, dimethylsulfoxide, lower aliphatic alcohols, and mixtures thereof.

The reaction proceeds satisfactorily over a relatively wide temperature range. Generally, the reaction is carried out at a temperature in the range of 20 to 150 ° C. The reaction time depends on the reaction temperature and the reactivity of the starting compounds; it is generally 10 minutes to 40 hours. The reaction is preferably carried out in the presence of a hydrogen halide binding compound, as this increases the reaction rate.

Examples of useful hydrogen halide binding compounds include inorganic bases such as potassium hydroxide, sodium hydroxide, potassium or sodium carbonate, and tertiary amines such as pyridine and triethylamine. The amount of the base used is preferably from 1 to 5 moles per mole of ortho-substituted ω-haloalkoxybenzene derivative.

If the hydrogen halide binder is not used, then the ortho-substituted ω-aminoalkoxybenzene derivative reacts with the hydrogen halide formed in the reaction to form the corresponding salt.

Salts of ortho-substituted ω-aminoalkoxybenzene derivatives are prepared by reacting the basic compounds with an acid.

The ortho-substituted ω-aminoalkoxybenzene derivatives and their salts are purified by crystallization from a solvent such as a mixture of ethanol and diethyl ether.

The compounds of formula I are valuable drugs with thymoleptic and anticonvulsant activity. This has been proven by animal experiments.

The compounds of formula I were tested in mice for their possible antidepressant, sedative, anticonvulsant and anticholinergic effect. For this purpose, the compounds are injected intraperitoneally in mice, and their effect is compared to that of 3- (3-dimethylaminopropylidein) -1,2,4,5-dibenzocyclohepta-1,4 diene (amitriptyline).

The antidepressant effect was determined by antagonism of reserpine-induced hypothermia at a dose of 5 mg / kg i.p.

S. Garattina and Μ. N. G. Duhes, Excerpt Medica Foundation, Amsterdam 1967, pp. 194-204). Antireserpine potency is expressed as relative potency, with amitriptyline having potency of 1.

Acute toxicity was calculated according to the procedure of Litchfield and Wilcoxon.

Central nervous system depression was followed by the ability of the compounds to induce catalepsy after measurement by the assay described

S. Courvoisier, R. Ducrot, L. Julou in "Psychotropia Drugs", edited by S. Garattin, V. Ghetti (1957), p. 373, as well as using compounds affecting spontaneous motility. (Spontaneous motility is measured using an "Animex" device).

Anti-inflammatory efficacy has been determined by electroshock-induced tonic seizure antagonism [L. Goodman S, M. Singh Grewal, W. C. Brown, and E. A. Swinyard, J. Pharmacol. Exptl. Therap. 108, 168 (1953)].

Central anticholinergic efficacy was determined on the basis of tremor induced in mice by tremorin [G. Everett, L. Bloucus, L., and Sheppard, J. M., Science 124, 79 (1956)].

The results are shown in Tables I and II, where the ED 50 values represent the dose of the test compound that suppresses 50% of the corresponding response.

