DE2821410A1 - AMINO ALKYLBENZENE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE - Google Patents

Description

KRAUS & WEISEERT

PATENT LAWYERS

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DK / ALTER KRAUS DIPLOMAL CHEMIST ■ DR.-ΙΝΘ. ANNEKÄTE WEISERT DIPL-ING. SPECIALIZATION CHEMISTRY IR 3AR D STRAS S E 15 D-8000 MÜNCHEN 71 -TELEFON 0 8 9/79 7 O 77-79 7 O 78 TELEX O5-212 15 6 kpat d

TELEGRAM CRAUS PATENT

1889 WK / rm

ALLEN & HANBURYS LIMITED London / England

Aminoalkylbenzene derivatives

subsequently j changed [

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description

The invention relates to new aminoalkylbenzene derivatives with selective Effect on histamine receptors. The invention also relates to processes for the preparation of these compounds, pharmaceutical preparations containing these compounds and their use in therapy. The invention relates to also new intermediates that are used in the processes mentioned.

It has been found that certain novel aminoalkylbenzene derivatives are selective E ^ antagonists and that they inhibit gastric acid secretion when stimulated by histamine Hp receptors (Ash and Schild - Brit. J. Pharmacol. Chemother, 1966, 22, 427). Their ability to prevent the secretion of gastric juice when this is stimulated by histamine Hp receptors can be demonstrated in the perfused rat stomach, using the method of Ghosh and Schild - Brit. J. Pharacol., 1958, 13, 54 - which has been modified in the manner described below. The ability of these compounds can also be demonstrated in conscious dogs equipped with Heidenhain bags using the same method as described by Black et al in "Nature" 1972, 236 , 385. The compounds of the invention do not modify histamine-induced contractions of isolated gastrointestinal smooth muscle.

Compounds with histamine Hp blocking activity can be used to treat conditions where gastric acid hypersecretion occurs, for example in Gastric and intestinal ulcers / as well as for the treatment of allergic conditions, for which histamine is a known cause is. They can either be used alone or in combination with other

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ren components for the treatment of allergic and inflammatory Conditions such as urticaria can be used.

The invention relates to aminoalkylbenzene derivatives of the general formula:

NAlk>

(I)

in the JL and Rp, which can be the same or different, for Hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups or lower alkyl groups represented by a Oxygen atom or a group -N-, in which R /, the meaning

Has hydrogen or lower alkyl, is interrupted, or R ₁ and Rp together with the nitrogen atom to which they are attached form a heterocyclic ring which can contain the heterofunctions -0- and -N-, R ^ represents hydrogen,

^R 4
Lower alkyl, NLedrigalkenyl or alkoxyalkyl, X is -0-, -S- or -CH ₂ - or -N-, in which R _{5 is} hydrogen or

Has lower alkyl, Y is = S, = 0, = NRg or = CHRy, where Rg is hydrogen, nitro, cyano, lower alkyl, Aryl, arylsulphonyl or lower alkylsulphonyl, R ^ for Nitro, lower alkylsulfonyl or arylsulfonyl, m is an integer from 2 to 4, η is 0, 1 or 2 and Alk represents a straight or branched alkylene chain with 1 to 6 carbon atoms,

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as well as the physiologically acceptable salts and hydrates, N-oxides and bioprecursors of such salts and of those salts in which the substituents attached to the benzene ring are are in ortho, meta or para position to one another.

The term used herein in connection with "alkyl" "Low" is intended to mean that the group has a small number of carbon atoms, preferably 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. In connection with "alkenyl" this term means that the group is preferred Has 3 to 6 carbon atoms. The term "aryl" preferably denotes phenyl or substituted phenyl, such as phenyl, which with one or more alkyl, alkoxy or Halogen groups is substituted.

The compounds of the formula I can show tautomerism and the formula is intended to include all tautomers. If Alk is a branched-chain alkylene group, then optical Isomers exist. In this case, the formula is intended to encompass all diastereoisomers and optical enantiomers.

The preferred compounds are those in which R ^ and R _{2 are} independently hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, Alk for a straight-chain alkylene chain with 1 to 3 carbon atoms, η is 0 or 1, Y is = S, = 0, = CHN0 ₂ or = NRg, where Rg is hydrogen, nitro, cyano or alkylsulfonyl, R- * is hydrogen, alkyl or Alkoxyalkyl and m and X have the meanings given above.

The compounds in which the side chains are meta to one another are particularly preferred.

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In a preferred class of compounds the substituents are R ^ and Rp independently of one another represent hydrogen or methyl or these form together with the nitrogen atom

a yrrolidine ring, Alk stands for a methylene group, η has the value 0, Y stands for = CHN0 ₂ or = NRg, where Rg has the meaning nitro, cyano or methylsulfonyl, R, stands for hydrogen or methyl, m has the value 3 and X stands for oxygen.

Particularly preferred individual compounds are the following compounds:

N-methyl-N '- [2 - [[3- (N, N-dimethylaminomethyl) phenyl] methylthio] ethyl] -2-nitro-1,1-ethenediamine N-Methyl-N * - [2 - [[3- (N-methylaminomethyl) phenyl] methylthio] ethyl] -2-nitro-1,1-ethenediamine

N-methyl-N '- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine

N-methyl-N '- [3- [3- (N-methylaminomethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine

N-methyl-N ^f - [3- [3- (1-pyrrolidinylmethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine

N-nitro-N ^f - [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] guanidine

N-cyano-N'-methyl-N "- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] guanidine

N-Methyl-N '- [3- [3- (N, N-dimethylaminoethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine

N-methanesulfonyl-N ^! -methyl-N "- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] guanidine.

The compounds of formula I form with inorganic and organic Acids physiologically acceptable salts. Particularly suitable salts are e.g. hydrochloride, hydrobromide and suI-

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fate as well as the acetates, maleates and fumarates. The compounds can also form hydrates.

The compounds according to the invention can be administered orally, topically or parenterally or in the form of suppositories. The preferred route of administration is the oral route. The compounds can be in the form of a base or a physiological acceptable salt can be used. Generally they are used in conjunction with a pharmaceutically acceptable carrier or diluent used in the form of a pharmaceutical preparation.

The compounds of the invention can be used in combination with other active ingredients such as conventional antihistamines if necessary. For oral administration, the pharmaceutical composition can be very useful in the form of capsules or tablets, which can also be sustained release tablets. The composition can also take the form of dragees or it can be in syrup form. Suitable topical preparations are e.g. ointments, lotions, creams, powders and sprays.

A suitable daily dose for oral administration is in the region of 10 mg to 2 g per day in unit dose form with 2 mg to 200 mg per dose unit.

Parenteral administration can be by injections at intervals or as a continuous infusion. Injection solutions can contain 1 to 100 mg / ml active ingredient.

A spray, ointment, cream or lotion can be used for topical application. The compositions an effective amount of the active ingredient, e.g. about 11/2 to 2% by weight, based on the total composition, contain.

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The above compositions can be used for human or veterinary medicine be suitable.

The compounds of the formula I can be prepared in such a way that a primary amine of the formula:

(CH ₂ ) _n X (CH ₂ ) _m NH ₂

(in which R ^, R ₂ , Alk, n, X and m have the meanings given above) with a compound which is capable of introducing the group -CNIffU, where R, and Y have the abovementioned

Il ■>■>

Y
have given meanings.

Compounds that are capable of the group -CNHR, a

Il ■>

feed are isocyanates R ₃ NCO, isothiocyanates RzNCS or compounds of the formula:

.NHR ₃

wherein Q is a group = NRg or = CHRy and P is a leaving group such as _# halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, but preferably thiomethyl.

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The reaction with the isocyanate or isothiocyanate can be carried out in such a way that the amine II and the isocyanate are allowed to stand in a solvent such as acetonitrile. The reaction of the amine II with a compound of formula III can be carried out in such a manner that 100 "to 120 ⁰ C, melts together the reactants at elevated temperature, for example. When Q is = NRg, then the reaction between the amine II and a compound III can also be carried out in a solvent, for example acetonitrile or ethanol, at elevated temperatures If Q stands for = CHRy, then the amine II and the compound III can be stirred in aqueous solution at room temperature.

If R ^ is hydrogen, then alkali metal cyanates and thiocyanates can be used, the reaction being carried out at an elevated temperature. Alternatively, organic isocyanates can be used and isothiocyanates can be used, such as ethyl carbon isothiocyanatidate, followed by basic hydrolysis.

In an alternative procedure, an amine of formula II is combined with a compound of formula:

(IV)

implemented, wherein P and Q have the above meanings and P ^{1 can have} the same meaning as P or, when Q is = CHN, can be a group -SA, where A is a lower

alkyl group, e.g. methyl.

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The resulting compound of the formula:

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■ NAHc

(V)

(CH ₉ ) X (CH ₉ ) MIC-P

2'nf

can then with an amine FUNHL to the compound of the formula I implemented. Both reaction stages can be carried out in one solvent, e.g. ethanol or acetonitrile, at temperatures from ambient to reflux temperature v / earth.

