DE1620574A1 - New substituted 1,2,4-oxadiazole compounds and processes for their preparation - Google Patents

Description

in which mean

R is a low molecular weight alkyl radical, which is preferably 1 contains up to 3 carbon atoms, or a low molecular weight alkylene radical, in the latter case the two Alkylene radicals via one carbon or another Heteroatom, preferably via a nitrogen atom, form a heterocyclic ring, which in turn, if the bridging heteroatom is trivalent, a hydrogen atom or optionally one on this heteroatom can carry phenyl radicals substituted by halogens and / or alkoxy groups,

Documents tArt. 7 Paragraph 1, Paragraph 2, No. 1 of State 3 of the amendment. v. 4. S.

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- X is a straight or branched chain low molecular weight

• *

Alkylene radical and

R, a phenyl radical or naphthyl radical, which can be substituted at various points by halogen, alkoxy radicals _r low molecular weight alkyl radicals and / or low molecular weight alkenyl radicals

and the salts formed therefrom with physiologically compatible acids. The invention also relates to a Process for the preparation of these new 1,2,4-oxadiazole compounds of the formula I. The inventive method is characterized in that either

(a) a compound of the general formula

R ₁ -O-CH ₂ -C-NH ₂ S · .R
N_0- CX-JT

in which the radicals R 1, X and R have the meaning given above, a customary ring closure reaction subject or

(b) a compound of the general formula Β, -0-OU-, * R ₁ -O-CH _2. ^

-CH ₂ -CH-CH ₂ ,

in which the radical R _{1 has} the meaning given above and the radical Z is a halogen atom, preferably a chlorine atom, or a group which, like dn

BAD ORlQiNAL

009818/1899 ^NAL

• t · f r t * t * ι * ι

Halogen atom reacts, represents, with a compound, the general formula

R H - W ^

in which the radicals R have the meaning given above, converts or

(c) a compound of the general formula

R ₁ -O-CH ₀ -C -NH ₀ , NOH

in which the radical R has the meaning given above with a. Connection of general formula

0 j »NH

ti ^ Il

YCXN ^ or R ₀ OCXN

^N R ^X R

wherein the radical Y represents the radicals -Hal, -NH ₀ , -OH or -OR-, where R _{2 represents} a low molecular weight alkyl radical and the radicals X, R and R _{g have} the meaning given above, for the reaction

brings or
ι ·

(d) a compound of the general formula

R ₁ -O-CH ₀ -C-Cl

1 C H

NOH

in which R. has the meaning given above, with a compound of the general formula

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NH
H ₀ NCXN

NH

t!

or RgO-C-X-N

or

NC-X-N

wherein the radicals R, Rp and X are those given above Have meaning, implements.

· In the formulas listed below, the R, R., X, Z and Y radicals are as defined above.

According to a preferred embodiment of the invention if an * oxime compound (I) of the general formula is used

NOH R ₁ -O-CH ₂ -C-NH ₂

(D

with a compound (II) of the general formula

R 0

I. Il

R-N-X-C-Y

(II)

to, initially as an intermediate compound (III) isolable compound of the general formula

R ₁ -0-CH ₀ -C -NH ₀ 1 2 ti H

N-O-C-X-N-R

It

(III)

arises. According to the invention, however, it is not necessary to isolate the interconnection - which is of course can do - as this interconnection in that

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Reaction medium in which it was formed> converted directly into the compound according to the invention by ring closure can be,. The reaction conditions in the first stage, that is, the conditions that lead to formation of the intermediate compound (III) are required depending on the Y group. Usually leads the reaction is carried out in an organic solvent in the presence of a condensing agent at boiling temperatures by. Preferred solvents include methanol, ethanol, propanol, butanol and toluene. from Of these solvents, however, those which are removed azeotropically with V / ater sole are less preferred can. Benzene or xylene can also be used as solvents. The condensing agent used is normally alkaline condensing agents, preferably alkali alcoholates. To achieve good yields the reaction component of the formula (II) is preferably used in excess. For example the molar ratio between the oxime compound (I) used and the ester according to formula (II) is preferred 1: 1.5 to 10 mol. The radical Y in the compound (II) is preferably an -ORp residue. In the case of Y = OH ', it is expedient to use, for example, the condensing agent a carbodiimide and tetrahydrofuran as a solvent.

