DE2318960A1 - N-SUBSTITUTED AMIDOXIME-O-CARBAMATE - Google Patents

Description

Cologne, April 12, 1973 AvK / Ax

EI du Pont de Nemours and Company , Wilmington, Delaware 19898 (USA).

N-substituted amidoxime O-carbamates

The invention relates to new N-alkylamidoxime Q-carbamates, which are valuable as antihypertensive agents.

• Amidoxime O-carbamate compounds have been known since the work of Tiemann and Krüger (Ber. 17 1685 »1884). The authors mistakenly referred to the compounds mentioned in their article as oximes of Ureideü. R. Buyle, F. Eloy and R. Lanaers (HeIv. Chim. Act. 46, 1073 j 1963) later showed after _r that the reaction of Tiemann and Krüger leads to carbamate of amidoximes, and reported on a number of such compounds, the made by them. These known compounds are not known as antihypertensive agents and differ in structure from the class of N-alkylamidoxime-O-carbamates according to the invention.

Bell and coworkers (Experientia, 23, 298, 1967) and Hoppe and coworkers (Fed. Proc. 26, 459, 1967) reported that certain indole acetamide oximes have antihypertensive activity in rats and dogs. The N-alkylamidoxime-O-carbamates according to the invention differ

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in structure also of these known compounds and are easier and cheaper to manufacture.

Applicant's U.S. Patent Application No. 150901 dated. 8.6.1971 describes a class of antihypertensive Amidoxime O ~ carbamates of the formula (D.

0 p1 II N-O-C-N

in which R is an aliphatic hydrocarbon residue with

12 is 3 to 12 carbon atoms and R and R each for one

A hydrogen atom or a lower alkyl radical with 1 to 3 carbon atoms is available with the proviso that the sum of the carbon atoms in R * and R is not higher than 3.

A large number of compounds with antihypertensive effects are known, but many of these " Compounds unwanted side effects. Examples are:

a) Mecamylamine and other ganglion blockers cause dry mouth, pupil dilation and posture retention.

20 conditional hypotension.

b) Produce reserpine and other catechinarain depleters Lethargy, nasal congestion, and mental depression. . ; . "

, c) Call pargyline and other monoamine oxidase inhibitors Liver and eye damage, postural hypotension, and toxic food interactions emerged.

d) Phenoxybenzamine and other α-adrenergic blocking agents produce orthostatic hypotension.

e) guanethidine and other adrenergic neuron blockers and catecholamine depleters produce sexual ones

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Impotence and other undesirable effects.

Some compounds are effective in certain people, but ineffective for others. Some are expensive to manufacture and therefore cannot be used on a large scale f? will. There is still a need for more effective and cheaper antihypertensive drugs and for agents that have no or no undesirable side effects.

The invention relates to a class of new chemical compounds which are useful as antihypertensive agents are. These compounds have the general formula (2)

■ oil T} 2 j

T ■? f

R _ CU-O- C -

Here the individual terms have the following meanings:

R is a saturated aliphatic or alicyclic one Hydrocarbon radical with 3 to 12 carbon atoms;

E is an alkyl radical with 1 to 6 carbon atoms;

E. Is a hydrogen atom or an alkyl radical with 1 to

20 6 carbon atoms;

12th
R and R can together with a polymethylene radical

Form 4 or 5 carbon atoms and

R- ^ and R stand independently for hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms with the proviso that the sum of the carbon atoms in Br and R is not higher than 3.

In addition to the free N-alkylamidoxime O-carbamates, the Invention also their salts with pharmaceutically acceptable acids.

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The compounds according to the invention are named after "Introduction to Subject Index", Chem. Abstracts, 56 , 1962. The name consists of a stem that is derived from the name of the corresponding acid (eg "" acetic acid "from acetic acid," hexano "from hexanoic acid) and the suffix" -amidoxime ". The stem includes the C atom to which the oxime group is attached

1 2
is »The substituents H and R are marked

"N-" ahead.

