FI65615C - OXIMETRY OF THE THERAPEUTIC FREQUENCY OF THERAPEUTIC EQUIPMENT - Google Patents

Description

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Patent · och raglrterityralaan Amtkan uttagd odi utl. * Krtft «n puMoirad 29.02. Ö4 (32) (33) (31) Pyydetty etuoikwii —Begird prtorhet (71) E GY T Gygyszervegyöszeti Gyär, 30, Kereszturi ut, Budapest X,

Hungary-Hungary (HU) (72) Zoltän Budai, Budapest, Aranka Lay ECE Könyä, Budapest,

Tibor Mezei, Budapest, Katalin Grasser, Budapest,

Enikö Szirt's wife Kiszelly, Budapest, Ibolya Kosöczky, Budapest,

Lujza E. Petdcz, Budapest, Hungary-Hungary (HU) (7 * 0 Oy Kolster Ab (5 * 0 Method for the preparation of new therapeutically useful oxime ethers - Förfarande för framstäi Ining av nya therapeutisktabarbara oximetrar

The invention relates to a process for the treatment of therapeutically useful compounds of general formula I R3 (ch <^ N / CmH2m- <4 (¾ ^ C = N - O R4

Rx ^ jrf: i for the preparation of new oxime ethers and their salts and quaternary annitrile derivatives, in which R represents a halogen atom, where x = 1, or a C1-C4 alkoxy or nitro group, in which case 1 2 -L ** x = 1 »2 or 3; R and R each represent a hydrogen atom or together a valence bond; m is an integer from 2 to 4; R and R represent a hydrogen or C 1-4 alkyl group, or R and R together represent an alkylene chain containing 4 carbon atoms, which may contain, as a heteroatom, in addition to an oxygen or nitrogen atom, and the nitrogen atom may further be attached to a C 1-4 alkyl group. or a benzyl substituent.

The novel oxime ethers of the general formula I also include all possible stereoisomers thereof and mixtures thereof.

The novel compounds of the general formula I are prepared according to the invention in that a) a compound of the general formula II (o £ 1 = Y (II) 2 n

B

A ketone in which the symbols R, R, R, x and n have the meanings of the seams as defined above and Y represents an oxygen or sulfur atom is reacted according to the formula R3 / CraH2nfN \, <m>

- O 'X R

with a hydroxylamine derivative in which the symbols m, 34 R and R have the meanings given above, or b) the ketone of the general formula II is reacted with phosphorus oxychloride, followed by the chlorine compound of the formula IV thus obtained, -C "\ ^ 2 ^ nl y ~ C1 (IV) KX ^ -C <R2

B

1 2 in which the symbols R, R, R, x and n have the same meanings as above, are reacted without isolation with a hydroxylamine derivative of the general formula III in which the symbols R3 and R4 have the meanings given above, or c) (αί ^ Γ '' c = N - OH v2 ny ^ K ^ --c - R "(V) Oi- * 1 1 2 oxime, in which the symbols R, R, R, x and n have the meanings given above, reacting R3 / CmH2m-N1 of general formula VI. (VI)

Hal 1, R 4, with a haloalkylamine derivative represented by the formula symbo-3 4 m and m, R and R have the meanings given above, and Hal represents an halogen atom, in an inert solvent and in the presence of a basic condensing agent, or d)

(CH 2 T = N - OH

/ 2 <V>

R - C - RZ

B

A compound in which the symbols R, R, R, x and n have the meanings given above is reacted with a compound of general formula VIII.

Hal - CH 2 - (VIII) 6561 5 4 with a dihaloalkane in which Hal or Hal 'represents the same or different halogen atom and m is an integer from 1 to 3, followed by amination of the resulting haloalkyl ether and, if desired, conversion of the resulting compound of general formula I into therapeutically acceptable as an acid addition salt or a quaternary ammonium derivative or, if desired, liberating a base from a compound of general formula I obtained in the form of a salt.

Ketones of general formula II can be prepared, for example, in J.Am.ChemSoc. 77, 624 (1955) or J. Chem. Soc. 1955, 1126, while hydroxylamine derivatives of general formula III can be prepared, for example, in J.Pharm. Sci. 58, 138/1969 /.

The oxime of general formula V can be prepared, for example, in Org.Synth. Coll. Butter. II, p. 70.

The reaction of the compounds of the general formulas II and III (method a) is preferably carried out in a reaction-inert solvent or a mixture of solvents. Solvents inert to the reaction include, for example, alcohols, preferably ethanol, or pyridine, triethylamine, etc. The reaction temperature can be varied within wide limits. Although the reaction also takes place at room temperature, the optimum reaction rate can be reached at the boiling point of the reaction mixture.

In the reaction of the compounds of general formulas IV and III (method b), the components can be reacted in an inert solvent in the presence of a base. Suitable inert solvents include e.g. diethyl ether, dibutyl ether, tetrahydrofuran and dioxane or aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, etc. while bases which may be used are e.g. pyridine, triethylamine and N-methylmorpholine. The reaction can also be carried out without an inert solvent, using only a base as a solvent. The reaction temperature can be varied within wide limits. The boiling point of the reaction mixture determines the upper limit.

When the final products are prepared by the reaction of compounds of general formulas V and VI (method c), the reaction is carried out in an inert solvent in the presence of a basic condensing agent. As inert solvents, benzene and its homologues such as toluene, xylene, cumene, etc. can be mentioned. In this case, sodium amide or sodium hydride is preferably used as the condensing agent. Obviously, the same result can be obtained with other alkali metal amides or hydrides. In this case, the use of alcohols, such as ethyl, propyl and butyl alcohols, proved to be the most preferred. When alkali metal hydroxide is used as a condensing agent, water can also be used as a solvent.

In preparing compounds of general formula I by reacting compounds of general formula V with compounds of general formula VIII (method d), the reaction may be carried out in a reaction-inert solvent or a mixture of solvents. As inert solvents, benzene and its homologues such as toluene, xylene, cumene, etc. can be mentioned. In this case, sodium amide or sodium hydride is used as the condensing agent. The result can be obtained by using an alkali metal as a condensing agent, but in that case ethanol is preferably used as a solvent. The amination of the obtained haloalkyl ether is carried out in an autoclave under pressure in the presence of the corresponding amine.

the compounds of general formula I can be converted into acid addition or quaternary ammonium salts in a known manner. For the preparation of acid addition salts, physiologically tolerable acids such as hydrogen halides, sulfuric acid, phosphoric acid, citric acid, tartaric acid, formic acid, maleic acid, acetic acid, propionic acid, methanesulfonic acid, such as with an alkyl halide or methanesulfonic acid ester.

The biological activity of the novel compounds of the invention has been demonstrated in numerous experiments. The most significant of the observed effects were local anesthetic effect, antispasmodic effect, nicotine lethal effect, tetrabenazine antagonist and tetracortic anticonvulsant effect.

