CA1077964A

CA1077964A - 4'-nitro-acetophenone-o-aminoethyloximes as antidepressive compounds

Info

Publication number: CA1077964A
Application number: CA248,103A
Authority: CA
Inventors: Hendricus B.A. Welle; Volkert Claassen
Original assignee: Philips Gloeilampenfabrieken NV
Current assignee: Koninklijke Philips NV
Priority date: 1975-03-20
Filing date: 1976-03-17
Publication date: 1980-05-20
Also published as: FR2304332B1; PL100040B1; AT340894B; ES446189A1; HU171160B; PL100612B1; DD128331A5; IL49236A0; AR213298A1; AU1214276A; ATA195276A; FI760696A; GB1533063A; BE839741A; JPS51125344A; FR2304332A1; IE43826L; GR60051B; IE43826B1; PL101882B1

Abstract

ABSTRACT

The novel compounds of formula I

Description

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The invention relates to novel anti-depressive compounds.
~ ritish Patent Specification 1,205,665 discloses a large group of oxiTne ether compounds having anti-depressive activity, which compounds are derived from alkylphenyl-ketone. The compounds have in a phenyl group one or more substituents which are selected from a very large group. Each of the possible substituents may be bound in any position of the phenyl group, but according to said patent specification substitutions with nitro groups are restricted to the meta-positions.
This suggests that oxime ether compounds which are derived from alkylphenone and which have a nitro-group in a position other than a meta-position, have no anti-depressive activity. The anti-depressive activity of the known compounds is based on monoamino oxidase (MAO) inhibition and/or noradrenaline potentiation.
However, compounds which inhibit monoamino oxidase are particular-ly difficult to administer. They often have serious side effects and are often incompatible with other medicines and with some nutrients.
Since the regulations governing the use of medicines have become more srtingent, only those compounds which are substantially free from side effects can be considered for adminstration to human beings.

, . .
The present invention pro~id~s compounds having a powerful anti-depressive activity which is expressed inter alia in an elevation of mood of the treated patient but which have no component based on MA0 in hibition. The compounds in view are substantially free from side effects.
In one aspect the present invention relates to a process for the preparation of compounds of the general formula I

02N ~ C N 0 CH2 CHR3 NH2 . . I
R CH2-(Rl~n-(cH2)3-(R2)p - and the pharmaceutically acceptable acid addition salts thereof, wherein R
is hydrogen, methyl or chlorlne, Rl is oxygen or sulphur, R2 is OCH2, CH20CH2 or OC2H40CH2, R3 is hydrogen or methyl, n and p are 0 or 1 and n + p is 0 or 1, which colT,prises ~. .

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(a) reacting a corresponding compound of the general formula II
O2N ~ _ f--R4 (II) R CH2-(Rl)n-(CH2)3 ( 2)p and the pharmaceutically acceptable acid addition salts thereof, wherein R4 is an oxygen atom, an oxime group or an alkylenedioxy group, with a compound of the general formula III
H2N-0-CH2-CHR3-NH2 (III) or an acid addition salt thereof; or (b) reacting a corresponding compound of the general formula IV
=N-0-M (IV) R CH2-(Rl)n-(CH2)3-(R2)p wherein M is hydrogen or an alkali metal, with a compound of the general for~la V
Hal-CH2-CHR3-NH2 (V) or an acid addition salt thereof, wherein Hal is halogen; or ; (c) reacting a corresponding compound of the general formula VI
~ ' O2N ~ IC N 0 CH2 CHR3 R5 (VI) R CH2-(Rl)n-(CH2)3 (R2)p wherein R5 is a leaving group, with ammonia; or (d) removing the protective group R6 from a corresponding compound of the general formula VII
02N ~ C=N-O-CH2-CHR3-NHR6 (VII) R CH2-(Rl)n-(CH2)3 (R2)p wherein R6 is trityl, by hydrolysis; or (e) converting the para amino (aromatic) group in a corresponding compound of the general formula ~III

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H2N ~ f 2 H 3 NH2 (VIII) R CH2-(Rl)n-(CH2)3-(R2)p-H
or acid addition salt thereof, into a nitro group; or (f) for the preparation of compounds of formula I wherein n + p =
1, reacting a corresponding compound of the general formula IX
O2N ~ C=N-0-CH2-CHR3-NH2 (IX) : R (CH2)q-Hal and the pharmaceutically acceptable acid addition salts thereof, wherein q is 1, 4 or 5 and Hal is halogen, with a compound of the general formula X
. M'R7 (X) wherein M' is an aIkali metal and R7 is propoxy, propylthio, methoxy or :
methoxyethoxy; or ~; (g) for the preparation of compounds of formula I wherein n + p = 1, reacting a corresponding compound of general formula XI

NO2 ~ f=N--CH2-CHR3-NH2 (XI)

