CH643238A5 - Aminoalkylbenzene derivatives having a selective action on histamine receptors - Google Patents

Abstract

The invention provides aminoalkylbenzene derivatives of the general formula <IMAGE> in which R1 and R2, which may be identical or different, represent hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups, or lower alkyl groups which are interrupted by an oxygen atom or a group <IMAGE> in which R4 has the meaning hydrogen or lower alkyl, or R1 and R2 form, together with the nitrogen atom to which they are attached, a heterocyclic rings which may contain the hetero functions -O- and <IMAGE>, R3 represents hydrogen, lower alkyl, alkenyl or alkoxyalkyl, X represents -O-, -S-, -CH2- or <IMAGE> in which R5 has the meaning hydrogen or lower alkyl, Y represents =S, =O, =NR6 or =CHR7, where R6 has the meaning hydrogen, nitro, cyano, lower alkyl, aryl, arylsulphonyl or lower alkylsulphonyl, R7 represents nitro, lower alkylsulphonyl or arylsulphonyl, m is an integer from 2 to 4, n has the value 0, 1 or 2 and Alk represents a straight-chain or branched alkylene chain having from 1 to 6 carbon atoms, and the physiologically acceptable salts and hydrates thereof, in which the substituents which are attached to the benzene ring are in the ortho, meta or para position with respect to one another; these compounds represent selective H2 antagonists. These compounds can be used for treating conditions involving hypersecretion of gastric acid and allergic conditions which are induced by histamine.

Description

The invention relates to new aminoalkylbenzene derivatives with a selective action on histamine receptors. The invention also relates to processes for the preparation of these compounds and pharmaceutical preparations containing these compounds.

Certain new aminoalkylbenzene derivatives have been found to be selective H: antagonists and to inhibit gastric acid secretion when stimulated by histamine H2 receptors (Ash and Schild-Brit. J. Pharmacol. Chemother. 1966, 27,427 ). Their ability to prevent gastric juice secretion when stimulated by histamine H; receptors can be demonstrated in the rat gastrointestinal tract, using the method of Ghosh and Schild - Brit. J. Pharmacol., 1958, 13, 54 - which has been modified in the manner described below. The ability of these compounds 30 can also be demonstrated in conscious dogs with Heidenhain pockets, using the same method as that described by Black et al. in "Nature" 1972, 236, 385. The compounds according to the invention do not modify contractions of isolated gastrointestinal smooth muscles induced by histamine SS.

Compounds with histamine H2 blocking activity can be used to treat conditions where gastric acid hypersecretion occurs, such as gastric and intestinal ulcers, and to treat allergic conditions for which histamine is a known cause. They can be used either alone or in combination with other ingredients to treat allergic and inflammatory conditions such as urticaria.

The invention relates to aminoalkylbenzene derivatives of the general formula:

R

NAlk

R,

(CH2) nX (CH2) mNIICNHR3

(X)

in which R 1 and R 2, which may be the same or different, form a heterocycli hydrogen or lower alkyl, cycloalkyl, aralkyl or see ring for the nitrogen atom to which they are attached, which have the hetero functions -O- and lower alkenyl groups or lower alkyl groups by 60 an oxygen atom or a group _jSf_

R4

-N-,

I.

65

may contain, R3 represents hydrogen, lower alkyl, lower al-n the R4 has the meaning hydrogen or lower alkyl, kenyl or alkoxyalkyl, X is -O-, -S- or -CH2-, or Ri and R2 together with the or

643238

4th

-N-,

I.

Rs where Rs is hydrogen or lower alkyl, Y is = S, = 0, = NRó or = CHR? where Rr> is hydrogen, nitro, cyano, lower alkyl, aryl, arylsulfonyl or lower alkylsulfonyl, R? represents nitro, lower alkylsulfonyl or arylsulfonyl, m is an integer from 2 to 4, n has the value 0.1 or 2 and Alk represents a straight-chain or branched alkylene chain having 1 to 6 carbon atoms, and the physiologically acceptable salts and hydrates thereof in which the substituents which are attached to the benzene ring are in the ortho, meta or para position to one another.

The term "low" as used herein in connection with "alkyl" is intended to mean that the group has a small number of carbon atoms, preferably 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms. In connection with "alkenyl", this term means that the group preferably has 3 to 6 carbon atoms. The term "aryl" preferably means phenyl or substituted phenyl, such as. B. phenyl which is substituted with one or more alkyl, allcoxy or halogen groups.

The compounds of formula I can exhibit a tautomerism and the formula is intended to encompass all tautomers. If Alk represents a branched chain alkylene group, then optical isomers can be present. In this case, the formula should include all diastereoisomers and optical enantiomers.

