DE1810836A1 - Novel benzamidine derivatives and processes for making the same - Google Patents

Description

November 1968

Chinoin Gyogyszer- 6s Vegyfcazeti Term6kek lyhra RT, Budapest IV, Τδ utca 1 - 5, Hungary

NIiUE BENZAMIDINE DERIVATIVES AND VERi ¹ AHHRf! i'.llH HIiIt. ! ΤιαΜ I) KRcJK UUiN

iiia itft announced ¹ . , viaß dae 4 Hüx.yi ^: λ. _; ;! /; ι i ¹ ^:!. y ^! - ν λ \ Λχ '. l ·. ι ϊϋΐαΐ r: -: -. hi ut'hydrate when fighting against! ^; ; -:;,! ·;,. '· * :( ^;; * »' ■ n.-iü.v, • v /: harlatina gymneLxJ a, Dip ■ · lldiiiai, -aniuin, Ta-MJn μ i. »1 f: u ini ti and hk'ui üüiiOv-.cua gi anai u.ju.i ii ^: fu] gr ^ i ν., .- w.-T \ l3t wtiMcn Can. This connection makes ahio an important Wurnunlttei (Nature 206, 408, 1965). Other 4-A.lkox, yN, N ~ dlalky] - -naphthamidina have aich. Ώα äi ;; döiu purpose ebeufallg aid wlrkaa / 7/128 alt.

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approve. ·

In the article mentioned, for the production of the Compounds a process "described, according to which as starting material 4-alkoxy-naphthonitrile and Ν, Ν-diaubatltuier- · te amino magnesium halides can be used. The weaen of the above method is that ethylinagnesium bromide implemented with a secondary aniine in ether as a medium and the obtained N, N-disubstituted arnihomagnealum halide is brought into reaction with a 4-alkoxy-napthonitrir « (See Belgian patent specification No. 645,534)

According to a general procedure, amidines are prepared by combining nitriles with primary or secondary amines be reacted in the presence of anhydrous aluminum chloride (Houben-Weyl: The methods of Org.Chem. XI. Volume 2. Page 46, Thieme, Stuttgart, 1958 ') “This general method forms the basis of the method described in the published Hungarian application no. WE-348 (Szab.Közl * 49 »February 1967,}.

It has been found that the new benzamidines of the "general formula

in which.

A hydrogen * halogen or an aietler

BAD GRlQlNAL

B ee alkoxy, dialkylaminoalkoxy, alkyloulfonyloxy, Arylaulfonyloxy or nitro group;

D signify hydrogen, halogen or a lower alkyl group

R and R each represent an alkyl group or an alkylene group, in which case the subatituents R and R together with the nitrogen atom to which they are attached form a heterocyclic ring which can contain an oxygen atom or an optionally substituted nitrogen atom as a further hetero atom, and which ring may optionally be substituted, and the salts thereof have anthelmintic properties. When administered orally, 'some representatives of these compounds by Dictiocaulus' cure lung worm disease of sheep and cattle caused with an efficiency of 6O-7O% "The tapeworm disease of rats, ducks, dogs and sheep could by applying to the -obi-. gen compound group derivatives with a potency of almost 100 #.

The symbols R and R can be seen to form a heterocyclic Ring be linked, ζ.B. a piperidino? Morpholino or piperazine groups or their alkyl, aryl or alkoxy-substituted groups Derivatives.

R and R can individually mean alkyl groups, which can be identical or different. (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobatyl »etc.)

The substituents A and D stand for hydrogen, halogen (advantageously chlorine or. bromine) or a lower alkyl. "

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group with 1-4 carbon atoms (like methyl, ethyl or Butyl). The substituents A and B can also subnti liii r-rfcn Alley oil groups represent e.g. TrI fluorine thy 1.