Compounds according to the invention in which η has the value 1, X stands for sulfur and the other groups have the meanings given above, with the exception that when both substituents R ^ and Rp are hydrogen, Y has a meaning other than -CBR ₇ can also be prepared from compounds of formulas VI or VII using a thiol of formula VIII.

CH ₉ L

^R 2

NAIk

CH ₂ OH

(VI)

HS (CH ₉ ) NHCNHR,

(VII)

(VIII)

Il

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In the above formula VI, L stands for a leaving group, for example halogen, such as bromine, or an acyloxy, for example acetoxy group. If compounds are to be prepared in which R ₁ and R _{2 are} hydrogen, then the amino group becomes NR ₁ R ₂ protected in compounds of formulas VI and VII, for example in the case of a primary amine with an eththalimido group. In this case, the protective group can be removed at a suitable stage in the reaction using a primary amine or a hydrazine such as methylamine or hydrazine hydrate.

The reaction between a thiol VIII and a compound of the formula VT is preferably carried out in the presence of a strong base, for example sodium hydride, at room temperature in an organic solvent, for example dimethylformamide. The reaction between a thiol VIII and a compound of the formula VII is preferably carried out at 0 ^° C. in a mineral acid, for example concentrated hydrochloric acid. The starting materials of Formula VI can be prepared from alcohols of Formula VII by conventional means.

Another process for the preparation of compounds according to the invention, in which Y is sulfur and R ₁ and R _{2 have} a different meaning than hydrogen, provides for the treatment of the amine II with carbon disulfide and the subsequent reaction with a chloroformate ester, for example ethyl chloroformate an isothiocyanate of the formula:

(CH ₂ ) _n X (CH ₂ ) _m NCS

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before. If the resulting compound of the formula IX is reacted with an amine RJNHp, preferably in a solvent such as acetonitrile, then the product is a compound of the formula I in which Y is sulfur and R. and R _{2 have} a meaning other than hydrogen to have.

Compounds of the formula I in which Y is a group = NCN can be selected from compounds of the formula I in which Y is the Meaning sulfur has to be prepared in such a way that the latter compounds with a heavy metal cyanamide, such as that of silver, lead, cadmium or mercury, preferably in an aqueous solution.

If the groups R ₁ and Rp in compounds of the formula I in which Y has a meaning other than ^ S are hydrogen, then they can be converted into alkyl or aralkyl groups by reaction with, for example, an alkyl or aralkyl halide. If compounds where R ^ or R ₂ and / methyl groups desired v / earth, then, according to an alternative formic acid and formaldehyde, for example, according to the Eschweiler-Clarke reaction may be employed.

In the above discussion of the methods available for preparing the compounds of the present invention, primary Amines of the formula II called. These amines are new compounds. The invention is also intended to include such compounds and their Acid addition salts with inorganic and organic acids lock in. These intermediates can be prepared by a number of methods which are described below should.

Amines of the formula II in which X stands for oxygen or sulfur can be prepared from compounds of the formula:

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(CH ₉ ) XH

where X is oxygen or sulfur and R _{8 is} the group R ₁ R ₂ NAIk or a group that can be converted into this group and η has the meaning given above, by reaction in the presence of a base, for example sodium hydride, with compounds of the formula:

L '(CH ₂ ) _m ¥ (XI)

where L ^{1 has} the meaning given above for L or can additionally stand for a sulfonyloxy group, for example mesyloxy or tosyloxy group, m has the above definition and ¥ stands for a group -NH ₂ or a group that can be converted into this group. If ¥ is a protected amino group, e.g. phthalimido, then the protecting group can then be removed by the measures described above.

Groups which can be converted into the group R ₁ R ₂ NAIk are, for example, aldehyde, nitrile, carboxylic acid or amide groups and phthalimido groups. For example, the -CHO group can be converted by reductive amination using an amine R ₁ R ₂ NH. Likewise, a carboxylic acid group can be converted into the corresponding acid halide or ester group, which is then _{reacted with an amine R 1} R ₂ NH, followed by reduction of the amide thus formed with, for example, lithium aluminum hydride to obtain a group R ₁ R.

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Amines of the formula II in which η has the value 1 and X is oxygen or sulfur can be prepared by reacting a compound of the formulas VI or VII with a compound which is capable of introducing the group -X (CHp) _n -NHo, where X is oxygen or sulfur and m is as defined above. When a compound of Formula VI is used, the presence of a base is desirable. If a compound of the formula VII is used, the reaction is carried out under acidic conditions.

Amines of the formula II in which η has the value 1, m has the value and X stands for oxygen or sulfur can be used in the Way can be obtained by a compound of the formula X in which η is 1 and X is oxygen or sulfur is treated with ethyleneimine.

Amines of the formula II in which η is O and m is 3 and X stands for oxygen can be selected from the corresponding nitrile of the formula:

(CH ₂ ) ₂ CN

by catalytic hydrogenation, for example using rhodium on alumina.

A compound of the formula XII can be prepared from a phenol of the formula!

(XIII)

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where Rg is a group which can be converted into RR ₂ NAIk, for example an aldehyde, can be prepared by reaction with acrylonitrile in the presence of a base, for example methanolic benzyltrimethylammonium hydroxide.

Amines of the formula II in which X is a methylene group can from compounds of the formula:

CH ₂ CH ₂ COOH (XIV)

wherein R _{Q is,} for example, a group R ^ R ₂ NAIk or a carboxamido or nitrile group, can be prepared by standard methods. For example, the reaction of the derived acid chloride or ester of a compound of the formula XIV with ammonia and the subsequent reduction of the resulting amide gives an amine of the formula II, where X is -CH ₂ -, η the value 0 and m the V / ert 2 Has.

An alternative reduction of a compound of the formula XIV, in which R _{Q is} , for example, a group R ^ R ₂ NAIk or a carboxamide or nitrile group, with, for example, lithium aluminum hydride gives an alcohol of the formula:

NAl

CH ₂ CH ₂ CH ₂ OH _(χν)

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which in a compound of the formula:

_(XVI)

wherein R _{Q stands} for R ₁ R ₂ NAIk and L ^{1 has} the meaning given above, can be converted.

Compounds of formula XVI can then be converted with ammonia , whereby an amine of the formula II is obtained in which X is -CHp-, η is 0 and m is 2 Has. Reaction of a compound of Formula XVI with an alkali metal cyanide, e.g., potassium cyanide, gives a compound the formula:

CH ₂ CH ₂ CH ₂ CN

(XVII)

which can then be reduced with, for example, lithium aluminum hydride, whereby an amine of the formula II is obtained where X stands for -CHo- and the sum of m + η = 3. Alternatively a compound of the formula XVII can form a compound of the formula:

(XVIII)

CH ₂ CH ₂ CH ₂ COOH

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are hydrolyzed, which can then be converted into an amine of the formula II, in which X is -CH ₂ - and the sum of m + η = J5, for example by reacting ammonia with the derived acid chloride and subsequent reduction, as above described.

Amines of the formula II in which η has the Yfert 0 and X is a group -NH- can be selected from starting materials of the formula:

(XIX)

wherein Rq is a group which can be converted into a group R ,. RpNAIk, 0

It

e.g. R ^ RpNC-, is convertible, by converting it to a compound of the formula XI and subsequent removal of any protective groups and reduction of the amide function will.

The starting materials of the formula XIV can, for example, by catalytic reduction of compounds of the formula XX be obtained with simultaneous or subsequent modification of the aldehyde function.

OCII

(XX)

If, for example, the reduction is carried out in the presence of an amine R ₁ RpNH, then the aldehyde can be converted into a group R ^ RoNCHp.

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In the reactions described above for the preparation of amines of Formula II, it is usually preferred to use intermediates which contain the desired R 1, RpNAIk group or a protected form thereof, e.g., phthalimido. However, intermediates containing a group _{convertible to the aforesaid R 1} RpNAIk group can also be taken and this group can be converted to _{R 1 RpNAIk at any suitable stage in the overall preparation.}

If both substituents R ₁ and Rp in intermediate products to amines of the formula II are hydrogen, then the primary amino function can be protected at any stage of the above reaction, for example as a phthalimido group, and the protective group can be removed at a suitable stage by the measures described above.

If R ₁ and / or Rp in intermediates to amines of the formula II are hydrogen, then they can, if necessary, be converted to alkyl or aralkyl groups, z E «being an alkyl or aralkyl halide. If R ₁ and / or Rp are methyl, then a reaction with formaldehyde and formic acid according to the Eschweiler-Clarke reaction can be suitable.

The invention is illustrated in the examples. The manufacturing examples 1 to 6 describe the preparation of the starting materials. Examples A to F describe the production of the intermediates of the formula II and Examples 1 to 8 the preparation of the compounds of the formulas V and I. In the examples, the procedure was as follows:

1) Thin layer chromatographic measurements (TLC measurements) were placed on silica gel plates with a thickness of 0.25 mm,

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which were attached to a plastic carrier.

2) The NMR values are given as X values.