In the context of the invention, N-alkylamidoxime-Q-carb-. amate preferred in which R is an alkyl radical with 3 to 6

C atoms, R a methyl radical or ethyl radical, Ir

2 4

Methyl radical and each radical R and R a hydrogen radical is. These preferred compounds have the greatest antihypertensive activity. To the special preferred carbamates include N-methylheptanamidoxime-O- (methylearbamate) and N-methylheptane amide oxime O-carbamate.

Addition salts of the N-alkylamidoxime-O-carbamates according to Invention with pharmaceutically acceptable organic and inorganic acids can also be effective Antihypertensive drugs are used. Suitable pharmaceutically acceptable acids are, for example, hydrochloric acid, Phosphoric acid, acetic acid, propionic acid, succinic acid, maleic acid, lactic acid, tartaric acid, 4,4'-methylenebis (3-hydroxy-2-naphthoic acid) (pamoic acid), adipic acid, cyclohexylsulfamic acid, p-toluenesulfonic acid, Methanesulfonic acid and sulfuric acid «, The salts can be obtained by neutralizing a solution of the N-alkylamidoxime-0-carbamate prepared in a suitable non-aqueous solvent with the desired acid will. Preferably solvents are used which have a good solubility for the free carbamate, however don't have for the salt. The salt is thus precipitated and can be isolated by filtration.

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The new N-alkylamidoxime-O-carbamates according to the invention are expediently by reacting corresponding hydroxamyl chlorides with amines to give the corresponding N-alkylamidoximes and reacting the latter isocyanate or carbamoyl halide. This reaction sequence is illustrated by the following reaction scheme:

> NOH XfI

HNR ¹ R

ψ 0

RC = NOS-NHR ⁵

R ⁵ R ⁴ NCOCl (base)

ν 0

I II χ 4 R-C = N-O-C-NR ^ R *

Another synthesis described by Takacs and Harsangi (Ber. 103 , 2530-2335, 19? 0) is limited to the preparation of N-monosubstituted amidoximes.

■ Production of export materials

All for making the new connections according to Amines, aldoximes, isocyanates and carbamoyl halides required for the invention are commercially available or can be made from readily available materials by known methods.

The hydroxamyl chlorides used as starting materials can, for example, by chlorination of aldoximes by the process described by Piloty and coworkers (Ber. J5 £, 31o1, 1902) and by M. H. Benn (Can. Jr. Chem. 42, 2393, 1964) will.

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Alkane hydroxamyl chlorides

A representative preparation of an alkane hydroxamyl chloride is described below.

Heptane hydroxamyl chloride '

+ Cl ₂ - > GE _Z

A solution of 29.2 g of n-heptaldoxime in 300 ml of chloroform was rapidly cooled to ^{0 ° C.} The cooled solution was chlorinated for 1 hour and concentrated under reduced pressure. The oil obtained was dissolved in ether, filtered and concentrated. This gave 35 g of the acid chloride as a crude oil.

When using the in column 1 of the following table I mentioned aldoximes instead of the above-mentioned n-heptaldoxime the hydroxamyl chlorides mentioned in column 2 of this table are obtained.

Table I.

1. AusKanprsmat er i al butanaldoxime pentanaldoxime hexanaldoxime octanaldoxime nonanaldoxine decanaldoxime

Tridecanal aldoxime 3-methylbutanal aldoxime 2'-Methy Ip ent an aldoxime 4-methylhexanaldoxime Cyclohexylaldoxime

2. Product

Butane hydroxamyl chloride Pentane hydroxamyl chloride Hexane hydroxamyl chloride octane hydroxamyl chloride Nonane hydroxamyl chloride decane hydroxamyl chloride tridecane hydroxamyl chloride 3-methylbutane hydroxamyl chloride 2-methylpontane hydroxamyl chloride 4-methylhexane hydroxamyl chloride CyclohexyIcarbhydroxamylchlorid

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Amidoximes

The reaction 1, which gives an amidoxime, is preferably carried out in an aprotic solvent at a temperature from about ⁰ ° C. to the reflux temperature of the solvent. Examples of suitable solvents are benzene, chloroform, dimethyl sulfoxide, tetrahydrofuran and diethyl ether. It is useful if a proton acceptor is present in the reaction medium in a stoichiometric amount in order to neutralize the hydrochloric acid released in this reaction. For example, an excess of the amine HNR R or any suitable tertiary amines, for example pyridine, triethylamine, tributylamine and IT, 2i-dimethylaniline, can be used as proton acceptors. Also suitable as proton acceptors are basic anion exchange resins, alkali carbonates, alkali hydroxides, etc. A representative preparation is described below.

