FI56523C - DETERMINATION OF THE PHARMACOLOGICAL PROPERTIES OF DIFFERENTIAL D- (4-AMINO-3-HALOGEN) -2-ALKYLAMINO-ETHANOL - Google Patents

Description

E3CT ΓβΙ ^ KULULUTJULKA.SU - LBJ () UTLÄGGNI NGSSKRIFT bob23 (45) C Patent sy3r ..: t-tiy 11 CC 1930 (51) Kv.lk. '/ Lnt.'ci.1 * “δ" * 0 ^ 1Ö "91/40 SUOMI — FINLAND (21) P * tenttlhak * nnu» - Patentaniöknlng 789/73 (22) Hakemlspilvl - · Aniöknlngadag 15.03.73 (23) Alkuplivl —Glltighetsdag Q2 yg (41) Has become public - Bllvlt Qent9g 2 73

Patent and Registration Board (44) Date of initial publication and hearing.

Patent- och registrstyrelsen 'Ansökan utlagd och utl.skriften publleerad 31.10.79 (32) (33) (31) Requested privilege — Begird prlorltet .03.72 08.01.73 Federal Republic of Germany-Förbunds-republiken Tyskland (DE) P 2212600.7., P 23006 6 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, D-7950 Biberach /

Riss, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Johannes Keck, Biberach / Riss, Giinther Engelhardt, Biberach / Riss,

Klaus-Reinhold Noll, Warthausen-Oberhofen, Gerd Kruger, Biberach / Riss,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (Jk) Leitzinger Oy (5 ^) Method for the preparation of pharmacologically valuable d- (4-amino-3-halo) -2-alkylaminoethanol - Förfarande för framställning av farma-kologiskt värdefull d - (U-amino-3-halogen) -2-alkylamino-ethanol

U.S. Patent 3,536,712 describes, inter alia, General Formula I.

. ^? "CH2 - N (I)

Racemic mixtures of the compounds according to Hai and their physiologically acceptable salts with inorganic or organic acids and the process for their preparation. These compounds have valuable pharmacological properties, in particular, however, a broncholytic effect.

In the above general formula I, Hal is a chlorine or bromine atom, R 1 is a hydrogen, chlorine or bromine atom, and R is a straight-chain or branched alkyl group having 2 to 5 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms.

It has now surprisingly been found that the optically active antipodes of the compounds of the above general formula I have a selective effect on adrenergic β-receptors.

The process according to the invention is characterized in that the d-compound is separated from the racemic mixture of the compound of the general formula I and, if desired, converted into its physiologically acceptable salts with inorganic or organic acids.

The racemic cleavage of the d, 1 forms of the compound of general formula I above is best effected by fractional crystallization of a mixture of its diastereomeric salt with an optically active acid, for example d-tartaric acid, d-dibenzoyltartaric acid, d-camphorsulfonic acid or da-bromocamphor-π-sulfonic acid or for example acetylcellulose a. Cleavage of the racemate can be further performed via diastomeric compounds by crystallization or chromatographic separation.

The compounds of the general formula 1 can be converted into their physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid and maleic acid.

As already mentioned above, the novel compounds of the general formula I have valuable pharmacological properties, in particular the compounds of the general formula I selectively inhibit receptors.

For example, 3 A = d-1- (4-amino-3,5-dichloro-phenyl) -2-cyclopropylamino-ethanol hydrochloride, B = 11- (1f-amino-3,5-dichloro-phenyl) of compounds 56523 was studied. Effect of -2-cyclopropylamino-ethanol hydrochloride and C = d-1- (4-amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol hydrochloride on β-receptors:

The Bj 2 inhibitory effect was studied in anesthetized cats in contrast to the effect of tachycardia * triggered by Ι, Πγ / kg i.v. standard dose of N-isopropyl noradrenaline sulphate. The EDgg value was determined graphically by extrapolating the percentage decrease in heart rate increase caused by N-isopropyl noradrenaline sulfate at different doses (see Table I, II). The β intravenously using 20 γ / kg iv to induce bronchospasm in narcotic guinea pigs. Acetylcholine-ketone. The ED50 value was determined graphically by extrapolating from the percentage reduction in seizures obtained at different doses (see Table I).