If the intermediate compound (III) is to be isolated, the reaction mixture only needs to be heated for a short time The reaction mixture is then worked up in the customary manner. The interim agreement thus obtained ; 5o bond (III) can then be subjected to a ring closure reaction in the usual way subject. This can be achieved, for example, by a pyrexia reaction, although one has to achieve it higher yields the intermediate compound (III) better in a suitable solvent, preferably

BATH ORIGINAL

009813/1899

in the presence of one of the aforementioned condensation agents, heated. Solvents that are useful for this ring closure reaction include for example the aforementioned organic • 5 solvents such as methanol, ethanol, propanol, dutanol, Toluene, benzene or xylene.

Preferably, however, the intermediate compound (III) prepared in this way is not isolated,
Instead, the intermediate compound (III) obtained in the reaction medium is converted directly to the desired compound (IV) of the formula by further boiling with ring closure

R ₁ -0-CH ₀ ..

T \ J *

\ Lx-N ^ (IV)

\ or \

converted. According to a particularly preferred embodiment

management form one works in such a way. that one, for example 2-methoxy-4-allylphenoxyacetamidoxime and ß-morpholino-propionic acid ethyl ester Dissolves in an ethanolic sodium ethylate solution in the heat and up heated to boiling for the ring closure reaction to take place.

Then the alcohol is then distilled off in vacuo, the residue is treated with ether and added to the ethereal Phase 2N hydrochloric acid added. After the two phases have been separated, the aqueous hydrochloric acid phase is then included 2N sodium hydroxide solution is strongly alkaline and extracted that way

25 obtained mixture with ether. After the ethereal phase has been dried with sodium sulphate, it is passed into the etheri- y see solution of hydrogen chloride, whereby the formed> - (2-methoxy-4-allylphenoxymethyl) -5- (2-morpholinoethyl) -l, 2,4-5xadiazole is precipitated as hydrochloride. To

j5o Recrystallization from absolute isopropanol melts the

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Connection at 111.5 to 115 ° C. The yield is about 8o # of the theory, based on what is used Amidoxime.

Another preferred route, which also leads to the intermediate compound (III), is that one first the abovementioned carbamidoxime compound (I) in a manner known per se with a compound the general formula

Y-C-X-Z

Io to a compound of the general formula

R ₁ -O-CH ₂ -C-NH ₂

N-O-C-X-Z (V)

implements and this connection is then known per se Way with a secondary amine of the general formula

H-N *

I ^

reacted to obtain the intermediate compound (III). The preferred compounds with the formula

Y-CO-X-Z

include those in which the remainder Y = OR «and the remainder Z = Cl. But you can also make the connection (V) subject to a ring closure reaction in a manner known per se, a compound of the general

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Formula (VI)

R ₁ -O-CH ₂ -

-X-Z (VI)

obtained, from which one then in a manner known per se by reaction with a secondary amine of the formula

5 ^

receives the desired connection.

Another one. The way to prepare the products desired according to the invention is that the Oxime compound (I) with a compound of the general formula

YC-CH ₀ -CH ₀ = CH ₀

ti 2 d d. 0

converts, where initially a compound of the general ^formula R ₁ -O-CH ₂ .

arises, which in turn - again with a secondary Amine is converted into the desired product in a manner known per se.

Yet another way of making the invention desired products is that the oxime compound (I) in a known manner with a Compound of the general formula

BAD OFHG'.MAL 009818/1899

R ₀ OCX-

CN ^
NH

implements. Yet another way of making the products desired according to the invention is that one a starting compound of the general formula -

R ₁ TO-CH ₀ -C-Cl ■■ '■. ■

1 c. κ

NOH

with a compound of the general formula NH R NH

H ₀ NCXN ^ or R ₀ OCXN 'or

R R

NC-X-N ^

implements.