N-methyl heptane amide oxime

> Ji-OH NHGH,

20 σΗ, (0Η _ο ) _ς -σ "+ ΟΗ, ΗΗρ— ^ CH, (CHp) CG ^

A solution of 17.5 g of heptane hydroxamyl chloride in 100 ml of ether was added dropwise with stirring to 150 ml of methylamine given. The volatile material was removed by boiling. The residue was extracted with ether and the ether evaporated. By recrystallizing the residue from ether-petroleum ether 5 »2 g of H-methylheptanamidoxim.vom Melting point 82 to 85 ° C obtained.

The process described above is also applicable to the preparation of other alkane amido oximes. For example are obtained by reacting the hydroxamyl chlorides mentioned in column 1 of the following table II with the in Corresponding amines mentioned in column 2 received the amidoximes mentioned in column.

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• Table II.

1 · Tested in hydroxamyl chloride butane hydroxamyl chloride pentane hydroxamyl chloride 3 methyl butane hydroxamyl chloride kexane hydroxamyl chloride butane hydroxamyl chloride 2-methylpentane hydroxamyl chloride

4-methylhexane hydroxamyl chloride Octane hydroxamyl chloride nonane hydroxamyl chloride Decane hydroxamyl chloride Tridecane hydroxamyl chloride Butane hydroxyl chloride Pentane hydroxamyl chloride hexane hydroxamyl chloride Octane hydroxamyl chloride pent anhydroxy ayl chloride Hexane hydroxamyl chloride, heptane hydroxamyl chloride Cyclohexylcarbhydroxamyl chloride

2. Anin

Dimethylamia

Ethyl atain

Dipropy ^ amine

Propylamine

Pyrrolidine

Piperidine

Butylamine

Hexylamine

Methylethylamine

Diethylamine

Methylamine

Methylamine

Methylamine

Methylamine

Methylamine

Dimethylamine

Dimethylamine

Dimethylamine

Methylamine

$. Amidoxime formed

1Y _? N-dimethylbutanamidoxime ii-ethylpentanamidoxime

N, N-Dipropy 1-3-möthy Ibut anamidoxim N-Propyl-hexanamidoxim

Ή _} NT et r ame thy I enbut anamidoxim K, F-Pentamethylene-2-methyl ~ pent anamidoxim

N-butyl- ^ methylhexanamidoxime, N-hexyloetanamidoxime
N-ethyl-N-methylnohamiüoxim N, N-diethyldecanamidoxim N-Methyltridecanamidoxim Ef-Methy! Butanamidoxim
N-Methylpentanamidoxime K-Methylhexanamidoxime
N-methyl octane amidoxime. · N, N-Dimethylpentanamidoxime N, H-Dimethylhexanamidoxime H, N-Dimethylheptanamidoxime N-Methylcyclohexylcarbamidoxime

N5 CO

-Λ OO CO (T) O

When Ir "and R both represent hydrogen atoms, will the corresponding carbamates by reacting corresponding amidoxime hydrochlorides with alkali metal cyanates produced in aqueous solution / It is also possible to prepare the free amidoximes with isocyanic acid, which is obtained by pyrolysis of cyanuric acid. It is most convenient to form gaseous isocyanic acid in situ and convert it into a solution of the amidoxime in one introduce inert solvents such as benzene or toluene.

