DE2257639A1 - NEW ESTERS AND ETHERS OF KETOXIMES, PROCESS FOR THEIR PRODUCTION AND THERAPEUTIC PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

LAWYERS

DR. J ¹ JR. Pi ¹ L-CHGAlVZALTGR BEIL ALFRED t>C'P; ^ MEX

DR. JUR. D!? I.-C.-f "M. RJ. WOLFF 23 Nov. 107 *

DB. JUS .. Ha; 13 LiU. SHiL *

623 FRAN KFU RMfct AUiN-HOCHSI

Our No. 18 281

Andrl BUZAS

Bi evr es, Easonne / Jranlcreicli and

LES LABOHATOIRES BRUNEAU EI GIB Pariah / ffrankreioh

New esters and ethers before Kstoximen, process for their production as well as therapeutic preparations containing these compounds *

The present invention relates to new derivative <! Θγ compounds 1-Pheü3rl-2-piperazinyl "ethanone-1 s 1 piperazinyi-propanön-1 and i-i

Me compounds according to the invention are pharmacologically effective, especially-as analgesics, and anti-inflammatories Muscle relaxer · Their toxicity is particularly low.

309829/1177

. 2-

The invention compounds are based on the formula

_x _ ^, y —Q -B ₂ -Ji μ - H, (ι)

0-E ₁

wherein X is a halogen, in particular chlorine or fluorine, R _{1 is} a lower aliphatic radical optionally substituted by a tertiary amino group, an alkylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, phenylcarbonyl, turanylcarbonyl or pyridyloarbonylrea, with all the alkyl and alkenyl groups lower groups aind, IU represent a linear or branched aliphatic heat with 1 to 3 carbon atoms, and R represent an arylaliphatic or aromatic heat, and their pharmacologically compatible salts with mineral and organic acids.

R ₁ can in particular be an allyl, propargyl, ü-diethylaiainoäthyl-, ß-Morpholinoäthyl-, JDi-n-propylaoetyl-. (p-Butoxyphenyl) acetyl,. Cinnamoyl- ^. 3,4,5-trimethoxybenzoyl-, 3,4-diahlobenzoyl-, (2,5-dimethylfuryl) -4-carbonyl- or a 2-chloro-niootin ^ lreat, R _{2 be} a Heat ^ GH ₂ , ^ CH ( CH ₃ ), -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ - and R _{3 is} a phenyl or piperonyl radical.

Suitable salts are, in particular, the hydrochlorides and ivialeates.

The organiachen oilure permitted with a phariuazeutiaoh, «.Fl. Citric acid, maleic acid or Mothansulfonaüui'e, or

309829/1177
COPY
BATHROOM OBlGiNAL

with a mineral acid, e.g. hydrochloric acid, non-petitic acid? or uchwefalaäure, available products raind crystalline, aie are soluble and stable in './uoaer.

The process for the preparation of the compounds according to the invention consists in being an oxime of the formula

H- (II)

in which λ, R “and R- * have the above meaning, with an alkyl halide, alkenyl halide, alkyne ^ lhalide or u). ^: .urehalogen? d the formula

where h. has the above meaning and Hai is a halogen, preferably chlorine, designated, converts.

Is the connection HaI-R ₁ . an alkyl, alkenyl or alkynyl hulogsnide, then the Üxim in J? ornj can use a sodium or K. lut i? rlzee and in an alcoholic diluent, for example in ilthauol or tertiary alcohol workers " If the compound Hal-It ^ is a jacid chloride, tjo can r.sn bi-ii.'jjielaweiae in a Vurdiinrunguu.mittel such as P ^ ridin urbciti-n, where, n.an directly receives the hydrochloride of the bosom.

309820/1 177

. COPY BAD ORIGINAL

The oximes of the formula II are new intermediate products for production pharmacologically active compounds.

The Oxime II can be made in the classic 'way from hydroxylamine' hydrochloride and the corresponding ketone, preferably in aqueous-alcoholic medium, possibly in G-egemvart of sodium hydroxide. The ketone in turn can be obtained by using the chlorinated ketone of the formula

with the piperazine of the formula H-N N-R,

preferably in an organic diluent such as benzene, toluene or chloroform.