The Βλ-inhibitory effect was studied as an adverse effect on the broncholytic effect observed at 5 γ / kg i.v. N-isopropyl nor-adrenaline sulfate in a Konzett-Rössler experimental set-up in anesthetized guinea pigs when these bronchospasms are triggered at a constant rate of 20 γ / kg i.v. asetyylikoliiniaiks. Table II).

The acute toxicity of the compounds was determined in groups of 10 mice. According to the method of Litchfield and Wilcoxon, the LD50 value was calculated from the dose at which 50% of the organs died within 7 days after intravenous administration of the compounds.

The following table gives the values obtained: 56523

Table I

Inhibitory effect mimetic effect on LD, O 2 receptors 32 receptors mg / kg i.v.

n ED50 γ / kg i.v., n ED5Q γ / kg i.v.

A 5 10.5 3> 5,000 49.5 B 5 28 42.5

Table II

substance inhibitory effect inhibitory effect on β-receptors β-receptors LD50 Q / kg i> v> n ED, .q γ / kg i.v. n dose prevent- γ / kg i.v. syt% C 10 54 3 500 0 50.0 3 5 000 0

In summary, the known β-inhibitors do not differentiate between different types of β-receptors, but generally have an inhibitory effect on β-receptors. Because known β-inhibitors do not selectively act on β 2 receptors, they can cause an increase in respiratory resistance not only in asthmatics (Mc Neill, Lancet II, 1101 (1964), Zaid a. Beall New England J. Med. 275, 580 ( 1966) and Meier et al., Dtsch. Med. Wschr. 9, 145 (1966)) but also in healthy subjects (Mc Neill a. Ingram, Am. J. Cardiol. 18, 473 (1966)). due to prevention. Their therapeutic utility is thus considerably limited.

The new d-compounds of the general formula I thus differ from the known β-inhibitors in principle by selectively inhibiting 3-receptors. Because the risk of triggering an asthma attack as a side effect is eliminated, their therapeutic use has considerable advantages over the known 5 S6S23 (S-inhibitors).

The new compounds of the general formula I can optionally be processed in combination with other active ingredients into customary pharmaceutical preparations. The single dose is then ΙΟ-ΙΟΟγ, but preferably 20-50γ.

The following examples further illustrate the invention:

In the following Examples 1-22, the partially different melting points of the corresponding d- and 1-compounds are due to polymorphism.

Example 1 d-1- (4-Amino-3,5-dichloro-phenyl) -2-cyclopropylamino-ethanol-hydrochloride 177 g (0.678 mol) of d, 11- (4-amino-3,5-dichloro-phenyl) 2-Cyclopropylaminoethanol and 122 g (0.340 mol) of d-dibenzoyltartaric acid are dissolved in 2 liters of hot absolute ethanol, filtered and allowed to stand at room temperature for 1 day for crystallization. The product obtained is recrystallized 6 times from methanol-ether to give pure d- [1- (4-amino-3,5-dichloro-phenyl) -2-cyclopropylamino-ethanol] -d-dibenzoyl tartrate, m.p. 5-167 ° C (decomposes).

[α] 25 D = + 211.7 ° (c = 2.082, dimethylformamide)

The salt is dissolved in ethanol and concentrated ammonia under ice-cooling, and the base is crystallized by adding water.

M.p .: 138-142.5 ° C.

[α] 32 D + 158.6 ° (c = 2.050, chloroform)

The base is dissolved in absolute ethanol, neutralized with absolute ethanolic hydrochloric acid, and the crystallization of d-1- (4-amino-3,5-dichlorophenyl) -2-cyclopropylaminoethanol hydrochloride is completed by adding ether.

M.p .: 180.5 - 181.5 ° C (decomposes) / α / 20 + 103.2 ° (c = 2.016, water).