^ O The making of the new connections is made by the The following examples are illustrated in which all parts, proportions and percentages are based on weight unless otherwise stated.

example 1

H-methylheptane amide oxime-Oj-carbamate , NHCH, O

. (Formula 2: R = hexyl; R ¹ = methyl; R ² «R ⁵ = R ⁴ » H)

20 "Jg (0.005 mol) of H-methylheptanamide oxime hydrochloride,

prepared by dissolving the amidoxime in ether and adding hydrogen chloride, was quickly cooled in an ice bath. A solution of 1 g (0.01 mol) of potassium cyanate in 10 ml of water was then added dropwise. The reaction mixture was stirred for 30 minutes and filtered. The solid obtained was recrystallized from benzene-cyclohexane. 0.7 g (70 %) of H-methylheptanamide oxime O-carbamate with a melting point of 91 to 92 ^° C. were obtained.

"V-

.-. This implementation takes about 15 minutes to 3 hours. at around 5o ^o

₃ : · .55 G
CM" 9 2 H 31 8960 Elemental analysis: ■ 54 , 98 9 »06 Calculated for CqH ^ q $ zO, »10 · , 10 ' Found:

When using the one mentioned in Column 1 of Table III Amidoxime in this experiment, this is shown in column 2 given corresponding amidoxime-0-earbamate.

Table III

1. Starting material ET-methylbutane amide oxime

M ", II-Whore thylpentane amide oxime

Ν, ϊϊ-tetramethylene butane ■ amidoxime

Ν, ϊϊ-diethyldecanamidoxime N-methyltridecanamide oxime

N-methylcyclohexylcarboxamidoxime

2. Product. . ■

N-methyl butane amide oxime 0-carbamate

F, N-Dimethy Ip ent anamidoxini-O ~ carbamate

N, N-tetramethylene butane amide oxime 0-carbamate

NVN-diethyldecanamido.xime-ocarbamate

IT-Methyltridecanaiiiidoxini-O-carbamate

If-methylcyclohexylcarboxamidoxime ~ 0-carb amat

.The reaction 2 between an amidoxime and an isocyanate, for example, in an aprotic solvent such a hydrocarbon or ether, preferably, for example, carried out at moderate temperatures between about 0 and 50 ⁰ C. This reaction can optionally be catalyzed by tertiary "amines, certain organotin compounds or other catalysts commonly used for the production of uretanes. The isocyanate is preferably gradually added to the amidoxime with good stirring.

Example 2

N-methylheptanamidoxime-O- (methylcarbamate)

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ο ■

"NC- NHCH, (Formula 2: R« hexyl; R ¹ = R ⁵ - methyl; R ² = R ⁴ = H)

A solution of 1.7 g (0.03 mol) of methyl isocyanate in 20 ml of benzene was added dropwise to a solution of 4.7 6 (0.03 mol) of N-methylheptanamide oxime in 50 ml of ether. The reaction mixture was stirred for 1 hour, concentrated and filtered. Here, a white solid was obtained which after recrystallization from ether-petroleum ether 0.6 g (10%) N-Methyl-heptanamidoxim-0- (methylcarbamate) gave a melting point of 39-40 ⁰ C.

Elemental analysis: Calculated for Ο ^^ Ηρ ^ Ν, Ορί 15 Found:

When using the one mentioned in column 1 of Table IV Amidoxime and the isocyanate mentioned in column 2 in the experiment described above is that in column 3 mentioned N-alkylalkanamidoxime-O-ialkylcarbamat) obtain.

0 H N 55.78 9.8 19.52 55, ^ 2 9.95 19.76

3 0 9 * l, ^r > I 1 1 7 3

Table IT

1. Amidoxime used
IT-methylbutane amidoxime
N-methylpentanamide oxime
IT-methylhexane amidoxime
N-methyloetanamide oxime
H, N-dimethylbutane amide oxime
IT, N-dimethylpentane amidoxime IT, N-dim ethylhexane amidoxime
IT, N-Dimethy! Heptane amidoxime N-Ethylpentanamidoxim

IT, N ~ dipropyl-3-niethylbutane

amidoxime

N-propylhexanamide oxime

N, N-tetramethylene butane amide oxime

I ¹ T, N-pentamethylene-2-methylpentanamide oxime
IT-Butyl-4-Met hy lhexan amidoxime
N-HexyIo et anami doxim