2 q 8 - wherein R8 is oxygen or sulphur, with a compound of the general formula XII
; Hal R7 (XII) -~ wherein ~ is methyl, propyl or methoxyethyl;
~ and where required converting any free base of formula I so produced into a pharmaceutically acceptable acid addition salt thereof.
In another aspect, the present invention relates to compounds of the general formula I
02N~ f 2 3 2 (I) CH2-(Rl)n-(CH2)3 (R2)p and their pharmaceutically acceptable acid addition salts, wherein R, Rl, R2, . R3, n and p are as defined above, when prepared by the process described above or, by an obvious chemical equivalent thereof.
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It hassurprisingly been found that the anti-depressive activity of these compounds is based for a considerable part, and in some compounds even exclusively, on serotonine potentiation, an activity which in a depressive patient results in an elevation of mood. However, most compounds show, in addition to serotonine potentiation, a very powerful noradrenaline potentiation as an anti-depressive activity component.
~ he absence of an activity based on MAO inhibition is surprising especially as the compounds proved to be substantially free from side effects, for example, stomach ulceration and broncho constriction, and have a low toxicity.
In the following table properties of the compounds according to the invention are compared with those of the closest related known compounds from British patent specification 1,205,665.

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~ I~IIIIIIIII
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o h l l l l l l l l l l l +
tn3 . :-oo ~1 U~ ~ 00 L~
C~ ,C ~ ~ _~ _I
5 ~ N N N N N N N N N N N N
~rl A A A A A A A A A A A A
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o Oo o~ a~ oo ~ ~ , t`l h ~ ~ ~ ~ ~ ~o N 00 e~ ~ t~ ~ t~
0 0~ _I _I ~I N ~ I 00 . . _ .
t_~ ~ a~ 0 ~1 1~ ~I N N O 00 ~ ~ ~ N L~
~N ~o O A A

~ ~ ~,:
Z
~ ~ C X
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~ t~ ~ N t~
O C~ xN ~ t~
~, c~ x ~ o o o ~ o a ~ O a ~ ~ ~ ~, ~ ~ U, ~ ~ ~ ~ C~ ~ ~
N~ONNNNNNON ~N
~ ~ N CN a ~ a X a a sN a ~N ~N a ~
. tn ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
. _ _ NNN
~N ~ 3 a ~ ~ z ~ ~
~ h NNNNNNNNNNN
U)~ ZO ~ ~ ~ ZO ZO ~ ~ ZO ~ ZO ~ O ~ ~
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The numbers in this table are ED50 values expressed in mg/kg.
It is remarkable that the compounds 9 and 10 neither potentiate noradrenaline nor inhibit MAO. The anti-depressive activity of these co~pounds is based entirely on serotonine potentiation.
These compounds therefore and in particular, compound 9 are to be preferred if a very specific serotonine potentiation is endeavoured.
Noradrenaline potentiation and serotonine potentiation in com-pounds 7 and 8 are of the same order of magnitude. Moreover, the ac-tivity is at a high level.
Both noradrenaline potentiation and serotonine potentiation in compound 5 are at a high level but the noradrenaline potentiation is stronger by well over a factor 4.
It appears from the table that the compounds according to the invention are substantially free from undesired side effects.
Although the known compounds 81 and B2 have a strong noradrenaline and serotonine potentiating effect, they also have a powerful MAO inhibition. In compound B3 not only both the noradrenaline potentia-, tion and the serotonine potentiation is of quite a different level, in addition the compound gives stomach ulceration. Therefore, none of the known compounds satisfy the object of the invention.
The data recorded in the table were determined by means of the following tests.
The noradrenaline potentiation was determined in the tetra- -.
benazine test. In this test a quantity of the compound to be tested was . .
administered orally to five male albino mice. After 45 minutes the animals were injected subcutaneously with 80 mg/kg of tetrabenazine. After another 45 minutes the ptosis was determined and compared with the ptosis of animals which had received tetrabenazine alone. The ED50 was determined from the results.
The serotonine potentiation was determined in the 5-hydroxytrypto-phan test. ~or this purpose the compounds to be tested were administered orally in a series of dosages to isolated male albino mice (5 mice per ., i .
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~077964 dosage) 1 hour prior to intraperitoneal administration of 150 mg/kg of dl-5-hydroxytryptopban. 30 minutes after this threshold dosage the mice were observed individually and the following parameters were scored:
stereotypical shaking of the head, spreading of the hindlegs, tremor, tendency to flee, lordosis and clonic stamping with the frontlegs. The ED50 value was calculated from the results.
The monoamino oxydase (MAO) inhibiting effect was determined in experiments in which a quantity of the compound to be tested was ad-ministered orally to fiYe male albino mice. One hour later the animals were injected subcutaneously with tryptamine hydrochloride in a quantity of 250 mg/kg. This quantity does not cause mortality in animals which did not receive the compound to be tested, but did cause mortality in animals to which an active substance had been administered. Eighteen hours after the administration of tryptamine hydrochloride it was determined how many treated animals had died. The ED50 was determined from the results.
By means of the method by Metysova, Arzneimittelforschung 13 1039 (1963) it was determined whether the oral administration of 200 mg of a compo~nd to be tested causes stomach ulceration.
By means of the method by Konzett-R~ssler, Arch. Esp. Path.
pharmakol, 195 71 (1940) it was investigated whether a compound to be tested causes bronchoconstriction after intravenous administration of