The local anesthetic effect on the sciatic nerves of rats was studied by the method of Truant and d'Amato (Truant, A.P. and Wiedling, S.: Acta Chirurg, Scand. 116, 351/1958 /). The reference substance was lidocaine. The number of animals with typical stroke and the duration of this effect were measured.

Table I shows the relative potency compared to lidocaine and the duration of action at lidocaine concentrations of 0.5-1.0%. Toxicity values observed with the oral route are also shown.

6561 5 6

Table I

Compound LD50 Relative duration duration (e.g. ,, min. Min. (0.5%) min. (1.0%) no.) 1 9/9 potency 10 210 1.8 94 127 2 430 3.2 72 111 8,450 1.8 68 96 9,950 2.1 88 113 1,560 1.7 99 115 11 450 1.1 66 129 18 880 1.7 92 160 lines * "220 1.0 28 52

Lidocaine ECjjq

Relative power = -

EC ^ of the test compound

The spasmolytic effect on smooth muscle was determined in isolated rat ileum by the method of Brock et al. (Brock, N., Geks.J. and Lorenz, D .: Arch. Exper. Path. U. Pharmacol. 215, 492 (1952)), using papaverine as reference substance. To characterize the potency of the individual compounds, Table II shows the potencies compared to papaverine and the LD5Q values observed using oral dosing.

7

SrtiaBa- V 6561 5

Compound LD ^ o Ρ- ° · Relative (eg No.) ^ power 14 325 3.01 21 650 2.43 13 550 2.42 27 650 2.21 Ί6 1000 1.96 N * 2 430 1.73

Papaverine 367 1.00

Relative power- Papaveriinln ^ 50

EC ^ q of the test compound

Inhibition of nicotine-induced mortality was determined in mice by the method of Stone (Stone · C.A. et al .: Arch. Intern. Pharmacodynamie 117: 419 (1930)) in groups of ten mice, using oral dosing. The results are shown in Table III.

Table III

LD50 ^ 50 mg A g mgAg 15 1450 40 36.3 38 600 47 12.8 5 1 ^ 50 43 33.7 29 600 56 10.7 25 650 43 15.1 7 400 11 36.4 47 1900 100 19.0 51 1200 40 30.0 53 1000 70 14.3 365 40 9.13 LD50 therapeutic index «« ^ «50 6561 5

Antiepileptic efficacy was studied in mice using oral dosing. Maximum electric shock (MES) was induced by electrodes attached to the cornea, using a method known from Swinyard (Swinyard et al .: J. Pharmacol. Exp. Ther. 106, 319-330 (1952)). The effect on tetracor spasm was studied by the modified method of Banziger and He (Banziger, R. and Hane, L.D .: Arch. Int. Pharmacodyn 167, 245-249 (1967)). The results are shown in Table IV.

Table IV

Compound Therapeutic Tetracor-Cure- Therapeutic- e.g. no.__ /. „EDcr> index support block index

Wkg »X_» 50 - * «_ 5 1450 150 9.7 50 29.0 32 1500 300 5.0 270 5.6 _4_620 105 5.9_24_8.4

TrAmetadion 2100 490 4.3 400 5.3 (Ptimal)

The antagonistic effect on tetrabenazine and reserpine was studied in groups of 10 mice, using oral dosing. The inhibitory effect or the cessation effect of the observed maximum dose was measured and the ED 2 values were calculated from the dose-response curves. The results are shown in Table V.

Table V

Compound 1; D50 Tetrabenazine- Therapeutic- Reserpine- Therapeutic (e.g. No.) ni-antagonist index antagonist index

8/8 mi, EDcq mg / kg mi ED Q

_ ^ _ mg / kg50_ 16 1000 70 14.3 80 12.5 1 560 80 7.0 27 20.7 38 600 120 5.0 18 33.0 30 900 34 26.5 * li ISO 5.0 32 1500 22 68.2 over 100 15.0 4 620 7 88.6 over 130 4.8 53 1000 28 36.0 about 250 4

Amitriptyline 225 15 17.3 65 3.5 6561 5 »

The following Tables VI and VII show the antispasmodic effect and the inhibitory effect of nicotine-induced mortality on the 1 2 compounds of the invention where R and R = H. .

Table VI

1 2

Spasmolytic effect (for compounds with R and R * H)

Compound LD50 P * ° * Relative power (eg low), „.

_ (mg / kg) _ 35 210 2.22 36 350 1.15 37 600 1.22 45 880 2.5

Papaverine 367 1.00

Table VII

1 2

Inhibition of nicotine mortality (for compounds where R and R = H)

Compound ED Therapeutic index (e.g. no.), _Mg / kg_ 37 47 12.8 45 27 32.6

Trihexyphenidyl 40 9.13

In addition, the compound of Example 36 has a local anesthetic effect of the same intensity as lidocaine.

6561 5 10

The novel compounds of formula I and methods for their preparation are further described by the following non-limiting examples.

Example 1 2-Benzylidene-1- (3'-dimethylaminoprocoxyimino) cyclohexane. A solution of 20.1 g (0.1 mol) of 2-benzylidenecyclohexanone oxime in 200 ml of anhydrous toluene is added dropwise at 85 ° C, with constant stirring, a suspension of 2.4 g (0 mol) of , 1 mole) of sodium hydride in 50 ml of anhydrous toluene. The mixture is kept at 130 ° C for 2 hours, and with further stirring, a solution of 13.3 g (0.11 mol) of dimethylaminopropyl chloride in anhydrous toluene is added. The mixture is heated for a further 6 hours, the toluene solution is cooled to 30 [deg.] C., washed with 100 ml of ether and extracted with an aqueous solution of 15 g (1.0 mol) of tartaric acid or an equivalent amount of dilute aqueous hydrochloric acid. The aqueous solution cooled to 0-5 ° C is basified with pH 10 ammonium hydroxide, and the oily base which separates is extracted with dichloroethane. The solvent is removed by distillation and the residue is fractionated in vacuo.

Yield: 19.6 g (68.6%); tr. 182-186 ° C at 53 Pa.

Fumarate: m.p. 134-135 ° C.

Analysis: C 22 H 30 N 2 O 5

Calculated: C 65.81%, H 7.53%, N 6.98% Found: C 65.61% H 7.65%, N 7.03.

Example 2 2-Benzylidene-1- (21-diethylaminoethoxyimino) cyclohexane.

Proceed as in Example 1, except that 14.9 g (0.11 mol) of diethylaminoethyl chloride are used instead of dimethylaminopropyl chloride.

Yield: 16.8 g (62.4%) of a yellow oil.

M.p .: 192-196 ° C at 53 Pa

Fumarate: m.p. 110-112 ° C.

Analysis: ^ 23H32N2 ^ 5

Calculated: C 66.33%, H 7.74%, N 6.72%, Found: C 66.16%, H 7.87%, N 6.75%,

Example 3 2-Benzylidene-1- (2'-dimethylaminoethoxyimino) cyclohexane.