IT-ethyl-N-methylnonan amidoxime

2. Isocyanate used

Methyl isocyanate

Methyl isocyanate

Methyl isocyanate

Methyl isocyanate

Methyl isocyanate

Methyl isocyanate

Methyl isocyanate

Methyl isocyanate

Ethyl isocyanate

Ethyl isocyanate

Propyl isocyanate

Propyl isocyanate

Ethyl isocyanate

Methyl isocyanate

Methyl isocyanate

Ethyl isocyanate 3 product

N-methylbutanamidoxime-O- (methyl ^ carbamate). ■

N-methyl pent anamidoxime-O- (methyl carbamate)

N-methylhexanamidoxime-0- (methylcarbamate)

N-methyloctanamidoxime-O- (methylcarbamate)

N, N-Dimethylbutanamidoxime-O- (methylcarbamate)

N, N-dimethylpentanamidoxime-O- (methyΙο arbamat)

Ν, Ν-Dimethylhexanamidoxime-O- (methyl- carbamate) _>

Ν, Ν-Dimethylheptanamidoxime-O- ^

(methyl carbamate) 'ι

N-ethylpentanamidoxime-O- (methylcarbamate)

^ N-Dipropyl-J-methylbutanamidoxä.mO- (methylcarbamate)
N-propylhexanamidoxime-0- (propylcarbamate)

N, N-tetramethylene butane amide oxime-0- (propyl carbamate)

N, N-Pentamethylene-2-methyIpentanamidoxim-O- (Ethylcarbamat) Ni N-Butyl-A-methylhexanamidoxim-O-U) (propylcarbamat) - * N-Hexyloctanamidoxim-O- (methylcarb- oo amat) <£>. N-ethyl-N-methylnonanamidoxim-O- ^ ⁰ (äthyIcarbamat) ^α

Table IV (continued)

Ν, Ν-diethyl propyl isocyanate ^ N-diethyl decanamide oxime decanamidoxime O- (propyl carbamate)

N-methyltri- methyl isocyanate, N-methyltridecanamide decanamide oxime oxime-O- (methyl carbamate)

Reaction 3j, which requires a carbamoyl halide, is preferably in the presence of a proton acceptor such as a tertiary amine or a metal halide such as sodium hydride. A solution of the corresponding Carbamoyl halide in an inert solvent gradually becomes a mixture of the amidoxime with the proton acceptor, which is usually dissolved in an inert solvent. As a solvent hydrocarbons, halogenated hydrocarbons and ither are suitable. The proton acceptor is not strictly necessary, but its use is appropriate.

Example 3

N-methylheptane amido oxime 0- (dimethyl carbamate) 20

CH ₃ (GH ₂

Formula 2: R = hexyl; R ¹ = R ⁵ = R ⁴ = methyl; R ² = M-

A mixture of 4.7 g of N-methylheptanamidoxime and 1.44 g of sodium hydride in mineral oil (50 %) in 50 ml of tetrahydrofuran is stirred for 30 minutes. After adding 3.23 g of dimethylcarbamoyl chloride in 25 ml of tetrahydrofuran, the mixture is heated under a reflux condenser with stirring for 2 hours. The sodium chloride is filtered off and the solvent is removed from the filtrate in a rotary evaporator under reduced pressure. The remaining as residue crystalline N-methylheptanamidoxime-0-

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(dimethylcarbamate) is washed with petroleum ether to remove the mineral oil.

Using those listed in Column 1 of Table V. Amidoximes instead of the aforementioned N-methylheptane amidoxime and the corresponding carbamoyl chlorides in column 2, the compounds mentioned in column 3 are obtained.