3 mg/kg. Reduction of the breathing function as a result of broncho-constriction is expressed in this method in a smaller volume of air taken in.
On the basis of their properties the compounds of formula I and their salts are particularly suitable for use in the treatment of depres-sive patients. This applies in particular to the compounds: 5-(2-meth-oxyethoxy)-4'-nitrovalerophenone 0-~2-aminoethyl)oxime, 4'-nitro-3'-methyl-valerophenone 0-(2-aminoethyl)oxime, 3'-chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminoethyl)oxime, 4'-nitrovalerophenone 0-~2-aminopropyl)oxime and 3'-chloro-4'-nitro-5-methoxyvalerophenone 0-(2-aminopropyl) oxime and their salts.

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The quantity, the frequency, and the way in which the compounds according to the invention are administered may differ for each individual patient and also in accordance with the severity of the disturbance to be treated. In general, an oral daily quantity of 25-500 mg will be chosen, as a rule 50-200 mg.
The compounds are preferably used in the form of tablets, coated tablets, capsules, pills, powders, injection liquids and the like.
They can be processed to such compositions according to methods which are known per se.
The invention also relates to compositions having a compound of formula I or a salt thereof formed with a pharmaceutically acceptable acid as an active constituent, and to methods to bring the compounds and their salts in a form suitable for administration, for example, by mixing an active substance with or dissolving it in solid or liquid pharmaceutical carrier materials.
As examples of pharmaceutically acceptable acids with which the bases of formula I can form salts may be mentioned: inorganic acids, for example hydrochloric acid, nitric acid, sulphuric acid and organic acids, for example, malic acid, citric acid, fumaric acid, maleic acid, tartaric acid, benzoic acid and the like.
The compounds of formula I and their salts can be prepared ; according to methods which are known for the preparation of this type of compounds and according to methods analogous thereto.
The invention also relates to the preparation of the compounds.
The compounds can be prepared inter alia by converting a compound of formula II with a compound of formula III or a salt thereof. In this case R4 is an oxygen atom, an oxime group or an alkylene dioxygroup, for ' example ethylenedioxy.
The reaction is preferably carried out in an inert solvent, .
for example an alcohol, dioxan, dimethyl formamide, tetrahydrofuran . . ~
or a mixture thereof, at temperatures between room temperature and the boiling point of the mixture and possibly in the presence of an acid ~ - 7 -.