In the following preparations 1 and 2 the production of the ozimes of the formula II used as starting materials. Examples 1 to 3 relate to the production of the compounds according to the invention of ifOrmel I.

i'abelle I f. ^^ the characteristics of various Oiime II, while in Table II the. Characteristic data of compounds according to the invention I have put together

309829/1177

Preparation 1 method A.

1- (4-I? LuQrphenyl) -4- (4-piperonyl-piperazinyl-1) -butan-1-one oxime (Comp. IX) _v

a) 1- (4-j-fluorophenyl) -4- (4-piperonyl-1-piperazinyl) -butanone-1.

To a solution of "2oo g (i mol) i - ^(- 4-l luorphenyl) -4-ctilorbutanon-1 in 3oo ml of toluene, a solution of 44o g (2 moles) is 4-piperonyl piperazine in Joo ml of toluene are added. 4 g of finely powdered potassium iodide are added, then the mixture is refluxed for 6 hours with stirring. The piperonylpiperazine hydrochloride which separates out is separated off, the solvent is removed in vacuo. The residue is crystallized from isopropyl saturated , 292 g (yield 7 6 <fo) of product S with a melting point of 88-90 ° C. are obtained.

b) 1- (4-fluorophenyl) -4- (4-piperonyl-piperazinyl-1) -butane-1-one oxime (Verb. -IX). '

A solution of 46 g (1.15 mol) of sodium hydroxide in too ml of water is added to a solution of 96 g (1.4 mol) of hydroxylamine hydrochloride in 100 ml of water. A solution of 92 g (0.42 mol) of the compound obtained under a) in 500 ml of ethanol is then added, followed by refluxing for 2 hours with stirring. After cooling, the solvent is removed in vacuo and the residue is removed washed with water and recrystallized from ethanol, giving 15 g (yield 78%) of compound IX with a melting point of 140 °.

309829/1177

Preparation 2

Method B.

(4 phenyl) -2- (4-pheriyl-pipera2inyl-1) -a1; han-1-one oxime

(Verb. III).

5 » 2 g (o »o75 mol) of hydroxylamine hydrochloride were added. The mixture is refluxed for 5 hours, then part of the solvent is evaporated off under reduced pressure and the mixture is made alkaline with sodium hydroxide solution. The precipitate is filtered off with suction * washed with water and recrystallized from ethanol, thus obtaining 11 g (yield 9afo) dea product III rom melting point 158 ⁰ G.

The following connections are obtained analogously »

309829/1177

Verb.

Tabel. I.

to / O

( ^υ Ο) method

II,

III ι

IV '

V.
VI ^

VII

VIII

ΓΙ

Cl -

1 "8o A

01 -

/ 2

Π τ, τ

J ¹

-OH ₂ -

.- (CHJ ₉ -

CH,

-OH-

^X 0F
^

133. A-

138 B

; i6o A

19o 'A

174 B

194 A

145

14o. A.

309829/1177

- B - ■

example 1

1- (2-Korph.olino-ethoxyimino) ~ 1- (4-fl "orpbenyl) -4-r (4-piperone / l-piperazinyl-1) -butane and its l'ricmleat (Verb. 14) ·

a) 1- (2-Morpholino-ät ho xy imino) -1- (4-fluorophenyl) -4- (4-pipero-

nyl-piperazinyl-1) -butane.

To a solution of 7.5 g (0.33 g atoms) of sodium in 500 ml of absolute ethanol, 12 o g (0.3 KI) of compound IX are added in portions with stirring. The mixture is then refluxed for 1 hour and, after cooling, 48 g (0.32 mol) of tt-morpholinoethyl chloride are added. The mixture is refluxed for a further 2 hours, then the solvent is evaporated off in vacuo, the residue is taken up in water and extracted with ether. After drying over sodium sulfate, the solvent is removed in vacuo. In this way 142 g (yield 93 $) of the desired compound are obtained, n ^ = 1.550, l _f = approx. 0.8 (thin-layer chromatography with elution with a 90: ίο mixture of ethylene chloride and methanol). IR spectrum: volumes at 920 and 160 cm ".

b) Trimaleate of the verb. 14.