The above-described reaction possibilities which lead to the product desired according to the invention are summarized in the reaction scheme below.

BATH ORIGiMAL

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ORIGINAL INSPECTED

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The products produced according to the invention represent effective medicaments, especially in the field of analgesics. and the antitussives. To the effectiveness of the invention To show the compounds produced, the following comparison will be made with those introduced in human medicine Antitussives

? 2 ^H 5 C ₂ H ₅ -N-CH ₂ -CH ₂

J-phenyl-5- (2-diethylaminoethyl) -1,2,4-oxadiazole (as citrate) and

3- (2,2-diphenylethyl) -5- (2-piperidinoethyl) -1,2,4-oxadiazole (as hydrochloride) drawn. The here manufactured according to the invention Compounds show an initial analgesic and antitussive activity with low toxicity. In the The following table shows the average effective doses (DE, -) for the analgesic and antitussive effect as well as for the toxic effect (DL-) of some according to the invention Compounds in comparison with the above-mentioned prior art compounds in various Species listed. The anaigetic effect was on the mouse in the hot plate test and on the rabbit in the electrical irritation of the tooth pulp noted. The values obtained in the hot plate test are defined as the Poses that, with a single oral application, reduce the Schnierz reaction time at 5o; S of the animals (licking the hind paw at a plate temperature of 56 C) to more than 2 kin-

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BATH ORIGINAL

ten extended. Those obtained in the analgesia test on rabbits Values are defined as doses which, with a single application, increase the electrical stimulus threshold in 5o / & of the animals to the Increase twice. The antitussive values obtained on guinea pigs are defined as the doses obtained with one-off Application of the artificially produced cough by sulfuric acid spray in 5c $ of the animals for at least 5 minutes suppress. The antitussive efficacy found in the experiment with cats is defined as the dose which is used in single application the cough caused by electrical irritation of the cranial laryngeal nerve in 5% of the animals completely suspends.

The values of the toxic effect are defined as the doses which, with a single application, for 5o / o of the animals over the course of time fatal after a seven-day observation period.

As a comparison of the compounds according to the invention with the two belonging to the prior art shows, is at 5- (2,2-Diphenylethyl) -5- (2-piperidinoethyl) -1,2,4-oxadiazole an analgesic effect in the non-toxic dose range not found with 3-phenyl-5- (2-diethylaminoethyl) -1,2,4-oxadiazole only a weak analgesic effect was found in rabbits. Both connections show a much lower antitussive effect, especially on cats Effect.

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Tabel

link

Analgesic effect DE ^ ₀ in mg / kg Antitussive effect ₀ 'in mg / kg

Mouse rabbit oral oral guinea pig cat s. C. oral i.V ..

Toxic effect DL ₅₀ in mg / kg

Mouse rabbit i.v. oral oral

3- (2-MethQxy-4-allylphenoxymethyl) -5- (2-morpholinoethyl) -1,2,4-oxadiazole hydrochloride

130

3- (2-methoxy-4-propylphenoxymethyl) -5- (2-piperidinoethyl) -1,2,4-oxadiazole hydrochloride

3- / Raphthyl- (1) -oxymethyl7 -5- (2-morpholinoethyl) -172,4-bxadiazole hydrochloride

3- (2,2-Diphenylethyl) -5- (2-> piperdinoethyl) -1, 2, 4-oxa _r diazole hydrochloride

2oo

170

I4o

> 2oo

> 2oo

2oo

2oo

2oo

I05

55o

46

4l

970

3-phenyl-5- (2-däthylamino-> 2oo ethyl) -1,2,4-oxadiazole citrate

290

2o.o 6.5

75 46o

The following examples illustrate the invention without it to restrict.

example 1

^ - (2-methoxy-4-allylphenoxymethyl) -5- (2-morpholinoethyl) -1, 2, ^ -oxadiazole hydrochloride

JiO g of 2-methoxy-4-allylphenoxyacetamidoxime and 24 g of ethyl 3-morpholino-propionate are dissolved in 15o ml of toluene, mixed with a suspension of sodium methylate (from 0.6 g of Na) in 25o ml of toluene and used for 1/2 hour

Io heated to boiling. After filtration, the toluene is distilled off, the residue dissolved in 2N hydrochloric acid, extracted with ether, then made alkaline with sodium carbonate and the freedom set Base etherified. The ethereal phase is dried and mixed with hydrogen chloride. That failed?