199956

TABLE I

Antireserpine Efficacy Compound

Relative activity

2- (4-methylaminobutoxy) diphenylmethane hydrochloride 0.73

2- (4-ethylaminobutoxy) diphenylmethane hydrochloride 0.53

2- (5-methylaminopentyloxy) diphenylmethane hydrochloride 0.54

2- (3-Dimethylaminopropoxy) diphenylmethane hydrochloride 0.00

2- (4-methylaminobutoxy) diphenyl ether hydrochloride 1.10

2- (4-Dimethylaminobutoxy) diphenyl ether hydrochloride 0.58

2- (5-methylaminopentyloxy) diphenyl ether hydrochloride 0.57

2- (4-Methylaminobutoxy) diphenylsulfide hydrochloride 0.90

2- (4-Dimethylaminobutoxy) diphenylsulfide hydrochloride 0.70

2- (3-Methylaminopropoxy) diphenylsulfide hydrochloride 0.60

2- (3-methylaminopropoxy) diphenylmethane hydrochloride 0.56

2- (3-Dimethylaminopropoxy) hydrochloride. Diphenylmethane 0.00

2- (2-Dimethylaminoethoxy) diphenylmethane hydrochloride 0.00

2- (2-methylaminoethoxy) diphenylmethane hydrochloride 0.00

2- (4-methylaminobutoxy) diphenylmethylmethane hydrochloride 0.66

2- (4-Dimethylaminobutoxy) diphenylmethylmethane hydrochloride 0.36

2- (3-Dimethylaminopropoxy) diphenylmethylmethane hydrochloride 0.34

2- (4-methylaminobutoxy) diphenyl hydrochloride 0.99

2- (4-Aminobutoxy) diphenyl hydrochloride 0.59

2- (4-Dimethylaminobutoxy) diphenyl hydrochloride 0.45

Amitriptyline 1.00

LD 50 (mg / kg) intraperltoneal

173

120

160

100 ALIGN!

120

130

135

160

140

110

155

137

100 ALIGN!

TABLE II

Inflammatory processes suppressing, anticonvulsant and central anticholinergic activities

Compound Anticonvulsant activity

ED50 - (mg / kg, i, p.)

2- (4-Methylaminobutoxy) diphenylmethane hydrochloride 45

2- (4-Methylaminobutoxy) diphenyl ether hydrochloride 32

2- (4-methylaminobutoxy) diphenylsulfide hydrochloride over 60

2- (3-Methylaminopropoxy) diphenylmethane hydrochloride 40

2- (4-methylaminobutoxy) diphenylmethylmethane hydrochloride 25

2- (4-methylaminobutoxy) diphenyl hydrochloride 14

2- (4-Aminobutoxy) diphenyl hydrochloride 14

Amitriptyline 16

Muscle relaxation efficiency ED50 (mg / kg, i.p.) Attenuation of spontaneous motility ED 50 (mg / kg, i.p.) Antitremorový effect ED50 (mg / kg, i.p.) 80 70 nad 60 60 60 30 50 nad 60 30 65 90 42 nad 60 32 20 May 40 ^{30 20 May} 50 40 60 15 Dec 18 4

Both Tables I and II show that the ortho-substituted phenoxyalkylamino derivatives of formula I have antireserpine activity, which can be compared to amitriptyline, with lower toxicity and weaker central nervous system depression, as well as lower anticholinergic activity.

The compounds of formula I may be administered orally, subcutaneously, intravenously, intramuscularly, or intraperitoneally. The dosage will depend, inter alia, on the age, health and weight of the subject being treated, the severity of the depression, the cadence of treatment and the type of effect desired. In general, the dosage of the drug is between 0.5 and 50 mg / kg, preferably between 1 and 30 mg / kg of body weight per day.

The form of administration of the drug is not limited in any way, and examples include tablets, capsules, powders, solutions or suspensions for oral or parenteral administration. The drug content in the dosage form ranges from 0.5 to 90%, based on the total weight of the preparation.

The compositions may contain, in addition to the medicament, a solid or liquid carrier. Examples of useful liquid carriers include water, peanut oil, soybean oil, mineral oil and sesame oil. Examples of carriers for parenteral use include sodium chloride and sugar solutions, and glycols such as ethylene glycol, propylene glycol and polyethylene glycol. The sodium chloride solution contains 0.5 to 20, preferably 1 to 10, by weight of _the drug.

The following examples illustrate the process of the present invention in more detail:

Example 1

A solution of 5.0 g of 2- (4-bromobutoxy) diphenyl ether and 30 ml of a 40% aqueous dimethylamine solution in 100 ml of ethanol was allowed to stand at room temperature for 8 hours, after which ethanol and excess dimethylamine were distilled off under reduced pressure. The solution in ether was concentrated, 2 N hydrochloric acid solution was added to the residue, and the solution was concentrated to dryness. 6 g of 2- (4-dimethylaminobutoxy) diphenyl ether hydrochloride, m.p. 131-135 ° C.

Example 2

A solution of 2- (5-bromopentyloxy) diphenyl ether (5.0 g) and methylamine (6 g) in ethanol (100 ml) was heated to 50 ^DEG C. in a sealed tube for 2 hours. N sodium hydroxide solution, and the alkalized reaction mixture was extracted with diethyl ether. A stream of dry hydrogen chloride is introduced into the solution in diethyl ether, the precipitate formed is filtered off, and the crude product is recrystallized from a mixture of ethanol and diethyl ether. Yield: 4.2 g of 2- (5-methylaminopentyloxy) diphenylleitheru, m.p. 88-90 ^° C.

Example 3

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

Examples 4 to 47

Using the procedures described in Examples 1, 2 or 3, and the appropriate starting materials, the following products were prepared:

TABLE

Example No. Compound Salt s Preparation of m.p.