A solution of 140 g (0.273 mol) of the above compound is added to a solution of 96 g (0.27 mol) of liialeic acid in 500 ml of ethyl acetate. , added in 100 ml of ethyl acetate. The salt which separates out is suctioned off and crystallized from ethanol, it melts at 2oo C.
IR spectrum: band at 1675-160 cm ". Analysis: found calculated

C f. 55.8o 55.58

'H Jt' 5.7o 5.66

N fo 5.5o 6.39

309829/1177

Example 2

1- (2 ^ diethylamino-ethoxyimino) -1 - (4 * -fluorophenyl) -4- (4 * -phenylpiperazinyl-1 ) -butane and its. Dimaleate (verb. 9)

a) 1- (4-i'luorophenyl) -4- (4-ptienyl-piperazinyl-1) -butanone-1 -

A solution of 1io g (0.68 mol) of phenylpiperazine is added to a solution of 68 g (0.34 mol) of 1- (4-i ^l luorph.enyl) -4-chloro-butanone-1 in 300 ml of l'oluene added in 500 ml of toluene. Then 1 g of finely powdered potassium iodide is added, followed by refluxing for 6 hours with stirring. The phenylpiperazine hydrochloride which separates out is separated off and the solvent is removed in vacuo. The residue is crystallized from isopropyl ether, yield 85 g ($ 77), melting point 93 ^° C.

■ »

b) i- (4-i'luorophenyl) -4 ' ⁱ - (4-plienyl-piperazinyl-1) -butanone-1-oxime. .

A solution of 14.4 g (0.36 mol) of sodium hydroxide in Too ml is added to a solution of 30 g (0.42 mol) of hydroxylamine hydrochloride in 30 ml of water. Then, addition is a solution of 47 g (o, 144 mole) of 1- ^(4-n luorphenyl l) -4- (4-ph.enylpiperazinylT * i) .- butanone-1 in 1oo ml ethanol. The mixture is refluxed with stirring for 2 hours, after cooling the oxime is filtered off with suction, washed with water and then with ethanol. Yield 43 g (88 ^), melting point 190 °.

c) 1- (2-Diethylamino-ethoximino) -1 - ^ - ^l fluorophenyl) -4- (4-phenylpiperazinyl-i) -butane.

To a solution of 66 g (0.6 mol) of potassium tert-butoxide in 500 ml of tgrt.-butanol, 185 g (0.54 mol) of 1- (4-I ¹ luophenyl) -4- (4- phenyl-piperazinyl-1) -butanone-1-oxime was added with stirring. Then it is refluxed for 4 hours

30 98297 1177

Then, 82 g (0.6 ml) of β-M-ethyl chloride are added. It is boiled for another 1 hour under the liückfluii, then the solvent is removed in vacuo and the residue is washed with barrels and extracted with ether. After drying over sodium sulfate, the solvent is removed in vacuo. A yield of 217 g (9V />), ⁿ B * ^ »546» iU = approx. 0.8 (thin-layer chromatography with elution with a 90: 10 mixture of methylene chloride and methanol) is obtained.
IR spectrum: bands at 920 and 160 cm.

d)) - (2-Diäth _<-ylaniino äthoximino) -1-0.-fluorophenyl) -4- (4-lpiperazinyl phenj ^r-1) butane, dimaleate.

To a solution of 172 g (1.48 mol) of maleic acid in 500 ml of ethyl acetate, a solution of 217 g (0.49 mol) of 1- (2-JDiäthylaiiino-ethoximino) -1- (4-fluorophenyl) -1-i 4-phenyl-piperazin, yl-1) -butane given in 2oo ml of ethyl acetate. One leaves the u-emic Stand in the refrigerator for 24 hours and it will precipitate

sucked off. The salt melts at 115 ° C

- 1 IR spectrum: band at 162o cm.

