SE443558B - PROCEDURE FOR THE PREPARATION OF AMINOAL REFRIGERATIVE SUBSTANCES WITH PHARMACEUTICAL EFFECT - Google Patents

Description

7805591-0 2 represents a hydrogen atom, a nitro group, a cyano group, a lower alkyl group or a lower alkylsulfonyl group, and R represents a nitro group or a lower alkylsulfonyl group; where m represents an integer from 2 to 4; where n represents 0, 1 or 2; and wherein Alk represents a straight or branched alkylene chain containing 1-6 carbon atoms.

The term "lower alkyl" means groups containing 1-6 carbon atoms, preferably 1-4 carbon atoms, and the term "lower alkenyl" refers to groups containing 3-6 carbon atoms.

The compounds of formula I may exhibit tautomerism, and the formula is intended to cover all tautomers. When Alk represents a branched alkylene chain, optical isomers may be present, and the formula is intended to cover all diastereoisomers and optical enantiomers.

The preferred compounds of formula I are those compounds in which the symbols R1 and H2 independently represent a hydrogen atom or a lower alkyl group or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring. ; wherein Alk represents a straight alkylene chain containing 1-3 carbon atoms; where n represents 0 or 1; where Y represents = S, = O, = CHNO 2 or = NR 6, where H 6 represents hydrogen, nitro, cyano or alkylsulfonyl; where R; represents a hydrogen atom, an alkyl group or an alkoxyalkyl group; and where m and X have the meanings given above.

Particular preference is given to those compounds in which the side chains are in the meta-position 1 relative to each other.

In a preferred class of the compounds of formula I, the symbols B1 and R2 each represent a hydrogen atom or a methyl group, or together with the nitrogen atom they form a pyrrolidine ring; Alk represents a methylene group; m represents 0; Y represents = CHNO 2 or = NR 6, where R 6 represents nitro, q fi mo or methylsulfonyl; H3 represents a hydrogen atom or a methyl group; m denotes 3; and X represents oxygen. __ H, _ pp _ _ Below are specific examples of preferred compounds; of formula I: of '- P ^ 3' N-methyl-N'-β- (N, N-dimethylaminomethyl) phenyl] methyltigl-ethyl7-2-nitro-1,1-ethylenediamine; N-methyl-N'-ÅÉQ / 23- (N-methylaminomethyl) phenylmethyltig7-ethyl7-2-nitro-1,1-ethylenediamine; N-methyl-N '- [E- [E- (N, N-dimethylaminomethyl) phenoxypropyl] -2-nitro-1,1-ethenediamine; N-methyl-N'-Å3- [§- (N-methylaminomethyl) phenoxy] propyl] -2--nitro-1,1-ethenediamine; nN-methyl-N'-N-N- (1-pyrrolidinylmethyl) phenoxy] propyl--2-nitro-1,1-ethenediamine; N-nitro-N'-13-ÅE- (N, N-dimethylaminomethyl) phenoxy] propyl7-guanidine; N-eyano-N '-me cyl-N ".ß-ß- (rmr-acetylaminomethyl) -phenoxy-propyl-7-guanidine; N-methyl-N' - [É- [É- (N, N-dimethylaminoethyl) -phenoxy] -propyl7- - 2-Nitro-1,1-ethylenediamine; N-methanesulfonyl-N'-methyl-N "- [E-13- (N, N-dimethylamino] methyl) -phenoxy] propyl] guanidine.

The compounds of formula I form physiologically acceptable salts with inorganic and organic acids. Particularly useful salts are hydrochlorides, hydrobromides and sulfates; malate acetates and fumarates. The compounds may also form hydrates.

The compounds of formula I may be administered orally, topically or parenterally, or they may be administered in the form of suppositories. Preferably, oral administration is used. The compounds can be used either in the form of base or in the form of physiologically acceptable salt. The compounds are usually mixed with pharmaceutically acceptable carriers or diluents to form pharmaceutical compositions. C The compounds of formula I may be administered in combination with other active substances, e.g. conventional antihistamines.

For oral administration, the pharmaceutical compositions are suitably in the form of capsules or tablets, which may be long-acting tablets. The compositions may also be in the form of dragees or in the form of syrups. Examples of suitable compositions for topical administration are ointments, tinctures, creams, powders and sprays.

A suitable dose for oral administration is from 10 mg to 2 g per day, usually in the form of dosage units containing 2-200 mg of active compound per dosage unit. Parenteral administration can be by intermittent injections or by continuous infusion. Injection solutions may contain from 1 to 100 mg of active ingredient per ml.

For topical application, you can use spray preparations fi, 7805591-Û ointments, creams or tinctures. These compositions contain an effective amount of the active ingredient, e.g. of the order of 1, 5-2% by weight, calculated on the total weight of the composition.

The compositions described above can be used in both human therapy and veterinary therapy.

The compounds of formula I can be prepared according to the invention by a primary amine of the formula: R NAlk 1 \ /.

Bg \\ 2äÉš ::> - (cH2) nx (cH2) mNH2 (II) where R1, R2, Alk, X, n and m have the meanings given above, are reacted with a compound which can introduce the group -CNHR3, II where R; and Y has the meanings given above.

Compounds which can introduce the group -¶NHR 5 are isocyanate- Y er RENCO, isothiocyanates RBNCS and compounds of the formula: P NHR \ C / Eg H 'Q where Q represents a group ÄNR 6 or = CHR 7, and P represents a leaving group, such as a halogen atom, a thiomethyl group, a 3,5-dimethylpyrazolyl group or an alkoxy group, preferably a (III) thiomethyl group.

The reaction with an isocyanate or isothiocyanate can be carried out by allowing the amine of formula II and the isocyanate or isothiocyanate to stand in a solvent such as acetonitrile.

The reaction between the amine of formula II and a compound of formula III can be carried out by melting the reactants at elevated temperature, e.g. 100 ° C-120 ° C. When Q represents = NR 6, the reaction between the amine of formula II and the compound of formula III can also be carried out in a solvent, e.g. acetonitrile or ethanol, at elevated temperature. When Q represents = CHR 7, the amine of formula II and the compound of formula III can be stirred in an aqueous solution at room temperature.

When R 2 represents hydrogen, alkali metal cyanates and alkali metal thiocyanates can be used, the reaction being carried out at elevated temperature. Alternatively, organic isocyanates and isothiocyanates can be used, for example ethyl carbonisothiocyanatidate, basic hydrolysis being carried out in a subsequent step.

According to an alternative method, the amine of formula II is reacted with P g P '\\\\ fi //// (IV) a compound of the formula: wherein P and Q have the meanings given above, and P' has the same meaning as P, wherein P 'may also represent a group -§-A, where A' - 0 represents a lower alkyl group, eg methyl, when Q represents = CHNO2.

The resulting compound of the formula: R1 / I NA1k // 2. g (cH2) nr (cn2) mNHg-P (V) QR is then reacted with an amine R3NH2 to give a compound of formula I. Both reaction steps can be carried out in a solvent, eg ethanol or acetonitrile, at a temperature between room temperature and reflux temperature. The compounds of formula V are new intermediates.

The primary amines of formula II used as starting materials are new compounds. These new intermediates can be prepared according to a number of different methods, which are described below.

The amines of formula II, where X represents oxygen or sulfur, can be prepared from compounds of the formula: “ß šïñ / (cH2) nxn (X) where X represents oxygen or sulfur, where n has the meaning given above, and where R8 represents a group R1R2NAlk or a group that can be converted to this group. A compound of formula X is hereby reacted in the presence of a base, eg sodium hydride, with a compound of formula: L '(CH 2) m W (XI) wherein L' has the same meaning as L below and may in addition denote a sulfonyloxy group, for example methyloxy or tosyloxy, where m has the meaning given above, and where W represents a group -NH 2 or a group which can be converted into this group. If W represents a protected amino group, for example a phthalimido group, the protecting group can be removed in a subsequent step in the manner described above.

