DE2310215A1 - NEW THIOPHEN DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

The present invention relates to Ν, Ν'-disubstituted diamines of the general formula (I) (see formula b "! att), wherein

Ii an at least mononuclear, sulfur-containing heterocyclic rust with at least one; · the none
Double bond and 5 to 10 atoms in the long system,
the unsubstituted. the at least once through
at least one substituent from the group halogen,
Nitri, alkoxy with 1-3 C atoms, the alkyl with
1-6 C atoms is substituted,

I. an at least mononuclear carbc- _: the heterocyclic radical with 5 to 10 atoms in the ring system is the
contains at least one oxygen, sulfur or nitrogen atom, has at least one or no double bond, is unsubstituted and / which is replaced at least once by at least one substituent from the group Hangen-, Nitro-, Trif Iu. rmethyl, alkyl with 1-6 carbon atoms, hydroxy, alkoxy with 1-3 carbon atoms of the amine, alkylamim- the dialkylamino is substituted with 1-3 carbon atoms each,

Κ no cder at most two identical or different substituents and:, was alkyl groups with up to 2
C-AL. represents men or phenyl groups.

^{; <} ί as well as Y identical or different and zero or an alkylene group with 1 to 3 carbon atoms in the chain dnrstelit,

the unsubstituted is the bis ;; u 3 alkyl groups with each contains up to 3 carbon atoms as side groups; the one phenyl or thienyl group in the side chain having,

A and B, identical or different, and a methylene group

c: they are with the condition that if X »is zero, A is a methylene group and when Ϊ is zero, B. Is a methylene group,

. η 2 ^. of 3 mean.

In R and H, halogen stands for chlorine, bromine, iodine and / or fluorine.

Acid addition salts of these compounds have the same therapeutic properties Effectiveness..

The compounds are mainly because of their psyche trap, "analgesic." and antiphlc look interesting.

In the compounds of the formula (I), ß can be both aromatic and

2
be cyclic aliphatic in nature. If R is a heter: cyclic radical, it is preferably 5- ^ of the 6-membered. where R does not have the hetero-

AtoB is bound.

The groups X-A and Y-B preferably denote unbranched alkylene radicals with 1 to ^ C atoms rder one substituted by a phenyl or thienyl group Alkylene, preferably ethylene radical. As particularly beneficial to ν the methylene group turned out to be.

Suitable groups R -X-A are, for example, thenyl- (2) -, thenyl- (3) - » 5-Chlcr-thenyl- (2) -, 5-methyl-thenyl- (2) -, thienyl- (2) -ethyl- (i) - and the Thienyl (2) ethyl (2) residue.

Suitable groups R -YB are, for example, benzyl-, cyclopentyjoethyl, -ethyl, cyclohexy-methyl- or -äthy " ¹ , Dipheny -methyl-, Diphenylpropyl-, Naphthyl-methyl-, Tetrahydronaphthy.-methyl-, Phenyläthyl-, Phenylprcpyl -, Indanylnethyl-, Furfuryl-, Tetrahydrofurfuryl-, Thenyl-, Quinolylmethyl-, Is-quin lyl-ethyl, Benz furfuryl-, Pyridyl- ■ ethyl or Pie lyl radicals, which in turn can carry the mentioned substituents.

Physically compatible monobasic and dibasic acids such as hydrochloric acid, nitric acid, Cyclehexylsu " ¹ famic acid, glucic acid, also phosph: acid. Sulfuric acid, citric acid, maleic acid of adipic acid are

409837/1 09Q

Creation of mono- or bending-a'u adducts of the cyclic ones according to the invention Suitable for diamines.

The invention furthermore relates to a process for the preparation of the compounds according to formula (I) or the acid addition salts, and their use in pharmaceutical compositions.