Analysis » calculated found

C $ »■ 6o, 85 6o, 43

H f _a 6.7o 6.76

N% ■. 8.33 8.29

Example 3

1- (2-0hlor-nicotinoyloxiüiind ^ _ _:: 1 _: - (4-fluorophenjl) -4- (4-piperonylpiperazinyl-1) -butane (comp. 26}, l_IIy d ro c hl ο rid.

2u of a solution of 150 g (0.376 mol) of the compound II in 500 ml of anhydrous Pyridina of 0 C is slowly stirred in a solution of 80 g (0.45 mol) of 2-chloro-niootinoylohlorid in

BATH ORIGINAL

309829/1177

500 ml of anhydrous pyridines were added. Completed encore compartment if the temperature is allowed to rise to room temperature, then will the mixture, yet. Maintained at this '!' Temperature for 12 hours.

Then, it is concentrated in vacuo, the baking stand -will taken up in ethanol. The product thus obtained melts.

25o ° o. ■; ■■■ '"".

—1 ■■ "" "'■" -

IR band at 1760 cm. . . .

Analysis:. . calculated found

H fr ^: ■ "- 5, o5 5, o4

"- I>'"''"9.759.66"''The base is characterized by the following data : nZ = 1.42o, E "'" = approx. 0.9 (thin-layer chromatography. Eluting with a 9o: Ιο mixture, from Iuethylene chloride and methanol).

Iß volumes at 1? 5o, 16 | O and 92ο ^: c'm ~ ¹ .

The following compounds according to the invention are obtained analogously:

3 09829/1174 , ■

O O

+ = -P Ό IF + * ^: ■ ■ ■. •1 CD CO • Η
Γ, Φ CO '": O) «D M.
O H m \, .-; H H , CO eg CO m . ; , e> a ο Ö ' •. ■ η •H • rl ο ■ ■ ■ ■ β lsi R. U U ! ■ : 0 H EH tJ • ■■ -H CO i> j ) ■ • "■■ pi W.

(M

CT>

ο cn

ΚΛ

CM

CVJ

CVJ

M O

ir \ ir » O CVl to K> ro CM CVj - «SI / ''.,: ί I cm W W I. W.
O
O W. §
J S ■ ^J
Il
¹ w W. Μ,? ·· ^: ■
° / ■ .. ■■■
ftj ¹ ■ ■ ■ ■ "'■ O ί ■ W- CVJ CVI CVJ O
O j O O Ο "''^; '<I r "ο O O W. I. I. I. ■ ti ^; ■■ '■ !:: v, j
f V /
• f
CVJ O K I C * ^: «^ - ^ H tx »■" ■ " • W · ν- ' CVJ O r : Β ·; : - ■; ■■ .. M. O O O * w H tt * ¹ '. ■■■■■, '■ I. O H O

CV)

ιη

309 & 2 9/1177

Table II (cont.)

Verb·. Ήτ. . X salt

( ⁰ C)

-GH "-

Dimäleat '. ■ 1ό5

Dimaleate 11o

O
CD

1o

OH

J-ö

Dimaleate

irimaleat

115

162 u »

12th

- (CH ₂ ) ₂ -K, 0

-CH "-

Dimaleate 144, ■ -CH -Hj - Dimaleate 174. __ / ^V CH

Table II (cont.)

Yerb. salt

F ( ⁰ C)

13th

14th

- (CH,

• (CH ₂ ) ₂ - -C

0,

Triiaaleate

Irimaleate

163

2oo

15th

16 17

^22nd

N- /

F -CQ-CH '

-CH- -CH

O,

r- -OH,

- (CH ₂ ) _r -

Trimaleate

Dimaleate

12o

Hydrochloride 118

163-170

18th

• -COCH = C

CL

⁴ GH,

L.7-0

Hydrochloride 22o

O ο • O O O CTV O ■ O ν— ' - Τ "* ' CM CNJ Ph

Kl

■■ τα

CD H H

• -W

CM

■ -Μ

ω ί>

-β

• Η O

H 3

CM I. CM Hj +. W. O ' -O I. I.

