DE1935301A1 - Compounds with pharmacological properties - Google Patents

Description

"Compounds with Pharmacological Properties."

The invention relates to new compounds of the formula -I

G = F - O - CH ₂ - CH ₂

and pharmaceutically acceptable acid-additive salts thereof, wherein in formula A and B either together form a benzo group, in which case R '= H or methyl, R = H or alkyl having 1 to 5 carbon atoms and X = O, NH or S. is, or each represent a hydrogen atom, a methyl group or a halogen atom (Cl, Br or J), in which case X = S, R ^f = H, halogen (Cl, Br or>) CH ₅ and R = H, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 "to 6 carbon atoms, phenyl, m- or p-chlorophenyl, m, p-dichlorophenyl, thienyl-2 or 5-chlorothienyl-2, while if A and B; each is a hydrogen represent atom and X is a sulfur atom, R and R 'together can also represent an orthobophenylene group or together a trimethylene group, where R' is bonded in the 2-position, or together can represent a thienylene-2, 3-G group, where R 'is bonded in the 3-position.,

The compounds of the invention have interesting pharmacological properties. You have in particular a very strong central effect, which is reflected in both an antidepressant, possibly through

ΡΗΪΓ 3358 (week) _ 2 -

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Monoamine oxidase inhibition induced, effect, than can also express itself in a sedative or anticonvulsant effect. . .

Namely the tricyclic compounds of the formula I. are very effective, while the 2-aetyl-3-me thy! benzofurane die ^ -Acetyl-H-methylbenztfaiophen-, the 3-acetylindole-, the 2-chloro-S-acetyl-thiGphen-, the 5-methyl-2-acetyl-thiophene and the dithiophene derivatives have a very powerful effect.

The monoaminoxydasehemmende effect of compounds of the formula I has resulted from experiments, h ± which five male albino mice, a quantity of the test compound was administered intraperitoneally or orally. After one hour, the animals were injected subcutaneously with tryptamine hydrochloride in an amount of 250 mg / kg. This amount did not cause mortality in animals to which the test compound had not been administered, but did in the. Animals treated with this compound ". 18 hours after the administration of tryptamine hydrochloride, the mortality rate of the treated animals was determined. The ED was derived from the results.

The antidepressant effect of the compounds of the formula I was determined by the tetrabenazine test. An amount of the test compound was administered intraperitoneally or orally to five male albino mice. The animals were injected subcutaneously with 80 sig / kg tetrabenazine for 45 minutes. Once awake for 45 minutes, the degree of ptosis was determined and compared with that of the animals to which only tetrabenazine had been administered. The ED ^ _{0 was} derived from the results.

The sedative effect of compounds according to the invention

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- 3 -. . ■■■■■ "■

was found by the hexobarbital sleep test. In this test, a test compound was administered intraperitoneally and orally, respectively, 30 minutes and 60 minutes before intravenous administration of a barely narcotic batch of hexobarbital (30 mg / kg). Induction of the anesthetic wax the criterion for the effectiveness of the substance. _{The ED 1} -Q was calculated from a series of experiments with changing dosages.

The anticonvulsant effect of compounds according to the ~, Invention against supramaximal electric shock was made in female mice 30 minutes after intraperitoneally or determined 60 minutes after oral administration of the test compound.

The influence of compounds on the convulsive effect a supramaximal intravenous dose of pentamethylenetetrazole (50 mg / kg) was also given in female mice 30 minutes after intraperitoneally or 60 minutes after oral administration of a compound.

The antidepressant compounds of the invention are particularly suitable for use in therapy for neurotic and psychotic disorders, namely the depressive syndrome, and also for the treatment of psychosomatic disorders. The fabrics can therefore be administered to depressed patients as a psychostimulatory agent. .

The sedative compounds are particularly suitable for Use as an ataractic. You can succeed to Treatment of mild psychoneurotic phenomena.

The anticohvulsive compounds can be found in the Treatment, use of epileptic patients.