10779~;4 .
binder, for example pyridine.
The compounds are also prepared by converting a compound of formula IV wherein N is a hydrogen atom or an alkali metal atom with a compound of formula v or a salt thereof wherein Hal is a halogen atom, preferably a chlorine atom or a bromine atom.
The reaction is preferably carried out in an inert solvent, for example alcohols, ethers or dimethyl formamide. When M is a hydrogen atom, an acid binder for example an alcoholate is preferably added as well. As a rule the reaction temperature is between 0 and 50C.
The compounds can also be prepared by converting a compound of formula VI wherein R5 is a leaving group, for example a mesyloxy group or a tosyloxy group, with ammonia. The reaction is preferably carried out in an inert solvent, for example an alcohol, as a rule at temperatures between room temperature and 150C.
The compounds of formula VI are prepared by converting a com-pound of formula IV in ethanol and in the presence of an alcoholate at temperatures up to 60C with ethylene oxide or propylene oxide. The reaction product is then converted with mesylchloride or tosylchloride dissolved in methylene chloride.
The compounds can also be obtained by removingthe protective group R6 by means of hydrolysis from a compound of formula VII. As a protective group may be mentioned, for example, the trityl group. The reaction is carried out, for example, in a water-miscible solvent in acid conditions at a temperature between room temperature and 100 C.
The compounds can also be obtained by converting the para amino taromatic) group in a compound of formula VIII into a nitro group.
The conversion can be carried out by a reaction with nitrous ; acid at -10 to +50C, followed by decomposition of the resulting diazonium compound in the reaction mixture at 20-75C in the presence of copper. The conversion of compounds wherein Rl does not represent sulphur may also be carried out with a peroxide, for example hydrogen peroxide or m-chloroperbenzoic acid, in an inert solvent, for example methylene iO77964 chloride or chloroform, at temperatures between room temperature and the boiling point of the mixture.
Compounds of formula I wherein n + p = 1 can furthermore be prepared by reacting a compound of formula IX with a compound of formula X. In these formulae q has the value of 1, 4 or 5, M' is an alkali metal atom and R7 is a propoxy group, a propylthio group, a methoxy group or a methoxyethoxy group. Hal is a halogen atom, preferably a chlorine atcm or a bromine atom. The reaction may be carried out, for example, in aqueous alcohol at ternperatures of 0C or possibly lower, to room tem-perature.
Compounds of formula I wherein n + p = 1 can also be obtained by reacting a compound of formula XI with a compound of formula XII. In these foxmulae q has the value 1, 4 or 5, R8 is an oxygen atom or a sulphur atom, M' is an alkali metal atom, R'7 is a methyl group, a propyl group or a methoxy ethyl group, and Hal is a halogen atom, preferably a chlorine atom or a bromine atom. The reaction may be carried out in a polar aprotic solYent, for example hexamethylphosphortriamide, at a temperature between 0C and room temperature. In all formulae the symbols not described haye the same meaning as in formula I.
The invention will be described in greater detail with refe-rence to the ensuing specific examples 1) 5-Methoxy-4'-nitrovalerophenone 0-(2-aminoethyl) oxime hydrochloride.
5.35 Mmol (1.27 g) of 5-methoxy-4'-nitrovalerophenone (melting point 64.5-65.5C), 5.35 mmol (0.80 g) of 2-aminooxyethylamine dihydrochloride and 0.34 ml of pyridine were refluxed for 2 hours in 5 ml of absolute ethanol. After evaporating the reaction mixtuxe to dryness in vacuo, 25 ml of water and 10 ml of 2N sodium hydroxide solution were added and extrac-ted with 25 and 10 ml, respectively, of methylene chloride. The extracts were dried over sodium sulphate and then evaporated to dryness in 3Q ~acuo. Toluene was added anothex two ti~es to the resulting base which was evaporated in vacuo. The residue was dissolved in absolute ethanol and an equi~olar quantity of alcoholic hydrochloric acid was added. After _ g _ 1~77964 the addition of diethyl ether, the title compound crystallized. Melting point 121.5-122.5C.
2) 6-Methoxy-4'-nitrohexanophenone 0-(2-aminoethyl)oxime hydrochloride.
135 Mmol (33.7g) of 6-methoxy-4'-nitrohexanophenone (melting point 50C), 135 mmol (20.1g) of 2-aminooxyethylamine dihydrochloride and 100 ml of pyri-dine were refluxed for 5 hours in 300 ml of absolute ethanol. The reaction mixture was evaporated to dryness in vacuo and the residue, after having been dissolved in 200 ml of water, was washed twice with lOOml of petroleum ether 40-60. The aqueous solution was rendered alkaline Wit}l 200 ml of 2N sodium hydroxide solution and then extracted four times with 100 ml of ether. The combined ether extracts were washed with 100 ml of waterJ dried on sodium sulphate and then evaporated to dryness in vacuo. The resulting oil, after the addition of toluene, was evaporated to dryness in vacuo another three times and then dissolved in absolute ethanol. After the addition of an equiv-alent quantity of alcoholic hydrochloric acid it was evaporated to dryness in vacuo again. The residue was crystallized from alcohol/ether. The resulting `; crystals were recrystallized twice from acetonitrile and alcohol/ether, respectively. Meltlng point 92-93C.
3) 3'-Methyl-4'-nitrovalerophenone 0-(2-aminoethyl)oxime fumarate (1 : 1).
20 5.7 Mmol of 3'-methyl-4'-nitrovalerophenone, 5.7 mmol of 2-aminooxyethylamine dihydrochloride and 0.9 ml of pyridine were refluxed for three hours in 15 ml of absolute ethanol. The base was isolated from the reaction mixture as de-scribed in example 2. It was dissolved in an equimolar quantity of ethanolic -fumaric acid. Melting point after recrystallization from ethanol 152.5-154 O

4) 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminoethyl)oxime fumarate .' (1: 1).
In the same manner as described in example 3, the title compound was obtained from 3'-chloro-5-methoxy-4'-nitrovalerophenone (melting point 54.5-56C) and 2-aminooxyethylamine dihydrochloride. After crystallization from ethanol the melting point was 148-148.5C.

5) 4'-Nitrovalerophenone-0-(2-aminopropyl)oxime hydrochloride.

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In the same manner as described in Example 2 the title compound was obtained from 4'-nitrovalerophenone (boiling point at 0.03 mm: 128-132C) and 2-aminooxy-l-methylethylamine dihydrochloride. The melting point after recrys-tallization from acetonitrile/ether was 148-149C.

