DE2035535A1 - Square bracket on 3 alkoxy 2 (diaryl) methyl square bracket on propylamine, its manufacture and use - Google Patents

Description

their_making

The invention relates to new / ~ 3-alkoxy-2- (diaryI) -methy1-7-propylamines and a method for their production. These new compounds are valuable drugs, in particular in the cardiovascular field.

The 2-hydroxy-3-alkoxypropylamines and the 2-hydroxy-3-aryloxypropylamines are known to be adrenergic ß-receptor blockers. There are numerous publications dealing with these compounds and their applications. Examples are the Belgian patent 669 401, the Dutch explanatory documents 6 409 883, 6 504 268, 6 600 177, 6 605 692 and 6 608 099, the French Specialty Medicines Patent No. 5190M and U.S. Patent 3,309,4o6. For example, were in the literature products of the formula

CH - CH ₂ - A

described, in which A is a tertiary amino group in which the nitrogen atom can form part of a heterocycle, and R _{1 is} an optionally substituted aryl radical.

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Belgian patent 669 789 also describes compounds of the above structure in which but R is an aliphatic radical "

Belgian patent 718 425 describes compounds the structure

Vo., ..

CH ₂ - 0 - R ^f

in which A has the meaning given above, R 'is an aliphatic Radical, an aryl radical or arylaliphatic radical, X a group of the formula 0 - CO - Ar or NH CO - Ar and Ar is an optionally substituted aryl radical.

However, while the β-receptor blocking effects predominate in the above-mentioned compounds in the compounds described in Belgian patent 718 425, the β-receptor blocking effects practically disappeared, while notable anti-arthmic and coronary dilatatory Effects are determined.

Mention should also be made of Belgian patent 710 852, which describes compounds which are coronary dilatatory Properties and structure

Ar OR

CvHe ^- CH ₀ CH - CH ₀ -

^CH 3

in which Ar is an aryl radical «The South African Patent 67/5 ^ 30 describes compounds of the 00988S / 2289

structure

O - CH ₂ - CH - CH ₂ - NH - R 'OH

in which Ar and Ar 'are aryl radicals.

In the German patent specification 1 100 031 and in the publications by Erhart (Arch. Pharm. 295 p. 196 (1962)) and Lindner (Arznei Forsch. 10 (8) p. 573 (1960)) compounds with cardiovascular effects are described, which are derived from 3,3 ~ diphenylpropylamine. One of those compounds that make up the structure

CH - CH ₂ - CH ₂ - N - CH - CH ₂ -

H CH,

has * is the active ingredient from Farbwerke Hoechst AG brought onto the market under the name "Segontine" Drug preparation.

The new chemical compounds according to the invention are / ~ 3-alkoxy-2- (diaryl) methy _< l7-propylamines of the general formula

Ar

- CH - CH ₂
CH 0

CH ₂ - A

CH ₂ - 0 - R

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In which Ar and Ar 'are identical or different, optionally substituted aryl radicals * which can be linked in the form of a polynuclear aromatic group by CC bonds or by chains containing heteroatoms such as oxygen atoms; R is an aliphatic radical, aryl radical or arylaliphatic ReSt ₁ , and A stands for a tertiary amino group in which the nitrogen atom can form part of a heterocycle.

The invention also includes pharmaceutically acceptable ones Salts of the abovementioned compounds of the formula (I) with organic and inorganic acids «

For the preparation of the compounds of the formula (I) is from Amino alcohols of the formula

RO _{- CH 0} - CH - CH ₀ - A

^{2 r 2} (H)

OH

assumed, in which A and R have the meanings given above for the formula (I). The amino alcohols (II) and their manufacture are described in Belgian patent 718,425.

The method according to the invention is through the two the following, successive reaction stages characterized;

l) An amino alcohol (II) is treated in a solvent with a compound that can replace the OH group of the amino alcohols with a chlorine atom, where an intermediate compound (III) of the formula

RO-CH ₂ -CH-CH ₂ -A

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■ - 5 is obtained.

2) The intermediate (UI) is reacted in a solvent with an excess of a diaryl derivative of methane previously converted into the sodium derivative, the aryl radicals of which correspond to the radicals Ar and Ar ^{1 of} the desired product of the formula (I).

In stage (1). Is used as a reactant who the OH group of the amino alcohols (II) replaced by a chlorine atom, most advantageously thionyl chloride SOCl, - used. For stage (1), the molar proportions of the amino alcohols (II) and the thionyl chloride chosen so that the thionyl chloride is present in excess. Preferably be 0.75 moles of amino alcohol (II) is used per 2 moles of thionyl chloride.