Groups that can be converted to the group R1R2NAlk are aldehyde groups, nitrile groups, carboxylic acid groups, amide groups and phthalimide groups. The group -CHO can be converted, for example, by reducing amination using an amine of the formula R 1 R 2 NH. Similarly, a carboxylic acid group can be converted to the corresponding acid halide or ester, which can then be reacted with an amine R1R2NH, after which the amide formed is reduced with, for example, lithium aluminum hydride to form a group R1R2NCH2-.

The amines of formula II, where n represents 1 and X represents oxygen or sulfur, can be prepared by reacting a compound of formula VI or VII below with a compound which can introduce the group -X (CH 2) mNH 2, where X denotes oxygen or sulfur and m has the meanings given above. When using a compound of formula VI, the presence of a base is suitable. When a compound of formula VII is used, the reaction is carried out under acidic conditions.

Rl Rl \ NAl _ NÅlk // _ R / I -ca on H2 ca L 2 2 (VI) gg g W7 (VII) In the above formula VI, L represents a leaving group, e.g. a halogen atom such as bromine, or an acyloxy group such as acetoxy.

The amines of formula II, where n represents 1, m represents 2 and X represents oxygen or sulfur, can be prepared by treating a compound of formula X, where n represents 1 and X represents oxygen or sulfur, with ethyleneimine.

The amines of formula II, where n represents 0, m represents 5 and X represents oxygen, can be prepared by catalytic hydrogenation of the corresponding nitrile of the formula: 's 0 (CH 2) 2 CN (XII) e.g. using rhodium on alumina.

The compound of formula XII can be prepared by a phenol of the formula: __; \ / 7 - on (XIII) 7805591-0 where R9 is a group which can be converted to the group R1R2NAlk, e.g. an aldehyde group, is reacted with acrylonitrile in the presence of a base, e.g. methanolic benzyltrimethylammonium hydroxide.

The amines of formula II, where X represents a methylene group, can be prepared according to standard methods from compounds of the formula: R CHECHQCOOH (XIV) where H8 e.g. represents a group R1R2NAlk, a carboxamide group or a nitrile group. An acid chloride or an ester of a compound of formula XIV may e.g. is reacted with ammonia, after which the resulting amide is reduced to give an amine of formula II, where X represents -CH 2 -, n represents 0 and m represents 2.

Alternatively, a compound of formula XIV, wherein R 8 may e.g. denotes a group R1R2NAlk, a carboxamide group or a nitrile group, is reduced by e.g. lithium aluminum hydride to form an alcohol of the formula: “in Wzxik ^ R / e a. (cV) acnecnaon, (XV) after which this alcohol is converted into a compound of the formula: Rs p _ c fl zc fl gcnzL '- (XVI) where R8 represents R1R2NA1k, and L' has the meaning given above.

The compound of formula XVI can then be reacted with ammonia to give an amine of formula II, where X represents -CH 2 -, n represents O and m represents 2. If a compound of formula XVI is reacted with an alkali metal cyanide, t. ex. potassium cyanide, a compound of the formula is obtained: 7805591-Û R8 _ w- cngcngcnzcn (XVII) This compound can then be reduced by e.g. lithium aluminum hydride to form an amine of formula II, wherein X represents -CH 2 -, and the sum of n and m is 3. Alternatively, a compound of formula XVII may be hydrolyzed to a compound of the formula: "s ~ -cn2cH2cn2cooH (xvIII) If the acid chloride of this compound is reacted with ammonia and the resulting amide is reduced as described above, an amine of formula II is obtained, where X represents -CH2-, and the sum of I n- and m is 3.

The amines of formula II, where n represents O and X represents a group -NH-, can be prepared by a compound of the formula: m2 (xxx) where R9 is a group which can be converted into a group R1R2NAlk, e.g. . a group 0 nlnanc-, is reacted with a compound of formula XI, after which any protecting groups are removed and the amide group is reduced.

The starting compounds of formula XIV can be prepared by catalytic reduction of a compound of formula NZ_ ___. \ * / cn = cucooxy (xx) during concomitant or subsequent modification of the aldehyde group. 7805591-0 10 About the reduction e.g. carried out in the presence of an amine R1R2N, the aldehyde group can be converted to a group RIRZNCHÉ.

In the above-described reactions for the preparation of amines of formula II, it is generally preferred to use intermediates containing the desired group R 1 R 2 Nlk or a protected form thereof, e.g. a phthalimido group. However, it is also possible to use intermediates containing a group which can be converted into the group R1R2NAlk, such a convertible group being converted into the group R1R2NAlk at any suitable stage of the preparation process. If R 1 and H 2 both represent hydrogen in intermediates used to prepare amines of formula II, the primary amino group may be protected in any reaction step, e.g. in the form of a phthalimido group, and the protecting group is removed in any suitable step in the manner described above.

When H1 and / or R2 denote hydrogen 1 intermediates used to prepare amines of formula II, the hydrogen atom or atoms may, if desired, be converted into alkyl or aralkyl groups using e.g. an alkyl or aralkyl halide. When B1 and / or R2 are to represent methyl, it may be appropriate to carry out an Eschweiler-Clarke reaction using formaldehyde and formic acid.

The invention is illustrated by the following non-limiting examples; Preparative Examples 1-6 describe the preparation of starting materials, Examples AG describe the preparation of intermediates of formula II, and Examples 1-9 describe the preparation of compounds of formula I. The thin layer chromatographic measurements given in the examples were performed on silica gel plates having a thickness of 0 , 25 mm mounted on a plastic carrier.

NMR data are given in ï values.

In Preparative Example 1. 3- (1-Pyrrolidinylmethylaphenol. 15.2 g of sodium borohydride were added to a solution of 48.8 g of 3-hydroxybenzaldehyde and 66.4 ml of pyrrolidine in ethanol.) After 18 hours, the ethanol was removed and the residual oil was acidified. The aqueous solution was then alkalized with ammonia and extracted with ethyl acetate. After evaporation of the organic extract, 21.4 g of the desired compound were obtained as an off-white solid with a melting point of ethyl acetate. 100 DEG-48 DEG C. R48 0.48 on silica gel on silica gel; methanol: 0.88 ammonia (80: 1).

Preparative Example 2. (a) 3- (N, N-dimethylaminomethyl) benzenemethanol. (1) 3- (N, N-dimethylaminocarbonyl) benzoic acid methyl fi å-- A mixture of 88 g of thionyl chloride and 33 g of benzene-1,3-decarboxylic acid monomethyl ester was heated at 10,000 for 1.5 hours. The excess thionyl chloride was then distilled off to give an oil which was used without further purification. A solution of the oil in dioxane was added to a cold solution of aqueous dimethylamine (40%; 56 ml) in dioxane, and the resulting mixture was stirred at 530 for 1 hour. The reaction mixture was then poured into dilute hydrochloric acid and extracted with chloroform. The organic phase was dried and evaporated to give 56 g of an oil.

Rf = 0.8 by thin layer chromatography on silica gel; ethyl acetate. NMR (CDCl 3): 1.8 m (2H); 2.2-2.7 m (2H); 6.1 s (3 H); 6.95 s (6H). (l) (b) The above examples were repeated using 70 g of ester and 118 ml of aqueous methylamine (25%). This gave 54 g of 5- (N-methylaminocarbonyl) benzoic acid methyl ester with a melting point of 128-13000. Rf = 0.57 by thin layer chromatography on silica gel; ethyl acetate. (2) 3- (N, N-dimethylaminomethyl) benzenemethanol. 36 g of 3- (N, N-dimethylaminocarbonyl) benzoic acid methyl ester in dry tetrahydrofuran were added to 16.6 g of lithium aluminum hydride in dry tetrahydrofuran. The reaction mixture was heated at 60 ° C for 3 hours, after which it was cooled and treated with water.