The compounds claimed according to the invention can be applied to a wide variety Way to manufacture, e.g. B. in that

a) an N'-substituted cyclic diamine in the formula (II) or (IV) (see formula sheet) with a compound of formula (Ilfi or (V) (see Forraelblatt) is implemented, where Z is a halogen, alkylsulfonyloxy or Arylsulfonyl group means, or

b) a Ν, Ν'-disubstituted cyclic diamine of the formula (VI), wherein at least one of the symbols Q ^ C = O and the other Λ or Bj öler "(fII), in which R stands for to to 2 oxo groups, (see each formula sheet) is deoxygenated in a manner known per se, preferably with the reduction of amide groups suitable metal hydrides or hydrogen compounds of Bore, or

c) a tertiary amine of the formula (VIII) or (X) (see formula sheet) with a Atnin of the formula (IX) or (XI) (see formula sheet) is implemented or

d) a disubstituted diamine of the formula (XII) (see formula sheet) is reacted with a compound of the formula (XIII) (see formula sheet), whereby under a) to d) R ¹ , R ² , R ³ , X, I, A , B ui

a) have given meaning or

a) to d) R, R, R, X, T, A, B and η those above) under c) and d) Z those below

e) a cyclic diamine of the formula (XIV) (see formula sheet) is reacted with a compound of the formula (III), where R ¹ = R ² , X = Y, A = B and R ¹ , R, X, A and η the above and Z have the meaning given under a), or

f) an H, monoaralkylated cyclic diamine of the formula (IV) (see formula sheet) is heated without a solvent or in an inert solvent and is aralkylated in the process, where R, R, X, A and η have the meanings given above.

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The advantage of method e) is that you can look at the Pipera-.in-

iar
ring can take advantage of the typical tendency towards bisalkylation.

In the reactions a), c), d) and e), the corresponding alkyl esters vm mineral acids or organic sulfonic acids are expediently in a solvent which is inert to the reaction, such as alcohols, for example. B. Äthancl, Ie.prcpanol and butanols BenzA, toluene, xylene or hesitylene with the free amines in the presence of at least an equivalent amount of an alkali metal carbonate or a tertiary amine or with an equimolar excess of the cyclic diamine or without acid acceptors equimolar in dimethylformamide at 70 to 160 C _{t of} course at most at the boiling point of the corresponding solvent, brought to reaction, under certain circumstances even at elevated pressure. Working under reflux is preferred. B. sodium hydrogen carbonate, f'ntriumcarbonat or potassium carbonate in question, as tertiary amines z. a, pyridine, picoline, triethylamine, tributylamine and Düscpropyläthylamin called. In the course of the conversion of an aralkyl chloride, a small addition of NaI can accelerate the reaction.

In the reactions according to b), the reaction is in the liquid phase in ethers such as Diethyl ether, diisopropyl ether, dibutyl ether, but preferably in tetrahydrofuran, if possible at the boiling point of the respective solvent with suitable metal! hydrides, such as. B. lithium aluminum hydride or suitable hydrogen connections of the Bore such. B. Diborane carried out. The decomposition deaf non-isolated adduct can be 'saturated' with ethyl acetate Sodium sulphate solution <which is better done directly with water.

In the case of the reactions a), c), d) and e), in the case of the equimolar reaction the reactant in dimethylformamide the corresponding end product (I) serve as an acid receptor themselves.

The ejfSetriech disubstituted cyclic diamines can also be passed through simply heating N-Minoaralkylated cyclic diamines after Implementation f) produce. The addition of catalytic amounts of acid accelerates the conversion process. The course of the synthesis can be carried out by thin-layer chromatography to be determined.