Hydrochloride crystallized from ether and methanol, melts at 111.5 to 113 ° C.

For C ₁₉ H ₂₅ N ₃ O ^. HCl:

Calculated: C 57.62? £ H $ 6.63 Cl $ 8.95 N lo, 6lfo

Found: C 57.1Qfo H 6.42 ^ Cl 9.15 ^ N lo.73

2o The pure base set free from this is a non-crystallizable one and nondestillable oil. The characterization was carried out by chromatography, infrared spectrum and through analysis.

For C ₁₉ H ₂₅ N ₃ O ₄ :

calculated: C 63.49 ^ H 7, olfo Ν 11 found: C 63.44 $ H 7.19 $ N 11

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Example 2

This example shows -, - that the same connection as in Example 1 can be made on a different tfege.

a) Q- (3-Chloropropionyl) -2- (2-methoxy-4-allylphenoxy) acetamidoxime

95 g of 2-methoxy-4-allylphenoxyacetamidoxim and 4o, 8 g of pyridine are dissolved in 2.2 1 of absolute isopropanol and treated within 2o minutes at 58 ⁰ C with 51> 4 g beta-chloropropionyl chloride in 80 ml of isopropanol, dropwise. The mixture is ^{then heated to about 60 °} C. for 1.5 hours, then cooled, the precipitate is filtered off and slurried several times in water and purified. The 0- (j5-chloropropionyl) -2- (2-methoxy-4-allylphenoxy) acetamidoxime obtained in 90% yield melts

15 at Io9 to lo9.5 ° C.

b) 0- (3-Morpholinopropionyl) -2- (2-methoxy-4-allylphenoxy) -aoetamidoxime

40 g of morpholine, dissolved in 2? O ml of chloroform, are added dropwise within 45 minutes at room temperature to a solution of 75 g of 0- (3-chloropropionyl) -2- (2-methoxy-4-allylphenoxy) acetamidoxime and then 2 , Heated to 5o ° C for 5 hours. After washing the chloroform solution with V / ater and Natriunibicarbonatlösung the chloroform is distilled off, the residue in Essigester, solved "and that Xösung" with. .Verdünnter ^J sulfuric acid extracted. AnschlxeßBnü will eis.-caite öcnwexel- / acid solution is alkalized The compound obtained after evaporation of the ethyl acetate melts at 88.5 to 90.degree.

c) 3- (2-Methoxy-4-allylphenoxymethyl) -5- (2-morpholinoethyl) -1,2,4-oxadiazole hydrochloride 40 g of 0- (5-morpholinopropionyl) -2- (2-methoxy -4-allylphenoxy) -acetamidoxim dissolved in 3 liters of benzene °° ^m, to a boiling suspension

009818/1899 SAD ORIQ.NAL

of sodium methylate (from 2.5 g of sodium) in 250 ml of benzene dripped in. After about 400 ml of benzene have been distilled off, the remaining solution is washed out with water, evaporated and worked up as in Example 1.

According to the two described in Examples 1 and 2 above Procedures, the following compounds were made and identified.