■■ ".-- 4 0098097 1 795. ;

After putting the compound in a suitable dosage form have been brought, they can be administered in the usual way. You can be injected and can also be administered orally or ractally. Suitable forms of administration are therefore, inter alia, injection liquids, pills, tablets, coated tablets, capsules, powders etc.

The way, the dose and the frequency of administration the substances can also be different for each patient depending on the degree of the disorders. In general, it will not be difficult for the attending physician to identify the patient for a particular patient to choose the right therapy.

The dosage of sedative and antidepressant compounds is generally 10 to 500 mg per day for adults. usually an amount is from 10 to 150 mg enough.

Anticonvulsant compounds according to the invention are used generally administered at doses of 100 to 500 mg / day. .

The compounds according to the invention can by in the Processes customary in pharmacy can be processed into preparations, e.g. by mixing an active ingredient with solid or liquid carrier materials is mixed or dissolved in these materials.

The usual carrier materials are suitable as such materials, e.g. water, which may have been made isotonic with blood, e.g. with the help of table salt is, glycerine, chalk, calcium phosphate, lactose, Powdered sugar, calcium carbonate. As a swelling agent can in tablets and coated tablets, e.g. potato starch, corn

00 9 809/1795

starch, arrow root (AmyIum Marantae), carboxymethyl cellulose, Gelatin and gum arabic can be used.

Talc, magnesium and calcium stearate can be used as lubricants and stearic acid can be used. To be delivered orally

Eliminating preparations can also contain flavorings, such as Contain sugar or vanilla extract. Propyl p-hydroxybenzoate and benzyl alcohol, for example, can be used as preservatives. The preparations can also still surface-active substances, such as mono-, di- and. Contains tri-esters of higher fatty acids.

Examples of acids with which the compounds are pharmaceutically can form acceptable acid-additive salts are:

Hydrohalic acids, such as hydrochloric acid, hydrobromic acid, also other inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and organic acids

S. "

Acids such as citric acid, acetic acid, oxalic acid, fumaric acid acid, lactic acid, succinic acid, sulfamic acid, benzoic acid, Tartaric acid, gallic acid, malic acid and maleic acid.

The compounds according to the invention can by per se known processes are produced.

The invention therefore also relates to a method for producing new oxime ethers, characterized in that is that compounds of formula I

-If-O- 'CH ₂ - CH ₂ -NH ₂ "I

and pharmaceutically acceptable acid additive salts thereof, where in formula A and B either together

009809/1795

form a benzo group, in which case R ¹ = H or methyl, R = H or alkyl with 1 to 5 carbon atoms and Z = O, NH or S, or a hydrogen atom, a methyl group or a halogen atom (Cl, Br or J ), in which case X = S, R '= H, halogen (Cl, Br or, J) or CH ₅ and R = H, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, m- or p-chlorophenyl, m, p-dichlorophenyl, thienyl-2 or 5-chlorothienyl-2, while when A and B each represent a hydrogen atom and X is a sulfur atom, R and R 'together also represent an orthophenylene group or together a trimethylene group can represent, wherein R 'is bonded in the 2-position, or together represent a thienylene-2,3 group, wherein R ¹ is bonded in the 3-position, prepared by methods customary for the preparation of this type of compounds and by methods analogous thereto will.

Thus, compounds according to the invention can be prepared by adding a compound of the formula II R.

.C-F-OM ■

in which M is a hydrogen atom or an alkali metal atom represents, with a compound of formula III

Z - CH ₂ -

(III)

or a salt thereof can react, wherein in the formula Z is a halogen atom, preferably a bromine or Chlorine atom, or a losyloxy group and Y represents a hydrogen atom or an acyl group, and if Y

00 9 8097 1-7 8 5

■ ^: ■ - 7 - ■ ·

represents an acyl group, the acyl group after the Coupling reaction is split off by hydrolysis. The acyl group can be, for example, the ethoxycarbonyl group or the Carbobenzoxy group can be used.

