DE2053192C3 - l-Amino-3-phenoxy-propanol- (2) derivatives, their therapeutically acceptable salts and medicaments containing them - Google Patents

Description

3 l-Cyclopropylamino-S-io-cyclopropylphenoxy) -propaaol- (2) and its cyclohexyl sulfamate. as The compounds of general formula I and

4. Medicaments, characterized by one of their salts are prepared by adding a content of a compound according to claims 1 amine of the general formula II
to 3.

^3O

HN (II)

The invention relates to new 1-amino in which R ₁ and R »have the meaning already given

3-phenoxy-propanol- (2) -derivatives, which therapeutically have 35, in a manner known per se with an epoxide

compatible salts and medicaments containing them. of the general formula III

The new l-amino-3-phenoxy-propanol- (2) -deri-

vate correspond to the general formula Ar - OCH, - CH - CH,

O '

Ri 4 »

Ar nru ru ru w ^{in the Ar} also has the meaning already given

Ar-U ^ n ₁₈ - lh -1-H ₄ - converted into ₍ , _} ^ _and possibly the one obtained in this way

R ₂ product of general formula I with a therapeutic

^0H table acceptable mineral acid or organic

45 treated with acid or a quaternizing agent.

in which Ar is an o- or p-cyclopropylphenyl radical The procedure is preferably as follows:

and R ₁ and R _{2 represent} hydrogen or a linear one brings a mixture of the epoxy

or branched alkyl radical with 2 or 3 carbon- general formula III and excess amine der

atoms are or a cyclopropyl radical, with general formula II within one compared to the

at least one of the radicals R ₁ or R ₄ no water 50 reaction products inert solvent to a

fabric is. Temperature between 50 and 100 ^c C. As a solution

The therapeutically acceptable salts of the compounds can be, for example, an aliphatic one

fertilizers of the general formula I are those with alcohol of low molecular weight used

Mineral acids or organic acids as well as thera- be. This reaction mixture is kept from 1 to

therapeutically compatible, quaternary ammonium salts. 55 in motion for 10 hours and separates after

Among the reaction ended with mineral acids or organic the solvent and excess acids formed salts of the compounds of the general. Siges amine of the general formula II by concentration

my formula I, those are preferred with starting and isolating the desired product for example

Chlorine, bromine or hydroiodic acid, nitric acid by distillation.

acid, sulfuric acid, phosphoric acid, acetic acid, Ma * 60 The acid addition salts of the designated

Oleic acid, fumaric acid, succinic acid, tartaric acid, compounds of the general formula I are

Citric acid, benzoic acid, alkanesulfonic acids and preferably in a solvent or a mixture

Cyclohexylsulfamic acid can be obtained. of solvents such as ethyl ether, ethanol or

Among the quaternary ammonium salts of Vef acetone, which can be aqueous or anhydrous,

bonds of the general formula I are preferably established. The quaternary ammonium salts of the

selected those who are treated with alkyl halides, such as compounds of the general formula I

Methyl chloride, bromide or iodide or with Hy-, half of an anhydrous solvent or one

hydroxyalkyl halides, such as 2-hydroxyethyl chloride, mixture of solvents such as ethyl

ether, acetonitrile, acetone, dioxane, methanol or ethanol

In view of their very interesting properties, the compounds according to the invention find therapeutic in particular because of their inhibitory effect on adrenergic ^ receptors Use in the treatment of constriction of the heart and cardiac arrhythmias, especially in the case of atrial fibrillation.

The usual dose is depending on the product used, the person to be treated, the ailments and the type of administration variable. When administered orally to adults, for example, it can range from 5 to 100 mg per day.

The compounds of the invention can be in the form of pharmaceutical compositions intended for peroral or parenteral administration. You can fixed or be liquid and in the form of simple or coated tablets, capsules, granules, solutions, suppositories ao rien or injectable preparations are present; they are produced by conventional methods. The river Oder the active ingredients) can be brought together with excipients usually used in such pharmaceutical compositions, such as with Talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, various wetting agents, dispersants or emulsifiers and preservatives.