Example 3

3 - ^ - Methoxy - ^ - allylphenoxymethyl) -5- (2-piperidinoethyl) -1,2,4-oxadiazole hydrochloride, P. 123 to 124 ° C

PUr C ₂₀ H ₂₇ N ₃ O ₃ ..HCi

Calculated: C $ 60.98 H $ 7.16 Cl 9, o $ N $ 10.67

found: C 60.96 $ H 7.13 $ Cl 8.75 $ N lo.87 $

Example 4

3- (2-Methoxy-4-allylphenoxymethyl) -5- (2-diethylaminoethyl) -1,2,4-oxadiazole hydrochloride, P. 138 to 139 ° C

For C ₁₉ H ₃₇ N ₃ O ₃ · HCl:

Calculated: C $ 59.75, H 7.39 ^ Cl 9.28 ^ N 11.00 ^ found: C 59.6o # H $ 7.28. Cl $ 9.12 N $ 11.14

2o example 5

3- (2-Methoxy-4-allylphenoxymethyl) -5-L2- / 3-phertylplperazinyl- (1) 7-ethyl3 -1,2,4-oxadiazole dihydrochloride, P. 155-157 ° C

For C ₂₅ H ₃₀ N ₄ O ₃ · 2 HCl:

Calculated: C $ 59.16 H $ 6.35 Cl $ 13.97 N Il, o $ 4 found: C $ 58.45 H $ 6.55 Cl $ 13.9o $ N lo.62

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Example 6

? - (2-Methoxy-4-allylphenoxymethyl) -5-t3 - / ^ -

nyl- (1) 7-propyl \-1, 2, ^ - oxadiazole hydrochloride,

P. 164.5 to 165 ^° C '. ''

5 For C ₂₆ H ₃₂ N ₄ O ₃ -HCl:

Calculated: C $ 64.38 H $ 6.86 Cl 7.31Ji N 11, found: C $ 64.55 H $ 6.72 Cl $ 7.46 N 11,

Example 7

^ - (2-Methoxy-4-propylphenoxymethyl) -5- (2-piperidinoethyl) 1,2,4-oxadiazole hydrochloride, m.p. 129 to 130 ° C

For C ₂₀ H ₂₉ N ₃ O ₃ -HCl:

Calculated: C $ 60.67. H $ 7.64 Cl $ 8.95 N lo, 6l $ • found: C 6l, ol $ H 7.59 $ Cl 8.9o $ N 10.63 $

Example 8

3- (2-Methoxy-4-propylphenoxymethyl) -5- (2- diethylaminoethyl) -1, 2,4-oxadiazole hydrochloride, m.p.

For C ₁ QH ₂₉ N ₃ O ₃ * HCl:

Calculated: C $ 59.44 H 7 * $ 88 Cl $ 9.23 N lo, $ 94 found; C $ 59.42 H $ 7.83 $ 019.15 N $ 11.19

2o - example 9 ^: '

3- (2-Methoxy-4-propylphenoxymethyl) -5- | g- / 4-phenylpiperazinyl- (1) 7-ethyl3-1, 2,4-oxadiazole hydrochloride mp 157-159 ° C

For C ₂₅ H ₃₂ N ^ O ₃ -HCl:

Calculated: C $ 63.48 H $ 7.03 Cl $ 7.5o N $ 11.85 • , found; C $ 63.76 H $ 7.08 Cl $ 7.80 N $ 11.88

BATH ORIGINAL

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Example Io 3- (a-Methoxy - ^ - propylphenoxymethyl ^ -S- (3- / 3-Phenylpipera -

zinyl- (l) 7-propyl! -1,2,4-oxadiazole hydrochloride

P. 177 to 178.5 ° C '

PUrO ₂₆ H ₃ ^ O ₃ -HCl:

Calculated: C $ 64.11 H $ 7.24 Cl $ 7.28 N $ 11.51

Found: C $ 64.33 H $ 7.38 Cl $ 7.2 N $ 11.3

Example 11

3-Phenoxymethyl »-5- (2-morpholinoethyl) -1, 2,4-oxadiazole hydrochloride, P. 172 to 173 ° C

For C ₁₅ H ₁₉ N ₃ O ₃ «HCl:

Calculated: C $ 55.31 H $ 6.18 Cl $ 10.89 N $ 12.9o. found: C $ 55.36 H $ 5.87 Cl lo.73 $ N $ 12.92