The solvent was removed, and the residue was treated with dilute hydrochloric acid. The mixture was made alkaline with sodium hydroxide and extracted with chloroform. The organic extracts were dried and distilled to give 16 g of an oil having a boiling point of 95 DEG-100 DEG C. at 0.1 mm Hg. Rf = 0.57 by thin layer chromatography on silica gel; methanol. (2) (b) The above examples were repeated using 25 g of the ester from (b) above. This gave 9.2 g of 3- (Nemethylaminomethyl) bonsone methanol with a boiling point of 110-115 ° C at 0.02 mm Hg. Rf = 0.36 by thin layer chromatography on silica gel; methanol.

Preparative Example 1. (a) 2- [3- [4- (N, N-dimethylaminomethyl) phenoxy] propyl] -1H-1SO- 7805591-12 12-indole-1 "2-§2H2-dione.

A mixture of 2.2 g of 80% sodium hydride and 6.95 g of 5- (N, N-dimethylaminomethyl) phenol in dry dimethylformamide was stirred at 5 ° C for 2 hours. Then 12.2 g of N- (3-bromopropyl) -phthalimide were added, and after 16 hours the reaction mixture was treated with water and extracted with ethyl acetate. After evaporation of the dried organic extracts, 15 g of the desired compound were obtained as a yellow oil. Rf = 0.35 by thin layer chromatography on silica gel; ethyl acetate. The oxalate salt of the product melts at 204-207 ° C.

The following compounds were prepared in a similar manner starting from the corresponding phenol (Å) and the appropriate bromoalkylphthalimide (B). (b) 14 g (A) plus 21.5 g (B) gave 21.4 g of 2- [3- [3- (1-pyrrolidinylmethyl) phenoxy] propyl] -1H-isoindole-1,5- (2H) - dion. nf = io, 46 by thin layer chromatography on siiikagei; methanol: 0.88O ammonia (80: 1). The oxalate salt of the compound melts at 167-169 ° C.

(G) 5 e (Å) plus 9.3 s (B) gave 8.7 s of 2- [3- (N, N-dimethylaminomethyl) phenoxy] butyl] 11H-isoindole-1,3- (2H) -dione . Rf = 0.56 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1). The oxa-ausaic of the compound melts at 169-170 ° C. (d) 5 g (A) plus 8.1 g (B) gave 5 g of 2-β-β- (N, N-dimethyl-aminoethyl) phenoxy; 7propyl7-1H-isoindole-1,5- EH) -dione with a melting point of 59-6o ° c. nf = 0.45 in thin layer fi s- chromatognaphy on silica gel; ethyl acetate isopropanolz water = 0.88 ammonia (25 = 15 = 8 = 2). (e) 2.0 g (A) Pins 3.4 g (B) gave 2.8 g of 2-β-β- (N, N-d1-methylaminoethyl) phenoxy] butyl7β1H-isoindole-1,3- (2H) - Ådion with a melting point of 522 ° C. RI = eO; 55ßvid thin-layer chromium fi agraphy on sïi1kage1; 'etv1acetan = ¿. isopropanol: water: 0.88 ammonia (25 [mu] l5: 8: 2). (f) 2.2 e (Å) plus 5.2 s- (B) gave 2.5 to 2-β-β- (N »N-dimethylaminopropyl) phenoxy] propyl7-1H-isoindole-1, } - (2H) -diem with an xo point of 25 ° C at 0.1 mm Hg: Rf = 0.5 by thin layer chromatography on silica gel; ethyl acetate: isopropanol-aqueous ammonia (25: 15: 8: 2). (s) 2.2 s (Å) plus 5.4 s (B) gave 2.6 α 2-β1- [3- (NN-d1-methylaminopropyl) phenoxy] butyl] -1H-180inO1-1,5- (25) - (h) ) (1) 7805591-Û 13 -dldn with a boiling point of 225 ° C at 0.4 mm Hg. Rr = 0.5 by thin layer chromatography on silica gel; ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2). 7.0 g (A) plus 14.1 g (B) gave 3.8 g of 2-β- (N, N-d1-methylaminomethyl) phenoxy] butyl7 -1H-isoindole-1,3- ( 2H) - dione oxalate salt. Rf = 0.5 by thin layer chromatography on silica gel; methano1: 0.88 ammonia (80: 1). 5 g (A) plus 9.7 g (B) gave 7.1 g of 2-β-βH- (N, N-dimethylaminomethyl) phenox; 7propyl7-1H-isoindole-1,3- (2H) - -dion. Rf = 0.5 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1). The oxalausal compound of the compound melts at 166-170 ° C.

Preparative Example 4. (a) 2- [5- [1- (N, N-dimethylaminyl) phenox17]: 177-1H-150-indole-1,2- (EH) -dione. 5.0 g of 3- (N, N-dimethylaminomethyl) phenol, 1.2 g of 80% sodium hydride and 15 g of 2-β- (α-methylbenzenesulfonyl) ethyl 7-1H-isoindole-1,3- (en) -dldn was precipitated at 90 ° C in dimethylformamide. After 12 hours, the reaction mixture was cooled, poured into ice water and extracted with ether. After evaporation of the organic solvent, 5.2 g of product were obtained in the form of a viscous yellow oil. Rf = 0.37 by thin layer chromatography on silica gel; methanol zetylacetate (lzl).

The product's melt melts at 166 DEG-167 DEG C.

The compounds listed below were prepared in a similar manner starting from the corresponding phenol (A) and 2- [§- (4-methylbenzenesulfonyl) e] y; 7-ln-1solnddl-1,3- (an) -dldn (c). (b) (0) 5 g (A) plus 11.7 G (c) gave 2, ug 2 <[š, ¿š- (N, N-d1-methylsminoeuyl) fsnsx¿7e fi yl7_1H-lssinddl-1,3- (an) _ -dlsn with a melting point of 84-85 ° c. Rf = 0.45 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). 2.2 g ()) plus,, 2 g (C) gave 0.5 g of 2-β-β- (N, N-dimethylaminopropyl) phenoxyethyl] -1H-isoindole-1,1- (2H) - -dion. Rf = 0.45 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2).

Preparative Example Q. (a) 2- [E- / E- (N, N-dimethylaminomethyl) phenoxy] propyl] 71H-isoindole-1,2H-digg, - r Q 7805591-Û 14 (1) 2- / 3- / 3- (Formyl) phenoxy7bropyl7-1H-isoindole-1,3- (2H2-dione. 0.61 g of 3-hydroxybenzaldehyde, 1.31 g of 3-bromopropylphthalimide and potassium carbonate were stirred in dimethylformamide at room temperature for 16 hours. After precipitation and drying, 1.37 g of product with a melting point of 102 DEG-10 DEG C. were obtained, Rf = 0.65 by thin layer chromatography on silica gel, methanol (toluene) (1: 9).