Table V

1. Amidoxime used

N-methylbutane amidoxime

N, N-dimethylpentane amide oxime

N-Buty1-4-methyl-1-hexanamidoxime

2nd carbamoyl 3rd product
chloride _______

- Dimethylcarb- N-methylbutanamidoximamoyl chloride O- (dimethyl carbamate)

N-Ethyl-N-me- Ν, Ν-Dimethylpentanamidthylcarbamoyloxim ~ 0- (ethylmethylchloride carbamate)

Dimethylcarb-H ~ butyl-4-methylhexanamoyl chloride amidoxime-0- (dimethyl-carbamate)

li-methyltridecandto, amidoxime

N, N-Pentanmethylene dto, 2-methylpentanamidoxime

N-methyltridecane amidoxime-0- (dimethy Ic arbamat)

N, N-pentanemethylene-2-

methylpentanamidoxime-O-

(dimethyl carbamate)

Example 4 N-Methylpentanamidoxime

CH, - (CH ₀ )

S -0-

3SHCH

+ MH ₀ OH -

N-OH
CH, (CH ₀ ), -C-NHCH

A. 23 grams of hydroxylamine hydrochloride was dissolved in 120 ml of hot methanol. The solution was allowed to cool to 40 ⁰ C. A solution of 2? g of potassium hydroxide in 120 ml of hot methanol was produced and allowed to cool to 40 ^° C. The solution containing the potassium hydroxide was added dropwise (under nitrogen)

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added to the solution containing the hydroxylamine. After adding a solution of 11.5 g of N-methylthiovaleramide in 50 ml of methanol, the reaction mixture was refluxed overnight, cooled and filtered. The filtrate was concentrated. 4.7 g of N-methylpentanamide oxime were obtained. A recrystallized from hexane-benzene sample melted at 69 ° to 72 ⁰ C.

B. The N-methylpentanamidoxime obtained was with Methyl isocyanate reacted to the 7 / iron described in Example 2, with N-methylpentanamide oxime-0- (methyl carbamate) from melting point 55 to 57 ° C was formed.

The compounds according to the invention can also be prepared by reducing the corresponding 3-alkyl-4-acetyloxadiazoles with lithium aluminum hydride by the method of D ¹ AIo, Il Farmacao ed. Sc. 21, bevel. 5, 346 (1965), or by hydrolysis of the corresponding 3-alkyl-4-methyloxadiazoles. Other procedures are described in Examples 5 and 6 below.

Example 5

A solution of 9.2 g (0.05 mol) of 3-butyl-4-acetyloxadiazole in 50 ml of tetrahydrofuran was added dropwise to a suspension of 5-7 g (0.15 mol) of lithium aluminum hydride in 200 ml of tetrahydrofuran. The reaction mixture was refluxed for 4 hours, treated with ethyl acetate and filtered. The solid was extracted twice with hot benzene. The combined extracts were concentrated. Here, 3.2 g (49%) of N-Methylvaleramidoxim were obtained with a melting point of 69-70 ⁰ C. The infrared spectrum showed a characteristic absorption at 1648 (-C = N), a broad -N-OH absorption between 2800 and 3200 and an -NH absorption at 3300 cm * " ¹ .

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for G ₆ H H "O · RR
• 'J Λ. Ο * ^/ '' G 10 2318960 55 * 55 1 Calculated example 21.52 Found: 6th 21.3-1 S. , 64 , 98

Α, A mixture of 20 g (0.14 mol) 3-butyloxadiazoli 5.6 g (0.14 mol) sodium hydride and 20 g (0 * 14 mol) methyl iodide in 200 ml tetrahydrofuran was heated in a reflux condenser for 4 hours. The reaction mixture was filtered and concentrated. This gave 16 g (72 W) 3-butyl-4-methyioxadiäzöi * Infrared absorption at 1775 (G * 6) and 1599 em "' ¹ (G ^).

B. iine ioäüng vöji 7, ä g (0j05 mol) crude I-butyl-4-methylöxädiazöl, 60 ml ( ^; iö% i§effi) Ma-yriüMydrö5cyd üiäd 70 ml Ithaübl one hour m Ünbkf iußlBihler was received, with today and evaporated iäür fr'öc'iine. The solids were extracted with hot in benzene. By econcentration dei? If oil extracts from Behzol-hexane were used, 1.5 l (25 Ψ) 5-butyl -4-methylvaierämidöxim from the SBHmäizpühitl ft> up to 72 C; The 3äiffäfötspe'js; trüm the connection was idehtiochi with that of an authentic sample

The compounds according to the invention can be administered in any manner for the treatment of hypertension where the active ingredient of the site of action in the body of warm-blooded animals i For example administration can be parenteral, i.e. subcutaneously, intravenously, be done intramuscularly or intrapperitorially. Oral administration can be used as an alternative or at the same time to be made *

In the context of this description are among warm-blooded animals To understand members of the animal kingdom who see one homoostat Have mechanism. They include mammals and bird.