364

Example 2 6 S6S23 1-1- (4-Amino-3,5-dichloro-phenyl) -2-cyclopropylamino-ethanol hydrochloride d- [1- (H-amino-3,5-dichloro-phenyl) -5- The mother liquors of the -cyclopropylamino-ethanol / -d-dibenzoyl-tartrate precipitate and the first recrystallization are combined, evaporated to a small volume and the base is precipitated by adding concentrated ammonia and water 100 g (0.383 mol) of 1- (4-amino-3.5 -dichloro-phenyl) -2-cyclopropylamino-ethanol (1-enriched) is dissolved in 1.7 liters of absolute ethanol and a solution of 75.3 g (0.20 mol) of 1-dibenzoyltartaric acid hydrate is added. In 3 liters of absolute ethanol, allow to stand for several days for crystallization at room temperature, recrystallize the product 5 times from methanol-ether to give 1- [1- (4-amino-3,5-dichlorophenyl) -2-cyclopropylamino]. ethanol p-dibenzoyl tartrate in pure form.

M.p .: 175-176.5 ° C (decomposes) [α] 20 D = 211.8 ° (c = 2.067, dimethylformamide).

The salt is dissolved in methanol and concentrated ammonia by heating and the base is precipitated by adding water.

M.p .: 138-142 ° C

[α] 20 D - 153.4 ° (c = 2.040, chloroform).

The base is dissolved in absolute ethanol, neutralized with ethanolic hydrochloric acid, and 1- (1- (4-amino-3,5-dichloro-phenyl) -2-cyclopropylamino-ethanol hydrochloride is precipitated by adding ether.

M.p .: .84.5 - 185.5 ° C (decomposes)

Example 3 1-1- (4-Amino-3,5-dichloro-phenyl) -2-isopropylamino-ethanol Hydrochloride M.p .: 151-152 ° C (decomposes) [α] 20 D - 135.5 ° (c = 2,010, water) 7,56523

Prepared according to Example 1 from d, 1- * 1- (4-amino-3,5-dichloro-phenyl) -2-isopropylamino-ethanol by tail crystallization of 1-dibenzoyl tartrate.

Example H

d-L- (4-amino-3,5-dichloro-phenyl) -2-isopropylamino-ethanol

Melting point of hydrochloride: 176-179 ° C (decomposes) / α / 3 gj + 134.3 ° (c = 2.018, water)

Prepared according to Example 2 by fractional crystallization of d, 1-1- (4-amino-3,5-dichlorophenyl) -2-isopropylaminoethanol from d-dibenzoyl tartrate.

Example 5 d-1- (4-Amino-3,5-dibromo-phenyl) -2-tert-butylamino-ethanol

Melting point of hydrochloride: 182-185 ° C (decomposes).

[α] D 3 + 106.2 ° (c _ 2.004, water)

Prepared according to Example 1 by fractional crystallization of d, 1-1- (4-amino-3,5-dibromo-phenyl) -2-tert-butylaminoethanol from 1-dibenzoyl tartrate.

Example 6 1-1- (4-Amino-3,5-dibromo-phenyl) -2-tert-butylamino-ethanol

Hydrochloride melting point: 170-173 ° C (decomposes) / a / 3gj - 106.7 ° (c = 2.010, water)

Prepared from fractional crystallization of d, 1-1- (4-amino-3,5-dibromo-phenyl) -2-tert-butylaminoethanol according to Example 2 d-dibenzoyl tartrate *

Example 7 d-1- (4-Amino-3,5-dibromo-phenyl) -2-tert-pentylamino-ethanol

Melting point of the hydrochloride: 188-189.5 ° C (decomposes).

[α] 20 D + 103.4 ° (c = 2.030, water) δ 56523

Prepared from fractional crystallization of 1, dibenzoyl tartrate from d, 1-1- (4-amino-3,5-dibutylphenyl) -2-tert-pentylaminoethanol according to Example 1

Example 8 1-1- (4-Amino-3,5-dibromo-phenyl) -2-tert-pentylamino-ethanol

Melting point of hydrochloride: 193.5-194 ° C (decomposes) / α / -104.8 ° (c = 2.026, water)

Prepared from d, 1-1- (4-amino-3,5-dibromo-phenyl) -2-tert-pentylamino-ethanol by fractional crystallization of d-dibenzoyl tartrate according to Example 2.