According to the process according to the invention, yields of over 95% can be achieved achieve the theory. The efficiency of type a) is generally more special Easily technically feasible because they are particularly smooth and in good yield runs. 409837/1090

The cyclic ones suitable as starting material for procedure a) Diamines of the formula (II) are, for example, N-benzyl-piperazine, N-phenylethyl-piperazine, N- (ά, -phenylethyl) -piperazine, N-phenylpropylpiperazine, N-phenylpropyl- (2) -piperazine, N-tetrahydronaphthylmethylpiperazine, N -Indanylmethyl-piperazine, N-diphenylmethyl-piperazine, N-naphthylmethyl-piperazine and the respective corresponding homopiperazine compounds; also cyclopentylmethylpiperazine, such as N-cyclopentylmethylpiperazine, N-cyclopentylethylpiperazine, N-cyclopentylethylpiperazine, N-cyclohexylethylpiperazine and the corresponding Hcmopiperazine connections; also N-heterocycloalkyl-piperazines or Hooopiperazines, such as N-furfuryl-piperazine, N-tetrahydrofurfuryl-piperazine, N-thenyl-piperazine, N-pyridylmethyl-piperazine, N-picolyl-piperazine ^ N-quinolylmethyl-piperaein,

N-Isoquinolylmethyl-piperazine, N- [ßenzc-1, ⁱ f-dioxan (2) -methyll-piperazine

and 2,5n-dimethylprperazine as well as the corresponding homopiperazine compoundsL furthermore in each case aromatic nucleus halogenated, nitrated, alkylated, alkoxylated, aminated or OH derivatives of the above-mentioned compounds.

Suitable cyclic diamines of the formula (IV) are, for example, N-thenyl- (2) -piperazine, N-thenyl- (5) -piperazine, 5-chloro-thenyl- (2) -piperazine, 5-methyl-thenyl- (2 ) -piperazine or the corresponding Hcmopiperazine and 2,5-dimethylpiperazine.

The alkyl halides required by method a), c), d), e) are preferably chlorides or bromides, the sulfonic acid esters are preferably toluene » sulfonic acid ester.

The stability of the crystalline compounds allows the production of Medicinal preparations for oral, parenteral and rectal administration. The production of these preparations can take place according to the usual practice Mixing in suitable and compatible aids, such as starch, miIchsucker. Cellulose derivatives, stearic acid or its salts, solvents, solubilizers. Cone mass, chlorides, phosphates and carbonates, to » Example sodium bicarbonate, done in a manner known per se to powders, tablets, coated tablets, capsules, suppositories, solutions, pastes or suspensions.

The therapeutic effectiveness of the substances according to the invention was determined by means of reserpine antagonism (B. Rubin et al., J. Pharmacol. Exp. Therap. 120, 125 (1957)) and tetrabenazine catalepsy in mice (modification according to S. Sulser et at., Fed. Proc. J ^, 268 (1960), Aon. ii, _AtoJ . _{W. &} »9.W « w 409837/1090

The compounds show intense antidepressant effects at beneficial Toxicity. In addition to their anti-depressive effect, they also show strong analgesic / duf ^ fi ^ Sn'Sirithing test proven «The anti-inflammatory Effects can be seen from Table 3.

On reserpine hypothermia in mice (B.M. Askew, Life Science JO, 725 (I963)) a clear antagonistic effect can be demonstrated »which, interestingly enough, lasts much longer than 6 hours - ·

The known side effects of tricyclic antidepressants, such as strong spasmolytic and adrenolytic effects, such as anti-convulsive effects against pentetrazole, nicotine and electric shock convulsions not found in the compounds according to the invention.

The hexobarbital anesthesia in the mouse is insignificantly prolonged. In the difference the fighting behavior of mice does not become the tricyclic antidepressants influenced. It is particularly advantageous that therapeutic doses do not result in any cardiovascular damaging effects on dogs.

Unless otherwise stated, the percentages in the examples are based on weight.

Examples

1) K - [_ Thenyl- (2) J-Ä'-benzyl-piperazine dihydrochloride (see table ^, Mr. 1)

A) 705.2 g of N-benzylpiperazine are dissolved in about 750 ml of benzene and a solution of 265.0 g of 2-thenyl chloride in about 250 ml of benzene is added. The mixture is held at about 80 ° C. for 1 hour. After cooling, the solid product (N-bensylpiperazine hydrochloride, from which the base can be released again in the usual way) is filtered off with suction and the filtrate is concentrated. The residue can be distilled at 1 ^ 9-151 ° C (0.2 Torr) or recrystallized from petroleum ether (melting point 68-69 ° C). Yield 425 g (78% of theory).