Proceed as in Example 1, except that 11.8 g (0.11 mol) of dimethyl-11,656-5 chloride are used instead of dimethylaminopropyl chloride.

Yield: 20 g (73.9%) of a yellow oil.

kp .; 174-176 ° C at 40 Pa.

Fumarate: m.p. 140-142 ° C.

Analysis: C 21 H 28 N 2 O 5

Calculated: C 64.92%, H 7.27%, N 7.21%, Found: C 64.92%, H 7.16%, N 7.27%.

Example 4 2-Benzylidene-1- (N-benzylpiperazinylpropoxyimino) cyclohexane.

A solution of 20.1 g (0.1 mol) of 2-benzylidenecyclohexanone oxime in 200 ml of anhydrous toluene is added dropwise at 85 ° C with stirring to a suspension of 2.4 g (0.1 mol) of sodium hydride in 50 ml. in anhydrous toluene. The mixture is kept at 130 [deg.] C. for 2 hours, then a solution of 27.8 g (0.11 mol) of N-benzylpiperazinylpropyl chloride in 50 ml of anhydrous toluene is added. The mixture is kept at 130 ° C for 12 hours, cooled and shaken with a solution of 35 g of tartaric acid in 150 ml of water. The aqueous phase is cooled to 0-5 ° C and basified to pH 10 with ammonium hydroxide. After extraction with dichloroethane, the solvent is removed by filtration and the remaining crude phase is converted into fumarate without distillation.

Yield: 35 g (84.3%).

Difumarate: m.p. 196 ° C.

Citrate: m.p. 125-126 ° C.

Maleinate: m.p. 190 ° C (dec.).

Tartrate: m.p. 198-200 ° C.

Iodomethylate: m.p. 134-135 ° C (dec.).

Hydrochlorides: m.p. 211-212 ° C.

Analysis: C35H43N309

Calculated: C 64.70%, H 6.67%, N 6.46%, Found: C 64.35%, H 6.70%, N 6.38%.

Example 5 2-Benzylidene-1- (N-methylpiperazinylpropoxyimino) cyclohexane.

Proceed as in Example 4, except that 19.5 g (0.11 mol) of N-methylpiperazinylpropyl chloride are used instead of N-benzylpiperazinylpropyl chloride.

ΐΐ 6561 5

Yield: 27.4 g (80.5%)

Difumarate: m.p. 192 ° C.

Analysis: C 29 H 31 N 3 O 4

Calculated: C 60.71%, H 6.85%, N 7.32%, Found: C 60.58%, H 7.28%, N 7.36%.

Example 6 2-Benzylidene-1- (3-morpholinopropoxyimino) cyclohexane Proceed as in Example 4, except that 18.0 g (0.11 mol) of N- (γ-chloropropyl) morpholine are used instead of N-benzylpiperazinylpropyl chloride. .

Yield: 3 0.5 g (93%).

Fumarate: m.p. 133-134 ° C Analysis: CH 2 Cl 2 / g

Calculated: C 60.87%, H 7.20%, N 6.28%.

Found: C 60.44%, H 7.35%, N 6.32%.

Example 7 1- (2'-Aminoethoxyimino) -2-benzylidenecyclohexane To a sodium methylate solution prepared from 9.2 g (0.4 mol) of sodium metal and 200 ml of anhydrous ethanol was added 20.1 g (0, 1 mole) of 2-benzylidenecyclohexanonyloxime and 23.2 g (0.2 moles) of N-chloroethylamine hydrochloride. The mixture is stirred for 4 hours at room temperature, the sodium chloride is removed by filtration and the solution is evaporated in vacuo. The residue is taken up in water, extracted with chloroform and evaporated. Yield: 25 g (50%).

Hemifumarate: m.p. 165 ° C Analysis: c17H22 ° 3N2

Calculated: C 67.50%, H 7.30, N 9.27% Found: C 67.45%, H 7.18% N 9.35%.

Example 8 2-Benzylidene-1- (2'-dimethylaminoethoxyimino) cyclopentane The sodium salt is prepared in the usual manner from 2.4 grams (0.1 mole) of sodium hydride and 18.7 grams (0.1 mole) of 2-benzylidenecyclopentanone oxime in toluene and administered react with 11.8 g (0.11 moles) of dimethylaminoethyl chloride. The reaction is then continued as in Example 1.

Yield: 16.1 g (62.2%) of a boiling oil M.p .: 172-174 ° C at 40 Pa.

Fumarate: m.p. 125-127 ° C.

13 6561 5

Analysis: C 20 H 26 N 2 O 5

Calculated: C 64f 18%, H 7.00%, N 7.48%, Found: C 64.33% H 7.13%, N 7.43%.

Example 9 2-Benzylidene-1- (2'-dimethylaminopropoxyimino) cyclopentane The sodium salt is prepared from 2.4 grams (0.1 mole) of sodium hydride and 18.7 grams (0.1 mole) of 2-benzylidenecyclopentanone oxime in toluene and reacted with 18.2 grams (0.17 moles) of dimethylaminopropyl chloride. The reaction is then continued as in Example 1.

Yield: 23.65 g (57.9%) of a yellow solid oil.

M.p .: 193-194 ° C at 53 Pa

Fumarate: m.p. 122-124 ° C.

Analysis: C 21 H 28 N 2 O 5

Calculated: C 64.95%, H 7.26%, N 7.21%.

Found: C 64.93%, H 7.20%, N 7.08%.

Example 10 2-Benzylidene-1- (2'-diethylaminoethoxyimino) cyclopentane Starting from 2.4 grams (0.1 mole) of sodium hydride, 18.7 grams (0.1 mole) of 2-benzylidenecyclopentanone oxime and 14.9 grams (0 , 11 moles) of diethylaminoethyl chloride, is carried out as described in Example 1.

Yield: 26.8 g (75%).

M.p .: 178-180 ° C at 40 Pa

Fumarate: m.p. 123-124 ° C.

Analysis: C 22 H 30 N 2 O 5

Calculated: C 65.65%, H 7.51%, N 6.96%.

Found: C 65.83%, H 7.67%, N 6.95%.

Example 11 2-Benzylidene-1- (2'-diisopropylaminoethoxyimino) cyclopentane Starting from 2.4 grams (0.1 mole) of sodium hydride, 18.7 grams (0.1 mole) of 2-benzylidenecyclopentanone oxime and 18.01 grams (0.11 moles) of diisopropylaminoethyl chloride, proceed as described in Example 1.

Yield: 18.7 g (59.4%)

kp .; 197-198 ° C at 40 Pa

Fumarate: m.p. 123-125 ° C Analysis: C24H34N2O5

Calculated: C 66.97%, H 7.96%, N 6.51%.

Found: C 66.73%, H 7.95%, N 6.46%.

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Example 12 2-Benzyl-de-eni-1- (2'-dimethylamino-octo-imino) -cycloheptane Proceed as in Example 1, except that 21.5 S (0.1 mol) 2 is used. -benzylidenecycloheptanone oxime and 11.8 g (0.11 moles) of dimethylaminoethyl chloride.