The compounds listed below were prepared in a similar manner. . (l) (b) 5 g of 4-hydroxybenzaldehyde and 10.4 g of the appropriate phthalimide gave 1.3 g of 2β-(formyl) phenoxyethyl] -1H-isoindole-1,3- (2H) -dione with a melting point of 131.5-135.5 ° C. Rf = 0.5 by thin layer chromatography on silica gel; methanol / chloroform (100: 100). (1) (c) 6.1 g of 2-hydroxybenzaldehyde and 12 g of the appropriate phthalimide gave 12.2 g of 2 [3 H] -β (phenyl) phenoxyl; 7-butyl; 2H) -dione with a melting point of 99.5-110 ° C. Rf = 0.8 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1). (2) 2- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl; 7-1] isoindole-1,3- (QH) -dione. 132 g of 2-β-β- (formyl) pure α, β-β-β, β-1H-isoamino-1,3- (one) -dione and 300 ml of 33% ethanolic dimethylamine were hydrogenated temperature and atmospheric pressure 1 ethanol over 10% palladium on charcoal. The catalyst was then filtered off and the filtrate was evaporated to give 142 g of the desired compound as a yellow oil. Rf = 0.35 by thin layer chromatography on silica gel; ethyl acetate. The oxalate salt of the compound melts at 204-20700. The following compounds were prepared in a similar manner starting from 53% ethanolic acetylamine and the corresponding phthalimide (B); (") (2) (b) 1.2 g P plus 20 ml 33% ethanolic dimethylamine gave 1.3 g of 2- [§- [F- (N, N-dimethylaminomethyl) phenoxy] ethyl] -1H- -isoindole-1,3- (2H) -dione Rf = 0.3 by thin layer chromatography on silica gel, methanol: 0.88 ammonia (80: 1) (2) (c) 10 g P plus 50 ml 33% ethanolic dimethylamine gave 7 g 2-¿ï-¿É- (N , N-dimethylaminomethyl) phenoxy7butyl7 -1H-1so-indole-1,3- (2H) -dione Rf = 0.55 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1) The product oxalate salt melts at 162 DEG-163 DEG C. 7805591-Û Preparative Example 6. 2- [R 3,3'-N, N-dimethylbenzenecarboxamide 57 ml of acetylamine in toluene was added at 5 ° C to 46 g of 3,5'-dithio- (chlorocarbonyl) benzene in toluene. tat. After evaporation of the extracts, 49 g of the desired compound were obtained as an orange oil. NMR (CDCl 5): 2.4-2.8 m (8H); 7.05 br (12H). (2) Ditio-bis-3,3'-N, N-dimethylbenzenemethanamine. 48 g of 3,3'-dithio-N, N-dimethylbenzenecarboxamide in dry ether were added to 20 g of lithium aluminum hydride in dry ether. The reaction mixture was stirred at room temperature, then cooled, treated with water and filtered. The filtrate was extracted with ethyl acetate, and the extract was dried and distilled. This gave 8.8 g of a colorless oil having a boiling point of 25 DEG C. at 0.1 mm Hg.

NMR (cncl) = 2.5-2.9 m (8H); 6.66 s (4 H); 7.8 s (6 H). (5) 2- [3- [75- (N, N-methylaminomethyl) phenyl] -167propyl] -1H-isoindole-1,1 (2H) -dione. 2.3 g of 80% sodium hydride and 7.8 g of dithio-bis-N, N-dimethylbenzenemethanamine were stirred at room temperature in dry dimethylformamide for 24 hours. Then 12.6 g of N- (3-bromopropyl) phthalimide were added. After 2 hours, the reaction mixture was treated with water and extracted with ethyl acetate. The organic extracts were evaporated, and the residue was purified by column chromatography on silica, eluting with a mixture of ethyl acetate and methanol. This gave 11.3 g of the desired compound as a light orange oil. NMR (CDCl 3): 2.0-2.4 m (4H); 2: 6 "'2: 9 m 6:15 t (Qlnf s (21%): 7.02 t (QIÜÉ 5 (6H); 7.98 m (EH) - Example A. 3- (3-aminopropoxy) -N-methylbenzenemethanamine dioxalate (1) 3- [E- (formyl) phenoxy] progignitrile.

A solution of 50.5 g of m-hydroxybenzaldehyde in 265 ml of acrylonitrile and 5 ml of 40% methanolic benzyltrimethylammonium hydroxide was refluxed for 20 hours. The reaction mixture was then diluted with 500 ml of ether, and the resulting solution was washed with a 5% sodium hydroxide solution and then with water. The ether solution was dried over magnesium sulfate, filtered and evaporated in vacuo. 32 g of a clear, colorless oil were obtained. Rf = 0.4 by thin layer chromatography on silica gel; chloroform. (2) 3- (2-Cyanethoxy fl-N-methylbenzenemethanamine hydrochloride.

A solution of 8.75 g of 3- [3 (phenyl) phenoxylpropionitrile in a mixture of 50 ml of 55% ethanolic methylamine and 200 ml of ethanol was stirred at room temperature with 0.8 g of 5% palladium on charcoal under a hydrogen atmosphere with pressure 1 atmosphere. After the uptake of hydrogen ceased, the mixture was filtered and the residue was washed with ethanol. The ethanolic filtrate and the washing solutions were combined, after which the volume of the resulting mixture was reduced and the concentrate was treated with an excess of an ethereal solution of hydrogen chloride. The precipitated hydrochloride was recrystallized from a mixture of ethanol and ether to give 7.9 g of the desired compound as colorless plates, m.p. 125-12800.

Analysis: Calculated for C 11 H 15 ClN 2 O: c 58.3 H 6.5 N 12.35% Found: C 58.1 H 6.5 N 12.5% (3) 5- (3-aminopropoxy) -N-methylbenzenemethanamine dioxalate .

A solution of 5.39 g of N-methyl- [ε (2-cyanethoxy) benzenemethanamine hydrochloride in 50 ml of methanol was eluted through an anion exchange column (Amberlyst A-26), and the eluate was evaporated to give the free base. such as a colorless oil. The free base was dissolved in 1,500 ml of ethanol and 25 ml of 0.88 ammonia solution, and the resulting solution was shaken with 2.5 g of 5% rhodium on alumina at room temperature for 6 hours under a hydrogen pressure of 280 kPa.

The resulting suspension was filtered, and the filtrate was evaporated in vacuo. The resulting residue was dissolved in ethanol and treated with an excess of ethanolic oxalic acid. The precipitated dioxalate salt was filtered off and dried, yielding 6.6 g of dioxalate salt, m.p. 196-198 ° C. Rf = 0.1 in thin layer chromatography on silica gel; methano1: 0.88 ammonia (99: 1).

Example B. 3- (3-Aminopropoyl) -N-methylbenzenemethanamine-dioxalate 8.5 g of 2-β-β: (formyl) phenoxy; 7propyl; 7-in-isoindol-1,3- (an) - The dione was stirred for 1 hour in 300 ml of a 53% ethanol solution of methylamine and then hydrogenated at room temperature and atmospheric pressure in ethanol over 10% palladium on charcoal. The reaction mixture was then filtered, and the filtrate was evaporated to dryness. The residue was dissolved in 50 ml of ethanol, and the resulting ethanol solution was treated with an excess of ethanolic oxalic acid, the precipitate formed was recrystallized from a mixture of ethanol and water to give 5.9 g of the desired compound. in the form of colorless grains with a melting point of 196-19800.

Rf = 0.1 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (20: 1) Example 2 C. (a) 3- (5-aminopropoxy) -N, N-dimethylbenzenemethanamine. 25 g of 2- [2- (N, N-dimethylaminomethyl) phenoxyl] propyl] -1H-isoindole-1,3- (QH) -dione were treated with 150 ml of a 50% ethanol solution of methylamine. After 24 hours at room temperature, 100 ml of ether were added, and a solid was filtered off. The filtrate was distilled to give 12.3 g of the desired compound as a yellow oil having a boiling point of 102-112 ° C at 0.2 mm Hg. Rf = 0.25 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia.

The following compounds were prepared in a similar manner starting from the corresponding phthalimide (C). (b) 5.4 g (C) gave 0.45 g of 3- (2-aminoethoxy) -N, N-dimethylbenzenemethanamine. Rf = 0.04 in thin layer chromatography on silica gel; m @ uan01 = ammon1ax (8o = 1). NMR (cnci) 2.8-5.1 m (1H); 6.05 t (2H); 6.55 S (2H); 6.98 t (arm 7.80 s (en), 8.4 base (an). '(E) 2.9 g (c) gave 0.8 g of Iz- (1s-aminobuuoxy) -Nm-dimethyl- benzene methanamine bisoxalate salt Rf = 0.17 by thin layer chromatography on silica gel, methanol: 0.88 ammonia NMR (1320): 2.5-2.9 m (lm), 5.7 s (2H), - 5.8 m (2H), 6.85 m (an), - 7.12 s (6H), 8.09 m (1m). (D) 6.6 g (C) gave 1.2 g 4 - (3-aminopropoxy) -N, N-dimethylbenzenemethanamine bisoxalate salt NMR (D 2 O): 2.5-2.87 m (4H); 5.72 s <2H>; 5.75 h (2H); 6, 7 c (2H); 7.13 S (6H); 7.78 m (2H) - 'Exemgel D. (a) 3- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine 90 g 2-1? N - (N, N-dimethylaminomethyl) phenoxy] propyl 7 -1H- -isoindole-1,3- (EH) -dione and 200 ml of a 30% aqueous solution of methylamine were heated at 80 ° C. After 4 hours the reaction was cooled. The mixture was alkalized with 5 N sodium hydroxide solution and extracted with toluene, the toluene extract being distilled to give 43.1 g of the desired compound as a light yellow oil with a biscuit puncture at 102-112 ° C at 0.2 ° C. mm Hg. nr = 0.25 at uunnexixn chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2).