Suitable solvents for stage (1) are chlorinated hydrocarbons, e.g. B. chloroform or methylene chloride. The reaction temperature is generally the reflux temperature of the particular solvent used.

In step (2), a diaryl derivative of methane which has previously been converted into the sodium derivative is used. The attachment of sodium to such derivatives is described in the literature. For example, describe Normant and Staff (Bull. Soc. Chim. Fr. (1962) p. 810) the implementation of diphenylmethane with naphthalene sodium.

The compounds which are most advantageous for uses as medicaments are obtained when Ar and Ar ¹ each represent a phenyl radical. For this purpose, diphenylmethane is used as a diaryl-substituted methane derivative in step (2). To prepare the sodium derivative of diphenylmethane with the aid of naphthalene sodium, essentially equimolar amounts of the three reactants are used

on participant, d. H. Naphthalene (1 mol), sodium (Ig-Atorn) and diphenylmethane (1 mole) reacted. For the actual reaction of stage (2) this is converted into the sodium derivative converted diphenylmethane used in excess over the intermediate (III). For example be about 0.5 mole of the latter compound is used to at least 1 mole of the former compound.

The reaction of step (2) is also carried out in a solvent, preferably in tetrahydrofuran, at the reflux temperature of the solvent carried out. In an analogous manner for the preparation of compounds of the formula (Ϊ) worked, in which the radicals Ar and Ar "are included in an aromatic group, for example if of fluorene (or diphenylenemethane) or xanthene is assumed.

The preparation of a certain number of compounds according to the invention is described in the following examples.

example 1

Preparation of the hydrochloride of N, N-diethyl / 2 (diphenyl) -methyl-3-isobutoxy / propylamine (Connection 1)

la) First stage: Preparation of N, N-diethyl / 2-chloro-5-isobutoxy ^ Z-piOpylamine

The reaction can be represented by the following scheme:

- CH ₂ -O- CH ₂ - CH - CH ₂

SOCl ₂

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- CH ₂ --O _{- CH 2} - CH - CH ₂ - N

^C 2 ^H 5

To a solution of 153 g (0.75 mol) of N, N-diethyl / 2- hydroxy 3-isobutoxy7-propylamine in 100 ml of chloroform, 150 ml of SOGl ₂ in 150 ml of chloroform are slowly added with good stirring, being careful that the temperature does not exceed 45 ° C. After the SOCIg has been added, the reaction mixture is refluxed for 4 hours. The solvent and the excess SOCl _{2 are then} driven off under reduced pressure. The residue is poured onto crushed ice. It is then neutralized with 40 # strength aqueous NaOH and the oil formed is extracted with ether. After the ether has been distilled off, the residue is fractionated under reduced pressure, 140 g of a colorless liquid having a boiling point of 92 to 93 ° C./4 mm Hg being obtained. Refractive index n _D =. Yield: ■ 80 % of theory.

Ib) Second stage: preparation of the compound (1) defined above

To a solution of L30 g of naphthalene (1 mol) in 600 ml Tetrahydrofuran is 23 g (1 g atom) of sodium in small Pieces given, whereupon left to react for 3 hours at room temperature. Then you quickly add 170 g (1 mol) Diphenylmethane and allowed to react for 4 hours at room temperature. Then, with good stirring, are added dropwise 120 g (0.54 mol) of the halogenated derivative of the first Level added. The reaction mixture is 2 hours on Heated to reflux.

The mixture is allowed to cool to room temperature and a solution of 40 g of NH ^ Cl in 100 ml of H ₃ O is added. The organic phase is decanted and the solvent is driven off under reduced

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temp pressure. The residue taken up in the ether is extracted with aqueous 4N HCl. The aqueous solution obtained is washed with ether and made alkaline with 40% NaOH. The oil obtained is extracted with ether. After distilling off the solvent, the residue is rectified under reduced pressure to obtain 110 g of a viscous oil of boiling point 155 ⁰ CyO ^ mm

20th

Hg can be obtained »refractive index n ~ = 1.5232. Yield: 61 %.

^ The hydrochloride is prepared in the usual way in anhydrous isopropanol. After recrystallization from the same solvent, 100 g of the hydrochloride are obtained in the form of a water-soluble, white crystalline powder after drying.