Yield »20 g (69.6 i)

Pumaraattis sp. 130-132 ° C.

Analysis: CH 2 Cl 2 / N 2 O 3.

Calculated: C 65.60 #, H 7.52 #, N 6.98 i · Found: C 65.60 i, H 7.73 it N 6.87 #.

Example 15 2-Benzylidene-1- (3'-dimethylaminopropoxyimino) cycloheptane Proceed as in Example 1, except that 21.5 g (0.1 mol) of 2-benzylidenecycloheptanone oxime are used instead of 2-benzylidenecyclohexanone oxime.

Yield: 16.7 g (72.4 l) of a yellow oil.

M.p .: 178-180 ° C at 27 Pa.

Pumarate: m.p. 134 - 135 ° C ·

Analysis: CgjHjgNgO ^

Calculated: C 66.34 it H 7.74 #, N 6.72 #, Found: C 66.23 i, H 7.80 N 6.66 #.

Example 14 2-Benzylidene-1- (2'-diisopropylaminoethoxyimino) cycloheptane Starting from 2.4 grams (0.1 moles) of sodium hydride, 21.5 grams (0.1 moles) of 2-benzylidenecycloheptanone oxime and 17.95 grams (0.31 moles) of diisopropylaminoethyl chloride, is carried out as in Example 1.

Yield: 26.0 g (76.2 l) of a yellow oil.

Pumarate: m.p. 132-134 ° C.

Analysis: CggHjgNgO

Calculated: C $ 68.08, H 8.35 it N 6.11 i% Found: C 68.16 #, H 8.46 it N 6.07 i ·

Example 15 1- (31-Dimethylaminopropoxyimino) -2- (p-chlorobenzylidene) cycloheptane

Proceed as described in Example 1, except that 24.9 g (0.1 mol) of 2- (p-chlorobenzylidene) cycloheptanone oxime are used instead of 2-benzylenedicyclohexanone oxime.

* v * 15 6561 5

Yield: 16.06 g ($ 60.1) of a yellow oil.

Fumarate: m.p. 159-160 ° C Analysis: C 18 H 19 ClN 2 O 2

Calculated: C 61.22 H 6.94 N $ 6.22, Cl $ 7.86 Found: C 61.44 i °% H $ 7.09 »N 6.12 Cl $ 7.86.

Example 16 1- (3 * -Dimethylaminopropoxyimino) -2- (p-methoxybenzylidene) cycloheptane

Proceed as described in Example 1, except that 24.5 g (0.1 mol) of 2- (p-methoxybenzylidene) cycloheptanone oxime are used instead of 2-benzylidenecyclohepsanone oxime.

Yield: 15.6 g (67 * $ 5) of a yellow oil.

Fumarate: m.p. 133-135 ° C.

Analysis: C24H34W206

Calculated: C $ 64.57 »H 7 * $ 67, N 6.27 9 ^ · Found: C $ 64.39, H 7 * $ 84» N $ 6.18.

Example 17 1- (2'-Diethylaminoethoxyimino) -2- (o-methoxybenzylidene) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.1 grams (0.1 moles) of 2- (o -methoxybenzylidene) cyclohexanone oxime and 14.9 grams (0.11 moles) of diethylaminoethyl chloride are treated as described in Example 1.

Yield: 21 g ($ 65.1)

Fumarate: m.p. 142-143 ° C.

Cyclamate: m.p. 126-127 ° C.

Analysis: C ^ H ^ N ^

Calculated: C 64.50 #, H 7.64 #, N 6.28 <f> Found: C 64.02 H 8.08 #, N $ 6.23> ·

Example 18 1- (3'-Dimethylaminopropoxyimino) -2- (o-methoxybenzylidene) cyclohexane.

Starting from 2.4 grams (0.1 moles) of sodium hydride, 23 grams (0.1 moles) of 2- (p-methoxybenzylidene) 8-cyclohexeanone oxime and 13.5 grams (0.11 moles) of dimethylaminopropyl chloride, proceed as described in Example 1.

16 6561 5

Yield: 22.6 g (71 * 6 $).

Kp. mp 185-190 ° 6.7 Passaa.

Fumarate: m.p. 122-123 ° C.

Analysis: C23H32N2 ° 6

Calculated: C 63 * 86 H 7 * 45 $ »N $ 6.48, Found: C 63 * 78 $ * H 7 * 67 $» N 6.42.

Example 19 1- (3'-Dimethylaminopropoxyimino) -2- (m-methoxybenzylidene) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23 * 1 grams (0.1 moles) of 2- (m -methoxybenzylidene) cyclohexanone oxime and 13.3 grams (0.11 moles) of dimethylaminopropyl chloride, proceed as described in Example 1.

Yield: 28.2 g (39 * $ 3) ·

Fumarate: m.p. 115-116 ° C.

Analysis: C 20 H 20 N 2 O 6

Calculated: C 63 * 86 $, H 7 * 45 $ »N 6.48 ji, Found: C 63.42 #, H 7.27 N 6.45 1>.

Example 20 1- (2 * -methyl-3'-dimethylaminopropoxyimino) -2- (p-methoxybenzylidene) cyclohexane From 2.4 grams (0.1 moles) of sodium hydride, 23 * 1 grams (0.1 moles) ) 2- (p-methoxybenzylidene) cyclohexazionione oxime and 16.5 grams (0.11 moles) of dimethylaminoisobutyl chloride are treated as described in Example 1.

Yield: 22.4 g ($ 68).

M.p .: 189 ° C 6.7 Passaa.

Fumarate: m.p. 153-154 ° C.

Analysis: C24H34N2 ° 6

Calculated: C 64.74 H 7.66 #, N 6.26 #, Found: C 64.34 #, H 7.75 N 6.30

Example 21 1- (2 "Methyl-3'-dimethylaminopropoxyimino) -2- (o-methoxybenzylidene) cyclohexane] Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.1 grams (0.1 moles) 2- (o-methoxybenzylidene) cyclohexanone oxime and 16.5 grams (0.11 moles) of dimethylaminoisobutyl chloride are treated as described in Example 1.

j - 6561 5 17

Yield: 30.0 g (90).

Fumarate: m.p. 159-160 ° C.

Maleinate: m.p. 113 - H4 ° C.

Analysis: 024Ε34Ν2 ° 6

Calculated: C 64.74 #, H 7 * 66 <j6, N 6.26 # Found: C 64.25 # »H 7.54 #, N 6.38 96.

Example 22 1- (N-Methylpiperazinylpropoxyimino) -2- (o-methoxybenzylidene) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.1 grams (0.1 moles) of 2- (o-methoxybenzylidene) ) cyclohequeanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride, proceed as described in Example 4.

Yield: 35.2 g ($ 95) ·

Fumarate: m.p. 189-191 ° C.

Analysis: C30H41N3 ° 10 *

Calculated: C $ 59.69, H 6.85 96, N 6.96 96.