After the base has been dissolved in ethanol, hydrochloric acid becomes strong with ethanolic acid acidified and the resulting dihydrochloride recrystallized from water. Melting point: 270 - 28o ° C with decomposition, from 170 ° C sublimation.

A09837 / 1090

The same product can also be obtained in the following ways ι

B) 9.1 g of N- LThenyl- (2) J-piperazine are dissolved in 100 ml of dimethylformamide, treated with a solution of 6, k g of benzyl chloride in 100 ml of dimethylformamide and kept for about 3 hours at reflux · After evaporation of the The residue was taken up in methylene chloride, washed with potassium hydroxide solution and dried over anhydrous sodium sulfate. After removing the methylene chloride, 12.8 g (9 ^ % of theory) of base are obtained which can be distilled at 148 ° -152 ° C. (0.2 torr). After dissolving in ethanol, the dihydrochloride can be prepared in the usual way with ethanolic hydrochloric acid. Melting point: 280 ° C with decomposition

C) 9.1 g of N- \ _? Heiiyl- (2) J -piperazine are dissolved in 100 ml of pyridine, a solution of 6.4 g of benzyl chloride in 100 ml of pyridine is added and the mixture is refluxed for about 3 hours. The course of the reaction can be checked by thin-layer chromatography using the methods given below. After evaporation, the residue is taken up in methylene chloride, washed with ratron hydroxide solution and dried over anhydrous sodium sulfate. After removing the methylene chloride, the base is distilled in vacuo. Boiling point: 152-157 ° C (0.2 torr).

After dissolving in ethanol, ethanolic hydrochloric acid becomes practical quantitative yield, the dihydrochloride is produced, which is uakrystallisiert from water. Melting point: 280 ° C. with decomposition.

2) N, N ^l -BieQthenyl- (2) J -piperazine dihydrochloride (see Table 4, No. 2)

¹ 5t3 β Ν, Ν'-Bis-L. ^Tni ° Pk ^en ~ (2) -carbonyl_J -piperazine are in a refluxing suspension of 7.6 g of lithium aluminum hydride in 800 ml of. Tetrahydrofuran registered. After about 8 hours, the boiling reaction mixture is decomposed dropwise with water, cooled, separated from the precipitate, which is washed out well with tetrahydrofuran, and concentrated in vacuo. The remaining residue is dissolved in ethanol and precipitated as dihydrochloride with ethanolic hydrochloric acid solution, which, after recrystallization from ethanol, melts at 285 ° C. with decomposition. Yield: 9.8 g (56 % of theory)

3) N - [_ Thenyl- (2) j -N'-furfuryl-piperazine dihydrochloride (see Table 4, Mr.3)

13 _t 8 g of N - [_ Thenyl- (2) J -N '- [furan- (2) -carboxylic acid piperazidJ in 100 ml of abs. Dissolved tetrahydrofuran and in a refluxing suspension of clay 3.8 g of lithium aluminum hydride in 100 ml of abs. Added dropwise tetrahydrofuran. After about 5 hours, the boiling reaction mixture is decomposed dropwise with a tetrahydrofuran-water mixture (5 + 1 vol.), Cooled and separated from the precipitate, which is washed out well with tetrahydrofuran or acetone

and concentrated in vacuo. The remaining residue is dissolved in methanol, strongly acidified with hydrochloric acid and the dihydrochloride obtained after evaporation is recrystallized from a methanol-water mixture. Melting point: 280 ° C with decomposition. Yield: 12.5 g (75 % of theory)

4) H- {3 * henyl- (2 ^ -H ^l -Cl-nitrobenzyl) -piperazine dihydrochloride (see table 4, Mr. 9)