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The dose administered depends on the age, health and weight of the recipient, the severity of the disease, the type of treatment that may be carried out at the same time, the frequency of treatment and the type of effect you want. In general the daily dose of the active ingredient is about 0.01 to 50 mg / kg body weight «0.05 is common to 40, preferably 0.1 to 20 mg / kg per day in one or more doses per day effective to achieve the desired Achieve results. In the more potent compounds according to the invention, e.g. N-methylheptanamidoxime-O- (methylcarbamate), the daily dose is in the range from about 0.1 to 24 mg / kg, preferably 0.2 to 10.0 mg / kg, especially 0.6 to 4.0 mg / kg.

The antihypertensive effect of the N-alkylamidoxime-O-carbamates according to the invention is demonstrated by tests carried out on hypertensive rats. In these experiments, hypertension is produced in rats by repeated injections of deoxycorticosterone acetate (DOCA) according to the method described by Stanton and White (Arch. Intern. Pharmacodyn, 154 , 351, 1965). N-Methylheptanamidoxim-O- (methylcarbamate) is intraperitoneally nine test animals in increasing doses injected _s with three doses are used, of which the next in each case is three times the previous one. The compound is prepared in aqueous polyvinyl alcohol / acacia vehicle and administered in a volume to body weight ratio of 5 »0 ml / kg.

The first low dose is given immediately after a blood pressure control measurement. The second and third dose follows after blood pressure measurements 2 hours or 4 hours later. The systolic blood pressure will determined after a modification of the microphone manometer method (M. Friedmann and S. 0. Freed, / Soc. EXp. Biol.

309845/1173 ^Proc

and Med. 22 »670, 1959).

As a result of the test, it is found that the Compound in a 'dose of 2.0 mg / kg blood pressure decreases by 30 mm Hg from the control value measured before administration when administered intraperitoneally (effective dose JO = ED, q). Other. Connections according to of the invention tested in the same manner also show a potent antihypertensive Effect .. For example, the The same test method determined that the oral effective dose was 30% (oral ED ^ q)% methylheptanamide oxime-0-carbamate 10 mg / kg.

The compounds according to the invention can be used in pharmaceutical Preparations, e.g. in injection liquids and dosage forms for oral use, e.g. tablets, hard gelatine capsules, soft gelatine capsules, Suspensions, syrups and elixirs, are used «These preparations contain the active ingredient usually in an amount of at least 0.5% by weight and no more than 90% by weight based on the total weight the preparation. ..- ■ - ""

In addition to the active ingredient according to the invention the antihypertensive agents a solid or liquid non-toxic pharmaceutical carrier for the active ingredient. They can also contain other common additives, e.g. lubricants or binders.

As an embodiment of the pharmaceutical preparations according to the invention, capsules come into consideration, which can be ordinary gelatin capsules. In the capsules are JO; about 5 to 90% by weight of a compound according to the invention and 95 to 10 % of a carrier. In another embodiment, the active ingredient is tabletted with a suitable extender. These capsules and

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Tablets generally contain about 1 to 95 %
preferably 5 to 90% by weight of the active ingredient. These
Medicinal forms preferably contain about 5 to 500 mg
Active ingredient, with about 10 to 100 mg being particularly preferred.

Suitable pharmaceutical carriers are sterile liquids, for example water and oils including the oils and oils of animal and vegetable origin derived from petroleum
and of synthetic origin, e.g., peanut oil, soybean oil, mineral oil and sesame oil. In general, water, saline solution, aqueous dextrose (glucose) and related sugar solutions and glycols, for example propylene glycol and polyethylene glycol, are preferred as liquid carriers, particularly for injection solutions. Sterile InQection

solutions, e.g.; Saline, normally contain about 0.5 Ms 25 % preferably about 1 to 10% by weight
des / active ingredient s.