Example 9 1-2- (Ethylamino-1- (4-amino-3,5-dichloro-phenyl) -ethanol

Melting point of hydrochloride: 174-176 ° C (decomposes).

/ a / 364 '139> 8 ° (c = 2.040, water)

Prepared from 1,1-2-ethylamino-1- (-4-E-amino-3,5-dichloro-phenyl) -ethanol by fractional crystallization according to Example 1, 1-dibenzoyl tartrate.

Example 10 d-2-Ethylamino-1- (4-amino-3,5-dichloro-phenyl) -ethanol

Melting point of hydrochloride: 17H-177 ° C (decomposes) / Ct / 364 + 139 »2 ° (c = 2.018, water)

Prepared from fractional crystallization of d-dibenzoyl tartrate according to Example 2 from d, 1,2-ethylamino-1- (4-amino-3,5-dichlorophenyl) ethanol.

Example 11 1-1- (4-Amino-3,5-dichloro-phenyl) -2-butylamino-ethanol

Melting point of the hydrochloride: 175-177 ° C: / ® / 364 "106» 3 ° (c s 2.004, water) 9 56523

Prepared from d, 1-1- (4-amino-3,5-dichloro-phenyl) -2-butylamino-ethanol by fractional crystallization of 1-dibenzoyl tartrate according to Example 1.

Example 12 d-1- (H-Amino-3,5-dichloro-phenyl) -2-butylamino-ethanol

Melting point of the hydrochloride: 174-176 ° C.

[α] + 105.7 ° (c = 2.008, water).

Prepared from fractional 1,1-1- (4-amino-3,5-dichlorophenyl) -2-butylaminoethanol by fractional crystallization of d-dibenzoyl tartrate according to Example 2.

Example 13 d-1- (4-Amino-3-bromo-5-chloro-phenyl) -2-isopropylamino-ethanol

Melting point: 126-128 ° C

/ α / 4 ^ β + 35> 2 ° ^ c = 2 »°> ^ ethanol)

Prepared from fractional crystallization of d, 1-1- (4-amino-3-bromo-5-chlorophenyl) -2-isopropylaminoethanol by d-dibenzoyl tartrate according to Example 1.

Example 14

1-1- (4-amino-3-bromo-5-chloro-phenyl) -2-isopropylamino-ethanol Melting point: 12 7 ° C

[α] 436 - 36.9 ° (c = 2.0, methanol)

D-1-1- (4-amino-3-bromo-5-chlorophenyl) -2-isopropylaminoethanol is enriched by fractional crystallization of 1-dibenzoyl tartrate according to Example 1.

Example 15 d-1- (4-Amino-3-bromo-phenyl) -2-tert-butylamino-ethanol

Melting point: 150 ° C; [α] D 5 + 15.1 ° (c = 2.0, methanol)

Prepared from 1-1- (4-amino-3-bromo-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of 1-dibenzoyl tartrate according to Example 1.

Example 16 10 56523 1-1- (4-Amino-3-bromo-phenyl) -2-tert-butylamino-ethanol

Melting point: 148 ° C * / α / 589 (14 »2 ° * c = 2» ° »» ethanol).

Prepared from d, 1-1- (4-amino-3-bromo-phenyl) -2-tert-butylamino-ethanol by fractional crystallization of d-dibenzoyl tartrate according to Example 1.

Example 17 1-1- (4-Amino-3,5-dichloro-phenyl) -2-cyclopentylamino-ethanol

Hydrochloride melting point: 131.5-133 ° C; / a / 364 "116» ^ ° (c = 2 »088» water).

Prepared from d, 1-1- (4-amino-3,5-dichloro-phenyl) -2-cyclopentylamino-ethanol by fractional crystallization of 1-dibenzoyl tartrate according to Example 1.

