DE1493941A1 - Process for the production of the levorotatory form of 1- (4'-nitrophenyl) -2-isopropylamine-ethanol and its salts - Google Patents

Description

Process for the production of the levorotatory form of 1- (4 ^t -nitroph.enyl) - ⁱ -2-isopropylam ± n-Mthanol and its

Salts.

The invention relates to the cleavage of a new beta- adrenolytic i dl ~ 1- (4 * -nitrophenyl) -2-isopropylamine-ethanol (Federation Proc, 2_2 (2), Part I, 326 1964} into its optically active forms, as well the production of their salts.

The preparation of the racemic compound was of the Applicant already in British patent specification 950 described. i

^{The M} in vivo experiments listed below show that only the levorotatory isomer of 1- (4 ^t -nitrophenyl) -2-isopropylamine-ethanol (optical activity determination in alcoholic or dilute hydrochloric acid solution) is the biologically active form.

The experiments were carried out on dogs anesthetized with pentobarbital, in which by rapid intravenous Injection of 100 ^ / kg adrenaline caused cardiac arrhythmias became.

Before testing the effect of the left or right form of 1- (4 ^I -nitrophenyl) -2-isopropylamine-ethanol, a control experiment with adrenaline was carried out in each animal. 10, 30, 60 and 120 minutes after administration of the 1 or

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The ci form of the antagonist was again given adrenaline .

The electrocardiograms were evaluated according to the method of Moran et al. ( ^N J. Pharmacol. ^W , 136 , 727 (1962)).

In those with l _; -1- (4 ^t -nitrophenyl) -2-isopropylamine-a ^l THANOL (5 ^m g / kg) pre-treated dogs resulted adrenaline, in contrast to the observed pre-treatment prior to the tachycardia, to a marked bradycardia. The blood pressure dropped only insignificantly.

Treatment with d-1- (4 ^t -nitrophenyl) -2-isopropylamine ethanol, even in very high doses (50 mg / kg), did not affect the positive chronotropic effect of adrenaline.

Also the occurrence of means of a combination of methyl chloroform plus adrenaline in the anesthetized dog could cause ventricular fibrillation caused by the Pre-treatment with the! .- form, but not the el-form, is prevented will.

In the following tables there are some more test results of the two process products combined.

In tests on urethane-anesthetized rats (i, ^ g / kg i.p.) both the intrinsic effects of these compounds (50 mg / kg i.v.) and their effects (in equal doses) on the increase of the external metabolism, the heart rate and body temperature by continuous intravenous infusion of adrenaline (1 V "/ min / 100 g).

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9 0 9 8-feQ / 0 8 3 θ ^BAÜ

The test results contained in Table I show that, on the one hand, the IL form has practically only a very slight, whereas the d form has a significant caloric effect; on the other hand, only the 1-porin is able to completely inhibit the increase in the external metabolism triggered by adrenaline.

From the results in Table II it can be seen that also the 1 ^ form that caused by adrenaline Able to prevent rise in body temperature.

From the results of Table III it can be seen that, while the cL-form does not have any, or a potentiating Effect on the heart rate increase through adrenaline, the JL form not only this adrenaline effect able to prevent completely, but beyond that, under these conditions, has a slowing effect on the heart rate.

The numerical values in Tables I, II and III show that, by blocking the beta receptors by means of the specifically acting ^ -! - (^ '- nitrophenyiy-S-isopropylamineethanol, the possibility is given to aeben the di- % rect cardiac effects also to largely prevent the general metabolism-increasing effects of the body's own sympathetic substances, such as adrenaline, and to protect the heart against indirect stimulation that results from a sympathetically-induced increase in the metabolism of the entire organism.