Found: C 59.43 #, H 7.00 96, N 6.92 #.

Example 23 1- (N-Methylpiperazinylpropoxyimino) -2- (m-methoxybenzylidene) cyclohexane.

Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.1 grams (0.1 moles) of 2- (m-methoxybenzylidene) cyclohexanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride, proceed as in the example 4 as described.

Yield: 31.2 g (84.2 l).

Fumarate: m.p. 187-189 ° C.

Analysis: O ^ qH ^ NjO- ^ q

Calculated: C 59.69 96, H 6.85 96, TS 6.96 #.

Found: C 59.45 #, H 7.00 96, N 6.81 96.

Example 24 1- (N-Methylpiperazinylpropoxyimino) -2- (p-methoxybenzylidene) -ecyclohexane.

Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.1 grams (0.1 moles) of 2- (p-methoxybenzylidene) cyclohexananone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride, proceed as described in Example 4. way.

6561 5 18

Yield: 30.5 g ($ 82.5).

Pumarate: ep. 190 ° C.

Analysis: C30H41N3 ° 10 *

Calculated: C 59 * 69 H $ 6.85 »N $ 6.96 Found: C 59.54 #, H 6.65 56, N 6.92 Example 25 1- (N-benzylpiperazinylpropoxyimino) -2- ( m-methoxybenzylidene) -cyclohexane.

Starting from 2.4 grams (0.1 moles) of sodium hydride, 23 tl (0.1 moles) of 2- (m-methoxybenzylidene) cyclohexanone oxime and 27.8 grams (0.11 moles) of N-benzylpiperazinylpropyl chloride, proceed as described in Example 4.

Yield: 21.3 g (95.5%)

Difumarate: m.p. 195 - 197 ° C Analysis:

Calculated: C $ 63.61, H 6.67 ^, N $ 6.18 Found: C $ 63.90, H $ 6.78, N 6.12 'fo.

Example 26 1- [2'-Methyl-31- (4 "-methylpiperazinylpropoxyimino)] - 2- (p-methoxybenzylidene) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, from 23.1 grams (0.1 mole) of 2- (p-methoxybenzylidene) cyclohexanone oxime and 21.0 grams (0.11 moles) of N-methylpiperazinyl isobutyl chloride are treated as described in Example 4.

Yield: 32.5 g (84.4 °) ·

Difumarate: m.p. 186-190 ° C.

Analysis: C 31 H 43 N 3 O 10

Calculated: C $ 60.28, H 7.01 56, N 6.81 96.

Found: C 59.92 #, H 7.25 96, N $ 6.74>.

Example 27 1- (N-Methylpiperazinylpropoxyimino) -2- (3 ', 4'-dimethoxybenzylidene) cyclohexane.

Starting from 2.4 grams (0.1 moles) of sodium hydride, 26.1 grams (0.1 moles) of 2- (3 ', 4'-dimethoxybenzylidene) cyclohexanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride, proceed as described in Example 4.

Yield: 34.1 g ($ 85).

Difumarate: m.p. 186-188 ° C.

Analysis: ° 31H43N3 ° U

6561 5 19

Calculated: C 58.76 36f H 6.84 N 6.63 έ Found: C 58.58 H $ 6.64, N 6.61 Example 28 1- (N-methylpiperazinylpropoxyimino) -2- (3 ' , 4 *, 5 'trimetoksibentsy-methylethylidene) cyclohexane.

From 2.4 grams (0.1 moles) of sodium hydride, from 29.1 grams (0.1 moles) of 2- (3 '* 4' »5 '- * trimethoxybenzylidene) cyclohexanone oxime and from 19.5 grams (0.11 moles) N-methylpiperazinylpropyl chloride, proceed as described in Example 4.

Yield: 39.0 g (90.5 g).

Difumarate: m.p. 185-186 ° C.

Cyclamate: m.p. 166-167 ° C.

Analysis: C32H45N3 ° 12 *

Calculated: C 57.92 H 6.83 #, N $ 6.33 Found: C 58.24 #, H 7 # 00 #, N 6.30 f>.

Example 29 1 - (N-Benzylpiperidinylpropionimino) - (- (4 ', 4-trimethoxy-benzylidene) cyclohexane).

Starting from 2.4 grams (0.1 moles) of sodium hydride, 29 # 1 grams (0.1 moles) of 2- (3 ', 4', 5'-trimethoxybenzylidene) cyclohexanone oceimide and 27.8 grams (0.11 moles) of N -benzylpiperazinylpropyl chloride, proceed as described in Example 4.

Yield: 46.5 g (92 ¢).

Difumarate: m.p. 188-189 ° C.

Analysis: C58H49N3 ° 12

Calculated: C 61.6 <fot H $ 6.7 »N 5» $ 7> »Found: C 61.5 #» H 6.9 #, N 5 # $ 63> ·

Example 30 1- (Dimethylaminopropoxyimino) -2- (p-chlorobenzylidene) cyclohexane. Starting from 2.4 grams (0.1 moles) of sodium hydride, 23 # 5 grams (0.1 moles) of 2- (p-chlorobenzylidene) cyclohexanone oxime and 13 * 3 grams (0.11 moles) of dimethylaminopropyl chloride, proceed as described in Example 4.

Yield: 24.3 g ($ 76)

Fumarate: m.p. 142-143 ° C Analysis: C 22 H 29 ClCl 2 O 5

Calculated: C 60.47 H $ 6.69>, Cl 8.11 N 6.41 # Found: C 60.67 #, H 6.87 #, Cl 8.2 96, N 6.43 #.

Jr '·: 20 6561 5

Example 51 1- (Dimethylaminopropoxyimino) -2- (m-chlorobenzylidene) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 25.5 grams (0.1 moles) of 2- (m-chlorobenzylidene) cyclohexanone oxime and 15 * 5 grams (0.11 moles) of dimethylaminopropyl chloride, proceed as described in Example 1.

Yield: 25.0 g (72 #).

Fumarate: m.p. 142-144 ° C.

Analysis: C 22 H 29 ClN 2 O 5

Calculated: C 60.47 #, H 6.69 #, Cl 8.11 #, N $ 6.41> Found: C 60.58 #, H 6.90 #, Cl 8.20 #, N 6.22 #.

Example 52 1- (Dimethylaminopropoxyimino) -2- (o-chlorobenzylidene) cyclohexane Starting from 2.4 grams (0.1 mole) of sodium hydride, 25.5 grams (0.1 mole) of 2- (o-chlorobenzylidene) cyclohexanone oxime and 15> 5 grams (0.11 moles) of dimethylaminopropyl chloride, proceed as described in Example 1.

Yield: 21.5 g (67.2 #)

Fumarate: m.p. 112-115 ° C Analysis: C 22 H 29 ClN 2 ° 5

Calculated: C 60.47 H $ 6.69>, Cl 8.11 #, N 6.41 # Found: C $ 60.25>, H 6.47 Cl 8.10 #, N $ 6.55 ·

Example 55 2-Benzyl-1- (2'-dimethylaminoethoxyimino) cyclohexane.