The subatituent B advantageously means a lower alkoxy group with 1-4 carbon atoms (e.g. methoxy, ethoxy, Propyloxy, terc. Isobutoxy etc.), an alkylaulfonyloxy group (advantageously with 1-4 carbon atoms, like the Mezyloxy group), an arylbulfonyloxy group (e.g. an optionally substituted phenylsulfonyloxy groupjLike the p-toluenesulfonyloxy group) a dialkylaminoalkoxy group (e.g. the dimethylaminomethoxy group) or a nitro group

Particularly advantageous representatives of the compounds of formula I. are the following derivatives: 4-n * -alkoxy ~ K, N "- -dl-n-alkylbenzamidines _; such as 4-n-butoxy-N, N-di-n ~ butylbenza. - mldin and 4-n-Hex ^ loxy-N, N-di-n '~ butylbenzaraidine; 4-n ~ alkoxy ~ -N-morpholino-benzamidlne _f like 4-n-butoxy-N-morphollno-benz-amidln ; 4-n ~ alkoxy-N-pentamethylene-benzamidine, such as 4 ~ n- -butoxy-II-pentaraethylene-benzamldinj 4-Nltro-N, N-dl - n-ßlkyl ~ -benzamidinei, e.g. 4-lfitro-- N, W-dl-n-'butyl ~ ~ benzamldinji 4HMethylsulfonyloxy Br, Ii-di- "n-alkyl-benzamidljne such as 4 ~ methyl ~ aulfonyloxy-N _J N-di-n-butyl-benzaml DINj · 4 ~ PhenyloUlfonyloxy ~ -ΙΓ, Ν-dl-n-alkyl-benzamidine, e.g. 4-phenylsulfony.lOxy-IT ,, N * ~ -dl-n-buthyl-benzamidine 3HBTaIogen-4-methyIsulfon ^ loxy ~ 5 ~ -alkoxy-N, N-di-n-alkylbenzamidines, such as 3-bromo- "4-methylsulfonyloxy-5-niethoxy-N, ir-di- ^ n -but; y 1-benzamidine. The term" halogen * ¹ includes all four halogen atoms d »H» chlorine »bromine» iodine and fluorine.

The amidines of the formula I are basic compounds

vC / äw; _S Ä 90 9 88 27 1773 "■""■■■."

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Character and capable of forming acid addition salts. The salts can be mixed with inorganic acids (e.g. with hydrogen halides, Sulfuric acid or phosphoric acid) or organic acids (e.g. tartaric acid, salicylic acid, formic acid, Acetic acid, propionic acid, emboxylic acid, oleic acid, maleic acid »fumaric acid or sulfonic acids, such as naphthalenesulfonic acid) are formed.

It was found that the benzamldines of the general Formula · I and salts thereof can be prepared according to the invention by using benzonitriles of the general formula

II.

where A, B and D have the above meanings, with secondary Amines of the general formula

in.

i; B and R have the above meaningü, umjetafc, Naoh ei

In an embodiment of the invention, the "/ er ~ fahrsiia" are based on the formula "it" form of Grignard compounds. The method is particularly suitable for the preparation of the "Ii, If-Dia, lky! derivative". Sa namely, that the triethylamine ": omplex of Ath, / l! n'i _: tnü; jium-

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bromide with secondary amines e.g. with a dialkylamine very advantageously in the corresponding Ν, Ν-Dlalkylamino- -magnesium bromide can be transferred, which with the Nitrile gives the corresponding amidine.

This method can also be used in the case of cyclic secondary Bases are used. The solvents used are advantageously hydrocarbons, especially benzene or toluene into consideration.

Completion of AmiUnbildung is done with benzene or the reaction mixture formed by toluene is decomposed with ice and ammonium chloride. From the amidine solution thus obtained the impurities are removed by washing with dilute acids or with water. Through this procedure e.g. the 4-butoxy-N »N ~ butyl ~ benzamidine chlorohydrate in a yield of 75 "" 80 ^ in ^ rather pure, to the immediate medical use appropriate condition obtained «The above and detailed in the examples Embodiment is much simpler than the known one

11th

Isolation of the N.HHDialkylaniidines {J. At · Upper. So c «XL» 3932, 1949).

In this known process, the IfsBI-dlaubstitulei * te amidln is separated from the iniin by YafcwMdeatlllation or the mixture consisting of the unreactive BTitrile amin and amldin is siasi? Sfaaeerdaiapfdeatillatlon unterlYOrfsn "after which with washing" mimiscliti & re Amiäin in solvent (aB ^ .Athe-ri aufeaoBmieia and - ■ separated wlrö

BIe SaI ζM.ld. uiig kaati nm? nsioh this ilailaahaea "done J? aoii einar wisiteroa- fort el! adhere

08tö2 / t7f3 "■

BADORlGfNAL

¹ ■■ ■■?