The reaction can be carried out in a suitable solvent. Suitable solvents include alcohols, such as methanol, ketones such as acetone and M.E.K., and ethers such as dioxane and dimethyl glycol ether. The split an AcyIs Y can e.g. with KOH in alcohol, e.g. ethanol, occur.

When M in formula II represents a hydrogen atom, it can be advantageous to the reaction mixture To add acid binders. As such can be mentioned i.a.

/ ■ "'.-- are: alcoholates, potassium and sodium carbonate, tertiary

Amines, pyridine and the like.

The temperature of the reaction mixture can vary between relatively wide limits. As a rule, however, it is between 0 and 50 C. _t

The oximes of the formula II can be prepared in a customary manner from the corresponding aldehydes or ketones with the aid from hydroxylamine. The Oximate can are prepared from the oximes in that the latter, optionally dissolved in alcohol, a solution of Sodium or potassium alcoholate or sodium or potassium hydroxide in alcohols can be added.

The aeylated amines of the formula III can be prepared by using the corresponding primary or secondary amine and an acid chloride, e.g. Benzene dissolved, assumed, is.

Connections According to the invention can also be

■■.;. ■ - β - '"■ , 009809/1785

will keep that one is a compound of the formula IY

A.

(IV)

/ * ~ ■. ^t 2 ^^^ R ^l

B. '

in which the substituents have the same meaning as in of formula I with a compound of formula V

H ₂ N- Ö - CH ₂ - CH ₂ - NH ₂ (Y)

lets react.

The reaction is preferably carried out in a solvent at room temperature. Suitable solvents are alcohols, pyridine, dioxane, dimethylformamide, tetrahydrofuran and the like.

The compounds of the formula I can also be obtained in this way be that you have a compound of formula VI

. R.

= N - 0 - CH ₀ - Z (YI)

χ R
B. -

can react with ammonia. '

In formula VI, Z represents a halogen atom, preferably represents a bromine atom, or a tosyloxy group. The reaction can be carried out, for example, in alcohols.

The starting materials of the formula VI can thereby be obtained be that oximes of the formula II (M = H) in the presence of an acid binder with a halogen compound of Formula VII

■ 00 9 8 09/1795

- 9 Hal - CH ₂ - CH ₂ -Z (VIl)

lets react, where in the formula Z has the same meaning as in the formula YI and Hal represents a halogen atom, preferably a bromine atom.

Execution examples:

1. O- (2-Aminoethyl) -2-acetylbenzofuranoxime.HCl

8.75 g of 2-acetylbenzofuranoxime and then 20.5 g of 2-bromoethylamine hydrobromide were added to a solution of 4.60 g of sodium in 100 ml of absolute ethanol with stirring. The mixture was stirred at room temperature for 2 1/2 hours, after which the precipitated sodium bromide formed was filtered off with suction. The filtrate was concentrated in vacuo until most of the solvent had been removed, after which the remainder was mixed with about 50 ml of water and 50 ml of ether. The mixture was shaken and the layers formed were separated. The ether solution was washed twice with about 30 ml of water and then extracted with 50 ml of 2N hydrochloric acid. The acidic extract was made alkaline with 75 ml of 2N sodium hydroxide solution and then extracted three times with 50 ml of ether. The ethereal solution thus obtained was washed three times with 30 ml of water and then dried over sodium sulfate. ¹ After the ether had been removed in vacuo, the basic residue was neutralized with 2N alcoholic hydrochloric acid. After this solution was diluted with absolute diethyl ether, the above-mentioned substance crystallized. After it had been crystallized again from a mixture of ethanol and diethyl ether, the substance melted at 199.5-2O1.5 ° C.