The following compounds were prepared in a similar manner starting from the corresponding phthalimide (C). (b) 6.7 g (C) gave 1.2 g of 3- (4-aminobutoxy) -N, N-dimethylbenzenemethanamine. Rf = 0.24 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1). (c) 2.6 g (c) gave 1.3 g of 5- [3- (1-pyrrelidinylmecyl) renoxyl] propylamine in the form of bisoxalate salt with a melting point of 184-185 ° C. Rf = 0.3 in cunn layer gel cegraphy on silica gel; methanol: 0.88 ammonia (19: 1).

Example gel E) (a) 3- (5-aminopropoxy) -N, N-dimethylbenzenemethanamine. 12.2 g of 2-β-β- (N, N-dimethylaminomethyl) phenoxypropyl] -1H-isoindole-1,3- (2H) -dione and 2.1 ml of hydrazine hydrate were refluxed in ethanol for 3 hours. The reaction mixture was then cooled and filtered, and the filtrate was distilled. This gave 2 g of the desired compound as a colorless oil with a hex point: possibly 127 ° C at 0.6 mm Hg. The hydrochloric acid of the compound melted at 212-215 ° C. The compounds listed below were prepared in a similar manner starting from the corresponding phthalimide (C). (b) 2.8 g (C) gave 1.7 g of 3- (2-aminoethoxy) -N, N-dimethylbeneneeneemine with a boiling point of 135 ° C at 0 ° 3 'mm Hg. Rf = 0.5 in case of uneven layer exremegrefi on siiikegel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). (C) 4.2 g (C) gave 2 g of 3- (3-aminopropoxy) -N, N-dimethylbenzenetanamine having a boiling point of 95 ° C at 0.03 mm Hg.

Rf = 0.3 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). (d) 2.5 g (C) 'gave 0.9 g of 5- (4-aminobutoxy) -N, N-dimethylbenzenethanamine having a boiling point of 150 ° C at 0.04 mm Hg. Rf = 0.3 at thin layer chromato fi lfi On silica (e) (f) (e) (h) (1) (J) 7805591-0 19 ethyl acetate: isopropanol: water: 0.88 ammonia (25:15: 8: 2) . 0.5 g (C) gave 0.26 g of 3- (2-aminoethoxy) -N, N-dimethylbenzenepropanamine having a boiling point of 13000 at 0.03 mm Hg. Rf = 0.45 by thin layer chromatography on silica gel; ethyl acetate water: isopropanol: 0.88 ammonia (25: 8: 15: 2). 2 g (C) gave 0.95 g of 3- (3-aminopropoxy) -N, N-dimethylbenzenepropanamine with a boiling point of 160 ° C at 0.04 mm Hg. Rr = 0.3 by layer chromatography on si11¿ cone; ethyl acetate: water: isopropanol: 0.88 ammonia (25 = 8 = 15 = 2). 2 g (C) gave 1.05 g of 3- (4-aminobutoxy) -N, N-dimethylbenzenepropanamine with a boiling point of 130 ° C at 0.04 mm Hg. Rf = 0.25 by thin layer chromatography on silica gel; ethyl acetate water zisopropanol: 0.88 ammonia (25: 8: 15: 2). 1.5 g (C) gave 2.3 g of 3- [X5-aminopropyl) tig7-N, N-dimethylbenzenemethanamine with a boiling point of 14200 at 0.1 mm Hg. NMR (CDCl 3): 2.5-3 m (4H); 6.6 s (2 H); 6.99 h (3H); 7.17 t (2 H); 7.76 S (6H); 8.22 m (2H); 8.58 broad (2H). 1.3 g (C) gave 0.28 g of 4-12-aminoethoxy7-N, N-dimethylbenzenemethanamine with a boiling point of 90 ° C at 0.04 mm Hg. Rf = 0.2 by thin layer chromatography on silica gel; methano1: 0.88 ammonia (80: 1). 7 g (C) gave 2.7 g of 2- (4-aminobutoxy) -N, N-dimethylbenzene methanamine with a boiling point of 90 ° C at 0.07 mm Hg. Rf = 0.2 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1).

Example Gel F. (a) 2- [YEL (N, N-dimethylaminomethyl) phenyl] methylthio7ethanamine. . 17.4 g of 3- (N, N-dimethylaminomethyl) benzenemethanol and 12 g of cysteamine hydrochloride were heated in concentrated hydrochloric acid at 10,000 for 4 hours. After cooling, the reaction mixture was treated with solid sodium carbonate and extracted with ether. The organic extracts were distilled to give 21.5 g of the desired compound as an oil, b.p. 154-158 ° C at 1.5 mm Hg. The hydrochloride salt of the product melted at 180 DEG-180 DEG-180 DEG. Rf = 0.37 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). (b) Starting from 10.1 g of 3- (N-methylaminomethyl) benzenemethanol and 7.7 g of cysteamine hydrochloride, 6.5 g of 2- [ZÉL (N-methylaminomethyl) phenyl] methyltigetanamine with a boiling point of 140 -145 ° C at 0.1 mm Hg. Rf = 0.28 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). (c) Starting from 0.8 g of 2- (N, N-dimethylaminomethyl) benzenemethanol and 0.57 g of cysteamine hydrochloride, 0.38 g of 2- [ZÉ- (N, N-dimethylaminomethyl) phenyl] methyltig7ethanamine were prepared in a similar manner with a boiling point of 100-105 ° C at 0.01 mm Hg. Rf = 0.22 by thin layer chromatography on silica gel; ethyl acetate: methanol: 0.88 ammonia (10: 10: 1). (d) Starting from Ä g of 4- (N, N-dimethylaminomethyl) benzenemethanol and 2,2.8 g of pysteamine hydrochloride, 3.6 g of 2-ZZH.ÉN} N-dimethylaminomethyl) pheny were prepared in a similar manner; 7mecy1c197euanamine with a boiling point of 148-15000 at 0.01 mm Hg. 7 "Analysis: Calculated for C 12 H 20 N 2 S = c 64.2 H 9.0 N 12.5% Found: C 63.8 H 9.2 N 12.1% Example G. 3- (N, N-dimethylaminomethyl) benzenebutanamine 5- (N, N-Dimethylaminomethyl) benzenepropanoic acid ethyl ester 5.5 g of jeformyl cinnamic acid were heated at 60 ° C for 45 ml of a 30% ethanol solution of dimethylamine for 30 minutes and then stirred at room temperature with 1.5 g. % palladium oxide on charcoal under a hydrogen pressure of 1 atmosphere After the hydrogen uptake had ceased, the mixture was filtered and the filtrate was evaporated, the residue was refluxed with ethanol and concentrated sulfuric acid for 4 hours. thereby obtained 4.2 g of the desired product as a colorless liquid with a xox point of 130 DEG C. at 0.5 mm Hg. isopropanol: water: 0.88 ammonia (25: 15: 8: 2) 3- (N, N-dimethylaminomethyl) benzopropanol 0.5 g 3- (N, N-dimethylaminomethyl) benzenepropane acid-ethyl ester and 0.2 g of lithium aluminum hydride were stirred at room temperature in dry tetrahydrofuran for 2 hours. Reaction mixture flfl 7805591-Û 21 was then treated with water and filtered. The filtrate was evaporated to give 0.34 g of the desired product as a colorless liquid.