6) 4'-Nitro-2-propoxyacetophenone 0-(2-aminopropyl)oxime fumarate ~1 : 1).
In the same manner as described in Example 3 the title compound was obtained from 4'-nitro-2-propoxyacetophenone (melting point 49-50C) and 2-aminooxy-1-methylethylamine dihydrochloride. The melting point after recrystallization from ethanol was 141-142 C.

7) 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminopropyl)oxime fumarate (1: 1).
In the same manner as described in Example 3 the title compound was obtained from 3'-chloro-5-methoxy-4'-nitrovalerophenone (melting point 54.5-56C) and 2-aminooxy-1-methylethylamine dihydrochloride. After crystallization from ethanol/acetonitrile the melting point was 140-142C.

8) 4'-Nitrovalerophenone 0-(2-aminoethyl)oxime hydrochloride.
10 Mmol of 4'-nitrovalerophenone 0-(2-tritylaminoethyl)oxime were dissolved in 50 ml of 90% acetic acid. After standing for three days at room tempera-ture, this reaction mixture was evaporated to dryness in vacuo after which the residue was dissolved in 50 ml of ether. The resulting solution was ex-tracted with 50 ml of 0.2N hydrochloric acid and the extract, after being rendered alkaline with 10 ml of 2N sodium hydroxide solution, was extracted with 50 and 25 ml, respectively, of methylene chloride. After drying on sodi-um sulphate and evaporating in vacuo the resulting base was converted into the title compound with alcoholic hydrochloric acid. After crystallization and recrystallization from ethanol/ether the melting point was 107-108 C.

9) 4'-Nitro-2-propoxyacetophenone 0-(2-aminoethyl)oxime hydrochloride.

10 Mmol of 4'-nitro-2-propoxyac0tophenone oxime, 10.4 mmol of 2-chloroethyl amine hydrochloride and 1.4 g of powdered potassium hydroxide were added to 25 ml of dimethyl formamide while stirring at 10C. Afte-r stirring for two days at room temperature the dimethyl formamide was evaporated in vacuo, the residue was brought in water and then 2N hydrochloric acid was added until

- 11 -.

1~77964 pH 3. The remaining oxime was removed by means of ether, after which 30 ml of 2N sodium hydroxide solution were added. Then three extractions with ether were carried out. The collected ether layers were washed twice with a 5% sodium bicarbonate solution and then dried on sodium sulphate. After removing the ether in vacuo the residue was dissolved in absolute ethanol and -- converted into the title compound by means of alcoholic hydrochloric acid.
After recrystallization from alcohol/ether the melting point was 128-130C.
10) 4'-Nitro-2-propoxyacetophenone 0-~2-aminoethyl)oxime hydrochloride.
a) 2.3 g of ethylene oxide were led into 30 mmol of 4'-nitro-2-propoxyace-10tophenone oxime in 50 ml of absolute ethanol in which 0.007 g of lithium had been previously dissolved while stirring and at 45C by means of a flow of nitrogen, after which stirring at 60C was continued for another hour. After the addition of 0.6 ml of acetic acid it was evaporated to dryness in vacuo.
The residue was taken up in ether and washed with water. After drying on sodium sulphate and evaporating the ether a residue was obtained which was purified by means of a silica gel column using methylene chloride as an eluent. After evaporation of the solvent the 0-(2-hydroxyethyl)oxime was obtained as an oil.
b) To a solution of 22 mmol hereof in 120 ml of methylene chloride 4.5 ml of triethylamine were added while stirring at -5 to -10C, and then 24 mmol ~1.9 iml) of mesyl-chloride were added dropwise in 20 minutes. Stirring was con-tinued for another 30 minutes at 0C and the reaction mixture was then washed with water, as sodium bicarbonate solution and a saturated sodium chloride solution. After drying on sodium sulphate the methylene chloride was evapo-rated in vacuo. In this manner the 0-(2-mesyloxyethyl)oxime was obtained.
c) A mixture of 26 mmol thereof in 100 ml of methanol which contained 12 g of ammonia was kept in an autoclave at 80C for 16 hours. After cooling, the methanol was removed in vacuo. The residue was stirred with 50 ml of 2N sodi-um hydroxide solution and extracted ~ times with ether. The ether layer was washed twice with a 5% sodium bicarbonate solution. After drying on sodium ;sulphate and distilling off the other under reduced pressure the resulting oil was converted into the title compound by means of alcoholic hydrochloric ; - 12 -..
acid. After two crystallizations from alcohol/ether the melting point was 128-130C.