2. 0- (2-Aminoethyl) -3-acetylindoloxime.HCl

A solution of 4.60 g of sodium in 125 ml of absolute

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- ίο -

Ethanol became 8.70 g of 3-acetylindole oxime with stirring added. After this was solved, it became 20.5 g 2-Bromoethylamine hydrobromide was added to the mixture, after which the whole was stirred after 2 hours. Afterward the precipitated sodium bromide was suctioned off and the piltrate was concentrated in vacuo. The rest was shaken with water and ether and the ethereal layer was after its separation with twice Water washed. The ethereal layer was then extracted with 50 ml of 2N hydrochloric acid. This salt acid extract was mixed with 75 ml of 2N sodium hydroxide solution and then extracted three times with 50 ml of ether. These ethereal solution was washed three times with 30.ml water, then dried over sodium sulfate and then concentrated in vacuo. The residue obtained was neutralized with 2N ethanolic hydrochloric acid, after which the above-mentioned substance slowly crystallized after the addition of a little ether. It was sucked off and crystallized again from a mixture of ethanol and ether. Melting point: 174-177 ° C.

3. 0- (2-aminoethyl) -8-H-indeno-

oxim.HOl.
A mixture of 5.56 g of 8-H-indeno

2.1-b-

-thiophene-8-one-

J>, 1-bJ -

thiophene-8-

on, 4.91 g of O-CZ-aminoethyl / hydroxylamine dihydrochloride and 2.71 g of sodium acetate with 175 ml of ethanol and 20 ml of water were stirred at room temperature for 1 1/2 hours. This gradually dissolved the solid in the solvent. The reaction mixture was then left to stand for a further 18 hours, after which it was ^{concentrated at about 40 °} C. in vacuo. The residue was mixed with 150 ml of water and this mixture was extracted with a total of 750 ml of diethyl ether. The aqueous solution was then made alieLisch with 30 ml of 2N sodium hydroxide solution and then extracted with a total of 200 ml of diethyl ether. The latter

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The extract was washed with water and dried over sodium sulfate. The residue obtained after distilling off the solvent in vacuo was dissolved in 15 ml of absolute ethanol and then neutralized with 2N ethanolic hydrochloric acid. After a little ether had been added to the neutralized solution, the above-mentioned substance crystallized with a melting point of 188 ^° C. with decomposition.

4. 0- (2-Aminoethyl) -2-acetyl-5-methylthiophene-oxime.HCl

A solution of 1.40 g of 2-A3etyl-5-methylthiophene and 1 * 4-9 g of 0- (2-aminoethyl) hydroxylamine dihydrochloride in a mixture of 5 ml of dry pyridine and 10 ml of absolute ethanol was 3 1/2 hours refluxed. Then the solvents were distilled off in vacuo. The residue obtained was dissolved in 20 ml of water and this solution was washed with 20 ml of diethyl ether. The aqueous solution was then made alkaline with 15 ml of 2N sodium hydroxide solution and then extracted three times with a total of 30 ml of diethyl ether. The ether extract was then washed three times with 5 ml water, then ~~ closing concentrated dried over sodium sulfate and subsequently in vacuum. The residue obtained was dissolved in 10 ml of absolute ethanol and then neutralized with 3N alcoholic hydrochloric acid, the hydrochloride of the substance mentioned above crystallizing. The hydrochloride was dissolved again by heating the mixture and adding 10 ml of ethanol. After this solution had been mixed with 10 ml of absolute ether, the hydrochloride crystallized again. The mixture was placed in the refrigerator overnight and then mixed with a further 40 ml of absolute ether. The crystallized substance was filtered off with suction, washed three times with absolute ether and dried, after which it melted ^{at a temperature between 189 and 191 ° C.}

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009809/1 79 5

- 12 5a. 0- (2-Aminoethyl) -2-hexaneQiLthiophenoxime.HCl

19.7 g of 2-hexanoylthiphenoxime were dissolved in a solution of 4.6 sodium in 100 ml of absolute ethanol. This solution was added with stirring at 20 ⁰ C is added a mixture of 60 ml of 1,2-dibromoethane and 50 ml of Ν, Ν-dimethylformamide. The reaction mixture was then heated to 65 ° C. and held at this temperature for 16 hours. The precipitate formed was then filtered off with suction and the filtrate was concentrated in vacuo. After adding 200 ml of water, the concentrate was extracted twice with 100 ml of chloroform. The extract was dried over sodium sulfate, concentrated in vacuo and then distilled under high vacuum (0.005 mm Hg). In addition to p-hexanoylthiophenoxime, the distillate also contained 0- (2-bromoethyl) -2-hexanoylthiophenoxime.