Proceed as described in Example 1, starting from the following substances: 2.4 grams (0.1 moles) of sodium hydride, 20.2 grams (0.1 moles) of 2-benzylcyclohexanone oxime and 11.85 grams (0.11 moles) of dimethylaminoethyl chloride.

Yield: 20.4 g ($ 74.5) ·

M.p .: 174-176 ° C at 40 Pa.

Fumarate: m.p. 155-154 ° C.

Analysis: C 21 H 50 N 2 O 5

Calculated: C 64.52 56, H 7.75 #, N 7.1Ö #, Found: C 64.71 H 7.80 <fo, N 7.15

Example 34 2-Benzyl-1- (5'-dimethylaminopropoxyimino) cyclohexane Proceed as described in Example 1, starting from the following substances: 2.4 g (0.1 mol) of sodium hydride, 20.2 g (0.1 mol) 2-benzyl-cycloheekeanone oxime and 15 * 56 g (0.11 moles) of dimethylaminopropyl chloride.

21 6561 5

Yield: 23.7 g (02.3 #)

M.p .: 172-174 ° C at 53 Pa.

Fumarate: m.p. 134-136 ° C.

Analysis: C22K32N2 ° 5

Calculated: C $ 65.4, H 8.32 N $ 6.97> Found: C $ 65.5 »H $ 8.10, N $ 6.95 ·

Example 35 DL-2-Benzyl-1- (2'-methyl-3'-dimethylamino-propoxyimino) -cyclohexane.

Proceed as described in Example 1, starting from the following substances: 2.4 g (0.1 mol) of sodium hydride, 20.2 g (0.1 mol) of 2-benzyl-cyclohexanone oxime and 14.91 g (0.11 mol) of 2- methyl-3-dimethylamino-propyy1ikloridia.

Yield: 24.1 g ($ 80.0) ♦

M.p .: 150-155 ° C at 6.7 Pa.

Fumarate: m.p. 166-167 ° C.

Analysis: C23H34N2 ° 5

Calculated: C 66.1 E 8.15 N $ 6.7 · Found: C 66.3 ° fa% H $ 8.29, N $ 6.6 ·

Example 36 DL-2- (p-methoxybenzyl) -1- (2'-methyl-3'-dimethylaminopropoxy) cyclohexane

Proceed as described in Example 1, starting from the following substances: 2.4 g (0.1 mol) of sodium hydride, 23 * 63 g (0.1 mol) of 2- (p-methoxybenzyl) cyclohexanone oxime and 14.91 g (0, 11 moles) of 2-methyl-3-dimethylaminopropyl chloride.

Yield: 26.9 g ($ 81.0) ·

kp .; 168-170 ° C at 6.7 Pa.

Analysis: C24H36N2 ° 6 *

Calculated: C 64.3 H 8.10 #, N 6.25 # Found: C 64.4 #, H 8.25 #, N 6.18 #.

Example 37 2- (p-Methoxy Benzyl) -1- (3 * -dimethylaminopropoxyimino) cyclohexane. Proceed as described in Example 1, starting from the following substances: 2.4 g (0.1 mol) of sodium hydride, 23.63 g (0.1 mol) of 2- (p-methoxybenzyl) cyclohexanone oxime and 13.36 g ( 0.11 moles) of dimethylaminopropyl chloride.

*% y 6561 5 22

Yield: 22.65 g (72 #).

M.p .: 184-185 ° C 53 Passaa.

Fumarate: m.p. 09-91 ° C.

Analysis: C23H34N2 ° 6

Calculated: C 63.75 #, H 7, ΘΟ #, N 6.45 # · Found: C 63.50 #, H 7.76 N 6.45 # ·

Example 38 2-Benzylidene-1- (2'-dimethylaminoethoxyimino) cyclopentane 34.4 grams (0.2 moles) of 2-benzylidenecyclopentanone and 35.4 grams (0.2 moles) of dimethylaminoethoxyamine hydrochloride are boiled for 3 hours at 3 ° 0 ml of anhydrous ethanol and 150 ml of pyridine in the mixture, after which the mixture is evaporated in vacuo. The residue is basified, the base is extracted with chloroform and the solvent is removed by distillation.

Yield: 50 g (95 → 2 ^ ^)

Fumarate: m.p. 126-127 ° C

Analysis: C 20 H 26 N 2 O 5

Calculated: C 64.18 #, H 7.00 #, N 7.48 <fo Found: C 64.03 i, H 7.25 96, N 7.39 # ·

Example 39 2-Benzylidene-1- (2'-methyl-3 "-dimethylaminopropoxyimino) cyclohexane

Proceed as described in Example 1, using 16.5 g (0.11 mol) of dimethylaminoisobutyl chloride instead of dimethylaminopropyl chloride.

Yield: 21 g (70 l) of a yellow oil.

M.p .: 182 ° C at 53-67 Pa.

Fumarate: m.p. 77-78 ° C.

Citrate: m.p. 98-99 ° C.

Iodomethylate: m.p. I63 - 164 ° C.

Analysis: C23H52N2O5

Calculated: C 66.33 #, H 7.74 it N 6.72 96.

Found: C 66.18 fof H 7.82 N 6.66 96.

Example 40 2-Benzylidene-1- [2'-methyl-3 '- (4'-methylpiperazinyl) propoxyimino] cyclohexane Starting from 2.4 grams (0.1 mol) of sodium hydride, 20.1 grams (0.1 moles) of 2-benzylidenecyclohexanone oxime and 20.76 grams (0.11 moles) of 2-methyl-3 ”(4'-methylpiperazinyl) propyl chloride, proceed as described in Example 1.

6561 5 23

Yield: 29.5 g (S3 en) of a pale yellow oil Difumarate: m.p. 190-191 ° C.

Analysis: C 30 H 41 N 3 O 9

Calculated: C 61.31 fit H 7.05 fit 7.15 en · Found: C 61.15 fit H 7.19 fit N 7.28 en.

Example 41 2- (p-Methoxybenzylidene) -1- (3'-dimethylaminopropoxyimino) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.1 grams (0.1 moles) of 2- (p -methoxybenzylidene) cycloheekeanone oxime and 13.5 grams (0.11 moles) of dimethylaminopropyl chloride, is carried out as described in Example 1.

Yield: 24.5 g (77.5 en) ·

Fumarate: m.p. 125-126 ° C

Analysis: G23H32N2 ° 6

Calculated: C 63.94 fit H 7.92 fit N 6.47 fi Found: C 64.00 fi, H 7.83 fit N 6.41 fi.

Example 42 2- (m-Chlorobenzylidene) -1- [3 '- (4-methylpiperazinyl) propoxyimino] cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.5 grams (0.1 moles) 2- (m-chlorobenzylidene) cyclohexanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride are treated as described in Example 1.