11) 5-(2-Methoxyethoxy)-4'-nitrovalerophenone 0-(2-aminoethyl)oxime fumarate -(1: 1).
10 M~lol (3.25 g) of 5-(2-methoxyethoxy)-4'-nitrovalerophenone ethylene ketal, 10 mmol ~1.49 g) of 2-aminooxyethylamine dihydrochloride and lO ml of meth-anol were refluxed for 6 hours. The resulting residue, after evaporating the methanol, was washed three times with ether after having been dissolved in water. The aqueous solution was extracted three times with methylene chlo-ride after previously being rendered alkaline with a sodium hydroxide solu-tion. The combined extracts were washed with a 5% sodium bicarbonate solu-tion and then with water. After drying on sodium sulphate and evaporating the methylene chloride, the free base was obtained, which was converted into ': the title compound by means of an equimolar quantity of fumaric acid. After crystallization from alcohol the melting point was 134.5-135.5 C.

12) 4'-Nitrovalerophenone 0-(2-aminoethyl)oxime hydrochloride.
4 Mmol (1.23 g) of 4'-aminovalerophenone 0-(2-aminoethyl)oxime dihydrochlo-ride (melting point 175-177C) were converted into the free base by means of 1 2N sodium hydroxide solution. A solution hereof in 5 ml of methylene chlo-ride was added dropwise while stirring at 25 to 40C to 12.3 mmol ~2.5 g) of m-chloroperbenzoic acid (85%) in lO ml of methylene chloride. Stirring at 30 to 35C was then continued for another three hours. The precipitate was sucked off and washed with methylene chloride. After the addition of 50 ml of ether to the filtrate and the washing liquid, the mixture was washed three times with 2N sodium hydroxide solution and finally twice with a 5% sodium bicarbonate solution. After drying on sodium sulphate and removing the ether under reduced pressure, the residue was chromatographed over silical gel with methylene chloride as an eluent. The methylene chloride was distilled off from the eluate, after which the residue was converted into the title com-; 30 pound by means of alcoholic hydrochloride acid. After crystallization from alcohol/ether the melting point was 107-108C.

13) 4'-Nitro-2-propylthioacetophenone 0-(2-aminoethyl)oxime hydrochloride.

6 Mmol (0.54 g) of propylmercaptan were added while stirring to a solution of 6 mmol (0.24 g) of sodium hydroxide in 10 ml of 50% alcohol cooled with ice-water. Stirring was continued for another 10 minutes after which 3 mmol (1.02 g) of 2-bromo-4'-nitroacetophenone 0-(2-aminoethyl)oxime hydrochloride (melting point 197C) were added within 30 minutes while stirring at a tem-perature between 0 and 5C. Stirring was continued for another hour at 5C
and then one hour at room temperature. The reaction mixture was evaporated in vacuo and the residue was washed with water and dissolved in methylene chloride. The solution was washed with water and dried over sodium sulphate.
After evaporation, a base was obtained which was converted into the title compound by means of alcoholic hydrochloric acid. After recrystallization from acetonitrile/ether the melting point was 122.5-123.5C.

14) 4'-Nitro-2-propoxyacetophenone 0-(2-aminoethyl)oxime hydrochloride.
0.09 g of 55-60% sodium hydride in mineral oil was added to a solution of 2.0 mmol (0.48 g) of 2-hydroxy-4'-nitroacetophenone 0-(2-aminoethyl)oxime (melt-ing point 97-98C) in 5 ml of hexamethyl phosphoric acid triamide while stir-ring at room temperature. After 4 minutes, 0.20 ml of propyl bromide was added while stirring. The reaction mixture was then stirred at room tempera-ture for another 4 hours, diluted with 50 ml of water and extracted two times with 25 ml of ether. The combined ether extracts were dried on sodium sul-phate and evaporated to dryness in vacuo. The residue was chromatographed by means of ethanol/ammonia 95/5 over 15 g of silica gel. The eluate was evap-orated to dryness in vacuo and then converted into the title compound by means of alcoholic hydrochloric acid. After crystallization from alcohol/
ether the melting point was 128-130C.

15) Tablet 50 mg of 4'-nitro-3'-methylvalerophenone 0-(2-aminoethyl)oxime HCl 335 mg of lactose 60 mg of potato starch 25 mg of talc 5 mg of magnesium stearate 5 mg of gelatin.

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1~7796~

16) Suppository 50 mg of 4'-nitrovalerophenone 0-(2-aminopropyl)oxime HCl 1500 mg of suppository mass.

17) Injection liquid 25 g of 3'-chloro-4'-nitro-5-methoxyvalerophenone 0-(2-aminopropyl)oxime HCl 1.80 g of methyl-p-hydroxybenzoate 0.20 g of propyl-p-hydroxybenzoate 9.0 g of sodium chloride : 4.0 g of poly-~oxyethylene)20 sorbitan monooleate water to 1000 ml.