Example 12

3-Phenoxymethyl-5- (2-piperidinoethyl) -1, 2,4-oxadiazole hydrochloride, P 158 to 159 ^Q C

PUr C ₁₆ H ₂₁ N ₃ O ₂ -HCl

Calculated: C $ 59.35 H $ 6.85. Cl lo, $ 95 N $ 12.9 ^ found: C $ 59.46 H $ 6.77 Cl lo.8o $ N $ 12.93

Example 13

3-phenoxymethyl-5- (2-diethylaminoethyl) -1,2,4-oxadiazole hydrochloride, P. 103 to "lo4.5 ° C

For C ₁₅ H ₂₁ N ₃ O ₂ -HCl:

Calculated: C $ 57.78 H $ 7.11 Cl $ 11.37 N $ 13.48 found: C 57.99 $ H 7, o2 $ Cl Il, o7 $ JJ 13.31 $ '

8AD0R, _GfNAL

- 19th example l4

° C

dlazolhydrochlorId , m.p. 166.5 to l67ö ° C

PUr C ₁₅ H ₁₈ ClN ₅ O ₅ · HCl:

Calculated: C 5o, oo $ H 5.32% Cl $ 19.68 N $ 11.66

found: C 5o, 3o $ H 5.31 $ Cl 19.82 $ N ll, 7o $

Example 15

3, (4-Chlorophenoxymethyl) -5- (2-plperdlnoethyl) -1,2,4-oxadiazole hydrochloride, P. 156 to 159 ° C

Io PUr ^ 6H ₂₀ ClN ₅ O ₂ · HCl:

Calculated: C $ 55.63 H $ 5.91 Cl $ 19.79 N $ 11.73 found: C $ 53.63 H $ 5.89 Cl $ 19.86 N $ 11.73

Example l6

3- (4-Chlop phenoxyniethyl) -5- (2-diethylaminoethyl) - 1,2,4-oxaäiazolhydrochlorld , m.p. 136.5 to 137.5 ° C

PUr ^c ₁ 5 ^H 2o ^C1N 3 ° 2 * ^HCli

calculated: C 52, o2 $ H 6.11 $ Cl 2o, 48 $ N 12.14 $ found: C 52.49 $ H 6.34 $ Cl 2o, 39 $ N 12.4o $

Example 17

3- / Raphthyl ~ (1) -oxymethylZ-S- (2-morpholinoethyl) ~ l, 2,4-oxadiazole hydrochloride, P. 173 to 175 ° C

PUr C ₁₉ H ₂₁ N ₅ O ₅ · HCl:

Calculated: C $ 60.71 H $ 5.9o Cl 9.43p N $ 11.18 found: C 6o, 77 $ H 5.67 $ Cl 9.29 $ N 1Γ, 2ο $

25 Example l8

3- / Raphthyl- (1) -oxymethylJ-S- (2-piperidlnoäthyl) -1,2.4-oxadlazolhydrochlorid, F. 163 to 165.5 ⁰ C

FlIr C ₂₀ H ₂₅ N ₅ O ₂ · HCl:

Calculated: C 64.24.1 H 6.47 $ Cl 9.48 $ N 11.24 found: C Ö3., 9of5 H 6.19 ^ Cl 8.96 $ N ll, 29th t

0 0 9 818/1899

- BATH

Example 19

' 3- / Raphthyl- (1) -oxymethyl7-5- (2-diethylaminoethyl) -1,2,4-oxadiazole hydrochloride, m.p. 143 to "145.5 ° C

PUr C ₁₉ H ₂₅ N ₃ O ₂ «HCl;

5 calculated: C $ 63.06 H $ 6.68 Cl $ 9.79 N $ 11.61 found: C $ 62.84 H $ 6.55 Cl $ 9.97 N $ 11.61

Example 2o .