CM W O

O ιη LTv ο * - 'CM

CM CM h-j IN THE i-4 O '- Ό I. 1

CM I to - CM 1-4 ) -rj> τ { * '■ W O - O -5O O > - »- I. I. I--

to . to ■. , tr * \ CO [Tj N t < W ¹ ". • W. I. ο t W. H O W. Λ O. ' ο · O·.' O CO O W. O ttj O O σ W. O O
• W. ο O O O O Ο '': 'O ^? O P. Γ O r O O - ' ¹ I. O O , O
I. Ί ψ I.
d O Cf- O O O O
I. • ο O

Ph

CTi

O CM

r- CM

CM - CM

CM

CM

177

table II (Ports.)

Verb.

salt

-CO _n -,

H M

3

Eq

H,

- —via.

Hydrochloride 2o5

Compounds T to 26 were pharmacological as follows subject to soldering process:

Acute toxicity in the mouse after oral administration with determination of a toxicity limit or calculation of the IAr ₀ according to Behrens and Karber (Arch * exp. Pathol .., Phamiakol., 1935, 177-379); '

Actimetry according to Boissier (Arch. Int. Pharmacodyn., 1961, 158 , 212). in the mouse under oral ye ra. br eic hung;

Determination of the anticonvulsant effect of maximum electric shock (ECM) and intoxication with pentetrazole

iff i. T * ltu ώ st

Evidence of tranquilizers., Naoh Boisser (Therapy, 1958,

13 , 1o74) in the mouse, oral administration}

Potentiation of bariburate anesthesia in mice (administration the compound orally 45 minutes before the limit dose of sodium mebubarbital (.25 mg / kg intraperitoneally), the Activity is indicated by 0 to 3 crosses; . ■

Method by Hendershot and fforsaith (J. Pharmacol, exp. Therap., 1959, 125 , 237) where phenylbenzoquinone causes painful abdominal cramps in the mouse. The test compounds are administered orally 30 minutes before the phenylbenzoquinone,

ED _{5 is} determined j

Anti-inflammatory effects on injection of rats Carrageenan produced paw edema according to Winter '(Proc. Exp. Biol. Med., 1962, J5, 515). The various connections will be administered orally and compared to phenylbutazone;

Action on the ileum of guinea pigs stimulated by histamine or barium chloride in vitro and on by

309829/1 177

Isolated guinea pig chamois vesicles stimulated by adrenaline »The ED ₁ - is given in / Ug / ml.

The results are summarized in Table III below J

309829/117 7

Table III

Yerb.
No.

(mg / kg) EGi:

orally

I activated ^one TAHQ _-. T anesthesia cramps Carra-

Hi

/ ^ ₀ "- ^ 5 η me trie EDt -Pot. D.Phenyl- geenln

fmi / k ^) fme / k ^) ^ED 5o (ms / k *) U'irkg. benzochilYergl. orfl o? fl ° ( _E g / kg) o? Il ° ^} J ₁ ObXS ₁₁ OnED ₅₀ m .. Phenyl, oral ⁺⁺⁺⁾ (mg / kg)

orally

m. phenyl butazone i)

5o

Ba

5o

Ad

,

.,

■

'
13th
14th
15th
1 6

17th
18th

5oo

45o

> 16oo

> 16 OO

3oo

- 2oo

6oo

24o

635

1000

1ooo

75o

β σο

> looo

3oo
> 1ooo

> 10uO

> 16Oo

> 2oo

> 2oo

> 2oo

> 2oo

> 2oo.

> loo

> 2oo
150

> 2oo

> 2oo

> 2oo

> 2oo.