Rf = 0.7 by thin layer chromatography on silica gel; ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2). NMR (CDCl 5): 2.81 m (4H); 6.33 tr (2H); 6.59 S (2H); 7.28 m (2 H); 7.75 S (7H); 7.7-8, h m (en). 3- (N, N-dimethylaminomethyl) benzenesbutanenitrile. 0.9 g of 5- (N, N-dimethylaminomethyl) benzenepropanol and (L9 g of p-toluenesulfonyl chloride were stirred in pyridine for 2 hours. The solvent was then evaporated, and the residue was treated with 0.7 g of potassium cyanide 1 dimethiformamide at 45 ° C under Then water was added and the resulting mixture was extracted with ethyl acetate, the extract was distilled to give 0.3 g of the desired product as a colorless liquid with a boiling point of 110 ° C at 0.2 mm Hg.

Rf = 0.75 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). 3- (N, N-dimethylaminomethyl) benzenebutanamine. 0.9 g of 3- (N, N-dimethylaminomethyl) benzenesbutanitrile and 0.5 g of lithium aluminum hydride were stirred in tetrahydrofuran at room temperature for 2 hours. Water was then added, and the resulting suspension was filtered. The filtrate was evaporated to give 0.8 g of the desired compound as a colorless oil.

Rf = 0.1 by thin layer chromatography on silica gel ethyl acetate: isopropanolEwater: 0.88 ammonia (25: 15: 8: 2). The oxaiecsaiu of the compound melts at 125-127 ° c.

Example 1. (a) N-methyl-N '- [3- [3; (N, N-methylaminomethyl) renex17-propyl] -2-nitro-1,1-ethenediamine.

A mixture of 1 g of 3- (3-aminopropoxy) -N, N-dimethylbonsenemethanamine and 0.78 g of N-methyl-2-nitroimidothioic acid methyl ester in 4 ml of water was stirred at room temperature for 4 hours. The resulting solution was acidified with glacial acetic acid and then washed with ethyl acetate. The acidic solution was alkalized with sodium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated to an oil which crystallized in ether solution. 0.6 g of the desired compound was obtained as a white solid, m.p. 81-8300. 7805591-0 22 Rf = 0.6 by thin layer chromatography on silica gel; ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2).

The compounds listed below were prepared on. fragrant starting from the corresponding diamine and N-methyl-2-nitroimido-thioacid methyl ester (D). (b) (0) (6) (e) (f) (s) 2 g of diamine and 1.4 g of (D) gave 0.8 g of N-methyl-N'-β- - [Z3- (N) -methylaminomethyl) phenyl7methyl] ethyl7-2- -nitro-1,1-ethenediamine. Rf = 0.3 in thin layer chromatography on silica gel; methanol: ammonia (50: 1). The fumarate salt of the compound melts at 163-165 ° C. 1 g of diamine and 0.75 g of (D) gave 0.25 g of N-methyl-N'--3- [Z3- (N, N-dimethylaminomethyl) phenyl] bi97bropyl7- -2-nitro-1,1-ethylenediamine. NMR (CDCl 3): 0.5-0.5 brm (1H); 2.5-3 m (4H); 3.4 s (1H); 6.2 - 6.8 m (4H); 6.8 - 7.4 m (5H); 7.72 S (6H); 8.02 m (EH). 2.5 g of diamine plus 1.8 g of (D) gave 0.35 g of N-methyl-N'-α, (N-methylaminomethyl) phenoxy7bropyl7-2-nitro-1,1-e-enamine; Rf = 0.35 in nunnchix chromatography on silica gel; methanol: 0.88 ammonia (20: 1).

NM (cDc15): 2.68 m (2H); 2.9 - 3.4 m (3H); 5.9 h (2H); 6.29 s (2 H); 6.55 h (2H); 7.12 br.s (3H); 7.58 s (3 H); 7.62-8.2 m (en). 0.45 g of diamine plus 0.24 g of (D) gave 0.35 g of N-methyl-N'--α-EE- (1-pyrrolidinylmethyl) phenoxy7bropyl-2-nitro-1,1-ethylenediamine. Rf = 0.35 in thin-layer chromatography on silica gel methanol: 0.88 ammonia (80: 1). NMR (cnc13); 2.8 m (1H); 2.9 - 5.5 m (4H); 5.90 h (an), 6.4 s (2H); 6.50 m (2 H); 7.1 br (HH), 7.5-8.3 m (TH). 0.8 g of diamine plus 0.78 g of (D) gave 0.55 g of N-methyl-N'-. (5, (N, N-dimethylaminomethyl) phenox; 7-yl] -2-nitro- 1,1-esenediamine with a melting point of 130-131 ° C.

Hf = 0.3 for thin-layer chromium fi graph on silica gel; methanol: 0.88 ammonia (80: 1). 0.7 g of diamine plus 0.52 g of (D) gave 0.38 g of N-methyl-N'- - [E-ÅE; (N, N-dimethylaminomatyl) phenoxy] butyl] -2-nitro--1,1-ethylenediamine . Rf = 0.34 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1). NMR (cnc13) = 0.3 bf (1H); 2.82 t (1 H); 3.0-3.5 m (5H); (1) (K) (1) (m) (H) (0) 7805591-23 23 6.08 br (2H); 6.67 m (nn), 7.15 br (3H); 7.81 δ (6 H); 8.2 br (4H). 0.6 g of diamine plus 0.6 g (D) gave 0.58 g of N-methyl-N'-β-β- (N, N-dimethylaminoethyl) phenoxy] propyl] -2-nitro-1,1 -ecenediamine with a melting point of 93-94 ° C. Rf = 0.45 by thin layer chromatography on silica gel; ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2). 0.5 g of diamine plus 0.56 g (D) gave 0.12 g of N-methyl-N'--β-β- (N, N-dimethylaminoethyl) Ianoxy7butyl7-2-nitro--1,1- ecendiamine with a melting point of 59-65 ° C. Rr = 0.4 by thin layer chromatography on silica gel; ethyl acetate: 1sopropanol: water: 0.88 ammonia (25: 15: 8: 2). 0.26 § diamine plus 0.22 g (D) gave 0.2 g of N-methyl-N'-β2 [[ ethylenediamine with a melting point of 82-85,500. Rf = 0.4 by thin layer chromatography on silica gel; ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2). 0.2 g of diamine plus 0.15 g (D) gave 0.14 N-methyl-N'- -15-15- (N, N-dimethylaminopropyl) phenoxy] propyl 7-2-nitro--1,1-euenediamine with a melting point of 59.5-61 ° C. Rf = 0.55 by thin layer chromatography on silica gel; ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2). 0.5 g of diamine plus 0.56 g of (D) gave 0.45 g of N-methyl-N'-N-N- (N, N-dimethylaminopropyl) phenoxy] butylZ-2-nitro-1,1-ecenediamine with a smäinpunuu of 79-8o, 5 ° c. Rr = 0.5 by thin layer chromatography on silica gel; ethyl acetate waters: isopropanol: 0.88 ammonia (25: 8: 15: 2). 0.28 g of diamine plus 0.5 g of (D) gave 0.11 g of N-methyl-N'¿ -β- (N, N-dimethylaminomethyl) phenoxylethyl-2-nitro-1, 1-ethylenediamine with a melting point of 1ü1-142 ° C. Rf = 0.39 by thin layer chromatography on silica gel, methanol: 0.88 ammonia (50: 1). 0.56 g of diamine plus 1.19 g (D) gave 0.12 g of N-methyl-N'- -15-ÅE- (N, N-dimethylaminomethyl) phenoxy] propyl 7-2-nitro--1,1-ethylenediamine with a melting point of 135-15600. Rf = 0.5 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (19: 1). 0.45 g of diamine plus 0.3 g of (D) gave 0.25 g of N-methyl-N'- - [N-alE- (N, N-dimethylaminoethyl) phenoxy] butyl7-2-nitro-7805591-0 24 1,1-ethylenediamine with a melting point of 98-100 ° C. Rf = 0.45 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1). (p) 2.5 g of diamine plus 2.0 g of (D) gave 1.9 g of N-methyl-N'-β-α- (N, N-dimethylaminomecyl) phenoxylbutyl-2-n-hydroxy- -1,1-ethylenediamine with a melting point of 98.5-100 ° C.