3) The distillation pressures were measured as mm Hg. Production example 1

3- (1-pyrrolidinylmethyl) phenol

Sodium borohydride (15.2 g) was added to a solution of 3-hydroxybenzaldehyde (48.8 g) and pyrrolidine (66.4 ml) in ethanol. After 18 h the ethanol was removed and the remaining oil was acidified with hydrochloric acid and washed with ethyl acetate. The aqueous solution was then made alkaline with ammonia and extracted with ethyl acetate. When the organic extracts were evaporated, the compound mentioned was obtained as an off-white solid (21.4 g), melting point 100 to 102 ^° C. TLC silica; Methanol; 0.88 ammonia (80: 1), Rf 0.48.

Production example 2

(a) 3- (N, N-dimethylaminomethyl) benzene methanol

(1 ) Methyl 3- (N, N-dimethylaminocarbonyl) benzoate

A mixture of thionyl chloride (88 g) and benzene-1,3-dicarboxylic acid-monomethylester (33 g) was heated 1.5 h at 100 ⁰ C. The excess thionyl chloride was distilled off, leaving an oil which was used without further purification. The oil in dioxane was added to a cold solution of aqueous dimethylamine (40%; 56 ml) in dioxane and stirred at 5 ° C. for 1 hour. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform.

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The organic phase was dried and evaporated to give an oil (36 g). TLC silica · ethyl acetate, Rf 0.8. NMR (CDCl ₃ ) 1.8 m (2H); 2.2 to 2.7 m (2H); 6.1 s (3H); 6.95 s (6H).

(i) (b) The above example was repeated using the ester (70 g) and 25% aqueous methylamine (118 ml). It was 3- (N-methylaminocarbonyl) -benzoic acid methylester (54 g) Pp 128 to 130 ⁰ C, was obtained. TLC silica; Ethyl acetate, Rf 0.57.

(2) 3- (N, N-dimethylaminomethyl) benzene methanol

Methyl 3- (N, N-dimethylaminocarbonyl) benzoate (36 g) in dry tetrahydrofuran was added to lithium aluminum hydride (16.6 g) in dry tetrahydrofuran. The reaction mixture was heated to 60 ° C. for 3 h, 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, whereby an oil (16 g), boiling point 95 to 100 ^° C. (0.1 mm), was obtained. TLC silica / methanol, Rf 0.57.

(2) (b) The above example was repeated using 25 g of the ester from (b) above, using 3- (N-methylarainomethyl) -benzenemethanol (9.2 g), bp 110-115 ° C (0.02 mm). TLC silica; Methanol, Rf 0.36.

Production example 3

(a) 2- f 3- f 3- (N, N-dimethylaminomethyl) -phenoxy "| -propyl] -1H-isoindole-1,3- ( 2H) -dione

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A mixture of 80% sodium hydride (2.2 g) and 3- (N, N-dimethylaminomethyl) phenol (6.95 g) in dry dimethylformamide was stirred at 5 ° C. for 2 h. N- (3-bromopropyl) phthalimide (12.2 g) was then added and after 16 h the reaction mixture was treated with water and extracted with ethyl acetate. That Evaporation of the dried organic extracts gave the named compound as a yellow oil (13 g). TLC silica; Ethyl acetate, Rf 0.35, m.p. (oxalate salt) 204-207 ° C

The following compounds were similarly prepared from the corresponding phenol (A) and the corresponding bromoalkylphthalimide (B) manufactured:

(b) A (14 g) + B (21.5 g) provided 2- [3- [3- (1-pyrrolidinylmethyl) phenoxy] propyl] -1H-isoindole-1,3- (2H) -dione (21.4 g). TLC silica; Methanol: 0.880 ammonia (80: 1), Rf 0.46. FP (oxalate salt) 167-169 ° C.

(c) A (5 g) + B (9.3 g) gave 2- [4- [3- (N, N-dimethylaminomethyl) -phenoxy] -butyl] -1H-isoindole-1,3- (2H) -dione (8.7 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.56, m.p. (oxalate salt) 169 to 170 ⁰ C.

(d) A (5 g) + B (8.1 g) gave 2- [3- [3- (N, N-dimethylaminoethyl) phenoxy] propyl] -1H-isoindole-1,3- (2H) -dione (5g), m.p. 59 to 60 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8 _: 2), Rf 0.45.

(e) A (2.0 g) + B (3.4 g) gave 2- [4- [3- (N, N-dimethylaminoethyl) phenoxy] butyl] -1H-isoindole-1,3- ( 2H) -dione (2.8 g), m.p. 52-53 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.55.

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(f) A (2.2 g) + B (3.2 g) gave 2- [3- [3- (N, N-dimethylaminopropyl) phenoxy] propyl] -1H-isoindole-1,3- ( 2H) -dione (2.5 g), bp 250 ⁰ C (0.1 mm). TLC silica: ethyl acetate isopropanol: water: ammonia (25: 15: 8: 2), Rf 0.5.

(g) A (2.2 g) + B (3.4 g) gave 2- [4 ~ [3- (N, N-dimethylaminopropyl) -phenoxy] -butyl] -1 H-isoindole-1,3- (2H) -dione (2.6 g), bp 225 ⁰ C (0.04 mm), TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia, Rf 0.5.

(h) A (7.0 g) + B (14.1 g) gave 2- [4- [4- (N, N-dimethylaminomethyl) phenoxy] butyl] -1H-isoindole-1,3- ( 2H) -dione, Oxalate salt (3.8 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.5.

(i) A (5 g) + B (9.7 g) gave 2- [3- [4- (N, N-dimethylaminomethyl) -phenoxy] -propyl] -1H-isoindole-1,3- (2H) -dione (7.1 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.5, m.p. (oxalate salt) 166 "to 170 ⁰ C.

Production example 4

(a) 2-f2-f3- (NN-dimethylaminomethyl) -phenoxy] -ethyl] -1H-isoindole-1,3- (2H) -dione

3- (N, N-dimethylaminomethyl) phenol (5.0 g), 8O? 6 sodium hydride (1.2 g) and 2- [2- (4-methylbenzenesulfonyl) ethyl] -1H-isoindole-1,3 - (2H) ~ dione (13 g) were heated ^{to 90 ° C. in dimethylformamide.} After 12 h, the reaction mixture is cooled and poured into ice water and extracted with ether. On evaporation of the organic solvent the product was obtained as a viscous yellow oil (5.2 g). TLC silica; Methanol: ethyl acetate (1: 1), Rf 0.37. Mp (oxalate salt) 166-167 ⁰ C.

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The following compounds were prepared in a similar manner from the corresponding phenol (A) and 2- [2- (4-methylbenzenesulfonyl) ethyl] -iH-isoindole-1,3- (2H) -dione (C) manufactured:

(b) A (5 g) + C (11.7 g) gave 2- [2- [3- (N, N-dimethylaminoethyl) phenoxy] ethyl] -1H-isoindole-1,3- (2H) -dion (2.4 g), m.p. 84-85 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia, Rf 0.45.

(c) A (2.2 g) + C (4.2 g) gave 2- [2- [3- (N, N-dimethylaminopropyl) phenoxy] ethyl] -1H-isoindole-1,3- ( 2H) -dione (0.5 g). TLC silica; Ethyl acetate: isopropanol: water: 0.880 ammonia (25: 15: 8: 2), Rf 0.45.

Production example 5

(a) 2-Γ3-Γ3- (NN-dimethylaminomethyl) -phenoxy] -propylj-1H-

isoindole-1,3- (2H) -dione
(1) 2-f3-f3- (FormYl) -phenoxy1-propyl1-1H-13oindole-1,3- (2H) - dione

3-hydroxybenzaldehyde (0.61 g), 3-bromopropyl phthalimide (1.31 g) and potassium carbonate were stirred in dimethylformamide at room temperature for 16 h. The reaction mixture was poured into water, to precipitate the named compound (1.37 g). This was filtered off and dried, mp 102-104 ° C. TLC silica: Methanol: toluene (1: 9), Rf 0.65.

The following compounds were made in a similar manner:

(i) (b) 4-Hydroxybenzaldehyde (5 g) and the corresponding phthalimide (10.4 g) gave 2- [2- [4- (formyl) phenoxy] ethyl] -1H-isoindole-1,3- (2H) -dione (1.3 g), mp 131.5 to 133.5 ⁰ C TLC methanol chloroform (1: 100), Rf 0.5.

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(1) (c) 2 ~ Hydroxybenzaldehyde (6.1 g) and the corresponding phthalimide (12 g) gave 2- [4- [2- (formyl) -phenoxy] -butyl] -1H-isoindole-1,3- (2H) -dione (12.2 g), m.p. 99.5 to 101 ⁰ C. TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.8.

(2) 2-f 3-f3- (NN-dimethylaminomethyl) -phenoxy1-propyl1-1H-isoindole-1,3- (2H) -dione

2- [3- [3- (Formyl) -phenoxy] -propyl] -1H-isoindole-1,3- (2H) -dione (132 g) and 33% ethanolic dimethylamine (300 ml) were at room temperature and atmospheric pressure Hydrogenated in ethanol over 10% palladium on charcoal. The catalyst was filtered off and the filtrate was evaporated to give the title compound as a yellow oil (142 g). TLC silica (ethyl acetate), Rf 0.35, m.p. (oxalate salt) 204-207 ° C.