> 2oo,

> 2oo

> 1oo

> 2oo

> 2oo

> 2oo

> 2oo> 2oo

> 2oo

> 2oo

> 2oo

> 1oo

> 2oo

> loo

> 2oo> 2oo> 2oo> 2oo-> 2oo > 2oo> Too> 2oo

> 2oo

> 2oo

So
2oo

> 2oo> 2oo> 2oo 1oo 12o 8o 1oo> 5o> 2oo> 2oo> 2oo > 1oo> 2oo> 2oo

> 1oo

> 2oo

> 2oo 13o

O O

11 Q, 13th > o, 5 ■ t, 1, Ul > o, 5 ■ 120 o, 13 : .. O, 5 Ul ° » > o, 5 2oo o, 3o '; o, 2 > 5 Ui > o, 5 6 ' o, 55 > o, 5 VJl > 5 o, o5. 2.5 o, 65 , ο, o5. ■ ² V >. 5 ' > ο, 5,, 4.5 o, 3o o, 3 ■ > 5 5 > o, 5 1oo O o, 1> 5 O, > o, 5 5o o, 6o > o, 5 > 5 Ul > ο, 5 ^ 2o ' ο, 65 > o, 5 > 5 5 "> o, .5. * · 7o o, 97 > 0, o5 > 5 o, 5 23 1 > 'o, 5 · ; % > o, 5 45 0.14 ■ > o _; 5 ■ > o, 5 16 O > o, 5, ■ 2.5 3o ο, 9o ■ ο, 25 Ul > o, 5 So O ■■■> o, 5 > o, 5 15th o, 15 > o, 5j ^ 5 22nd 1 ■:> ^! o, 5 > o, 5 dr » 23 ■ o, 55 \>! o, 5 ■ > o, 5 5? Ca? ω

Table III (cont.)

Link LD no.

(mg / kg)

orally

5o

ΡϊΖ 3D

5o Akti - Tranq ..- T anesthesia convulsions carrametry EDt pot. d.Phenyl geeriin

t λ w λ ^ ED _1Γ / / _Λ s (effective. benzochi- (tergl. (mg / kg) (ng / kg) _# 5o_ (mg / kg) ^ ₀ * _non ^; .p _h ° _nvl _

oral * oral

(mg / kg) orally
orally

(mg / kg)

orally

.Phenylbutazone 1)

Hi

EDr

Hi)

Ba ED _C

ml)

19th > 16oo > 2oo > 2oo 14th 12o 2o > 16 oo. > 2oo > 2oo > 2o.o > 2oo 21 > 1-6oo > 2oo > 200 > 2oo 2oo 22nd 2ooo > 2oo > 2oo .100 > 2oo 23 > 1600 > 2oo > 2oo > 2oo > 2oo £ 4 1.SgO- > 2oo > 2oo Ho > 2oo 25th > T6oo > 2oo ■> 2 "oo 7o > 2oo 26th 115o > 2oo. > 2oo 85 loo

2oo

12o

15th

.200
18th
14th
3.5

o, 5o
o, 15
O

o, 75
o, 55
0.1o
o, 26

o, o5

0.4

o, 2

> ο, 5

> o, 5> 5

> o-, o5 5

- o, 2 5

0.3 5

2 2 5 o, 5

> o, 5> o, 5> o, 5> o, 5 ■> o, 5 > o, 5> o, 5> P, .5

From the above values one can see: - ■.

1. The low acute toxicity: Most of the investigated compounds are slightly toxic (ID ₁ - more than 1 g / kg);

2. Psychotropic effects: Certain compounds dampen this Central nervous system, especially connections 19 »6, 4, 25, 16, 1 and 11;

3. Analgesic effect: With the exception of compounds 3 and 23, all compounds tested are analgesic effective, especially the compounds of Examples 19 »5, 26, 6, 4, 1, 25, 13, 24 and 9,.

4 · Anti-inflammatory "effect: remove all compounds are anti-inflammatory, especially the compounds 22, 23 »11) 17» Io and 14 are stronger or as effective as the phenylbutazone? . \ ".