Yield: 26.8 g (71.4 g) ·

Difumarate: m.p. 194-196 ° C Analysis: CH 2 Cl 2 / CH 2 Cl 2

Calculated: C 57.25 fit H 6.3 fit Cl 5.84 fit N 6.4 fi Found: C 57.10 fi H 6.2 fit Cl 5.73 fit N 6.29 fi.

Example 43 2- (o-Chlorobenzylidene) -1- (3 '- dimethylaminoethoxyimino) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.5 grams (0.1 moles) of 2- (o -chlorobenzylidene) cyclohexanone oxime and 11.8 grams (0.11 moles) of dimethylaminoethyl chloride are treated as described in Example 1.

Yield: 23.38 g (76.25 fi)

Fumarate: m.p. 126-128 ° C Analysis: C 21 H 24 ClN 2 ° 5 / J.

6561 5 24

Calculated: C 59.64 #, H 5.72 Cl 8.39 H 6.62 # Found: C 59.52 #, H 5.90 #, Cl 8.40 H 6.58

Example 44 2- (p-Chlorobenzyl) -1- [3 '- (4' - methylpipererateinyl) propoxyimino] cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 25.74 grams (0.1 moles) of 2- (p-chlorobenzyl) cyclohexanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl clip, proceed as described in Example 1.

Yield: 33.8 g (89.5%)

Difumarate: ep. 194-195 ° C

Analysis: C29H40ClN3 ° 9

Calculated: C 57.09 #, H 6.60 #, Cl 5.31 N 6.89 # Found: C 57.13? & »H 6.82 #, Cl 5.77 N 6.84

Example 45 2- (p-Chlorobenzyl) -1- (31-dimethylaminopropoxyimino) cyclohexane Starting from 2.4 grams (0.1 moles) of sodium hydride, 23.7 grams (0.1 moles) of 2- (p- chlorobenzyl) cyclohexanone oxime and 13.3 grams (0.11 moles) of dimethylaminopropyl chloride, proceed as described in Example 1.

Yield: 25.4 g ($ 79) of a yellow oil B.p .: 160 ° C at 27 Pa.

Fumarate: Bp. 143 - 144 ° C Analysis! Cg2 h31cin2o

Calculated: C 62.25 H 7.37 Cl 8.35 #, N 3.30 £ Found: C 62.37 H 7.40 #, Cl 8.27 ·? Β, N 3.28

Example 46 2-Benzylidene-1- [3 '- (4 "-methylpiperazinyl) propoxyimino] cycloheptane Starting from 2.4 grams (0.1 moles) of sodium hydride, 21.5 grams (0.1 moles) of 2- benzylidenecycloheptanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride are treated as described in Example 1.

Yield: 26.5 g (72.5 #)

Difumarate: m.p. 196-197 ° C (decomp.)

Analysis: C 18 H 19 N 2 O 2

Calculated: C 61.31 #, H 7.03 3 *, N $ 7.15 Found: C 61.20, H 6.94 5 ^, N 7.10 '* * ··', ...

6561 5 25

Example 47 2-Benzylidene-1 - [(4''-methylpiperazinyl) propoxyimino] cyclopentane Starting from 2.4 grams (0.1 moles) of sodium hydride, 18.7 grams (0.1 moles) of 2 -benzylidenecyclopentanone oxime and 19.5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride are treated as described in Example 1.

Yield: 31.3 g (95.8%)

Didumarate: m.p. 205-206 ° C (decomp.)

Analysis ·, C 29 H 37 N 3 O 9

Calculated: C 60.09%, H 6.66%, N 7.51% Found: C 59.83%, H 6.50%, N 7.53%.

Example 48 2-Benzylidene-1- (2'-dimethylaminoethoxyimino) cyclohexane 20.23 g (0.1 mol) of 2-benzylidenecyclohexathione and 17.7 g (0.1 mol) of dimethylaminoethoxyamine hydrochloride are boiled in the mixture for several hours. with 150 ml of anhydrous ethanol and 75 ml of anhydrous pyridine, after which the solvents are removed in vacuo. The evaporation residue is basified to pH 10 with aqueous alkali metal hydroxide solution, the base is extracted into dichloroethane and the extract is separated from the solvent.

Yield: 22.3 g (81.5%) of a pale yellow oil

M.p .: 174-176 ° C at 40 Pa.

The starting 2-benzylidenecyclohexathione is prepared as follows: 60 g (0.565 moles) of freshly distilled benzaldehyde and 101.5 g (0.89 moles) of cyclohexathione are reacted for 3 hours in a solution of 20 g of potassium hydroxide in 350 ml of water. , at the boiling point of the solution, the reaction mixture is cooled to room temperature and neutralized with 70 ml of 18% hydrochloric acid. The mixture is extracted three times with 50 ml of dichloroethane, the extracts are combined and the solvent is removed in vacuo. The residue is purified by fractional distillation.

Yield: 112.5 g (62.5%) of a yellow, slowly crystallizing oil

M.p .: 152-157 ° C at 53 Pa.

Example 49 2- (p-Chlorobenzylidene) -1- (3'-dimethylaminopropoxyimino) cyclohexane 17.6 g (0.08 moles) of 2- (p-chlorobenzylidene) cyclohexanone are kept for one hour at 100 ° C in 65 ml. phosphorus oxychloride, then excess phosphorus oxychloride is removed by distillation in vacuo at 50 ° C. The residue is treated at 0-10 ° C with 65 ml of anhydrous pyridine and 19.8 g (0.11 mol) of 3'-dimethylaminopropoxyamine dihydrochloride, then the mixture is kept at 50 ° C for one hour and boiled further. for an hour. The residue is dissolved in a small amount of water and basified with 2N sodium hydroxide solution. The solution is extracted with 3 x 35 ml of dichloroethane, the combined dichloroethane solutions are distilled in vacuo until the solution is removed.

Yield: 27.2 g (85%) of a yellow thick oil

Fumarate: m.p. 142-143 ° C.

Example 50 2-Benzylidene-1- [2'-methyl-3- (4 "-methylpiperazinyl) propoxyimino] cyclohexane

A solution of 20.1 g (0.1 mol) of 2-benzylidenecyclohexanone oxime in 200 ml of anhydrous toluene is added dropwise at 85 ° C, with constant stirring, to a suspension of 2.4 g (0.1 mol) of sodium hydride In 50 ml of anhydrous toluene. The reaction mixture is boiled for 2 hours, after which 18.86 g (0.11 mol) of 1-bromo-3-chloro-2-methylpropane are added and the reaction mixture is boiled for a few hours. The mixture is cooled to 80 ° C, a solution of 11 g (0.11 mol) of N-methylpiperazine in 20 ml of anhydrous toluene is added dropwise, and the reaction mixture is kept at this temperature for a further 6 hours. The toluene solution is cooled and washed with water, after which a solution of 22 g of formic acid in 220 ml of anhydrous ethanol is poured in, the mixture is cooled and the precipitated crystals are filtered off.

Yield as difumarate: 48 g (81.7%); mp. 190-191 ° C.