5b. A solution of 9 g of this distillate in 50 ml of ethanol was mixed with 50 ml of concentrated ammonia. This mixture was then ^{stirred in a closed vessel for 16 hours at 65 °} C. and then concentrated in vacuo. The concentrate was extracted with 50 ml of ether and then three times with 20 ml of η-hydrochloric acid. The suare extract was washed with 50 ml of ether, then mixed alkaline with 40 ml of 2N sodium hydroxide solution and extracted again three times with 50 ml of ether. This ether extract was dried over sodium sulfate and concentrated, and the remaining oil was distilled in a high vacuum. The distillate was absorbed in diethyl ether and neutralized with 2N-ethanolic hydrochloric acid, whereby the 0- (2-aminoethyl) -2-bexanoylthiopbenoxime hydrochloride crystallized. Melting point between 100 and 110 ° C.

6. By method A (reaction of a compound of the formula II with a compound of the formula III) the process B (reaction of a compound of the formula IV with a compound of the formula V) or by the

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drive C (reaction of a compound of formula VI with ammonia) the following substances were obtained:

009809/1795

JIf

PI-Ci.

material

Procedure melting point
HCl salt

sedative

anti conv

anti depr

^ r

-NO-CH ₂ -CH ₂ -NH

Cl

CH.

H
H
K
H
Cl

H ..
CH

Cyclopropyl η 'Cj-H-] -ι

tni ^ nyl-2

5-chlorine

thienyl-2

73.NO-CH ₂ -CE ₂ -NH ₂

-0-CH ₂ -CH ₂ -NH ₂

-0-CH ₂ -CH ₂ -NE ₂

** R

CH

3 _H.

CH

rC H
nc: hJ

A C A A A

160-161 228.5-230.5 159-191

112-115 100-110 146-150 192-194 115-116 Maleate

249-25I 2O9-2II

168
decomposition

205
decomposition

199.5-201 ,; Base, OeI

174-177 base, OeI Base, 0el base, oil

ineffective or almost ineffective

009809/1795

TABLET

50 mg of 0- (2-aminoethyl) -2-acetylbenzofuranoxime.

HCl

335mg milk sugar

60mg potato starch
25 mg talc

5 mg magnesium stearate

5 mg gelatin

SUPPOSITORY

50 mg of 0- (2-aminoethyl) -3-acetylindoloxime.HCl mg of suppository mass

INJECTION LIQUID

25 g of 0- (2-aminoethyl) -8H-indeno- 2,1-b -thio-

phen-8-one-oxime.HCl 1.8Og methyl-p-hydroxylbenzoate 0.2Og propyl-p-hydroxy-similarate 9 * 0 g sodium chloride
4.0 g Polysorbate 80 USP
Water to 1000 ml

009809/1 785

Claims (7)