Melting point (according to Mettler) = 125.5 ° C

Elemental analysis: NC H calculated: 3 * 60 73.9 9 * 22

found: 3.64 73.4 8.32

HCl according to the Charpentier-Volhard method

φ calculated: 9.3 % HCl
found: 9.35 # HCl

Examples 2 to 17

Compounds of the formula (I) in which Ar and Ar ¹ each represent a phenyl radical and A and R have the meanings given in Table I below are prepared using the catfish described in Example 1. The connections thus have the following general structure:

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In the table % , the key figures for compound 1 prepared according to Example 1 are included in line 1. The table gives the number of the product in the first column, the meaning of A in the second column, the meaning of R in the third column, the melting point of the hydrochloride in the fourth column and the values calculated and found by analysis in the last column von N, C and H. The hydrochlorides of the compounds mentioned were also analyzed.

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Table I.

product
No.

Melting point of the hydrochloride

09 2

κ »-
m 3

CH

-CHg-CH

CH calcd. 3.60 73.9 9.2 125.5 ° C found. 3.64 73.4 8.32

^N O

CH 145 ⁰ C

⁰ C

ber.
found

3, ^ 7 3.40

66.6 67.6

7.95 7.91

-CHg-CH

CH calc. 3.61 74.3 8.83 125 ⁰ C found. 3.66 74.07 8.84

■ O

CHg-CH

CH

ber. 3, 50 75 CJN 9, 2 O 155 ⁰ C found 3, 66 74, 8th, 86

CH ₂ -CH ₂ -CH ^

calc. 3.43. 70.9 8.83 ^ ¹ 170 ⁰ C found. 3.39 71.03 8.80 ^

Product No.

Melting point
of the hydrochloride

-α

-CH ₂ -CH ₂ -CH 14l ° C

calc. 3.50 74.8 9.03 found 3.58 74.23 8.37

CO OO CO

KJ OO CD

-ο

-CH ₂ -CH ₂ -CH ^

186 ⁰ C

ber.

found

3.37

3.35

75.1 75.8

9.14 9.90

^C 2 ^H 5 120 ^° C

ber. 3.57 74.2 9.50 found. 3.52 73.6 9.32

^C 2 ^H 5

14O ⁰ C

ber.
found

3.41
3.40

76.0 76.2

7.79 8.06

10

-a

CH ₂ -CH, 176 ° C

ber.

found

3.89
3.85

73.4 72.9

8.34 8.20

NJ CD OO

-cn to co cn

11

-O

«» CH 229 ⁰ C

ber.
found

3.74
3.81

73.9 72.6

8.62 8.09

Melting point of the hydrochloride

155 ⁰ C

ber.
found

3.87 '3.89

73.0 73.03

8.91 7.76

147 ⁰ C

ber.
found 0

3.31
3.29

76.9 75.8

7.59

ber.

3.75
3.75

70.1 71.9

8.0 ^7t9 °

98.5

⁰ C

found

4.38
4.50

71.4 71.8

8.21

171.5 ° C

ber. 3.30 73.65 7.13 found . 3.29 73.58 7.24

158 ⁰ C

about ο 3, 43 76 54 7, 41 CD found 0 3, 41 75 91 6, 99 OO cn cn co cn

Product A.

No.

CH ₂ -CH ₃

■ o

CH

-CH ₀ -CH,

2

-CH

16

-O

17th

-N.

Example l8
Making connections of the structure

^ ₂ - A
C-CH

The preparation of these connections is carried out by the following "Example illustrates where R is isobutyl

CH

- CH ₂ -

and A is the piperidyl radical

■ Ό

is. In this case "the groups Ar and Ar ^{1 form} the fluorene ring in the above formula.

The reactions are carried out in the manner described in Example 1, using appropriate starting compounds. The product received has the following key figures:
Salt: hydrochloride
Melting point: 168 ° C

Elemental analysis:

calculated:

found:

The other compounds of the above formula are prepared in an analogous manner, where A and R are each 009885/2289

N 49 C. ,8th H 73 3, 50 7 * , 9 8th, 98 3, 73 6,

- 14 - have the corresponding meaning.