The compounds used as the starting material of the general formula III can be obtained by reacting a substituted phenol of the formula

Ar-OH

in which Ar has the meaning already given, be prepared with l-chloro-2,3-epoxypropane in the presence of an alkaline agent. One gives preferably the 1-chloro-2,3-epoxy-propane to the solution of the phenol Ar - OH in aqueous potassium hydroxide solution added. After the reaction at ambient temperature, the desired compound of the general formula Hl is separated off by customary means, such as extraction with ether and concentration and distillation.

The advantageous effect of the compounds according to the invention over the known in pharmacy, Vol. 23, 1968, p. 240, described 1-isopropylamino-3-naphthoxy-propanol- (2) result from the im the following comparative test results reported (see table), which were found on closer examination of the Compounds according to the following example 1, b) and 4, b) were obtained.

The inhibitory effect on isoprenaline and the toxicity of the products were examined. In the table shows:

1. in column A: the smallest doses for a subtotal Inhibition of isoprenaline hypotension;

2. in column 7 (C.E.): the lowest concentration for a subtotal inhibition of the cardiotonic Effect of isoprenaline (determination of the chronotropic and positive inotropic effects on the isolated guinea pig auricula);

3. In column B: the smallest doses for an inhibitory effect on the inhibiting effect of isoprenaline against the bronchoconstrictive Effects of acetylcholine in guinea pigs;

4. In columns C and D: doses which lead to an approximately 50% reduction in hyperglycaemia (C) or hyperlactacidaemia (D) caused by isoprenaline;

5. the last column contains DL ₄₀ -WeIIe when administered intraperitoneally to the mouse.

table Examined products Dose administered in mg / kg

DL 50

in mg / kg

Example 1, b

Example 4, b

Well-known product

0.01 0.01 0.1

0.01

0.2

0.05 to 0.1 0.01 to 0.1 0.1 to 1 0.1 to 1

0.01 to 0.1 0.1 0.1

131 239 131

The following examples serve to illustrate the Invention.

example 1

a) l-Isopropylamino-3- (o-cyclopropylphenoxy) -propanol- (2)

A mixture of 11 g (0.058 mol) - (o-Cyclopropylphenoxy ^ .S-epoxy-propane, 6.1 ml (0.071 mole) of isopropylamine and 50 ml of isopropanol for 4 hours in an autoclave at 8O ⁰ C. The Isopropanol and the excess isopropylamine are then separated off by concentration under reduced pressure and the residue is distilled. In this way 9.5 g of a product which crystallizes on cooling are obtained. The crystals obtained are recrystallized from hexane, and 7 g (48% ) 1 - Isopropylamino - 3 - (o - cyclopropylphenoxy) - propa nol- (2) in the form of white crystals with an instant melting point of 7O ⁰ C.

As far as is known, this compound has not yet been described in the literature.

The l- (o-cyclopropylphenoxy) -2,3-epoxy-propane used as the starting material is as follows Ways to be made:

To a solution of 11.2 g (0.2 mol) of potassium hydroxide in 92 ml of water, 18.9 g (0.14 mol)

o-CycIopropylphenol and then 12.2 ml (0.155 mol) l-chloro-l ^ -epoxy-propane added. The mixture is stirred at ambient temperature for 4 hours. The oil formed is extracted with ether and the ethereal phase dried over potassium carbonate.

The ether is then separated off by concentration under reduced pressure and the residue is distilled, and 11.6 g (44%) of l- (o-cyclopropylphenoxy) -2,3-epoxy-propane are obtained in the form of a colorless liquid

5 6

speed; Boiling point: 92 to 94 ° C at 0.001 torr; offset. The mixture is for 48 hours at 0 ⁰ C »£ - 1.549. ditched. One then sucks or hurls them

crystals formed from a mixture of

Molecular formula: C ₁₁ H ₁₄ O, · ethyl acetate and acetone are recrystallized. Man Calculated ... 0 75.8 ⁰ Z ₀ , H 7.4%; 5 thus receives 5.8 g (33%) [3- (o-Cyclopropyrphenoxy) -

found ... C75.6%, H 7.4%. 2-hydroxypropyl-diethyl-methyl-animonium iodide in

Form of white crystals with a melting point

As far as is known, this connection was in that of 106 ⁰ C (hot-stage microscope observation). LiteraJ-dr not yet described.

b) Hydrochloride ^{1O Molecular} formula: C ₁₇ H ₁₈ INO ₁

7 g (0.027 mol) of 1-isopropylamino-Mo-cyclopropyl- Calculated ... C 50.4%, H 7.0%, 1 31 3%;

phenoxy) propanol (2) are found dissolved in 100 ml of ether ... C 50.6 / ₀ , K /, u / ₀ , ι Ji, z / ₀ . and with hydrogen chloride. Ethanol added.