The following compounds were similarly made from 33% Ethanolic dimethylamine and the corresponding phthalimide (P) produced:

(2) (b) P (1.2 g) + 33 # ethanolic dimethylamine (20 ml) provided 2- [2- [4- (N, N-dimethylaminomethyl) phenoxy] ethyl] -1H-isoindole-1,3- (2H) -dione (1.3 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.3.

(2) (c) P (10 g) + 33% ethanolic dimethylamine (50 ml) provided 2- [4- [2- (N, N-dimethylaminomethyl) phenoxy] butyl] -1H-isoindole-1,3- (2H) -dione (7 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.55, m.p. (oxalate salt) 162-163 ° C.

Production example 6

2-f3-Γ Γ3- (NN-dimethylaminomethyl) -phenyl1-thio1-propyl1-1H-isoindole-1,3- (2H) -dio n

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(1) Dlthio-bis-3,3 '-Ν, N-dimethylbenzenecarboxamide

Dimethylamine (57 ml) in ¹ OIuOl was added at 5 ° C to 3.3 ^f ~ dithio (chlorocarbonyl) benzene (46 g) in toluene. After 4 hours, water was added and the solution was extracted with ethyl acetate. Evaporation of the extracts gave the product as an orange oil (49 g). NMR (CDCl ₃ ) 2.4 to 2.8 m (8H);
7.05 br (12H).

(2) Dithio-bis-3,3'-Ν, Ν-dimethyrbenzenemethanamine

3,3'-Dithio-N, N-dimethylbenzenecarboxamide (48 g) in dry ether was added to lithium aluminum hydride (20 g) in dry ether. The reaction mixture was stirred at room temperature, cooled, treated with water and filtered. The filtrate
was extracted with ethyl acetate and the extracts were dried and distilled to give a colorless oil (8.8 g),
Kp 25O ⁰ C (0.1 mm) was obtained. NI-IR (CDCl ₃ ) 2.5 to 2.9 m (8H); 6.66 s (4H); 7.8 s (6H).

(3) 2-1'3- Γ l "3- (N. N-Dimethylaminomethyl) -phenyl 1-thio] -propyl1-1H-isoindole-1,3- (2H) -dione

80% sodium hydride (2.3 g) and dithio-bis-3,3'-N, N-dimethylbenzenemethanamine (7.8 g) were stirred at room temperature in dry dimethylformamide for 24 hours. N- (3-bromopropyl) phthalimide (12.6 g) was then added. After 24 hours it became
Treated reaction mixture with water and extracted with ethyl acetate. The organic extracts were evaporated and the residue was purified by column chromatography on silica gel with ethyl acetate / methanol to give the title compound as a light orange oil (11.3 g). NMR (CDCI,) 2.0 to 2.4 m (4H); 2.6 to 2.9 m (4H); 6.15 t (2H); 6.59 s
(2H); 7.02 t (2H); 7.75 s (6H); 7.98 m (2H).

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Example A.

3- (3-Amino-propoxy) -N-methylbenzenemethanamine-dioxalate

(1) 3- f 3- (Formyl) -phenoxy "j-propionitrile

A solution of m-hydroxybenzaldehyde (30.5 g) in acrylonitrile (265 ml) and 40% methanolic benzyltrimethylammonium hydroxide (5 ml) was refluxed for 20 hours. The mixture was diluted with ether (500 ml) and the solution was diluted with 5% sodium hydroxide solution and water. The ethereal solution was dried over magnesium sulfate, filtered and evaporated in vacuo to give a clear colorless oil (32 g). TLC silica, chloroform, Rf 0.4.

(2) 3- (2-cyanoethoxy) -N-methylbenzenemethanamine hydrochloride

A solution of 3-i3- (Formyl) -phenoxy] -propionitrile (8.75 g) in a mixture of 33 ^ strength ethanolic methylamine (50 ml) and ethanol (200 ml) was at room temperature with 5% palladium oxide stirred on charcoal (0.8 g) under hydrogen of 1 atm. When the uptake of hydrogen is complete, the mixture becomes filtered and the residue was washed with ethanol. The ethanol filtrate and the washing waters were combined, concentrated and treated with excess ethereal hydrogen chloride. The precipitated hydrochloride became a mixture from ethanol and ether in the form of colorless platelets (7.9 g), melting point 125 to 128 ° C, recrystallized.

Analysis found: C, 58.1; H 6.5; N 12.3; theoretical values

for C ₁₁ H ₁₅ ClN ₂ O: C 58.3; H 6.5; N 12.3590.

(3) 3- (3-aminopropoxy) -N-methylbenzolmethanamine-dioxalate A solution of N-methyl- [3- (2-cyanoethoxy) -benzolmethanamin-

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hydrochloride (5.39 g) in methanol (50 ml) was eluted through a column with a basic ion exchanger (Amberlyst A-26). The eluate was evaporated to give the free base as a colorless oil. The free base was dissolved in ethanol (500 ml) and 0.88 ammonia solution (25 ml) and mixed with 5% rhodium on alumina (2.5 g) at room temperature under a pressure of 2.81 kg / cm of hydrogen for 6 hours shaken. The resulting suspension was filtered, evaporated in vacuo and the residue was dissolved in ethanol and treated with excess ethanolic oxalic acid. The precipitated dioxalate salt (6.56 g) was filtered and dried, mp 196-198 ⁰ C. TLC silica; Methanol: 0.88 ammonia (99: 1), Rf 0.1.

Example B.

3- (3-aminopropoxy) -N-methylbenzenemethanamine-dioxalate

2- [3- [3- (Formyl) -phenoxy] -propylI-1H-isoindole-1,3- (2H) -dione (8.5 g) was dissolved in 33% ethanolic methylamine (300 ml) for 1 hour stirred and then hydrogenated at room temperature and atmospheric pressure in ethanol over 10% palladium on charcoal. The solution was filtered, evaporated to dryness in vacuo and dissolved in ethanol (50 ml). The ethanolic solution was treated with excess ethanolic oxalic acid and the resulting precipitate was recrystallized from ethanol / water, whereby the compound mentioned was obtained in the form of colorless grains (3.9 g), melting point 196 to 198 ^° C. TLC silica; Methanol: 0.88 ammonia (20: 1), Rf 0.1.

Example C

(a) 3 ~ (3-aminopropoxy) -N, N-dimethylbenzene meth »r '» m1 _l ^j n

2- [3-L3- (N, N-dimethylaminomethyl) phenoxy] propyl] -1H-isoindole-

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1,3- (2H) -dione (25 g) was mixed with 30 # ethanolic methylamine (150 ml) treated. After 24 h at room temperature, ether (100 ml) was added and a solid was filtered off. That The filtrate was distilled, whereby the named compound was obtained as a yellow oil (12.3 g), b.p. 102-112 ° C. (0.2 mm). TLC silica: ethyl acetate: isopropanol: water: 0.88 ammonia, Rf 0.25.

The following compounds were prepared in a similar manner from the corresponding phthalimide (C):

(b) C (5.4 g) provided 3- (2-aminoethoxy) -N, N-dimethylbenzenemethanamine (0.45 g). TLC silica; Methanol / ammonia (80: 1), Rf 0.04. NMR (CDCl ₃ ) 2.8-3.1 m (4H); 6.05 t (2H); 6.55 s (2H); 6.98 t (2H); 7.80 s (6H); 8.4 br, s (2H).

(c) C (2.9 g) provided 4- (4-aminobutoxy) -N, N-dimethylbenzenemethanamine bis-oxalate salt (0.8 g). TLC silica; Methanol: 0.88 ammonia, Rf 0.17. NMR (D ₂ O) 2.5 to 2.9 m (4H); 5.7 s (2H); 5.8 m (2H); 6.85 m (2H); 7.12 s (6H); 8.09 m (4H).

(d) C (6.6 g) provided 4- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine bis-oxalate salt (1.2 g). NMR (D ₂ O) 2.5 to 2.87 m (4H); 5.72 s (2H); 5.75 t (2H); 6.7 t (2H); 7.13 s (6H); 7.78 m (2H).

Example D

(a) 3- (3-Aminopropoxy) -N, N ~ dimethylbenzolmethanami n

2- [3- [3- (N, N-diraethylaminomethyl) phenoxy] propyl] -1H-isoindole-1,3- (2H) -dione (90 g) and 30% aqueous methylamine (200 ml) were added heated to 8O ^{0 C.} After 4 h the reaction mixture is cooled, made alkaline with 5N sodium hydroxide solution and

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extracted with toluene. The toluene extract was distilled, whereby the named compound was obtained as a light yellow oil (43.1 g), b.p. 102 to 112 ° C (0.2 mm). TLC silica; Ethyl acetate : Isopropanol: water: 0.88 ammonia (25: 15: 8; 2), Rf 0.25.

The following compounds are prepared in a similar manner from the corresponding phthalimide (C):

(b) C (6.7 g) provided 3- (4-aminobutoxy) -N, N-dimethylbenzenemethanamine (1.2 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.24.

(c) C (2.6g) provided 3-L 3- (1-pyrrolidinylmethyl) -phenoxy] -propylamine, isolated as the bis-oxalate salt (1.3 g), m.p. 184-185 ° C TLC silica; Methanol: 0.88 ammonia (19: 1), Rf 0.3.

Example E.