Example 19 Preparation of compounds of structure

The preparation of these compounds is described by the following example, where R is an isobutyl radical

^CH 3 ^ and A is a diethylamino group

-M *

In this case, the groups Ar and Ar 'are the xanthene ring in the above formula, the reactions are as described in Example 1 carried out * the corresponding starting compounds are used The product obtained has the following characteristics..:

Salt: 009 Fumarate O
O M. 89 C. 56 H 66 Melting point: 75 ° C 2, 03 69 22nd 7, 20th Elemental analysis 3 * 69. 7, calculated: 8 85/2289 found:

The other compounds of the above formula will be produced in an analogous manner, each changing the meaning of λ and R.

The compounds of the formula (I) in which Ar and Ar ^f each represent a phenyl radical, and their pharmaceutically acceptable salts, in particular cause the coronary arteries to expand. Their influence on the peripheral vasomotors is small and they have no effect whatsoever on the adrenergic receptors, especially the β-receptors, but they still slow the heart rate without depression of the myocardium.

The uses of these latter compounds as Medicines are described below for those products that have the greatest pharmacodynamic effect.

Pharmacodynamic properties A. Acute Tcxizi tat

The LDf-Q was determined in the mouse by the method of B. Behrens and C. Karber (Arch. F. Exp. Path. Pharm. 177 : 379 (1935)). The results are given in Table II below.

LD in
mg / tcg Table II LD in
mg / kg link
No. orally link
No. orally 450 385 1 > 1OOO 10 500 2 570 11 C300 3 > 1OOO 12th ^ 1500 4th > 900 13th 500 5 1985 14th 550 6th > 1500 15th > 1000 7th 16 > 1000 550 17th > 1500 8th 1150 18th 600 9 19th

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In Table II above, the LD ^ _n for all compounds of Examples 1-19 is given either as a precise value or as a limit

Pharmacological experiments, for _o B ₀ tests on heart and blood vessels and testing as Lokalanästethikunis had the results listed below for the most representative products of the invention _o

B. Investigation of the effect on

Coronary vein flow rate Blood pressure

Heart rate

Force of contraction of the heart Partial oxygen pressure POp of the coronary veins

Examination method ( mouse)

After anesthesia with chloralosis, the thorax is opened by Re = sectioning of the 5th rib on the right. A contraction knife (jauge de contrainte) is sewn to the right ventricle »A catheter of the largest possible diameter is inserted into the coronary sinus through an opening in the right atrial appendage and attached with a mower, which is placed very close to the heart valve ₀

The venous Koronarblut flows into a rotameter, which is arranged in a room kept at constant temperature tank and then comes _# ,, without departing from this space, with a macro oxygen electrode (Beckman) into contact. It finally returns to the right jugularis through a line in which a fine catheter is inserted that draws blood to a "Technicon" autoanalyzer, where the total carbonic acid and ammonia are continuously quantified "■ The contraction of the myocardium, the electrocardiogram ( Dg), the outflow

00 ^ 8 85/77 $! @ L

U U ν ν U ti ί fe ^ O ty

total amount of coronary arteries, blood pressure and ■ the partial pressure of oxygen PO ^ will be on a Beckman dynograph registered.

The products of the test series were intravenously (outer "velne asphene") slowly within one minute in a « Amount of 5 mg / kg injected. The ones with the most representative Results obtained from compounds are shown in Table III below.

The slowing down of the heart's activity (bradycardia) does not increase the adrenergic ß-blocking influence. " The cardiac effects of isoprenaline and stimulation the heart-accelerating nerve pathways are not changed. -

Outflow Tabel III Ventri PO ₂ link the coronary
ar teri en Heartfree blood kel-meas
device C. No. quenz pressure (Jauge ventricular culaire) ^ 76 \ ^ 18 4120 1 ^ 116 i 35 ^ 50 4 40 f 30 3 ^ 60 | r20 ^ 95 4th ^ 95 4 ^ 30 4 Q J / 13 / ^ Ι8θ 6th f 45 4.25 ^ 43 ^ 13 Ϊ105 7th ^ 55 ψ 20 4.25 f 107 8th φ K) O V27 ^ 28 4 * 7 fl25 10 -tioo ^, 10 f ²² φ 18 . ^ 70 15th ^ t 120 ψ17 ^ 10 ^ 20 ^ 100 17th f66 ψιο 4-6 Α> 13 φ! 73 19th i-20

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C. Effects as an Anesthetic ■.