18.2 g of H-jjThenyl- (2) J -piperazine are dissolved in 100 ml of xylene and with 15 »2g

anhydrous, powdered potassium carbonate and 17 * 2 g of 2-nitro-benzyl chloride were added. The batch is kept at about 130 ° C. for 10 to 15 hours (An addition of a little HaJ accelerates the reaction), cooled, washed with water in a separating funnel and the xylene solution, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue is taken up in ethanol, strongly acidified with ethanolic hydrochloric acid (20 #ig) and the result accumulating precipitate sucked off. Yield: 33.0g (97 # of theory). That Product can be recrystallized from methanol. Melting point: 245 ° C below Decomposition"

5) H- [_Thenyl- (2) J -H'- [_benzo-1, * f-dioxane (2) - methyl f-piperazine dihydrochloride (see Table 4, Mr. 15) ~~

3t3 g of H-jjThenyl- (21Q-piperazine are dissolved in 50 ml of xylene and 2.9 g

2- (p-Tosyloxymethyl) -benzo-1,4-dioxane added. The mixture is refluxed for about 5 hours. The progress of the reaction can be followed by thin-layer chromatography. After cooling, the precipitate is separated off and the filtrate is concentrated. The oil which remains in almost quantitative yield is dissolved in ethanol and an excess of ethanolic salt is added. The resulting dihydrochloride is separated off and underistallized from methanol. Melting point: 245-253 ° C. with decomposition. Yield: 1.8 g (49.6 % of theory). Further product can be obtained from the mother liquor by evaporation.

6) 1,4-Bis-thenyl- (2) J-perhydro-i ^ -diazepine dihydrochloride (see Table 4, Mr. 22).

A solution of 88.3 g of perhydro-1,4-diazepine in 500 ml of xylene is mixed with 116.8 g of thenyl (2) chloride were added and the mixture was refluxed for about 1 hour. Of the The course of the synthesis can be determined by thin-film chromatography. To the cooling is suctioned off and concentrated. The suctioned solid product is dissolved in water, the aqueous solution extracted with xylene, the xylene solution evaporated and the evaporation residue with the evaporation residue Xylene solution of the original batch combined. These united return

409837/1090

levels are taken up in methylene chloride, with aqueous 30 # Sodium hydroxide solution and then extracted with water and the methylene chloride phase, after drying over sodium sulfate, concentrated in vacuo. The evaporation residue is distilled twice at 0.1 torr. Boil point: 161 - 165 ° C. Yield: ^ 5.7 g (5 ^ % of theory) The distillate is taken up in ether, ethereal hydrochloric acid is added, the solid product is suctioned off and after boiling with acetone from methanol (possibly in the presence recrystallized from activated charcoal. The dihydrochloride obtained melts at 218 ° -24 ° C. (sublimation from 195 ° C.).

The following table k shows the formulas of numerous compounds according to the invention and their most important characteristics. Their composition and structure was verified by elemental analysis as well as UV, IR and nuclear magnetic resonance spectrography. To characterize the substances obtained (see table k) , they were tested by means of thin-layer chromatography. The results are shown in Table k .

Thin layer chromatography as shown in the table k listed substances Sorbents:

Plate: Superplasticizer:

(Prefabricated panels from Merck AG, Darmstadt),

Running route:

Silica gel

5 x 20 cm

I chloroform-methanol conc. ammonia

(85 + 1 ^ + 1) (chamber saturation)

II chloroform-methanol-85% formic acid (85 + 10 + 5) (chamber saturation)

III chloroform-methanol (90 + 1θ) (chamber saturation)

10 centimeters

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Claims (1)