(a) 3- (3-aminopropoxy) - 'N _< N -dimethylben2olmethanamine

2- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -1H-isoindole-1,3- (2H) -dione (12.2 g) and hydrazine hydrate (2.1 ml) were added Heated to reflux in ethanol for 3 hours. The reaction mixture was cooled, filtered and the filtrate was distilled, whereby the product was obtained as a colorless oil (2 g), bp 127 ⁰ C (0.6 mm), mp (hydrochloride salt) 212 to 215 ° C, was obtained.

The following compounds were prepared in a similar manner from the corresponding phthalimide (C):

(b) C (2.8 g) provided 3- (2-aminoethoxy) -N, N-dimethylbenzenethanamine (1.7 g), bp 135 ° C (0.03 mm). TLC silica; Ethyl acetate: isopropanol: water: 0.08 ammonia (25: 15: 8: 2), Rf 0.3.

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(c) C (4.2 g) gave 3- (3-aminopropoxy) -N, N-dimethylben ~ zoläthanamin (2 g), bp 95 ⁰ C (0.03 mm). TLC silica; Ethyl acetate: isopropanol: water: 0.83 ammonia (25: 15: 8: 2), Rf 0.3.

(d) C (2.5 g) gave 3- (4-aminobutoxy) -N, N-dimethylbenzolethanamine (0.9 g), boiling point 150 ^° C. (0.04 mm). TLC silica, ethyl acetate: isopropanol: water: 0.88 ammonia, Rf 0.3.

(e) C (0.5 g) gave 3- (2-aminoethoxy) -N, N-dimethylbenzenopropanamine (0.26 g), boiling point 130 ^° C. (0.03 mm). TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf 0.45.

(f) C (2 g) gave 3- (3-aminopropoxy) -N, N-dimethylbenzenopropanamine (0.95 g), boiling point 160 ^° C. (0.04 mm). TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf 0.3.

(g) C (2 g) provided 3- (4-aminobutoxy) -N, N-dimethylbenzenopropanamine (1.05 g), boiling point 130 ^° C. (0.04 mm). TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf 0.25.

(h) C (11.3 g) provided 3 - [(3-aminopropyl) thio] -N, N-dimethylbenzenemethanamine (2.3 g), bp 142 ° C (0.1 mm), NMR (CDCl4) 2.5 to 3 m (4H); 6.6 s (2H); 6.99 t (3H); 7.17 t (2H); 7.76 s (6H); 8.22 m (2H); 8.58 brs (2H).

(i) C (1.3 g) provided 4- [2-aminoethoxy] -N, N-dimethylbenzenemethanamine (0.28 g), boiling point 90 ^° C. (0.04 mm). TLC silica; Methanol ^, 88 ammonia (80: 1), Rf 0.2.

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C (7 g) afforded 2- (4-aminobutoxy) -N, N-dimethylbenzolmethanamin (2.7 g), bp 9O ⁰ C (0.07 mm). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.2.

Example F

(a) 2-Γ f3- (NN-dimethylaminomethyl) -phenyl1-methylthio1-ethanamine

3- (N, N-dimethylaminomethyl) -benzenemethanol (17.4 g) and cysteamine hydrochloride (12 g) were heated for 4 hours in concentrated hydrochloric acid to 100 ⁰ C. The cooled reaction mixture was treated with solid sodium carbonate and extracted with ether. The organic extracts were distilled to give the product as an oil (21.5 g), b.p. 154-158 ⁰ C (1.5 mm), mp (hydrochloride salt) was 180-182 ° C, was obtained. TLC silica; Ethyl acetate: isopropanol / water: 0.88 ammonia (25: 15: 8: 2), Rf 0.37.

(b) From 3- (N-methylaminomethyl) benzene methanol (10.1 g) and Cysteamine hydrochloride (7.7 g) similarly became 2 - [[3- (N-methylaminomethyl) phenyl] methylthio] ethanamine (6.5 g), b.p. 140 to 145 ° C (0.01 mm). TLC silica; Ethyl acetate: isopropanol: water: 0.88 Ammonia, Rf 0.28.

(c) 2- (N, N-dimethylaminomethyl) -benzenemethanol (0.8 g) and cysteamine hydrochloride (0.57 g) similarly gave 2 - [[2- (N, N-dimethylaminomethyl) -phenylj-methylthio obtained] -äthanamin (0.38 g), bp 100 (0.01 mm) to 105 ⁰ C. TLC silica; Ethyl acetate: methanol: 0.88 ammonia (10: 10: 1), Rf 0.22.

(d) 4- (N, N-dimethylaminomethyl) -benzenemethanol (4 g) and cysteamine hydrochloride (2.8 g) similarly gave 2 - [[4- (N, N-dimethylaminomethyl) -phenyl] -methylthio] -ethanamine (3.6 g), bp 148 to 150 ⁰ C (0.01 mm) obtained.

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Analysis found: theoretical values for

Example G

282H1Q

C 63.8; H 9.2; N 12.1; C 64.2; H 9.0; N 12.5%.

3- (N, N-dimethylaminomethyl) -benzenebutanamine Ethyl 3- (N _y N-dimethylaminomethyl) benzene propanoate

3-formylcinnamic acid (5.5 g) was heated for 30 min in 30% ethanolic dimethylamine (45 ml) at 6O ⁰ C and then stirred at (1.5 g) under hydrogen of 1 at room temperature with 10% palladium oxide on charcoal. When hydrogen uptake was complete, the mixture was filtered and the filtrate was evaporated. The residue was refluxed in ethanol and concentrated sulfuric acid for 4 hours. The solution was neutralized with sodium carbonate and distilled, whereby the product was obtained as a colorless liquid (4.2 g), boiling point 130 ° C (0.05 mm),

TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.75.

3- (N, N-dimethylaminomethyl) benzene propanol

Ethyl 3- (N, N-dimethylaminomethyl) benzene propanoate (0.5 g) and lithium aluminum hydride (0.2 g) were stirred at room temperature in dry tetrahydrofuran for 2 hours, treated with water and filtered. The filtrate was evaporated to give the product as a colorless liquid (0.34 g).

TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.7. NMR (CDCl ₃ ) 2.81 m (411); 6.33 tr (211); 6.59 s (2H); 7.28 m (2H); 7.75 s (7H); 7.7 to 8.4 m (2H).

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3- (Ν, N-dimethylaminomethyl) -benzenebutanenitrile

3- (N, N-dimethylaminomethyl) benzene propanol (0.9 g) and p-toluenesulfonyl chloride (0.9 g) were stirred in pyridine for 2 hours. The solvent was evaporated and the residue was treated with potassium cyanide (0.7 g) in dimethylformamide at 45 ° C for 16 hours. Water was added and the mixture was extracted with ethyl acetate. The extract was distilled, thereby the product as a colorless liquid (0.3 g), b.p. 11O ⁰ C (0.02 mm) was obtained.

TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.75.

3- (N »N-dimethylaminomethyl) -benzenebutanamine

3- (N, N-dimethylaminomethyl) -benzenebutanenitrile (0.9 g) and lithium aluminum hydride (0.35 g) in tetrahydrofuran were added for 2 hours
stirred at room temperature. Water was added and the
Suspension was filtered. The filtrate was evaporated to give the product as a colorless oil (0.8 g).

TLC silica; Ethyl acetate isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.1, m.p. (oxalate salt) 125-127 ° C

example 1

(a) N-methyl-N '- [' 3- ί 3- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine

A mixture of 3- (3-aminopropoxy) -II, N-dimethylbenzenemethanamine (1 g) and Ii-IIethyl-2-nitroimidothioic acid methyl ester (0.78 g) in v / water (4 ml) was stirred for 4 h at room temperature. The resulting solution was acidified with mono-nig and then

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washed with ethyl acetate. The acidic solution was made alkaline with sodium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated to an oil which crystallized from ethereal solution, whereby the named compound was obtained as a white solid (0.6 g), mp 81 to 83 ^° C. TLC silica, ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.6.

The following compounds were prepared in a similar manner from the corresponding diamine and methyl N-methyl-2-nitroimidothioate (D) manufactured:

(b) Diamine (2 g) and D (1.4 g) gave N-methyl-N '- [2 - [[3- (N-methylaminomethyl) phenyl] methylthio] ethyl] -2-nitro- 1,1-ethylenediamine (0.8 g). TLC silica; Methanol: ammonia (50: 1), Rf 0.3, m.p. (fumarate salt) 163-165 ° C.

(c) Diamine (1g) + D (0.73g) provided N-methyl-N'-L '3- [[3- (N, N-dimethylaminomethyl) phenyl] -thio J-propyl] -2 -nitro-1,1 ethanediamine (0.25 g). MMR (CDCl ₃ ) -0.5 to 0.5 brm (1H); 2.5 to 3 m (4H); 3.4 s (1H); 6.2 to 6.8 m (4H); 6.8 to 7.4 m (5H); 7.72 s (6H); 8.02 m (2H).