According to the process according to the invention, the amides of the formula III. reacted with the nitriles of the formula II. in the presence of Lewis acids. Aluminum chloride is advantageously used as the Lewis acid, uzw. expediently in an anhydrous state. Other Lewie acids such as boron trichloride, boron pentachloride, zinc chloride can also be used. As a solvent, such as benzene or toluene are used in this Ausführungsfonn advanta- · way _{hydrocarbons}.}

The new compounds of the formula I prepared according to the invention can, if appropriate, be converted into their acid addition salts. The bases can be released from their salts or the salts can be converted into other salts. For salt formation, inorganic acids (e.g. hydrogen halides, sulfuric acid, phosphoric acid) or organic acids (e.g. tartaric acid, salicylic acid, formic acid, acetic acid, propionic acid, erabonic acid, oleic acid, maleic acid, fumaric acid or sulfonic acids ₍ such as naphthylinsulfonic acid) can be used is carried out in a known manner by adding an equivalent amount of the corresponding acid to the solution formed with an organic solvent, to the amidine base.

The compounds of the invention which can be prepared Formula I. and its salts can be used in veterinary or human therapy in the form of preparations, which the active ingredient and inert organic or inorganic

Contain carriers. As carriers, eg starch, gelatin, talc »liagneaiurastearat _f magnesium carbonate, poly

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alkylene glycols, vegetable oils, water, etc. are used will. The pharmaceutical preparations can be used in rectal, oral, or parenteral administration Forms, e.g. ala tablets, dragee3, capsules, suppositories, Solutions, suspensions, emulsions or injectable preparations to get finished. The preparations can also contain other auxiliaries (e.g. lubricants, fillers, wetting agents, Stabilizers, emulsifiers, etc.) and contain other pharmaceutically valuable compounds.

Further details of the procedure are given in the examples refer to. However, the scope of the invention should by no means be limited to the examples.

Example Ij

7i.3 g of Magneaium shavings, 100 ml of dry benzene and 30.3 g of triethylamine are used in a stirrer and heated to 40-45 ° C with constant stirring. To the reaction mixture are at once 15 ml of a solution in 100 ml

Il

poured dry benzene dissolved 32.7 g of ethyl bromide; the turbidity of the reaction device indicates the onset of the

It

Reaction. The residue of the benzene ethyl bromide solution is added dropwise to the solution over a period of 3 hours, after which the mixture is stirred for a further hour at this temperature. 38.8 g of di-n-butylamine are then added dropwise at a temperature of 40-45 ° C. over a period of 30 minutes. Athane escapes during the addition. The Reaktionsgemisoh is a further 20 minutes at a temperature of 40-45 ⁰ C ^- stirred, followed by a solution of dry 35tO4 g of 4-n-ButoxybeBLZOiiitril * • in benzene the reaction mixture, are added and. another 2 hours *

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which is refluxed. After cooling to room temperature, the reaction mixture is poured onto a chamber of 18 g of ammonium chloride and 400 g of ice. After separating the aqueous phase, it is shaken out with 200 ml of benzene, the benzene solutions are purified, washed with 2x100 ml of waaaer, whereupon 90 ml of concentrated hydrochloric acid After separating the aqueous phase, the benzene solution is washed with 2 × 100 ml of water, later concentrated to 200 g, diluted with 200 ml of acetone and, after standing for half an hour, the crystalline product is filtered, washed with acetone and dried g of 4-n-butoxy - N "N-di-n-butylbenzamldinchlorhydrat obtained (melting point: 219-221 ⁰ C).

Example 2t

15.5 g of di-n-butylamine are added to 30 ml of a dry suspension of 8 g of anhydrous aluminum chloride in toluene. After stirring for half an hour at a temperature of HO ⁰ G, 5 »3 g of 4-n-butoxy-benzonitrile are added, whereupon the mixture is stirred under reflux for a further hour. The dark brown solution is cooled to 60 ⁰ C, diluted with 100 ml of benzene and poured into the mixture of 20 ml η iJalzsäure and 20 ml of ice. The benzene-toluene solution is separated off after the phases have separated and the aqueous phase is extracted again with 50 ml of benzene. The combined benzene-toluene solution is washed with 3 × 50 ml of iawanser, filtered with charcoal and concentrated to 26 g, then the thick, crystalline paste is diluted with 25 ml of acetone and the 4-n-butoxy-N which is filtered after cooling for one hour »N-di-n-

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-benzamldine chlorohydrate washed with 3x10 ml acetone. After drying, 8.45 g of the product are obtained. Melting point: C. Aue 50 ml of hot water is recrystallized, 8 g of the product are obtained. Melting point: 214-220 ⁰ C.