The crystals formed are suctioned off or removed. As far as is known, this connection was found in the

centrifuged and recrystallized from benzene. Literature is not yet described. 6.8 g (85%) l-isopropylamino-S-io-cyclopropylphene

oxy) propanol (2) hydrochloride in the form of white ice The 13 "crystals; Melting point: 96 ^c C (hot stage microscope

observation). ao _a j i-isopropylamino-S ^ p-cyclopropylphenoxy) -

Molecular formula: C ₁₅ H ₁₄ Cl NO ₁ propanole Calculated ... C63.0%, H 8.5%, Cl 12.4%; In the same way as in example 1, but

found ... C 62.9%, H 8.6%, Cl 12.3%. using 20 g (0.105 moles) of crude

as Hp-Cyclopropylphenoxy ^^ - epoxy-propane and

As far as is known, this compound was obtained in the 11.3 ml of isopropylamine obtained by distillation Literature not yet described. 13.2 g of a product which crystallizes on cooling

sated. The obtained crystals are made from hexane

Example 2 recrystallized, and 12.1 g (46%) of 1-iso-

\ ι r \ ~ * u ι * / ι tu χ 3 ° propylamino-3- (p-cyclopropylphenoxy) -propanol- (2)

a) l-Diethylamino ^ o-cyclopropylphenoxy) - f «£ ^ _n U ^ _n . Instant melting

Propanol- (2) point: 70 <C.

With the same procedure as in Example 1, but this compound was, as far as known, in the

using 16.5 ml of diethylamine, literature has not yet been described, 26.9 g (75%) of 1-diethylamino are obtained by distillation. Propanol- (2) in the form of a propylphenoxy) -2,3-epoxy-propane can be in the following colorless liquid; Boiling point: 130 to 135 ⁰ C can be obtained in ways:

0.001 torr. To a solution of 10 g (0.18 mol) potassium

This compound was, as far as is known, in the hydroxyd in 76 ml of water, 15.6 g (0.116 mol) Literature not yet described. 40 p-cyclopropylphenol and then 10.2 ml (0.13 mol)

l-chloro-2,3-epoxy-propane given. The mixture

b) Cyclohexylsulfamate "is under for 20 hours at ambient temperature

stirred in a stream of nitrogen. The formed oil will

12.7 g (0.048 mol) of r-diethylamino-3- (o-cyc! Opro- extracted with ether and the ethereal phase over pylphenpxy) -propanol- <2) are dried in 880 ml of water 45 sodium sulfate. The ether is then through dissolved free ether and separated to 8.3 g (0.046 mol) in 55 ml of concentration under reduced pressure. Man Acetone dissolved cyclohexylsulfamic acid given. this gives 20 g (90%) of Hp-cyclopropylphenoxy) -The crystals formed are suctioned off or 2,3-epoxy-propane in the form of a colorless liquid, centrifuged and recrystallized from acetone. This compound was obtained, as far as is known, in the

so 13.4 g (64%) of 1-diethylamino-S-io-cyclopropyl-50 literature not yet described. phenoxy) propanol (2) cyclohexyl sulfate in the form

of white crystals with a melting point of _D ) hydrochloride

102 to 103 ° C (hot stage microscope observation).

With the same procedure as in Example 1, b), but Molecular formula: C _{11 HmN 1} O. S ^m using 11 g (0.04 mol) of 1-isopropyl Calculated C 59 7 ° / H 8 7 »/ N610 / amino-S-ip-cyclopropylphenoxy / propanol ^), obtained Calculated ... C 59.7 / «, H 8.7 / ₀ , N 6.3 / ₀ , _{after recrystallizing from Ββηζο} 1 9.5 g Findings C 59 7 "/ HR 70 / N fi 0" / ^{(83 %) 1} -I ^so P ^r opylarMno-3- (j> -cyclopropylphenoxy) -

found ... C 59.7 / * H 8.7%, N 6.2 / _m propanol (2) hydrochloride in the form of white crystals

'' * 60 stalls with a melting point of 124 ⁰ C (heating

table microscope observation). This connection was "as far as known, in the Literature not yet described.