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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of compounds of the general formula I

(I) and the pharmaceutically acceptable acid addition salts thereof, wherein R
is hydrogen, methyl or chlorine, R1 is oxygen or sulphur, R2 is OCH2, CH20CH2 or OC2H40CH2, R3 is hydrogen or methyl, n and p are 0 or 1 and n + p is 0 or 1, which comprises (a) reacting a corresponding compound of the general formula II

(II) and the pharmaceutically acceptable acid addition salts thereof, wherein R4 is an oxygen atom, an oxime group or an alkylenedioxy group, with a compound of the general formula III
H2N-0-CH2-CHR3-NH (III) or an acid addition salt thereof; or (b) reacting a corresponding compound of the general formula IV

(IV) wherein M is hydrogen or an alkali metal, with a compound of the general formula V

Hal-CH2-CHR3-NH2 (V) or an acid addition salt thereof, wherein Hal is halogen; or (c) reacting a corresponding compound of the general formula VI

(VI) wherein R5 is a leaving group, with ammonia; or (d) removing the protective group R6 from a corresponding compound of the general formula VII

(VII) wherein R6 is trityl, by hydrolysis; or (e) converting the para amino (aromatic) group in a corresponding compound of the general formula VIII

(VIII) or acid addition salt thereof, into a nitro group; or (f) for the preparation of compounds of formula I wherein n + p =

1, reacting a corresponding compound of the general formula IX

(IX) and the pharmaceutically acceptable acid addition salts thereof, wherein q is 1, 4 or 5 and Hal is halogen, with a compound of the general formula X

M'R7 (X) wherein M' is an alkali metal and R7 is propoxy, propylthio, methoxy or methoxyethoxy; or (g) for the preparation of compounds of formula I wherein n + p = 1 reacting a corresponding compound of general formula XI

(XI) wherein R8 is oxygen or sulphur, with a compound of the general formula XII

(XII) wherein R? is methyl, propyl or methoxyethyl;
and where required converting any free base of formula I so produced into a pharmaceutically acceptable acid addition salt thereof.

2. Compounds of the general formula I

(I) and their pharmaceutically acceptable acid addition salts, wherein R, R1, R2, R3, n and p are as defined in claim 1, when prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

3. A process according to claim 1, wherein reaction (d) or (e) is employed and in the starting materials R is hydrogen, R3 is hydrogen, n is O and p is 0.

4. A process according to claim 1, wherein reaction (f) is employed and in the starting materials R is hydrogen, R3 is hydrogen, R7 is propyl-thio and q is 1.

5. A process according to claim 1, wherein reaction (b) or (c) is employed and in the starting materials R is hydrogen, R1 is oxygen, R3 is hydrogen, n is 1 and p is 0; or wherein reaction (g) is employed and in the starting materials R is hydrogen, R3 is hydrogen, R7 is propyl, R8 is oxygen and q is 1.

6. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is hydrogen, R2 is OCH2, R3 is hydrogen, n is O and p is 1.

7. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is hydrogen, R2 is OC2H40CH2, R3 is hydrogen n is O and p is 1.

8. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is hydrogen, R2 is CH2 OCH2, R3 is hydrogen n is o and p is 1.

9. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is methyl, R3 is hydrogen, n is O and p is Q.

10. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is chlorine, R2 is OCH2, R3 is hydrogen, n is 0 and p is 1.

11. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is hydrogen, R3 is methyl, n is 0 and p is 0.

12. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is hydrogen, R1 is oxygen, R3 is methyl, n is 1 and p is 0.

13. A process according to claim 1, wherein reaction (a) is employed and in the starting materials R is chlorine, R2 is OCH2, R3 is methyl, n is 0 and p is 1.

14. A process for the preparation of 4'-nitrobalerophenone-0-(2-aminoethyl) oxime and its hydrochloride, which comprises removing the pro-tective trityl group from 4'-nitrovalerophenone O-(2-tritylaminoethyl) oxime by hydrolysis with aqueous acetic acid, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

15. A process for the preparation of 4'-nitrovalerophenone 0-(2-amino-ethyl) oxime and its hydrochloride, which comprises coverting the para amino (aromatic) group in 4'-aminovalerophenone 0-(2-aminoethyl) oxime dihydro-chloride into a nitro group by reaction with m-chloroperbenzoic acid in methylene chloride, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

16. 4'-Nitrovalerophenone 0-(2-aminoethyl) oxime and its hydrochloride when prepared by the process of claim 14 or 15, or by an obvious chemical equivalent thereof.

17. A process for the preparation of 4'-nitro-2-propylthioacetophenone 0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 2-bromo-4'-nitroacetophenone 0-(2-aminoethyl) oxime hydrochloride with propylmercaptan, and where required converting the free amine so formed into its hydrochoride by reaction with hydrochloric acid.