The representation of the optically active forms of the dl-1- (4'- -nitrophenyl) -2-isopropylamine-ethanol happened by frak-

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tioned crystallization of the D (-) - dib «oyltartrate of this compound from alcohol« This gives rise to two dietheromeric compounds which, when introduced into an alkaline reaction solution, are converted into the l_-b «w« d-form of 1 - (^ ¹ -nitrophenyl) - 2-isopropylamine-ethanol can be broken down. In the above-mentioned process, the following optically active acids can also be used for the cleavage of dl-1- (4 * -nitrophenyl) -2-isopropylamine-ethanol, for example: d (+) tartaric acid, L (+) glutamic acid and (+} camphorsulphonic acid .

The diastereoisomeric salts of 1- (4 ^t -nitrophenyl) -2-isopropylamine-ethanol with optically active doors can undergo fractional crystallization from water, ethanol; Methyl alcohol, propyl alcohol, ieopropyl alcohol, acetone or a mixture of these liophylene solvents.

The new compound 3 _l -1- (4 ^f -nitrophenyl) -2-isopropylamine-ethanol can be used as a remedy and prophylactic, especially for angina pectoris, myocardial infarction, cardiac arrhythmias, hypertension, for example in the form of pharmaceutical preparations. These contain the new substance, optionally in the form of its salts, mixed with another drug, or a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for entoral, parenteral or local administration.

The process product JL-1- (4 ^f -nitrophenyl) -2-isopropylanine-ethanol has valuable therapeutic properties and is well tolerated.

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Saakeit in angina pectoris, hear "rhythm! en" te. called. As clinical comparative experiments show, its beta- adrenergic blocking effect is clearly superior to the beta-adrenolytic drugs known to date.

To represent the salts of l ^ 1- (4 * -nitrpphenyl) -2-ieopropylamine-ethanol, inorganic or organic non-toxic acids which are suitable for the formation of therapeutically useful salts can be used.

The invention is described in the following examples without thereby restricting the scope of the invention the subject is intended "

EXAMPLE 1 1

116 g of dl-T- (4 ^t -nitrophenyl) -2-isopropylamine-ethanol are dissolved together with 170 g of D (-) dibenzoyltartaric acid in 14OO ml of hot absolute ethanol. After cooling and filtration, the residue is washed with absolute ethanol and split using an alkaline reaction solution. After filtration and washing with cold water, 4θ g of cl-i-CJM-nitrophenylJ-Z-isopropylamine-ethanol is obtained (yield = 69 $). j

It melts at 120-121 ⁰ C "

20 °

= + 20 ° (c = 2 ήο in ethanol)

20 °

»+ 43 ° (c = 2 $> in 1-N hydrochloric acid)

Potentiometric and spectrophotometric determination

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The alcoholic reaction medium is concentrated to 500-1, filtered off by means of a cooling mixture, the precipitate is filtered off, washed out with absolute ethanol and broken down by means of alkali. Yield: 50 g of l-1- (4 ^r -nitrophenyl) -2-ieopropylaiain-lthanol = 36 io. It melts at 119-120 ° G.

20 ·

»-19 · (c '« 2 # in ethanol) D.

20 ·

_a -k- \ · (c = 2 ^ in 1-N hydrochloric acid) D.

Potentiometric and spectrophotometric determination = EXAMPLE 2 :

22.4 g of IM- (4 * »nitrophenyl) -2-isopropylamine-ethanol are dissolved in ethanol and acidified with excess dry hydrogen chloride gas. After cooling by means of a cooling mixture, ether is added, whereby the hydrochloric acid 2 _; -1- (4 ⁱ -nitrophenyl) -2-isopropylamine-ethanol separates. (Yield = 95 %). Xe melts at 214-216 * C.

20 °

a -4ΐ (c = 2 % in Vasser) D

EXAMPLE g t

22.4 g l_-1- (4 ^l -nitrophenyl) -2-isopropylamine- * ethanol yellowed in benzene and added 25 β camphor sulfone curmonohydrate

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added.