Example 18 d-1- (4-Amino-3,5-dichloro-phenyl) -2-cyclopentylamino-ethanol

Melting point of hydrochloride; 131.5-133 ° C; /. 20 DEG-115.2 DEG (c = 1.996, water).

Prepare d, 1-1- (4-amino-3,5-dichlorophenyl) -2-cyclopentylaminoethanol by fractional crystallization of d-dibenzoyl tartrate according to Example 2.

Example 19 1-1- (4-Amino-3,5-dichloro-phenyl) -2-cyclobutylamino-ethanol

Melting point of the hydrochloride: 182-182.5 ° C (decomposes), / α / 364 - 107 * 5 ° (c = 2.054, water)

Prepared from d, 1-1- (4-amino-3,5-dichlorophenyl) -2-cyclobutylaminoethanol by fractional crystallization of 1-dibenzoyl tartrate according to Example 1.

Example 20 11 56523 d-1- (4-Amino-3,5-dichloro-phenyl) -2-cyclobutylamino-ethanol

Melting point of the hydrochloride: 183-183.5 ° C (decomposes) / <* / 364 + 108> 4 ° (c = 2.118, water).

Prepared from fractional crystallization of d, 1-1- (4-amino-3,5-dichlorophenyl) -2-cyclobutylaminoethanol by d-dibenzoyl tartrate according to Example 2

Example 21 dl- (4-Amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol hydrochloride 128.5 g (0.464 mol) of d, 11- (4-amino-3.5 -dichloro-phenyl) -2-tert-butylamino-ethanol and 88 g (0.234 mol) of 1-dibenzoyltartaric acid hydrate in 2 liters of ethanol are heated to boiling. After rapid dissolution, a precipitate begins to separate, which is separated after standing u-Sean for one hour. The material is recrystallized twice from methanol to give pure d- [1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminoethanol] -1-dibenzoyl tartrate, m.p. 5-202 ° C (decomposes).

λ max 364 ° 192 ° (c = 2.42, dimethylformamide).

The salt is dissolved in dimethylformamide, the solution is made alkaline with 2N ammonia and d-1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminoethanol is crystallized by adding water.

Melting point: 127-128.5 ° C; + 244 ° (c = 2.28, chloroform)

The base is dissolved in a small amount of absolute ethanol and a small amount of ether, neutralized with absolute ethanolic hydrochloric acid, and crystallized from d-1- (4-amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol hydrochloride by adding more ether.

M.p .: 19 7.5-198 ° C (decomposes); (c = 2.15, water).

Example 22 1-1- (4-Amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol hydrochloride 12,56523 d- [1- (4-amino-3,5-dichloro-phenyl) phenyl) -2-tert-butylamino-ethanol) / dibenzoyl tartrate precipitate and the first recrystallization mother liquor are combined, evaporated to a small volume and the base is precipitated by adding ammonia. 103 g (0.372 mol) of 1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminoethanol (1-enriched) are dissolved in 0.3 liter of boiling ethanol and a solution of 75 g (0.209 moles) of d-dibenzoyltartaric acid in 0.7 liters of ethanol. The separated precipitate is separated after standing for several hours and recrystallized from methanol. This gives 1- [1- (4-amino-3,5-dichlorophenyl) -2-tert-butylaminoethanol] -d-dibenzoyl tartrate in pure form.

M.p .: 207-208 ° C (decomposes); [Α] 334 + 194 ° (c = 3.19, dimethylformamide).

The salt is dissolved in dimethylformamide, adjusted to alkaline with 2N ammonia, and water is added to crystallize 1-1- (4-amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol.

Mp: 127-128.5 ° C; 35 ° - 243 ° (c = 2.65, chloroform)

To prepare the hydrochloride, the base is dissolved in a small amount of absolute ethanol, neutralized with absolute ethanolic hydrochloric acid, and 1-1- (4-amino-3,5-dichloro-phenyl) -2-tert-butylamino-ethanol hydrochloride is crystallized by adding ether.

M.p .: 187-188 ° C (decomposes); 33 ° - 126 ° (c = 2.72, water).