Similar to the procedure of Example 1, from The following amidines are prepared according to the starting materials will:

Example 3;

4-n-hexyloxy-N, N-di-n-butylbenzaniidine chlorohydrate. (Melting point: 178-180 ° G)

Example 4:

4-n-Butoxy-N-morpholino-benzamidine-3alicylate. (Melting point: 146-147 ° C)

Example 5ί

4-n-Butoxy-J! I-pentaraethylene ~ benzamidine sallcylate, (Melting point: 132-134 ° C)

Example 6:

4-n-Butoxy-N-pentamethylene-benzamldln-chlorohydrate. (Melting point: 188 ° C)

Example 7:

4-n-Butoxy-N-pentamethylene-benzamidine-tartXrate. (Melting point! 157-158 ° C)

Example 8:

4-lfitro-H »Jf-dl-n-butylbenzaniidln-chlorohydrate (Melting point * 147-148 ° G) Beiaplel 9 χ

The 2,2 ** - Hydrojcy-3,3 * -carboxy- ^ inaphthylmethan salt dea 4-i3 * -Dimethylaminopropaxy) ~ jy,

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. (Melting point: 221 ° C)

Example 10:

The mixture of 8 g of sublimated aluminum chloride, 20 ml of di-n-butylamine and 6 g of 4-mesyloxy-benzonyltrile (melting point: 96 ° C.) is heated for 2 hours. The thick, brown melt is split with a mixture of approx. 70 ml of ice and 30 ml of 5x5 b hydrochloric acid. The mixture obtained is boiled, clarified with charcoal, filtered and, after cooling with ice for three hours, the filtered crystalline product is covered with 20 ml of acetone. After drying, 7 E of 4-mesyloxy- -NjN-di-n-butylbenzamidine chlorohydrate are obtained. (Melting point: 211-212 ° C)

Example 11:

According to the method described in Example 10. 4-Phenylsulfonyloxy-benzoritrile (melting point: 62-64 ° C) 4-phenylsulfonyloxy-N, N-di-n-butylbenzamidine ~ -chlorohydrate (melting point 162 ° C) obtained.

Example 12:

According to the procedure described in Example 10, 3-bromo-4-mesyloxy ~ 5 ~ ^ ethoxy-benzonitrile (melting point j 162 ° C) the 3-bromo-4-meayloxy-5-methoxy-N, N ~ di - n- -butyl-benzamidine-chlorohydrate (melting point 155 ° C) obtained will.

Example 13 »

Following the procedure of Example 10. becomes from

3-ethyl-4-methoxy-benzonitrile (melting point 124 ° 0 / 0.2 Hgmrri) " the 3-ethyl-4-methoxy-N, N-dibutylbenzamidin-hydrochloride .manufactured. (Melting point * 178 ^ 179 ° C)

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Example 14s

The solution of 4 ~ nHi
2 _S 2 "-dihydroxy-lel'-tünaphthyl-methane -3 t 3'-dicarboxylic acid is reacted in acetone to give the BMBonet which melts at 162 ° C.

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Claims (1)