5. Antihistamine effects: certain compounds, for example the compounds 5, 10, 19 and 24, show antihistamine action, .

6. liusculotropic spasmolytic effect «Most of the compounds are effective, in particular products 9 »14» 22, 19, 5, 6, 2o, 1, 8 and 12f

7. Sympatholytic effect: Compound 4 is special

effective -

It is because of the above characteristics that they are inventively Compounds useful in human and veterinary medicine » useful as psychosedativa, analgesics, inflammatory, ^ ntiallergika, anti-wrinkle agents and vasodilators.

309829/1177

. . BATH

The compounds according to the invention can be administered in pharmaceutical forms such as capsules, sheets or injection solutions. The dose unit (tablets or capsule)
can contain 2o to 2oo mg of active ingredient, iSine injection solution of 1 to 5 ml can contain 1o to 1oo mg of active ingredient.

30 9829/1177 - · _Μ

• ■ BAD''ORiSlMAL

Claims (1)

wherein ^ a halogen atom, E. an optionally through, a tertiary amino group-substituted lower aliphatic Lest, an alkylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, Phen ^ lcarbonyl, i'uranylcarbonyl or I-yridylcarbonyl radical, where all alkyl and alkenel radicals are lower radicals, * H “reads a straight-chain or branched aliphatic 1 to 3 carbon atoms, and IU is an araliphatic or aromatic reads represent, and. their salts with -pharmacological permissible mineral and organic acids. 2. A compound according to claim 1, characterized in that dai3 α is a chlorine or fluorine atom and H is a phenyl or piperonyl radical is. . . -_ 3. A compound according to claim 2, characterized in that E allyl -, - propargyl, Li-Diäthylaminoäthyl-, ß-morpholino, JJI-n-propjlacetyl-, (p-Butozy-phenyl) acetyl-, cinnamoyl, _(CJinnai: ^ '-!), -3,4-, S-'i'rimethoxy-benzo ^ l-, 3, 4-Uichlor-benzoyl-, (2, i-jJimethjil-f ur ^ l) -3-carbonyl- or a 2-Ohlor- nicotinoyl radical and E ₀ one of the yes-este ^^ '^ »^ j: (u1I-), --Jxj. .-GTI ^ - or -CIJ:., - is ». ■. 3 0 9 8 2 9/1177 -et 4. Connection according to one of the ■ tests 1 to 3 inform dea Hydrochloride or a maleate. 13. A method for Iieratell the compounds according to claim 1, characterized in that one has a Gxim of the formula wherein X, R ₂ and R, have the above meaning, with an alkyl, alkenyl or alkynyl halide or an acid halide of the formula Hal - where Hai denotes halogen, preferably chlorine, and R _{1 has} the above meaning, converts. 6. The method according to claim 5 »characterized in that one when using an alkyl, alkenyl or alkynyl halide HaI-R the oxime in the form of its sodium or potassium saline einseta.t and works in an alcoholic thinner. 7. The method according to claim 5i, characterized in that one when using a acid chloride HaI-R. the reaction In a diluent and directly the HydrocWorid the corresponding base wins. 8. Oximes of the formula. ■. '. ■ 309 8 29/1 17.7 IS N / OH wherein X is a halogen atom, Rp is a straight-chain or branched one aliphatic radical with 1 to 3 carbon atoms and R ~ represent an araliphatic or aromatic radical ": l · 9. Process for the preparation of the oximes according to claim 8, characterized in that characterized in that one with Hydroxylaminhyd.rochlorid a ketone of the formula wherein X, H ₂ and R, have the above meaning. -1o. Method according to claim 9 »daduroht characterized in that one in aqueous-alcoholic medium äraiiseti * " 11. The method according to claim 1o, characterized ^ that one works in the presence of sodium hydroxide. ' 12. ' Pharmaceutical preparations containing at least one of the compounds of claims I to 4. BMIr: Antlrfe HUiiAtS ', Riwvrfjs, ßijaonne / yrankrelch and IBU LAHüRil'L'O EREii BHUiIJiAU IiT (JIE ₁ Λ / kroioh ' j η ■ / F IhAl, I WvWi Ιίαχ'.ϊιΙ r \ iVir \ l \ i 3C9 8 29/1177
ΐηοίΐϋ ¹ ) ^f H77