3- / Raphthyl- (i) -oxymethyl7-5 - ^ - _< / ^ - phenylplperazinyl- (lj7-ethylj-l, 2,4-oxadiazole hydrochloride, Io P. '180 to 182 ° C

PUr C ₂₅ H ₂₆ N ₄ O ₂ ·· HCl:

Calculated: 0 ^ $ 66.57 H $ 6.05 Cl $ 7.86 N $ 12.42 found: C66.63 $ H 6.42 $ Cl 7.64 $ N 12.23 $

Example 21

15 3- (2-Methoxy-4-propylphenoxymethyl) -5 "(2-morpholnoethyl)" 1,2,4-oxadiazole hydrochloride, P llo to 112 ° C

PUr G ₁₉ H ₂₇ N ₃ O ₄ * HC1:

Calculated: C 57 * 34 $ H 7, o9 $ Cl 8.91 $ N 10.56 $ found: C $ 56.93, H $ 7.00. Cl 8.4l $ N lo.31

Example 22

3- / flaphthyl- (l) -oxymethyl7-5-L3 - / ^ "Phenylpperazlnyl · - (1) 7-

propyll-l ^^ - oxadiazolhydrochlorld,

P. 169 to 17o, 5 ° C

PUr C ₂₆ H ₂₀ N ₄ O ₂ -HCl:

Calculated: C $ 67.15 H $ 6.29 Cl 7.63 ^ N 12, o $ 5 found: 'C $ 67.41 H $ 6.66 Cl $ 7.37 N $ 12.15

009818/1899

Claims (2)

Claims R is a low molecular weight alkyl radical, which .vorvors Contains 1 to 3 carbon atoms, or a low molecular weight Alkylene radical, where in the latter Pall'e * "the two alkylene radicals via a carbon or another heteroatom, preferably via a nitrogen atom, form a heterocyclic ring, which in turn, if the bridging heteroatom is trivalent, on this heteroatom a hydrogen atom or one optionally by halogens and / or alkoxy groups substituted phenyl radical 15 can wear, X is a straight or branched chain, low molecular weight Alkylene radical and R, a phenyl radical or naphthyl radical, which is replaced at various points by halogen, alfcoxy radicals, low molecular weight Alkyl radicals and / or low molecular weight alkenyl radicals can be substituted, and the salts formed therefrom with physiologically compatible acids. New documents 009818/1899 bad * ·· • a Ϊ620574 2. Process for the preparation of compounds according to claim 1, characterized in that either (a) a compound of the general formula R ₁ -O-CH ₀ -C-NH ₀ 0 R 1 2 h 2 ti ^ - N-O- C-X-N ' in which the radicals R 1, X and R have the meaning given above, a customary ring-closure reaction subject'or (b) a compound of the general formula R ₁ -O-CH ₂ -H r. R ₁ -O-CH ₂ - U- ^ Q ₁ X ^ CH ₂ -CH = CH ₂ , in which the radical R. has the meaning given above and the radical Z has a halogen atom, preferably a chlorine atom, or a group such as a Halogen atom reacts, represents, with a compound of the general formula ^ ^R. H-N ^^ ^ * R in which the radicals R have the meaning given above, converts or (c) a compound of the general formula R ₁ -O-CH ₀ -C-NH ₀ i d ff d NOH 009818/1899 ie I * * C in which the radical R has the meaning given above with a compound of the general formula 0 -R 'NH Y-C-X-N ^ or R ^ -O-C-X- wherein the radical Y is the radicals -Hal, -NH ₂ , -OH or -0R _g γ, where Rg is a low molecular weight alkyl radical, and the radicals X, R and R _{2 have} the meaning given above, brings or Io (d) a compound of the general formula R ₁ -O-CH ₀ -C-Cl NOH. in which R, has the meaning given above, with a compound of the general formula NH R NH R H ₂ NCXN ^ or R ₂ OCXN ^ or ^ R ₍ R 15 NC-XN " in which the radicals - R, R «and X have the meaning given above have implemented. BAD ORSGHMAL 00 9818/1 ^ 99