Rf = 0.45 by thin layer chromatography on silica gel; methanol ammonia (80: 1). (q) 0.7 g of diamine plus 0.44 g of (D) gave 0.4 g of N-methyl-N'- -14-ÅE- (N, N-dimethylaminomethyl) phenyl7butyl7-2-nitro--1,1 -ethenediamine, whose dihydrochloride melted at 137-139 ° C. Rr = 0.5 in cunn layer xromacography on 5111142.- gel; ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2).

Example 2. N-nitro-N '- / E phenoxysgrogylzguanidine. 0.77 g of N-nitrocarbamimidothioic acid methyl ester and 1.0 g of 3- (aminopropoxy) -N, N-dimethylbenzenemethanamine were charged with ethanol at 40 ° C for 20 minutes. The solution was then cooled to precipitate the title compound, which was filtered off and recrystallized from ethyl acetate. This gave 0.44 g of product as a white solid, m.p. 114-115 ° C. Rf = 0.48 by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1).

Example 3. N- / - / EJN, N-dimethylaminomethylphenoxyharopyl-guanidine dinitrate. 2 g of 3- (5-aminopropoxy) -N, N-dimethylbenzenemethanamine and 2.1 g of 3,5-dimethylpyrazole-1-carboxamidine nitrate were refluxed in ethanol for 16 hours. The solvent was then removed, and the residue was washed with boiling ethyl acetate, after which it was crystallized from ethanol. This gave 1 g of the desired compound as a white solid, m.p. 123-124 ° C.

Rf = 0.34 by thin layer chromatography on silica gel; ethyl acetate-isopropanol: water: 0.88 ammonia (25: 15: 8: 2).

Example Gel 4. (a) N-cyano-N'-methyl-N "- [N- [N- (N, N-dimethylaminomethyl) -gnoxysgroglyzguanidine. 0.8 g of N-cyano-N'-methylcarbamimidothioic acid methyl ester and 1.0 g of ε 4 -aminopropoxy7-N, N-dimethylbenzenemethanamine were heated together at 100 DEG C. for 12 hours, then melted and cooled. The resulting solution was filtered, and the filtrate was evaporated, the residue was purified by column chromatography on silica, eluting with methanol to give 0.5H g of the desired compound as a clear yellow oil. Rf = 0.51 by thin layer chromatography on silica gel, methanol: 0.88 ammonia (80: 1).

Analysis: Calculated for c 15 H 23 N 5 O = c 62.28 H 7.96 N 24.22% Found: C 62.54 H 8.51 N 23.93 (b) Starting from 5 g of the corresponding amine and 2.8 g of N- Cyano-N'-methylcarbamimidothioic acid methyl ester was similarly prepared in 2.3% 2.3 g of N-cyano-N'-methyl-N "- [27- (N, N-dimethylaminomethyl) phenyl] methyltigetethyl7guanidine. Rf = 0.47 at thin layer chromatography on silica gel; methanol NM (cncl) = 2.5-5 m (4H); 6.25 s (2H); 6.5-6.9 m (4H); 7.18 d (3H); 7-7.5 m (2H); 7.73 S (6H) - (c) Starting from 1.5 g of the corresponding amine and 0.86 g of the same ester as above, 1.1 g of N- cyano-N'-methyl-N "- [~- [Z§- (N, N-dimethylaminomethyl) phenyl] methyl] 74 ethylguanidine having a melting point of 107-108.5 ° C.

Example 5. N-methyl-N '- / E- / É- (N, N-dimethylaminomethyl) -phenoxysgropylzurea. 0.27 ml of methyl isocyanate and 0.97 g of 3 - (} - aminopropoxy) -N, N- -dimethylbenzenemethanamine were stirred at room temperature in acetonitrile for 2 hours. The title compound formed was then filtered off, washed with acetonitrile and recrystallized from ethyl acetate. 0.49 g of product were obtained in the form of colorless prisms with a melting point of 79.5-80 ° C. Rf = 0.1, by thin layer chromatography on silica gel; methanol: 0.88 ammonia (80: 1).

Example 6. N-methyl-N- / §- / 7§- (N, N-dimethylaminomethyl) -phenylmethyl-thio7ethylthiourea. 1.5 g of 2- [2α- (N, N-dimethylaminomethyl) phenyl] methyltigetanamine and 0.5 ml of methyl isothiocyanate were stirred at room temperature in acetonitrile for 6 hours. The solvent was then removed, and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and methanol as eluent. This gave 1 g of the desired compound as a white solid, m.p. 57-59 ° C.

Analysis: Calculated for c14n2} N5s = c 56.5 H'7.8 N 14.1% 7805591-0 26 Found: _ C 56.2 H 8.1 N 13.8% Emamel 7.la) Nzmštvl-N 1- [5- [7- (NN-dimethylaminomethyl) -phenyl] methylthio] ethyl] -2-nitro-1,1-ethenediamine. 5 g of 2- [Z5- (N, N-dimethylaminomethyl) phenyl] methyl] ethanamine and 2.2 g of 1-nitro-2,2-bis (methylthio) ethylene were refluxed in acetonitrile for 7 hours. The solvent was then removed, and the residual oil was used without further purification. The oil was treated with 54 ml of a 55% ethanol solution of methylamine and refluxed for 5 hours. The solvent was removed and the residual oil was purified by column chromatography on silica gel using methanol as eluent. The resulting orange oil was triturated with ether to give 0.25 g of the desired compound as a white crystalline solid, m.p. 62-64 ° C. Rf = 0.56 by thin layer chromatography on silica gel; ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2) (b) Starting from 5 g of the corresponding amine and 2.2 g of 1-nitro--2,2-bis (methylthio) ethylene were prepared in a similar manner 2.5 g of N-methyl-N'-α-εZE- (N, N-dimethylaminomethyl) -phenyl; 7-methyl: 37-ethyl-2,2-nitro-1,1-ethylenediamine with a melting point of 98.5 -100 ° C.

Analysis: Calculated, for C 15 H 21 N 4 O 2: C 55.5 H 7.45 N 17.5 ß Found: C 55.45 H 7.4 N 17.1% Example gel 8. (a) Ng / 5- / 5- (N, N-dimethylaminomethyl) phenoxy] propyl 7-N '-' - (2-methoxyecyl) -2-nitro-1,1-ethenediamine hydrochloride. (1) Ne / 5- [5- (N, N-dimethylamine> methyl) phenoxypropyl] -2-nitroimidothioic acid methyl ester. 10 g of 5- (5-aminopropoxy) -N, N-dimethylbenzenemethanamine and 16 g of 1-nitro-2,2-bis (methylthio) ethylene were boiled under reflux in tetrahydrofuran for 19 hours. Then 1.5 g of oxalic acid dihydrate was added, and the resulting precipitate was discarded. The solvent was removed to give 10 g of the desired compound as a crystalline solid, m.p. 59-63 ° C.