Oral administration can take place in suitable suspensions or syrups in which the active ingredient normally makes up about 0.7 to 10 %, preferably about 1 to 5 % by weight. As a pharmaceutical carrier in these
Drug forms, aqueous carriers, for example aromatic water, syrups or pharmaceutical mucilages, can be used.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W * Martin, a well-known Manual in this field.

The following examples further describe the production of pharmaceutical preparations according to
Invention.

Example A.

A large number of standard capsules are produced

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by using the usual two-part hard gelatin capsules with each 50 mg powdered N-methylheptanamidoxime-0- (methyl carbamab), 300 mg lactose, 32 mg talc and 8 mg magnesium stearate be filled.

5 Example B

For the production of soft gelatin capsules containing 35 mg des The active ingredient is a mixture of N-methylheptanamide oxime-O-carbamate Made in soybean oil and injected into gelatin with a positive displacement pump. The capsules are washed in petroleum ether and dried.

Example C

For the production of soft gelatin capsules, each 50 mg Contain active substance, a suspension of N-methylheptanamidoxime-O-Cmethylcarbamat) Made in mineral oil and vegetable fat and with a positive displacement pump splashed in gelatin. The capsules are washed in petroleum ether and dried.

Example D

A large number of tablets are produced according to conventional methods so that each tablet 100 mg of N-methylheptanamide oxime-O-r (methyl carbamate), 7 mg ethyl cellulose,

• 0.2 mg colloidal silicon dioxide, 7 mg magnesium stearate, Contains 11 mg of microcrystalline cellulose, 11 mg of corn starch and 98.8 mg of mannitol. To increase palatability or suitable coatings and blankets can be applied to delay resorption.

Example E.

A parenteral preparation suitable for injection is produced by 1.5 Gev /, -% N-methylheptanamide-

oxime-0- (methylcarbamate) hydrochloride in water, the

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Contains 10% by volume propylene glycol, are stirred. the Solution is sterilized by filtration

Example -F

An aqueous suspension is prepared for oral administration so that each 5 mL contain 50 mg one-piece £ N-Methylheptanamidoxim-O-carbamate, 500 mg of gum arabic, 5 mg of sodium benzoate and 1.0 g of sorbitol solution, USP, containing 5 mg ÜTatriumsaccharin and 0.025 ml Vanillentinktur.

Example G

läine suitable for injection preparation is prepared by adding 1 wt -% N-Methylbeptanamidoxim-O- (methylcarbamate) hydrochloride dissolved in sodium chloride injection USP, and the p "value of the solution is adjusted to 6 to 7.. The solution is sterilized by filtration. .

The most diverse falling within the scope of the invention Preparations can be made using other compounds of the invention including those above compounds mentioned (without limitation) instead of the compounds mentioned in Examples A to G and using other suitable pharmaceutical carriers such as those in the Martin handbook referred to above described carrier.

309845/1173

Claims (4)

Pa t e η t a η s ρ r Ü c h e j'l.yN-substituted amidoxime-O-carbamates of the general \ y formula R ¹ R ² = n-o-c-n in the , R is a saturated aliphatic or alicyclic hydrocarbon radical with 3 to 12 carbon atoms, R stands for an alkyl radical with 1 to 6 carbon atoms, ο
R is a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, 12th . R and R together can form a polymethylene radical with k or 5 carbon atoms and Br and R independently represent hydrogen atoms or alkyl radicals with 1 to 3 carbon atoms with the proviso that the sum of the carbon atoms in R ^ and R is not higher than 3, and salts of these compounds with pharmaceutically acceptable acids. 2. N-Methylheptanamidoxiπl · -0-carbamate 3. N-Methylheptanamidoxime-O-Cmethylcarbamat) ' 4. N-Methylpentanamidoxime-O-Cmethylcarbamat) 5 · Pharmaceutical preparations containing a compound according to claims 1 to 4 and a pharmaceutically acceptable carrier.