PATENT CLAIMS: 1. Compounds of the general formula A is hydrogen, halogen, or a lower alkyl group; B an alkoxy, dialkylaminoalkoxy, alkylsulfonyloxy, Arylsulfonyloxy or nitro group; D is hydrogen, halogen, or a lower alkyl group; R and R individually represent alkyl groups or together represent one Form alkylene group, where the substituents R and R along with the nitrogen atom to which it is attached are, a nitrogen-containing -heterocyclic Rj. ng dl the one which can optionally be substituted and optionally oxygen atoms as a further heteroatom and / or the optionally substituted nitrogen atom may contain. 2 »4-n-ükoxjf ~ N,! I-'dI-H ~ 'alfc ₁ ; yl tenzamidlne and d ^ ru Salts " 3 * 4 "^ - But03iy-'H» l ^| r'-di-'E- ^> 'hiitjl - biin2aoidtn and de- S0S882 / 1773 BATH Jf 4. 4 ~ n-Hexyloxy-N, N-di-n-buty 1-benzamide in unit desaen salts. 5. 4-n-AlkoxyHfi-morpholIno-benzamidines and their Salee. 6. 4-n-Butoxy-N-morpholinoHaenzamidine and its Salts. 7. 4-n-Alkoxy-N-pentamethylene-benzamidines and their Salts. 8. 4-n-Butoxy-N-pentamethylene-benzamidine and deaaen Salts. 9. 4-Nitro-N »N-di-n-alkyl-benzamides and their Salts. 10. 4-Nltro-N, N-di ~ n ~ butyl ~ benzamldine and its salts. 11. 4-Methylaulfonyloxy-N, N-di-n-alkyl-b.enzamidine and their salts. 12. 4HS5ethyl8Ulfonyloxy ~ N _s iT - di-n-butyl-benzamidine and its salts. 13. 4-Phenyl-3Ulfonyloxy-NjN-di-n-alkyl-benzamidine and their salts. 14. 4-Phenyl-bulfonyloxy-I, I-di - n-butyl-benzainidIn and its salts. 15. 3-halo-4-me —N — alkyl — benzamidine and. their salts 16. 3-Broffl-4 ~ methyl lo
Hsensamidine and aesea salsa " 17 ο feS-fg & I ⁵ © !! SÖJ? li © 2? St © liBßg TOE @a psssiel Sa tsai. ios ^ a iais®a _D wherein. I ₃ 'B ₅ B ₀ 1 ■ = 14 - JÜ ^ ea ^ / 1 /, 3 BAD ORIGINAL and R ^{1 have} the meaning given in claim 1, characterized in that a connec tion of the general formula II. where A, B and »d D have the above meaning, with a secondary Amine of the general formula III around where H and R are as defined above, and is desirable also a obtained benzamidine derivative into one Acid addition salt transferred, or the base is released from a salt * or a salt is converted into another salt. 18. The method according to claim 17 * characterized s that the amine of the formula III is used in the form of a Grignara yerbia length. 19. The method according to claim 17 »characterized that the reaction is carried out in the presence of a Lewis acid. 20. The method according to claims 17 and 19, as ¹ -characterized in that anhydrous Aluainiuachlorid is used as the Lewis acid. 21. The method according to any one of claims 17-20, - 15 ~ 909882/1773 by geke η η ζ. eichn, et that the reaction is present. one. K _; ohl enwaaa ers t qffes al a L ösurigemi 11 e 1 carried out. , ·. -. 22. The method according to any one of claims 17 ~ 21 -, characterized geke η η ζ calibration η e t in that the amidine base of the formula I. in their formed with organic or inorganic acids salts, preferably in the hydrogen halides, sulfates, phosphates , Tart ^ rates, salicylates, formates, acetates, propionates, elaborates, oleinates, maleinates, fumarates or sulfonates, such as naplithalinsulfonates, or the bases are released from the salts or one salt is converted into another salt. 23. Pharmaceutical preparations characterized in that they contain as active ingredient at least one benzamidine derivative of the general formula I, wherein A, B, D _f R and R have the meaning given in claim 1, or contain its salts and inert pharmaceutical carriers. - 24. Pharmaceutical preparations according to claim 23, characterized in that it comprises at least one compound _r · according to any one of claims 2-16 as active ingredient. 25. Process for the manufacture of pharmaceutical Preparations according to claim 23 or 24 »characterized in that a compound of the formula I in which A, B, D, R and R have the meaning given in claim 1 have, or its salt with inert liquid or solid organic or inorganic carriers and optionally mixed with other excipients and used for medicine! - 909882/1773 «A ORIG | _NAL see use suitable forms ferfcigate3.lt. 26. The method according to claim 25 »characterized in that the pharmaceutical preparations in the form of tablets, dragees »capsules, solutions, suppositories, suspensions, emulsions, or injectables Completes preparations. - 17 909882/1773 L e r s e i t e