After cooling, camphereulfoneaure crystallizes

l.-1- (it ^t -nitrophonyl) -2-isopropylaniine-ithanol

(Auebeut * 93 1a) .

£ ■ «oimilst at 132-13% ^C C,

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Table I - Oxygen Metabolism

substance number
the
try Oxygen substance
0-60 min
before treatment chsel, mean values in quay χ 100 in 15 min
6O-75iain 75-9Omin 90-1O5.mln 105-120 min
after treatment 28 28 28 Average
Change in $
in the period of
60 min after treatment Controls 9 24.8 26th 33 33 33 «13.1 i - shape 8th 25.4 28 41 45 49 126.6 co
O d - shape 8th 25.2 32 35 39 42 167.0 CD
00 adrenaline 13th 24.2 29 27 28 29 149.8 O IL - shape
+ Adrenaline 7th 25.1 26th 41 45 49 107.9 0838 <i - shape
+ Adrenaline 7th 25.2 32 167.0

I ₁ - Form = 1- (4 ^I -nitrophenyl) -2-isopropylarainethanol d. - Form = d-1- (4 ^l -nitrophenyl) -2-isopropylamine-ethanol

CD CO CO

Table II - Body Temperature

■ Subs dance number
the Temperature ⁰ C,
0-6O min Average over a period of 15 minutes
- - - - - -
60-75min 75-9Omin 90-1O5min 105-120 min 33.78 33.85 33.88 Mean values in # from
Starting level in
Period of 60 min try before treatment after treatment 34.69 34.89 ' 35.00 after treatment Controls 9 33.78 33.74 34.88 35.00 35.08 100.1 - "· i - shape 8th 34.56 34.38 35.10 35.82 36.47 100.5 CO d - shape 8th 34.63 34.61 34.36 34.54 34.73 100.8 CD
approx adrenaline 13th 33.96 34.36 35.99 36.94 37.79 104.3 00
«« ■ * - -
O 1 - shape
+ Adrenaline 7th 34.43 34.4o 100.1 CO
U)
OO d - shape
+ Adrenaline 7th 34.49 35.06 105.1

1 - Form = l _t -1- (4 ^t -nitrophenyl) -2-isopropylamine-ethanol d - Form = d-1- (4 ^f -nitrophenyl) -2-isopropylamine-ethanol

CJD CO CD

Table III - Heart Rate

substance number Heart rate / min., Average in 60-75min 75-9Omin period of 15 min Mean values in $ from the after treatment Starting level in 0-6O min 385 385 90-105min 105-120 min Period of 60 min Controls try before treatment 378 393 after treatment 1. - shape 9 359 418 419 375 373 106.2 d - shape 8th 368 401 401 108.6 8th 361 349 410 413 412 116.9 CD adrenaline O 13th 372 306 319 442 465 111.1 CO 1 - shape
+ Adrenaline 401 437 CO d - shape
+ Adrenaline 7th 383 331 344 84.9 O 7th 367 478 500 124.5 083

I ₁ - form = JL-I- (4'-nitrophenyl) ~ 2-i8opropylamine-ethanol d - form »d-1- (4'-nitrophenyl) -2-isopropylamine-ethanol

CO CO

Claims (1)

PATENT CLAIM Process for the production of the levorotatory form of 1- (4 ^< -nitrophenyl) -2-isopropylamine-ttthanol and its salts, characterized in that 1- (4 * -nitrophenyl) -2-isopropylamine-ttthanol of the racemic base by salt formation with D (-) dibenzoyltartaric acid, purification of the resulting D (-) dibenzoyl tar entered s of _1-1- (k * -nitro- ^ phenyl) -2-isopropylamine-ethanol by means of fractional crystallization and subsequent breakdown by alkali, which is also split off pharmacologically active l _i -1- (4 ^t -nitrophenyl) -2-isopropylamine-ethanol, which is used to form salts with inorganic or organic therapeutically usable acids. -ft- 909810/0833