PATENT CLAIMS ϊ 1. Process for making new oxime ethers, thereby characterized in that compounds of the formula I R ³ C = NO-, CH ₀ - CH ₀ - NH ₀ ²²² (ι) and pharmaceutically acceptable acid-additive salts thereof, wherein in the formula A and B either ^ together form a benzo group, in which case R '= H or methyl, R = H or alkyl with 1 to 5 carbon atoms and X = 0, NH or S, or one hydrogen atom, one methyl group or one halogen atom (Cl, Br or J), in which case X = S, R ¹ = H, halogen (Cl, Br or J) or CH ₅ and R = H, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, m - Or p-chlorophenyl, m, p-dichlorophenyl, thienyl-2- or 5-chlorothienyl-2, while when A and B each represent a hydrogen atom and X is a sulfur atom, R and R 'also together form an orthophenylene group or together a trimethylene P can represent group, where R ¹ is bonded in the 2-position, or together represent a thienylene-2,3-group, where R ^f is bonded in the 3-position, by processes customary for the preparation of this type of compounds and by processes analogous thereto Process are produced. 2. The method according to claim 1, characterized in that that a compound of the formula II C = N - OM (II) 009809/1795 with a compound of the formula III Z-CH ₂ - CH ₂ - N (III) or a salt thereof reacts, the substituents in the formulas having the same meaning as in the formula I and N have a hydrogen or alkali metal atom, Z a halogen atom or a Tosyl group »and Y represents a hydrogen atom or an acyl group, and if Y represents an acyl group represents, this splits off after the coupling reaction by hydrolysis. 3. The method according to claim 1, characterized in that that a compound of the formula IV R (IV) in which the substituents have the same meaning as in formula I, with a compound of Formula V - 0 - CH CH ₂ - NH ₂ (V) lets react. 4. The method according to claim 1, characterized in that a compound of formula VI R. IC C = N - O - CH ₂ - CH ₂ - Z 009809/1795 (VI) - 18 - in which the substituents have the same meaning as in formula I and Z is a halogen atom or represents a TosyIoxygruppe, react with ammonia leaves. 5. Compounds of the formula I C = N - 0 - CH ₂ - CH ₂ - NH ₂ (I) and pharmaceutically acceptable acid-additive salts thereof, wherein in formula A and B either together form a benzo group, in which case R ¹ and H or methyl, R = H or alkyl with 1 to 5 carbon atoms and X = 0, NH or S, or each hydrogen atom represents a methyl group or a halogen atom (Cl, Br or J), in which case X = S, R '= H, halogen (Cl, Br or J) or CH ₃ and R = H, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, m- or p-chlorophenyl, m, p-dichlorophenyl, thienyl-2 or 5-chlorothienyl-2, while when A and B each represent a hydrogen atom and X is a sulfur atom , R and R 'together can also represent an orthophenylene group or together a tr! ^{Methylene group, where R 1} is bonded in the 2-position, or together represent a thienylene-2,3 group, where R' is bonded in the 3-position . 6. A method for producing pharmaceutical preparations, characterized in that a compound of Formula I. - 19 - 009809/1795 O = N-O- (D CH ₂ - CH ₂ - and pharmaceutically acceptable acid-additive salts thereof, wherein in formula A and B either together form a benzo group, in which case R ¹ = H or methyl, R = H or alkyl with 1 to 5 carbon atoms and X = C, NH or S, or each represent a hydrogen atom, a methyl group or a halogen atom (Cl, Br or J), where X = S, R ¹ = H, halogen (Cl, Br or J) or CH ₅ and R = H, alkyl with 1 to 5 carbon atoms, Cycloalkyl with 3 to 6 carbon atoms, phenyl, m- or p-chlorophenyl, m, p-dichlorophenyl, "Thlenyl-2 or 5-chlorothienyl-2, while when A and B each represent a hydrogen atom and X is a sulfur atom, R and R ¹ together can also represent an arthophenylene group or together a trimethylene group, where R 'is bonded in the 2-position, or together represent a thienylene-2,3 group, where R ¹ is bonded in the 3-position, in a to form suitable for therapeutic administration. 7. Pharmaceutical preparations, characterized in that they contain a compound of the formula I. C = HO- CH ₂ ~ ^CH 2 " and pharmaceutically acceptable acid additive salts thereof, wherein in formula A and B either together form a benzo group, where R '= H or methyl, R = H or alkyl with 1 to 5 carbon - 20 009809/179 5 atoms and X = 0, NH or S, or each represent a hydrogen atom, a methyl group or a halogen atom (Cl, Br or J), in which case X = S, R '= H, halogen (Cl, Br or J) or CH, and
R = H, alkyl with 1 to 5 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, phenyl, m-
or p-chlorophenyl, m, p-dichlorophenyl, thienyl-2 or 5-chlorothienyl-2, while when A and B each represent a hydrogen atom and X is a sulfur atom, R and R 'together also represent one
Drthophenylene group or together can represent a trimethylene group, where R ¹ is bonded in the 2-position, or together represent a thienyl-2,3 group, where R * is bonded in the 3-position. 009809/1795