1Z

O-CH 2 N (CH ₃ ) _z ⁴

O-CH 2 NHCl · 4

HCl

HCl

HCl

HCl

HCl

135-138

87.5 - 89.5

104-106

112-113

114-119

(0p ^CP 2 — clay)

HCl

HCl

HCl

HCl

87-91

173-177

139-142

129-133

Example #

193656

Compound

Salt s Preparation of m.p.

HCl

82.5 - 84.5

HCl

HCl

O- (CH _{z) N} (CH _{3) from}

O ° Ó

O- (CH _{z) of ¥} NH

HCl

HCl

139-141.5

112-116

104-108-95

7?

0 'f ^ Xp-0-γ ^ř iv>>

HCl

141-144

0 ° - ^%% -O

HCl

106-110

HCl

200 - 208

OCH 2 N 2 O 2

HCl

140-146

O-CH3 NHC4

HCl - 102

Q’TÓ

0- (0Η _ζ ^ ΝΗ _ζ)

HCl - 81

22>

Example #

Compound Salt β Preparation according to example

Mp ° C

o- (ch _z ) ^ nhch ₂

HCl

143-147

O- ( ^CH 3 ^R 1 ^{N (CH} 3 ⁾ 2.

HCl

- 100,5

Q-CH 2 NHCH 3

HCl powder

o-CH3Nfc4

HCl - 98 ze

, v__y

HG1

106 - 109 of

σΥΟή, ν, θ

HCl

126-128

O-

2HCl

180-187

O ~ (CHJ NHCH) Ο ^ -τ5

HCl

148-152

O- (CH _z) NHC ₂ H _{5 from}

HCl

153-154

OrxÓ

HCl

HCl

155-158

117.5 - 119

Example #

Compound

Salt s Preparation of m.p.

HCl

109-111

VóCU let ^ fc _% ”ΟΠζτΟ

O-OCH ^ sNHCWj 'QSO

HCl

HCl

HCl

153-154

142-144

102-105

3 * QC

Vcw.vx

OiCH2NfCH3

HCl

121-122

O-CH 2 N (CH 2 Cl 2)

HCl

115-118

O ~ (CH _{z) from H} Nti

ΟΓΊ

HCl

155-158

Ύγ, -O- (CH _{2) 3} NHCH

HCl

142-144 o- (ch _z ), nhch _z ch ₃

OF

HCl

146-148

O- (CHJ _S N (CH ₃ ))

Cn

HCl

98-104

Cn

Cr (CH ^ n _of

HCl

124–126

199636

Example #

Compound

Salt Preparation of m.p.

Claims (6)

A process for the preparation of ortho-substituted phenoxyalkylamino derivatives of the general formula I wherein R 2 is benzyl, n is 4 or 5 and R 1 is C 1 -C 5 alkylamino or 1-piperidyl, or R 2 is benzyl, n is 3 and R 1 is C 1 -C 5 alkylamino, or R 2 is phenoxy, n is 4 or 5 and R 1 is amino, C 1 -C 5 alkylamino or dialkylamino Or 2 to 6 carbon atoms; R 2 is phenylthio, n is And R 1 is C 1 -C 5 alkylamino, or R 2 is phenylthio, n is 4 and R 1 is amino, alkylamino, C 1 -C 5 or C 2 -C 6 dialkylamino or morpholino, or R 2 is phenylthio, n is 5 and R 1 is a dialkylamino group of 2 to 5 Or a morpholino group, or HCl 3 146-150 HCl 3,153-158 VYNALEZU R 2 is 1-phenylethyl, n is 4, R 1 is amino, C 1 -C 5 alkylamino or C 2 -C 6 dialkylamino, or R 2 is 1-phenylethyl, n is 3 and R 1 is dimethylamino, or R 2 is phenyl, n is 4, and R 1 is amino, C 1 -C 5 alkylamino or C 2 -C 6 dialkylamino, as well as the corresponding pharmaceutically acceptable acid addition salts, characterized in that it is ortho-substituted ( ω-haloalkoxy) benzene derivative of general formula II Where X is a halogen atom, and R 6 and n have the same meanings as above, are treated with an amine of formula III R 1 -H, (III) wherein R 1 is as defined above, and optionally converting the obtained compound to a salt by treatment with an acid.