(d) diamine (2.5 g) + D (1.8 g) gave N-methyl ~ N '- [3- [3- (N-methylaminomethyl) -phenoxy] -propyl] -2-nitro-1, 1-ethenediamine (0.35 g). TLC silica; Methanol: 0.88 ammonia (20: 1), Rf 0.35. NMR (CDCl ₃ ) 2.68 m (2H); 2.9 to 3.4 m (3H); 5.9 t (2H); 6.29 s (2H); 6.53 t (2H); 7.12 br, s (3H); 7.58 s (3H); 7.62 to 8.2 m (2H).

(e) diamine (0.45 g) + D (0.24 g) provided N-methyl-N '- [3- [3- (1-pyrrolidinylmethyl) phenoxy] propyl] -2-nitro-1, 1-ethenediamine (0.35 g). TLC silica; Methanol: 0.88 ammonia (80: 1]

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Rf 0.35. HMR (CDCl ₃ ) 2.8 m (1H); 2.9 to 3.5 m (4H); 5.90.t (2H); 6.4 s (2H); 6.50 m (2H); 7.1 br (4H); 7.5 to 8.3 m (7H).

(f) Diamine (0.8 g) + D (0.78 g) provided N-methyl-N ¹ [2- [3- (N, N-diraethylaminomethyl) phenoxy ethyl] -2-nitro-1,1 ethenediamine (0.55 g), m.p. 130 to 131 ⁰ C TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.3.

(g) diamine (0.7 g) + D (0.52 g) provided N-methyl-N '- [4- [3- (N, N-dimethylaminomethyl) -phenoxy] -butyl] -2-nitro- 1,1-ethylenediamine (0.38 g). TLC silica; Methanol: 0.88 ammonia (80: 1). Rf 0.34. NIIR (CDCl ₃ ) 0.3 br (1H); 2.82 t (1H); 3.0 to 3.5 m (5H); 6.08 br (2H); 6.67 m (4H); 7.15 br (3H); 7.81 s (6H); 8.2 br (4H).

(h) diamine (0.6 g) + D (0.46 g) gave N-methyl-N «- [3- [3- (N, N-dimethylaminoethyl) phenoxy] propyl] -2-nitro- 1,1-äthendiamin (0.58 g), mp 93-94 ⁰ C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.45.

(i) Diamine (0.5 g) + D (0.36 g) gave N-methyl-N «- [4- [3- (N, N-dimethylaminoethyl) phenoxy] butyl] -2-nitro- 1,1-äthendiamin (0.12 g), mp 59 to 63 ⁰ C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.4.

(j) diamine (0.26 g) and D (0.22 g) provided N-methyl-N '- [2- [3- (N, N-dimethylaminopr opyl) phenoxy ethyl] -2-nitro-1,1-ethenediamine (0.2 g), m.p. 82-83.5 ° C TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf 0.4.

00 diamine (0.2 g) + D (0.15 g) provided N-methyl-N '- [3- [3- (II, N-dimethyl aminopropyl) -phenoxy] -propyl] -2-nitro-1,1-ethene-

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diamine (0.14 g), m.p. 59.5 to 61 ^° C. TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf 0.35.

(1) Diamine (0.5 g) + D (0.36 g) provided N-methyl-N «- [4- [3- (N, N-dimethylaminopropyl) -phenoxy] -butyl] -2-nitro- 1,1-ethylenediamine (0.45 g), m.p. 79-80.5 ° C. TLC silica; Ethyl acetate: WasserrIsopropanolι0.88 ammonia (25: 8: 15: 2), Rf 0.5.

(m) diamine (0.28 g) + D (0.5 g) provided N-methyl-N '- [2- [4- (N, N-dimethylaminomethyl) phenoxy] ethyl] -2-nitro- 1,1-ethylenediamine (0.11 g), m.p. 141-142 ° C. TLC silica; Methanol: 0.88 ammonia (50: 1), Rf 0.39.

(n) diamine (0.56 g) + D (1.19 g) provided N-methyl-N '- [3- [4- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro- 1,1-äthendiamin (0.12 g), mp 133 to 136 ⁰ C. TLC silica; Methanol: 0.88 ammonia (19: 1), Rf 0.5.

(ο) diamine (0.45 g) + D (0.3 g) provided N-methyl-N '- [4- [4- (N, N-dimethylaminoethyl) phenoxy / butyl] -2-nitro-1 , 1-äthendiamin (0.25 g), mp 98 to 100 ⁰ C. TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.45-

(ρ) diamine (2.5 g) + D (2.0 g) gave NM _e thyl-N '- [4- [2- (N, N-dimethylaminomethyl) phenoxy] butyl] -2-nitro- 1,1-äthendiamin (1.9 g), m.p. 98.5 to 10O ⁰ C. TLC silica; Methanol: ammonia (80: 1), Rf 0.45.

(q) Diamine (0.7 g) + D (0.44 g) provided N-methyl-N • - [4- [3- (N, N-dimethylaminomethyl) -phenylj-butyl] -2-nitro-1 , 1-ethenediamine (0.4 g), m.p. (dihydrochloride) 137 to 139 ° C TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.5.

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Example 2

N-Nitro-N '- [* 3- f 3- ( N, N-dimethylaminomethyl) phenoxy] propyl] guanidine

N-Nitrocarbamimidothiosäure-methylester (0.77 g) and 3- (3-aminopropoxy) -N, N-dimethylbenzolmethanamin (1.0 g) were heated for 20 minutes in ethanol at 4O ⁰ C. The solution was cooled, whereby the named compound was precipitated. This was filtered off and recrystallized from ethyl acetate as a white pesticide (0.44 g), m.p. 114-115 ° C. TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.48.

Example 3

N- [3- [3- (N, N-dimethylaminomethyl) -phenoxy] -propylj-guanidine dinitrate

3- (3-aminopropoxy) -N, N-dimethylbenzolmethanamin (2 g) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.1 g) was added 16 h at reflux in _a Äth nol heated. The solvent was removed and the residue was washed with boiling ethyl acetate before being crystallized from ethanol. In this way the named compound was obtained as a white solid (1 g), mp up to 124 ° C.

TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.34.

Example 4

(a) N-cyano-N ^t -methyl-M "-r3 ~ i3- (N, N-dimethylaminomethyl) -phenoxy] -propyl- guanidine

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N-cyano-N'-methylcarbamimidothioic acid methyl ester (0.8 g) void 3- [3-aminopropo3cy -] - N, N-dimethylbenzenemethanamine (1.0 g) were ^{heated together at 100 °} C. for 12 h. The melt was cooled, dissolved in methanol, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel with methanol, whereby the title compound was obtained as a clear yellow oil (0.54 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.51.

Analysis found: C, 62.54; H 8.31; N 23.93;

Theoretical values for C ₁₅ H ₂₃ N ₅ O: C, 62.28; H 7.96; N 24.22%.

In a similar way, the following compounds were prepared from the corresponding amine (5 g) and N-cyano-N ^t -methylcarbamimidothioic acid methyl ester (2.8 g) »

(b) N-cyano-N "-methyl-N" - [2- [ [3- (N, N-dimethylaminomethyl) phenyl] methylthio] ethyl] guanidine (2.3 g). TLC silica; Methanol, Rf 0.47, NMR (CDCl3,) 2.5-3m (4H); 6.25s (2H); 6.5-6.9m (4H); 7.18d (3H); 7 to 7.5 m (2H); 7.73 s (6H).

(c) Amine (1.5 g) and ester (0.86 g) provided N-cyano-N'-methyl-N "- [2 - [[2- (N, N-dimeth> laminomethyl) -phenyl] methylthio] ethyl] guanidine (1.1 g), mp 107 to 108.5 ⁰ C.

Example 5

N-methyl-N'-f3-i3- (N, N-dimethylaminomethyl) phenoxy] propyl] urea

Methyl isocyanate (0.27 ml) and 3- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine (0.97 g) was stirred in acetonitrile at room temperature for 2 hours. The named compound was filtered off, washed with acetonitrile and taken from ethyl acetate in the form

809848/0806

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from colorless prisms (0.49 g), melting point 79.5 to 80 ^° C., recrystallized. TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.45.

Example 6

N- methyl-Nf 2-ff 2- (N, N-dimethylaminomethyl) -phenyl-1-methylthio-1-ethyl-1-thiourea

2 - [[2- (N, N-dimethylaminomethyl) -phenylI-methylthio} -ethanamine (1.5 g) and methyl isothiocyanate (0.5 ml) were stirred in acetonitrile at room temperature for 6 h. The solvent was removed and the residue was column chromatographed on silica using a mixture of ethyl acetate and methanol as Eluent was used. In this way, the named compound was obtained as a white solid (1 g), m.p. 57 to 59 ° C, obtain.

Analysis found: C, 56.2; H 8.1; N 13.8;

theoretical values for C ₁ → II ₂₃ N ₃ S: C 56.5; H 7.8; N 14.1%.