The product is identical to the product described in Example 40.

Example 51 1- (N-Methylpiperazininylpropoxyimino) -2-benzylidene-cyclooctane difuroarate Starting from 2.4 grams (0.1 moles) of sodium hydride, 22.9 grams (0.1 moles) of 2-benzylidenecyclooctanone oxime and 19, 5 grams (0.11 moles) of N-methylpiperazinylpropyl chloride, proceed as described in Example 4.

6561 5 ii

Yield: 33.8 g (95%)

Fumarate: m.p. 206-207 ° C.

Analysis: C31H43N3O9

Calculated: C 61.88%, H 7.20%, N 6.98% Found: C 61.33%, H 7.05%, N 6.92%.

Example 52 1- (N-Dimethylaminoethoxyimino) -2- (p-nitrobenzylidene) cyclohexane fumarate Starting from 17.7 grams (0.1 moles) of diethylaminoethoxyamine hydrochloride and 23.1 grams (0.1 moles) ) 2- (p-nitrobenzylidene) cyclohexanone, proceed as described in Example 48. Yield: 21 g (70%)

Fumarate: m.p. 148-150 ° C Analysis: C 21 H 27 N 3 O 6

Calculated: C 60.42%, H 6.52%, N 10.07% Found: C 60.57%, H 6.48%, N 9.92%

Example 53 2-Benzylidene-1- (β '- (4 "-benzylpiperazinyl) propoxyimino] -cyclopentane difumarate.

Starting from 2.4 grams (0.1 moles) of sodium hydride, 18.7 grams (0.1 moles) of 2-benzylidenecyclopentanone oxime and 27.8 grams (0.11 moles) of N-benzylpiperazinylpropyl chloride, proceed as described in Example 4.

Yield: 37.4 g (94%)

Difumarate: m.p. 210-211 ° C Analysis: C 34 H 4 N 3 O 9

Calculated: C 64.22%, H 6.50%, N 6.61% Found: C 64.12% H 6.61% N 6.60%

Claims (1)

A process for the preparation of novel oxime ethers of the general formula I which are used therapeutically for the purposes of R3 X, CH-N2 / 2 / m 2 m X4 (CH2 n C = N - Cr H R2 (I) - R1 \ = / for the preparation of salts and quaternary ammonium derivatives in which R represents a halogen atom, where x = 1, or a C 1 -C 4 alkoxy or nitro group, 1 2 1 q where x = 1, 2 or 3; R and R each represents a hydrogen atom 3 4 or together a valence bond, m is an integer from 2 to 4, R and R represent hydrogen or a C 1-4 alkyl group, or R and R together represent an alkylene chain containing 4 carbon atoms which may additionally contain oxygen as a heteroatom - or a nitrogen atom and the nitrogen atom may in addition have a C 1-6 alkyl or benzyl substituent, and n represents an integer from 3 to 10, characterized in that a) according to the general formula II «= 2> η" N 9bY Rx (II) -C - R1 H 1 2 ketone, in which the symbols R, R, R, x and n have the same meanings as above, and Y means an oxygen or sulfur atom, is reacted according to general formula III. «ΠΙ R4 with a hydroxylamine derivative in which the symbols m, R and R4 have the meanings given above, or b) the ketone of the general formula II is reacted with phosphorus oxychloride, followed by the chlorine compound of the formula IV thus obtained, 6561 5 29 z'-C ' N \ (CHJ. - Cl (IV) V n ”i JR V___s' 2 H 1 2 in which the symbols R, R, R, x and n have the same meanings as above, are reacted without isolation to give the hydroxyl compound of general formula III. with an amine derivative in which the symbols R and R have the meanings given above, or c) an oxime of the general formula V (CH3 ^ C = N - OH (V) H '1Q_C - R1 1 2, in which the symbols R, R, R, x and n is as defined above, is reacted with a haloalkylamine derivative of the general formula VI R3 ΛΗ2 .- <Γ „m) Hal1 / XR4, in which the symbols m, R34 and R have the meanings given above, and Hal represents a halogen atom, in an inert solvent and In an alkaline n in the presence of a condensing agent, or d) a compound of general formula V (CH 2 R 2 = N - OH (V), 2 ny Rx --C - R 2 - -r 1 '2, wherein R, R, R, x and n is as defined above, is reacted with a CH5-Halal »dihaloalkane of the general formula VIII, in which Hal and Hal 'denote the same or different halogen towers, and m is an integer from 1 to 3, and then the amino and, if desired, converting the resulting compound of general formula I into a therapeutically acceptable acid addition salt or quaternary ammonium derivative or, if desired, liberating the base from the compound of general formula I obtained in the form of a salt. 31 6561 5 Förfarande för framställning av terapeutiskt användbara nya oximetrar med den allmänna formuleln I R3 \ ΑΗ2πΓ * \ (I) «V» c - - o R. > ___ c- R2 H and the same salt and quaternary ammonium derivatives, in which formula R is a halogen atom, color x = 1, or C. -C.-alkoxy- or 1 2 1 4 nitro group, color x = 1, 2 or 3 ; R och R räda betecknar en väteatom eller tillsanunans en valensbindning »m är ett heltal mel-3 4 lan 2 och 4; R and R are hydrogen or C,, -alkyl groups or 3 4 1-4 R and R are alkylated with alkyl or alkyl having 4 carbon atoms, each of which is a heteroatom having the same radicals as C1-C3 alkyl or benzyl substituents can be used in combination with a quaternary form, and in the case of a mixture of 3 and 10, in which case a ketone with a base form of formula II (ch ~) "> N \: = YRKS l (II> \ - cr- r * k 1 2 color symbol R, R, R, x and the same symbol as oval, and Y are the same as in the case of a single or negative atom, which is a hydroxylamine derivative with the formula III R3 / / CmH2m- <4 (III ) - CT XR color symbol is m, R3 and R ^ are oval in the form of a mixture, or (b) a ketone in the form of phosphorus oxychloride, with the addition of chlorination in the form of form IV 32 c 65615 «Vn -i'V'1 '<ιν' Rx ^ YVc- »1 \ - ^ H 1 2 we then isolate the hydroxylamines with all the substituents 3 4 of formula III, i and then the formula of the symbols R and R har ovan angivna betydelser, ell c) en oxime with the substituents V (ch ^ T ^ c = n - oh (V) y 2 R -C - R t> 1 - 1 2 vari symbolerna R, R, R, x och n har ovan angivna betydelser, omsätts med et halogenalkylaminderivat med den almänna formuleln VI R3 CB, (VI> y »2m \ 4 Ha L · R 3 4 is a symbolic symbol m, R and R is a solid, and a halogen atom and a halogen atom, and an inert solution and a basic condenser, or d) and a mixture of the lower form V (ch ^ T c = n - OH (V) n / R V___r2 x \, Γ C - R X3-r '12 i is the formula of the symbols R, R, R, x and is an angular characteristic of the dihydroalkane with the formula VIII