Analysis: Calculated for C 15 H 23 N 3 O 5 S: C 55.55 H 7.05 N 12.9 ß Found = c 54.95 H 7.15 N 12.95% (2) N; / 5- / 5- (n, N- amylaminoemecyl) phenoxylpropyl17--N '- (2-methoxyethyl) -2-nitro-1,1-ethenediamine hydrochloride. A mixture of 0.8 g of N-β-β- (N, N-dimethylaminomethyl) -phenoxy] propyl] -2-nitroimidothioic acid methyl ester and 0.2 g of 2-methoxyethylamine was stirred at room temperature in ethanol. for 24 hours. The solvent was then removed to give an orange oil which was treated with an otanol solution of hydrogen chloride. 0.4 g of the desired compound with a melting point of 109-1126 was obtained. Analysis: Calculated for C 17 H 28 NuOn: C 52.5 H 7.45 N 14.4% Found: C 52.1 H 7.7 N 14.0 % The compounds listed below were prepared in a similar manner starting from the ester and the corresponding amine. (2) (b) 0.8 g of ester plus 3 ml of a 70% aqueous solution of ethylamine gave 0.69 g of N-ethyl-N'-N? -ÅÉ- (N, N-dimethylaminomethyl) phenoxy7propyl7-2-nitro-1,1-ethylenediamine hydrochloride having a melting point of 144-145 ° C. Rr = 0.55 in thin-layer metal feeders on silica gel; ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2). (2) (o) 0.8 g of ester plus 0.5 ml of 0.88 ammonia gave 0.6 g of N- [E- [E- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro-1,1- ethylenediamine hydrochloride having a melting point of 100-10200. Hf = 0.65 by thin layer chromatography on silica gel; ethyl acetate isopropanolz water: 0.88 ammonia (25: 15: 8: 2).

Example 9. N-Methanesulfonyl-N'-methyl-N "- [N- [N- (N, N-dimethylaminomethyl) phenoxy] propyl] guanidine. 3 g of N-methanesulfonylcarbonimidodithioic acid dimethyl ester and 2.5 g of 5- [E-aminopropox 7-N, N-dimethylbenzene methanamine was refluxed in ethanol for 4 hours, then methylamine was added and refluxing was continued for 1.5 hours, the solvent was then removed and the residue was purified by column chromatography on silica gel using methanol as eluent. 1.9 g of the desired compound as a yellow rubber, Rf = 0.65 on thin layer chromatography on silica gel, methanol: 0.88 ammonia (80 = 1), NM (cnci) = 2.85 m (1H); 2.9-5.5 m (5H); 3.0-4.3 brs (2H); 5.90 t (2H): 6.5 q (2H); 6.6 S (2H); 7.1 S (6H); 7.75 S (6H); 7.9 m (2H) - 5, ', H The new compounds of formula I have been shown to inhibit the gastric juice secretion induced by histamine, which has been demonstrated in experiments in rats. according to a modification of the method described by MN Ghosh and H.0 Schi ld in British Journal of Pharmacology 19§8, Vol. X5, p. 54. 7805591-0 28 As experimental animals, female rats weighing about 150 g were used. The rats are allowed to starve overnight and then given an 8% solution of sucrose in normal saline instead of drinking water.

The rats are anesthetized by a single intraperitoneal injection of a solution containing 25 g of urethane per 100 ml. The urethane solution is injected in an amount of 0.5 ml per 100 g body weight. After anesthesia, needles are inserted into the trachea and jugular veins.

The stomach is exposed through an incision in the middle of the abdominal wall, and the stomach is separated from the liver and spleen by cutting off the connecting tissues. A small opening is made in the upper sac-shaped enlargement of the stomach, and the stomach is washed with a 5% dextrose solution. The esophagus is inserted into a cannula consisting of a rubber tube, and the esophagus and nerves are then cut off above the cannula. A small opening is then made in the stomach port. A large plexiglass cannula is inserted into the stomach through the opening in the upper sac-shaped dilation of the stomach, and this cannula is placed in such a way that the inlet end of the cannula protrudes from the stomach through the opening in the gastric port. This cannula has such a shape that it reduces the effective volume of the stomach and causes a turbulent flow of the perfusion fluid over the mucosa. A drainage cannula is then inserted through the opening in the upper sac-shaped dilation of the stomach. Both cannulas are held in place by means of ligatures arranged in such a way that they do not come into contact with the main blood vessels. The needles extend through holes in the body wall. Through the cannulas in the esophagus and gastric port, a 5% dextrose solution is passed through the stomach. The dextrose solution has a temperature of 3900 and the flow rate through each cannula is 1.5 ml per minute. In the starting dextrose solution, the pH value is determined.

Normal gastric juice secretion is determined by measuring the pH of the perfusion effluent. An increased gastric juice secretion is then induced by a continuous intravenous infusion of a submaximal dose of histamine. In this way a stable elevated level of gastric juice secretion is achieved, and when this stable state has been reached, the pH value in the perfusion effluent is measured again.

The test compound is then administered by an intravenous injection, and the change in gastric juice secreted by this administration is determined by measuring the change in the pH of the perfusion effluent. 7805591-0 29 Using the pH measurements, the increase in gastric secretion effected by histamine is calculated, and this increase is expressed as moles of hydrogen ions per liter. The reduction in this increased gastric juice secretion, which is achieved by administering test compound, is also calculated as moles of hydrogen ions per liter. The percentage reduction in the elevated gastric juice secretion produced by the administration of the test compound can then be calculated. EDSO is calculated, ie. the dose of the test compound that gives an SO% reduction in the increased gastric secretion.

The table below lists ED 50 values for a number. representative compounds of formula I.

Association according to exemgel EQSO mglkg 1 (a) - 0.10 1 (b) I 0.80 Hc) I. 3.3 1 (d) 1.1 me) 0.039 ng) 2.7 un). '' om un) i 2.1 2 - '- 0.62 Mu)' i 0-67 nå) 'i I 0.9: 9 0.29

Claims (4)

7805591 -0 30 P a t e n t k r-a v Process for the preparation of compounds of the general formula: R 1. \ NA1L </ v H2 _. . wherein the symbols R1 and R2, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, or wherein the symbols R1 and R2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, wherein R 3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or an alkoxy-alkyl group; where X represents -O-, -S- or -CH 2 -; where Y represents = S, = O, = NR 6 or = CHR 7 , where R6 represents a hydrogen atom, a nitro group, a cyano group, a lower alkyl group or a lower alkylsulfonyl group, and É7 represents a nitro group or a lower alkylsulfonyl group, where m represents 2, 3 or 4, where n represents 0, 1 or 2, and where Alk represents a straight or branched alkylene chain containing 1-6 carbon atoms, known characterize V that (a) a primary amine of the formula: R 1 Nhlk / _ \ / where R1, R2, Alk, X, n and m have the meanings given above, if- (cn x (cn2) lIINu2 (11) 2 ) n is added with a compound which can introduce a group of the formula: -% NHR Y 3 where R 3 and Y have the meanings given above; or that (b) a compound of the formula: H1 NAlk / 112 \\ // - (CfI2) nx (c1-12), nN_f1ä-P (v) M 7805591-0 where RK, R2, Alk, X, n and m has the meanings given above, where Q represents a group = NR6 or = CHR7, where R6 and R7 have the meanings given above, and where P represents a leaving group, is reacted with an amine of the formula R3NH2, where R3 has the meaning given above; after which the prepared compound of formula I is isolated either in the form of a free base or in the form of a physiologically acceptable salt or a hydrate thereof. Process according to claim 1, alternative (a), characterized in that the compound which can introduce the group -% NHR 3 is a Y isocyanate of the formula R3NCO, an isothiocyanate of the formula R3NCS or a compound of the formula P NHR , / 3 HQ where Q represents a group = NR6 or = CHR7, where R6 and R7 have the meanings given in claim 1, and P represents a leaving group. Process according to Claim 1, characterized in that N-methyl-N '- [N- [N- (N, N-dimethylamine-methyl) -FEHOXL] -propyl] -2-nitro-1,1-ethylenediamine is prepared or a physiologically acceptable salt thereof. Process according to Claim 1, characterized in that N-methyl-N '- [E- [E- (1-pyrrolidinylmethyl) phenoxyl] propyl] -2-nitro-1,1-ethylenediamine or a physiologically acceptable salt thereof. -..___- .... .....__._..._-.... t ....