Example 7

N-Hethyl-N'-f2-f f3- (N, N-dimethylaminomethyl) -phenyl-1-methylthio] -ethylj-2-nitro-i, 1-ethenediamine

2- ['[3- (N, N-dimethylaminomethyl) phenyl] methylthio] ethanamine (3 g) and 1 _IIitro-2,2-bis (methylthio) -ethylene (2.2 g) were Refluxed in acetonitrile for 7 hours. The solvent was removed and the remaining oil became without further Cleaning used. The oil was treated with ethanolic methylamine (33 / S, 34 ml) and refluxed for 3 hours. The solvent was removed and the remaining oil was purified by column chromatography on silica with methanol cleaned. The resulting orange oil was made with ether

809848/0806

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stirred, whereby the compound mentioned as a white crystalline solid (0.23 g), mp 62 to 64 ⁰ C, was obtained. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.36 _o ^j

Similarly, from the corresponding amine (3g) and 1-nitro-2,2-bis (methylthio) ethylene (2.2 g) N-methyl-N '- [2 - [[4- (N, N-dimethylaminomethyl) -phenylJ-methylthio] ethyl] -2-nitro-1,1-äthendiamin (2.5 g), mp Ms 98.5 100 ⁰ C were prepared.

Analysis found:

theoretical values for C ₁₅ H ₂₄ N ₄ O ₂ S:

Example 8

C 55.45; H 7.4; N 17.190 C 55.5; H 7.45; N 17.3? Ό.

(a) N - f 3 - f 3- (H, N-Dimethylaminome thyl) -phenoxy 1-propyl] -N '- (2-methoxyethyl) _-2-nitro-1-r 1-äthendiamin hydrοChlorid

(1) N-1 3-13- (N, II-dimethylaminoethyl) -phenoxy-j-propyl j-2-nitroimidothioic acid, methyl ester

3- (3-aminopropoxy) -TT, N-dimethylbenzenemethanamine (10 g) and 1-nitro-2,2-bis (methylthio) -ethylene (16 g) were 19 h in Tetrahydrofuran heated to reflux. Oxalic acid dihydrate (1.3 g) was added and the resulting precipitate was discarded. The solvent was removed, leaving the named compound as a crystalline solid (10 g), m.p. 59 to 63 ° C, stayed behind.

Analysis found:

theoretical values for η τι M η q »
^L 15 23 3 3

C 54.95; H 7.15; N 12.95; C 55.35; H 7.05; N 12.9 ^.

(2) N-13-f3- (N, N-dimethylaminomethyl) -phenoxy-1-propyl] -N '- (2-methoxyethyl) -2-nitro-1,1-ethenediamine hydrochloride

809840/0006

⁵⁰ 282 14 IQ

A mixture of methyl N- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitroimidothioate (0.8 g) and 2-methoxyethylamine (0.2 g) was in ethanol at room temperature for 24 hours touched. The solvent was removed leaving an orange oil which was treated with ethanolic hydrogen chloride to give the named compound (0.4 g), m.p. 109 to 112 ° C.

Analysis found: C, 52.1; H 7.7; N 14.0;

Theoretical values for C ₁₇ H ₂₃ N ₄ O ₄ : C 52.5; H 7.45; N 14.4 #.

The following compounds were prepared in a similar manner from the ester and the corresponding amine:

(2) (b) Ester (0.8g) and 70% aqueous ethylamine (3ml) provided N-Ethyl-N H'3- L3- (N, N-dimethylaminomethyl) -phenoxy] -propyl] · 2-nitro-1,1-ethylenediamine hydrochloride (0.69 g), mp 144-145 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 Ammonia (25: 15: 8: 2), Rf 0.55.

(2) (c) Ester (0.8 g) and 0.88 ammonia (0.5 ml) provided JM- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro -1,1-ethenediamine hydrochloride (0.6 g), m.p. 100-102 ° C. TLC silica; Ethyl acetate: isopropanol / water: 0.88 ammonia (25:15: 8: 2), Rf 0.65.

Example 9

N-Hethanesulfonyl-N'-methyl-N "-1'3-f 3- (N, N-dimethylaminomethyl) phenoxy] prop yl] guanidine

N-methanesulfonylcarbonimidodithioic acid dimethyl ester (3g) and 3- [3-aminopropoxy] -N, N-dimethylbenzenemethanamine (2.5 g) were refluxed in ethanol for 4 hours. Methylamine

80: 1 848/0806

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^ 282U10

was then added and refluxed for an additional 11/2 hours. The solvent was removed and the residue was purified by column chromatography on silica with methanol. In doing so, the compound mentioned was obtained as a yellow rubber (1.9 g). TLC methanol: 0.88 ammonia (80: 1), Rf 0.65. NMR (CDCl ₃ ) 2.85 m (1H); 2.9 to 3.3 m (3H);

3.0 to 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).

Example 10 Pharmaceutical compositions

(a) Tablets for oral administration, 50 mg

for 10000 tablets

Active ingredient 500 g

anhydrous lactose U.S.P. 2.17 kg

Sta-Rx-1500 starch * 300 g

Magnesium stearate B.P. 30 g

The active ingredient is sieved through a sieve with a mesh size of 250 μm. The four powders then become intimate blended in a mixer and compressed in a tablet machine by a punch with a diameter of 8.5 mm .

* A form of directly compressible starch made by A.E. Staley Kind regards. Co. (London) Limited, Orpington, Kent.

(b) Injectable preparation for intravenous administration

809848/0806

- 54- - 282 H 10 SÄ % Weight / weight 2.5 Active ingredient to 100.0 Water for Injection BP to pH 5.0 diluted Hydrochloric acid BP

The active ingredient is dissolved in the water for injection with mixing and the acid is slowly added until the pH is 5.0. The solution is flushed with nitrogen and then clarified by filtration through a membrane filter with a pore size of 1.35 ρ. It is filled into 2 ml glass ampoules (2.2 ml each) and each ampoule is sealed under a nitrogen atmosphere. The ampoules are sterilized in an autoclave at 121 ^° C. for 30 minutes.

(c) Sustained release tablets for oral administration, 150 mg

for 10000 tablets

Active ingredient Cutina HR ** anhydrous lactose U.S.P.

Magnesium stearate

The active ingredient, the anhydrous lactose and most of the Cutina HR are intimately mixed with one another. The mixture is then moistened by mixing it with a 10% solution of the remainder of the Cutina HR in technical methylated fuel OP 74. The moistened Hasse is granulated through a sieve with an opening of 1.2 mm and ^{dried at 50 °} C. in a fluidized bed dryer. The granulate is then passed through a sieve with an opening of 0.85 mm, mixed with magnesium stearate and compressed to a hardness of at least 10 kg (Schleuniger tester) on a tabletting machine with punches with a diameter of 12.5 mm.

50 kg O, 40 kg 2, 060 kg 40 G

809848/0806

282U 10

* ■ * Cutina HR is a type of microfine hydrogenated castor oil from Sipon Products Limited, London.

(d) Capsules for oral administration, 50 mg

for 10,000 capsules

Active ingredient 500 g

Sta-Rx 1500 * 1700 g

Magnesium stearate BP 20 mg

The drug is passed through a sieve with a mesh size of 250 µm and then with the other powders mixed up. The powder is filled into hard gelatin capsules No. 3 on a suitable filling machine.

It has been shown that the compounds of the formula I are inhibitors for gastric acid secretion induced by histamine. This was done in rats using a modified method described by M.N. Ghosh and H.O. Sign in "British Journal of Pharmacology", 1958, Volume 13, Page 54, shown.

Female rats weighing about 150 g were starved overnight and then given 8% sucrose in normal saline instead of normal drinking water.

The rats were injected with a single intraperitoneal injection a 25% (weight / volume) urethane solution (0.5 ml / 100 g) anesthetized. The trachea and jugular veins were cannulated.

A midline incision is made in the abdominal wall to expose the stomach, liver and stomach

809848/0806

- 93 -

^S * 282U1Q

The spleen is severed by cutting the connective tissue. A ^ cleine opening is made in the fundic region of the stomach made and the stomach is washed with 5% dextrose solution. The esophagus is cannulated with a rubber tube and the The esophagus and vagus nerves are cut above the cannula.

A small opening is then made in the pyloric area of the stomach. A large Perspex cannula is then inserted into the stomach through the opening in the fundic area in such a manner that the inlet end of the cannula protrudes from the stomach through the opening in the pyloric area. The shape of the cannula is such that the effective volume of the stomach is reduced and that a turbulent flow of the perfusion fluid is created over the surface of the mucous membrane. A drainage cannula is then inserted through the opening in the fundic region of the stomach. Both cannulas are tied in place by ligatures around the neck. They are arranged so that the ⁿ auptblutgefäße be avoided. Puncture wounds are made in the conveyor wall and the cannulas are passed through. The stomach is perfused through the esophageal and pyloric cannulas with 5% dextrose solution at 39 ° C. at a rate of 1.5 ml / min per each cannula. The effluent is passed over a microflow pH electrode and recorded using a pH meter and flatbed recorder.

The basal release of acid secretion from the stomach is monitored by measuring the pH of the flow rate. Increased acid secretion is then achieved by continuous intravenous infusion of a submaximal dose of Histamine induced. This creates a stable acid secretion plateau. The pH of the flow-through effluent is determined when this state has been reached.

809848/0806

282U10

The test compound is then administered to the rat by intravenous injection. The change in the secretion of acidic acid is monitored by measuring the change in pH of the perfusion effluent.