These effects were by the method of Bulbring and tfajda "- determined" All compounds were of an aqueous solution of a concentration of 2 percent _o (Therap, 1954, VoI ₀ 35 78 84 - $ used J. of Pharmacology and Exp) "The. Results obtained with the most representative products are given below in Table IV., ·

1. Effect _fl 100 Table IV-. 10 Effect,, 99 link 3 «Ζ 99 link 11 % 100 Ir. % 86 Mr ₀ 12th 85 6th 97 . 15th ■ 100 7th 100 ■ 18 .. 99 8th 96 19th "84.

The effect of these products as a local anesthetic is- " thus comparable to the effect of xylokain "

D. Effects on the central nervous system

Some of the products examined above are also effective as anticonvulsants and have shown results an examination using the supratnaximal

Electric shocks in the mouse "For example, the Pro" takt Mr _a 15 has an ED ^ ₀ of 16 mg / kg ₀

Indications,

Y onnectivity of formula (I) _x, wherein Ar and Ar ⁸ are each a phenyl radical FLR _a are active compounds are suitable for the ^ drugs suitable: ;, therapeutic especially in the following indications t

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Anoxles of the myocardium coronary insufficiency, angor. Myocardial infarction

Heart failure in connection with disorders of the coronary circulation

Some of the above compounds are also available as non-sedative anticonvulsants as well as stimulants of the central nervous system effective.

The compounds according to the invention can be used in the form of the bases or their pharmaceutically acceptable salts with acids. They can be further used in conjunction with excipients and carriers _s which are commonly used for the production of pharmaceutical preparations and correspond to the intended modes of administration.

The pharmaceutical preparations according to the invention can especially be taken orally in the form of tablets, pills, capsules and granules at an average dosage of 0.25 E active ingredient as well as rectally in the form of suppositories and capsules containing about 0.5 g of active ingredient can be administered.

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Claims (1)

Claims -Alkoxy-2- (diaryl) methyl7-propylamine of the general formula CH-OH-CH ₂ -A :; ch - οή - CH ₂ CH ₂ - 0 - 'R. ■ in which Ar and Ar 'same or different », given · ■ if substituted aryl radicals and in the form of a polynuclear aromatic group through C-C bonds or by chains containing heteroatoms such as oxygen atoms contain »can be linked» R an aliphatic Radical »is an aryl radical or arylaliphatic radical and A stands for a tertiary amino group »in which the nitrogen atom can be part of a heterocycle» and pharmaceutically acceptable acid addition salts of these compounds with organic or inorganic ones Acids. 2) Compounds according to claim I ₄ , characterized in that Ar and Ar ⁸ in formula (I) are each a phenyl radical. are as well as the acid addition salts of these compounds " J5) Process for the preparation of compounds of the formula (I) according to claim 1 and 2 "characterized" that one in two successive reaction stages a) Amino alcohols of the general formula RO _{- CH n} - CH - GH «- A ² · Ϊ ² (II) ■■■. in a solvent with a compound "which can replace the OH group of the amino alcohols with a chlorine atom" to form an intermediate compound of the general formula '009 885/22 89 - 2Γ Η - O- CHo -CH- CH ₀ - A ² I ² (nt.) implements and b) the intermediate (III) in a solvent with one used in excess, previously in the Sodium derivative converted diaryl-substituted methane derivative converts whose aryl radicals each have the Ar and Af-V radicals of the desired product of the formula (I) correspond. 4) Method according to claim 3 *, characterized in that in der'Stufe .- (a) as a compound to replace the OH group of the amino alcohol (II) by a chlorine atom thionyl chloride SOCIp is used and in this case the thionyl chloride in excess, for .-B - ..: in an amount of 2 moles of SOCl ₂ per 0.75 mole of amino alcohol. (II) used. 5) Process according to claim 3 and 4, characterized in that the solvent in step (a) is a Chlorinated hydrocarbons, such as chloroform and methylene chloride, is used and the reaction is carried out at the reflux temperature of the solvent used. 6) Method according to claim 3 * characterized in that that in step (b) previously reacted with sodium Dipheny! Methane used, which by conversion in essence equimolar amounts of naphthalene, sodium and diphenylmethane has been obtained, and about 0.5 mole of intermediate (III) to at least 1 mole of the Sodium derivative of diphenylmethane used 7) Method according to claim 3 tocI 6, - characterized in that that the reaction of step (b) in'-TetraJiydro- - furan performs.,. . .-: .. - .- 8) Method according to claim j5 and 7 * marked dadureh ,, that fluorene or xanthene is used for the theory of stage (b) used 9) Use of compounds according to claim 1 and 2 as Active ingredients in pharmaceutical preparations.