Molecular formula: Cj ₆ H ₁₄ ClNO ₁

c) Iodine methylate _{6s Calculated c} 63.0%, H 8.5%, N 4.9%, 11 g (0.044 mol) of 1-diethylamineb-3- (o-cyclopropyl-Cl 12.4%;

phenoxy) -propanoK2) are found in 100 ml of anhydrous ... C 63.2%, H 8.5%, N 4.7%,

Ether dissolved and with 3.2 ml (0.051 mol) methyl iodide Cl 12.4%.

7 8

As far as is known, this compound has the sum formula: C ₅₁ Ha ₁ NsO ₅ S

Literature not yet described. Calculated ... C 59.1 ¹ Y ₀ . H 8.0%, N 6.6 ⁿ / ₀ ,

S 7.5'V _n;.

Example 4 found ... C 5K.8 "". H 8.0%, N 6.4%,

5 e 7 in

a) l-Cyclopropylamino-3- (o-cyclopropylphenoxy) - · ^0-

Propanol- (2) \ Ύ \ νχ compound was, as far as known, in the

The same procedure as in Example 1, but not yet described in the literature, using 5 ml (0.071 mol) of Cyelopropyl-

ainhi, 7.5 g (52%) of the example are obtained by distillation

l-C "yclopropylamino-3- (o-cyclopropylphcnoxy) -propa- _, _ ,,,,. _,

nol- (2) in the form of a colorless liquid with one, ^{Fs Wl} ' ^rdcn tablets of the following composition

Boiling point from 132 to 134 C at 0.1 Torr. manufactured:

This compound was, as far as is known, in the l-isopropylamino-S-io-cyclopropyl-

I iterature not yet described. - 15 phcno \ y) propanol (2) hydrochloride 10 mg

l ^: .x / ipient qs for a tablet of .. 250 mg

b) Cyclohexyisulfamate (Hx / ipicnt in detail: lactose,

Starch, talc, magnesium stcarate).

In the same way as in example 2. b). but

using 6.5 g (0.023 mol) of l-cyclopio- ao examples

pvlamino-3- (o-c \ clopropvlphenoxv) -propanol- (2), er _ "_,,

one holds 4.7 g after dissolving from benzene. Injectable preparations of the following composition were obtained

<4S ». ·") 1 - Cy clopropNlamina - 3 - (ο - eyelopropylpheu- composition made:

o \\) - propanol- (2) -cycloxylsulfamate in the form of l-isoproylannino-S-io-cyclopropylphen-

wciticn crystals; Melting point: 129 C (hot table 35 ox \) - prupano '.-; 2) hydrochloride 2 mg

microscope observation). Aqueous solvent 5 ml

Claims (1)

bromide or iodide or with alkyl sulfates, such as di-claims: methyl sulfate, with alkyl alkyl or aryl sulfonates, such as methyl methanesulfonate or methylbenzenesulfonate 1. l-Amino-3-phenoxy-propanol- (2) derivatives of or -toluenesulfonate, are obtained,
general formula 5 The new compounds according to the invention be sit very interesting pharmacological properties. Ri shafts: Ar - OCH, - CH- CH-- N ^{/ they} develop a remarkable one in particular ι - inhibiting effect on the adrenergic _OH ^R ä io ^ receptors of the organism and have the rest low toxicity. Among the compounds of the invention are in which Ar is an o- or p-cyclopropylphenyl radical, the following should be mentioned in particular:
and R ₁ and R. are hydrogen or a linear one
or branched alkyl radical with 2 or 3 carbons .5
Mean material atoms or a cyclopropyl radical,
where at least one of the radicals R, or R, no Is hydrogen, as well as its salts with therapeutic ^ Τ ^ Ψ ? compatible mineral acids or organic suction (o-Cydopropylph