Claims Compounds of therapeutically active thiophene derivatives Ν, Ν'-disubstituted cyclic diamines of the formula (I) (see formula sheet), thereby marked that No at least mononuclear, sulfur-containing heterocyclic heat with at least one or no double bond and 5-10 atoms in the ring? - system that is unsubstituted or at least once by at least one Substitutes from the halogen, nitro, alkoxy group with 1 to 3 carbon atoms or alkyl is substituted by 1 to 6 carbon atoms, R is an at least mononuclear carbo- or heterocyclic radical with 5 to 10 atoms in the ring system, which contains at least one oxygen, sulfur or Contains nitrogen atom, has at least one or no double bond, unsubstituted and / or at least once by at least one substituent from the group halogen, nitro, trifluoromethyl, alkyl with 1 to 6 C atoms, hydroxy, alkoxy, with 1 to 3 C atoms or amino, alkylamino or dialkylamino is substituted by 1 to 3 carbon atoms in each case, K no or at most 2 identical or different substituents and although alkyl groups with up to 2 carbon atoms or phenyl groups, X and Y are identical or different and have zero or an alkylene group Represents 1 to 3 carbon atoms in the chain which is unsubstituted or contains up to 3 alkyl groups with up to 3 carbon atoms each as side groups or has a phenyl or thienyl group in the side chain, A and B are the same or different and are a methylene group or zero, with the proviso that when X = zero ₍ A is a methylene group and when Y a is zero, B is a methylene group and η denote 2 or 3, or represent acid addition salts of these compounds. 2) Compounds according to claim 1, characterized in that they are acid addition salts of mono- or polybasic mineral or carboxylic acids. 3) Process for the preparation of N, N'-disubstituted cyclic diamines of formula (I), characterized in that oJ an N-substituted cyclic diamine of the formula (II) or (IV) (see Formula sheet) is reacted with a compound of the formula (III) or (V) (see formula sheet), where Z is a halogen, alkylsufonyloxy or aryl sulfonyloxy group, or 409837/1090 b) an N _t N'-substituted cyclic diamine of the formula (VI), in which at least one of the symbols Q ^ C = O and the other A or B / or (TCI) _t in which R can stand for up to two oxo groups, (see formula sheet in each case) is deoxygenated in a manner known per se, preferably with metal hydrides or hydrogen compounds of boron which are suitable for the reduction of amide groups, or e) a tertiary amine of the formula (VIII) or (X) (see formula sheet) with an amine of the formula (IX) or (XI) (see formula sheet) is reacted, or d) a disubstituted diamine of the formula (XII) (see formula sheet) with a Compound of formula (XIII) (see formula sheet) is set, where under a) to d) E, R, R, X, Ϊ, A, B and η are those in claims 1 and under c) and d) Z have the meaning given under a), or e) a cyclic diamine of the formula (XIV) (see formula sheet) with a 1 2 compound of formula (III) is implemented, where R sR, X = Y _t A «B and R, R ^, X, A and η are those given in claim 1 and Z are those given under α Have meaning «or f) an H'-monoaralkylated cyclic diamine of the formula (IV) (see formula sheet) is heated without a solvent or in an inert solvent and is aralkylated here, where R, R ^, X, A and η have the meaning given in claim 1. 4) Process according to claim 3 f, characterized in that catalytic amounts of acid are added for the aralkylation. 5) Process for the preparation of acid addition salts of Ν, Ν'-disubstituted cyclic diamines of the formula (I), characterized in that the compounds obtained according to claim 3 or k are reacted with suitable acids to form acid addition compounds. 6) Method according to claim 3 *, characterized in that the reactions a), c), d) and e) in an alcohol or in solvents which are inert towards the reaction in the presence of an acid acceptor or without the addition of one Acid acceptor take place in dimethylformamide. 409837/1090 7) Method according to claim 3 »characterized in that the implementations according to b) in ethers such as diethyl ether, diieopropyl ether or tetrahydrofuran be performed. 8) Method according to claim 3 »characterized in that the implementation after f) is carried out without a solvent or in an inert solvent such as xylene. 9) Process for the production of pharmaceutical preparations, characterized in that at least one compound of the general formula (I) optionally together with at least buckets of solid or liquid aid or carrier substance and optionally together with at least one other Bringing the active ingredient into a suitable dosage form. 10) Pharmaceutical preparation characterized by an effective dose a compound of the formula (I) in addition to at least one solid or liquid Carrier or additive. February 26, 1973 Dr. K / e 409837/1090