The change in the pH of the effluent flow becomes the difference in acid secretion between the basal output and the histamine-stimulated plateau value is calculated as the hydrogen ion concentration in mol / l. The diminution of Acid secretion caused by administration of the test compound is also shown as a change in the hydrogen ion concentration in mol / l based on the difference in the pH value, the Calculated through-flow fluid. The percentage reduction in acid secretion caused by administration of the test compound can then be calculated from the two values obtained.

809848/0806

Claims (33)

Claims 1. / Aminoalkylbenzene derivatives of the general formula: NAlte in the R ^ land Rg, which can be the same or different, for Hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups or lower alkyl groups represented by a Oxygen atom or a group -N- in which R; the meaning t ^ ^R 4
Has hydrogen or lower alkyl, is interrupted, or R ^ and Rp together with the nitrogen atom to which they are attached form a heterocyclic ring which can contain the heterofunctions -O- and -N-, R, represents hydrogen Lower alkyl, lower alkenyl or alkoxyalkyl, X is -O-, -S- or -CH ₀ - or -N-, in which R, - is hydrogen or ^ t o ^R 5 Has lower alkyl, Y is = S, = 0, = NRg or = CHRy, where Rg is hydrogen, nitro, cyano, lower alkyl, 809848/0806 282U10 Has aryl, arylsulfonyl or lower alkylsulfonyl, Ry for nitro, Lower alkylsulphonyl or arylsulphonyl, m is an integer from 2 to 4, η is 0, 1 or 2 and Alk is is a straight or branched alkylene chain with 1 to 6 carbon atoms, as well as the physiologically acceptable salts and hydrates, N-oxides and bioprecursors of such salts and of those salts in which the substituents attached to the benzene ring are are in ortho, meta or para position to one another. 2. Compounds according to claim 1, characterized in that R .. and Rp independently of one another for Are hydrogen or lower alkyl or together with the nitrogen atom to which they are attached, a 5- or 6-membered form heterocyclic ring. 3. Compounds according to claim 1 or 2, characterized in that Alk is a straight-chain alkylene chain with 1 to 3 carbon atoms. 4. Compounds according to any one of claims 1 to 3, characterized in that η has the value 0 or 1. 5. Compounds according to any one of claims 1 to 4, characterized in that Y = S, = 0, = CHN0 ₂ or ^ NRg, where Rg is hydrogen, nitro, cyano or alkylsulfonyl. 6. Compounds according to any one of claims 1 to 5, characterized in that ^R 1 represents hydrogen, alkyl or alkoxyalkyl. 809848/0806 7. Compounds according to any one of claims 1 to 6, characterized in that the attached to the benzene ring Substituents are in meta-position to one another. 8. Compounds according to any one of claims 1 to 7, characterized in that R ^ and R ₂ independently represent hydrogen or methyl or together with the nitrogen atom to which they are attached form a pyrrolidine ring, Alk represents a methylene group, η has the value O, Y stands for = CHN0 ₂ or = NRg, where R _{6 stands} for nitro, cyano- or methylsulfonyl, R 1 stands for hydrogen or methyl, m has the fourth 3 and X stands for oxygen. 9. Compounds "of the general formula Ia: - NCH ₂ V ^ O (CHg) ₃ NHCNHCH ₃ CHNO _n where R is hydrogen or methyl, as well as the physiological acceptable salts thereof, the N-oxides and hydrates of such compounds and such salts. 10. N-Methyl-N ^f - [2 - [[3- (N, N-dimethylaminomethyl) phenyl] methylthio] ethyl] nitro-1,1-ethenediamine. 11. N-methyl-N '- [2 - [[3- (N-methylaminomethyl) phenyl] methylthio] ethyl] -2-nitro-1,1-ethenediamine. 12. N-methyl-N ^! -C3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine. 809848/0806 282U1Q 13. N-Methyl-N • - [3- [3- (N-methylaminomethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine. 14. N-methyl-N ^! - [3- [3- (1-pyrrolidinylmethyl) phenoxy] propyl] -2-nitro-1,1-ethenediamine. 15. N-Nitro-N '- [3- [3- (N, N-dimethylaminomethyl) -phenoxy] -pro- ! -guanidine. 16. N-cyano-N • methyl-N "- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] guanidine. 17. N-methyl-N «- [3- [3- (N, N-dimethylaminoethyl) phenoxy I-pro pyl] -2-nitro-1,1-ethenediamine. 18. N-Methanesulfonyl- N «-methyl-N" - [3 - [(N, N-dimethylaminomethyl ) -phenoxy] -propyl] -guanidine. 19. Process for the preparation of aminoalkylbenzene derivatives according to claim 1, characterized in that that he (a) a primary amine of Formula II:. NAIk (CH ₂ ) _n X (CH ₂ ) _m NH ₂ (II) wherein R ₁ , R «, Alk, X, η and m have the meanings given in claim 1, reacted with a compound which is capable of forming a group -CNHR- ,, in which R, and Y are those in claim 809848/0806 - 5 - 282U10 1 have the meanings given, or (b) a compound of the formula V: NAIk (CH ₂ ) _n X (CH ₂ ) _m NHC-P (V) wherein R,., R ₂ , Alk, X, η and m have the meanings given in claim 1 and Q is the group = NRg or = CHRy (where Rg and Ry have the meanings given in claim 1) and P is a leaving group Group means, with an amine of the formula R-JÜHp, wherein R-2 has the meaning given in claim 1, reacts, or (c) for the preparation of compounds of the formula I in which η has the value 1, X stands for sulfur and the other groups have the meanings given in claim 1, with the exception that if both substituents R ₁ and Rp have the meaning Y have hydrogen, Y cannot be the group CHRy, where Ry has the meaning given in claim 1, a compound of the formula VI: (VI) 809848/0806 1410 (wherein R ^, Rp and Alk are those given in claim 1 Have meanings and L stands for a leaving group) or a compound of the formula VII: NAIk CH ₂ OH (VII) (wherein R ^, Rp and Alk are those given in claim 1 Have meanings) with a thiol of the formula VIII: HS (CH ₉ ) NHCNHR, (VIII) ^{£ m} Ii > Y wherein m, Y and R have the meanings given in claim 1, with protection of the amino group -NR ^ R ₂ , if the product is to be a compound in which both substituents R ₁ and Rp are hydrogen, or (d) for the preparation of compounds of the formula I in which Y stands for sulfur and R ^ and R _{2 have} a meaning other than hydrogen, an isothiocyanate of the formula IX: NAIk (CII ₂ ) _n X (CH ₂ ) _m NCS (IX) 809848/0806 282U10 wherein R ₁ and Rp have a meaning other than hydrogen and Alk, n, m and X have the meanings given in claim 1, with an amine of the formula R-JNH ₂ , where R has the meaning given in claim 1, or (E) for the preparation of compounds of the formula I in which Y stands for a group = NCN, a compound of Formula I, in which Y is sulfur, heated with a heavy metal cyanamide, or (f) for the preparation of compounds of the formula I in which Y has a meaning other than = S and R .. and R _{2 are} alkyl or aralkyl groups, a compound of the formula I in which R <j and R ₂ die Have meaning hydrogen, reacts with an alkyl or aralkyl halide, or (g) for the preparation of compounds of the formula I in which R ^ and / or R _{2 is} methyl groups, a compound of the formula I in which R ^ and / or R _{2 is} hydrogen, is reacted with formic acid and formaldehyde, where the compound of formula I in each case as a base or in the form of a physiologically acceptable salt or as Hydrate or N-oxide thereof isolated. 20. The method according to claim 19, characterized in that in variant (a) the compound which is able to introduce the group -CNHR ₃ , from the group of isocyanates of the formula R, NCO, isothiocyanates of the formula R ^ NCS and compounds of the formula: 809848/0806 282U10 It wherein Q stands for a group = NRg or = CHRy, where Rg and have the meanings given in claim 1, and P for one leaving group stands, selects. 21. Compounds of formula II according to claim 19 (a), namely wherein R ₁ , R ₂ , Alk, n, X and m have the meanings given in claim 1. 22. 3- (3-aminopropoxy) -N-dimethylbenzenemethanamine. 23. Compounds of formula V according to claim 19 (b), namely ■ ^NAlk - ^ = M. \ / ηττ \ Tr / ATr \ \ τττη τ » (V) 809848/0806 24. N- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl-2-nitroimidothioic acid, methyl ester. 25. Pharmaceutical compositions, characterized in that they contain a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent and, if desired, with other active ingredients contain. 26. Compositions according to claim 25, characterized in that they are in one for the oral, topical or parenteral administration or administration by suppositories are in suitable form. 27. Compositions according to claim 26, characterized in that they are in oral administration form in the form of tablets. 28. Compositions according to claim 27, characterized in that they are in the form of tablets with delayed release. 29. Compositions according to claim 27 or 28, .thereby characterized in that they contain 20 to 200 mg of active ingredient per tablet. 30. Compositions according to claim 26, characterized in that they are in one for the topical Application in suitable form as a spray, ointment or cream. 31. Use of compounds according to claim 1 for treatment of conditions mediated by histamine I ^ receptors will. 809848/0806 - 1C - 282H10 32. Use according to claim 31, characterized in that the conditions are gastric ulcers. 33. Use according to claim 31, characterized in that the conditions are allergic skin conditions are. 809848/0806