18. 4'-Nitro-2-propylthioacetophenone 0-(2-aminoethyl) oxime and its hydrochloride when prepared by the process of claim 17, or by an obvious chemical equivalent thereof.

19. A process for the preparation of 4'-nitro-2-propoxyacetophenone 0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 4'-nitro-2-propoxyacetophenone oxime with 2-chloroethyl amine hydrochloride, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

20. A process for the preparation of 4'-nitro-2-propoxyacetophenone 0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 4'-nitro-2-propoxyacetophenone 0-(2-mesyloxyethyl) oxime with ammonia, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

21. A process for the preparation of 4'-nitro-2-propoxyacetophenone 0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 2-hydroxy-4'-nitroacetophenone 0-(2-aminoethyl) oxime with sodium hydride and then propyl bromide, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

22. 4'-Nitro-2-propoxyacetophenone 0-(2-aminoethyl) oxime and its hydrochloride when prepared by the process of claims 19, 20 or 21, or by an obvious chemical equivalent thereof.

23. A process for the preparation of 5-methoxy-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 5-methoxy-4'-nitrovalerophenone with 2-aminooxyethylamine dihydrochloride, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

24. 5-Methoxy-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its hydrochloride when prepared by the process of claim 23, or by an obvious chemical equivalent thereof.

25. A process for the preparation of 5-(2-methoxyethoxy)-4'-nitro-valerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1), which comprises reacting 5-(2-methoxyethoxy)-4'-nitrovalerophenone ethylene ketal with 2-aminooxyethylamine dihydrochloride, and where required converting the free amine so formed into its fumarate (1:1) by reaction with fumaric acid.

26. 5-(2-Methoxyethoxy)-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1) when prepared by the process of claim 25, or by an obvious chemical equivalent thereof.

27. A process for the preparation of 6-methoxy-4'-nitrohexanophenone 0-(2-aminoethyl) oxime and its hydrochloride, which comprises reacting 6-methoxy-4'-nitrohexanophenone with 2-aminooxyethylamine dihydrochloride, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

28. 6-Methoxy-4'-nitrohexanophenone 0-(2-aminoethyl) oxime and its hydrochloride when prepared by the process of claim 27, or by an obvious chemical equivalent thereof.

29. A process for the preparation of 3'-methyl-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1) which comprises reacting 3'-methyl-4'-nitrovalerophenone with 2-aminooxyethylamine dihydrochloride, and where required converting the free amine so formed into its fumarate (1:1) by reaction with fumaric acid.

30. 3'-Methyl-4'-nitrovalerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1) when prepared by the process of claim 29, or by an obvious chemical equivalent thereof.

31. A process for the preparation of 3'-chloro-5-methoxy-4'-nitro-valerophenone 0-(2-aminoethyl) oxime and its fumarate (1:1), which comprises reacting 3'-chloro-5-methoxy-4'-nitrovalerophenone with 2-aminooxyethylamine dihydrochloride, and where required converting the free amine so formed into its fumarate (1:1) by reaction with fumaric acid.

32. 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminoethyl)oxime and its fumarate (1:1) when prepared by the process of claim 31, or by an obvious chemical equivalent thereof.

33. A process for the preparation of 4'-nitrovalerophenone 0-(2-aminopropyl) oxime and its hydrochloride, which comprises reacting 4'-nitrovalerophenone with 2-aminooxy-1-methylethylamine dihydrochloride, and where required converting the free amine so formed into its hydrochloride by reaction with hydrochloric acid.

34. 4'-Nitrovalerophenone 0-(2-aminopropyl) oxime and its hydrochloride when prepared by the process of claim 33, or by an obvious chemical equi-valent thereof.

35. A process for the preparation of 4'-nitro-2-propoxyacetophenone 0-(2-aminopropyl) oxime and its fumarate (1:1), which comprises reacting 4'-nitro-2-propoxyacetophenone with 2-aminooxy-1-methylethylamine, and where required converting the free amine so formed into its fumarate (1:1) by reaction with fumaric acid.

36. 4'-Nitro-2-propoxyacetophenone 0-(2-aminopropyl) oxime and its fumarate (1:1) when prepared by the process of claim 35, or by an obvious chemical equivalent thereof.

37. A process for the preparation of 3'-chloro-5-methoxy-4'-nitro-valerophenone 0-(2-aminopropyl) oxime and its fumarate (1:1), which comprises reacting 3'-chloro-5-methoxy-4'-nitrovalerophenone with 2-aminooxy-1-methylethylamine dihydrochloride and where required converting the free amine so formed into its fumarate (1:1) by reaction with fumaric acid.

38. 3'-Chloro-5-methoxy-4'-nitrovalerophenone 0-(2-aminopropyl) oxime and its fumarate (1:1) when prepared by the process of claim 37, or by an obvious chemical equivalent thereof.