The preferred compounds are those in which R 1 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 is up to 3 carbon atoms, n has the value 0 or 1, Y for = S, = 0, = CHNCh or = NRf. where Re is hydrogen, nitro, cyano or alkylsulfonyl, R3 is hydrogen, alkyl or alkoxyalkyl and m and X have the meanings given above.

The connections in which the side chains are in the meta position to one another are particularly preferred. In a preferred class of compounds, the substituents R 1 and R 2 independently of one another represent hydrogen or methyl or these form a pyrrolidine ring together with the nitrogen atom, Alk represents a methylene group, n has the value 0, Y stands for = CHN02 or = NR6, where R (> has the meaning nitro, cyano or methylsulfonyl, R3 stands for hydrogen or methyl, m has the value 3 and X stands for oxygen.

The following compounds are particularly preferred individual compounds:

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

propyl] -2-nitro-1,1-ethylenediamine

Other preferred connections are:

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

N-Methyl-N '- [2 - [[3- (N, N-dimethylaminomethyl) phenyl] methyl Ithio] ethyl] -2-nitro-1,1-ethylenediamine N-methyl-N' - [2 - [[3- (N-methylaminomethyl) phenyl] -me-10thylthio] ethyl] -2-nitro-1,1-ethylenediamine

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

N-Cyano-N'-methyl-N "- [3- [3- (N, N-dimethyiamino-methyl) phenoxy] propyl] guanidine is N-methyl-N '- [3- [3- ( N, N-dimethylaminoethyl) phenoxy] propyl] -2-nitro-1,1-ethylenediamine

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

20 The compounds of formula I form physiologically acceptable salts with inorganic and organic acids. Particularly suitable salts are, for. B. hydrochlorides, hydrobromides and sulfates 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 used in the form of a base or a physiologically acceptable salt. Generally, they are used in the form of a pharmaceutical preparation together with a pharmaceutically acceptable carrier or diluent.

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

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

Parenteral administration can be by injection at intervals or as a continuous infusion. Injection solutions can contain I to 100 mg / ml of active ingredient. 50 A spray, ointment, cream or lotion can be used for topical application. The compositions may contain an effective amount of the active ingredient, e.g. B. about V / 2 to 2 wt .-%, based on the total composition.

55 The above compositions may be suitable for human or veterinary medicine.

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

R,

L \

NAlk

(CH2) nX (CH ") mNH

2 'm 2

(II)

5

643238

(wherein Ri, R2, Alk, n, X and m have the meanings given above) with a compound which is capable of reacting the group

5

introduce, wherein R3 and Y have the meanings given above, isolating the compound of formula I as a base or in the form of a physiologically acceptable salt 10 or as a hydrate thereof.

Compounds that are able to introduce the group -CNHR3 are isocyanates R3NCO, isothio-

II

Y 15

cyanate R3NCS or compounds of the formula:

leads that the reactants at elevated temperature, for. B. 100 to 120 ° C, melts together. If Q is = NRf>, the reaction between the amine II and a compound III can also be carried out in a solvent, e.g. As acetonitrile or ethanol, are carried out at elevated temperatures. If Q is = CHR7, then the amine II and the compound III can be stirred in aqueous solution at room temperature.

If R3 is hydrogen, alkali metal cyanates and thiocyanates can be used, the reaction being carried out at elevated temperature. Alternatively, organic isocyanates and isothiocyanates such as e.g. B. ethyl carbonisothiocyanatidate followed by basic hydrolysis. In another preferred alternative method, an amine of formula II is combined with a compound of the formula:

-NHR3

"C '

(III)

-c-

(IV)

20th

where Q for a group = NRf, or = CHR? stands and P for a leaving group, such as B. halogen, thiomethyl, 3,5-dimethylpyrazolyl or alkoxy, but preferably thiomethyl. The reaction with the isocyanate or isothiocyanate can be carried out by allowing the amine II and the isocyanate to stand in a solvent such as acetonitrile. The reaction of amine II with a compound of formula III can be carried out

R

Rr

NAlk

30th

implemented, in which P and Q have the meanings given above and P 'can have the same meaning as P or, if Q stands for = CHNCh, a group

-S-A

II

O

where A is a lower alkyl group, e.g. Methyl.

The resulting compound of the formula:

(V)

(CH2) nX (CH2) mNHC-P

Q

can then with an amine R3NH2 to the compound of formula 1, wherein Y = NRf.bzw. = CHR ?, are implemented, isolating the compound of formula I as a base or in the form of a physiologically acceptable salt or as a hydrate thereof. Both reaction steps can be carried out in a solvent, e.g. Ethanol or acetonitrile, at temperatures from ambient to reflux.

Further production processes for the compounds according to the invention have been described below.

Compounds according to the invention in which n is 1, X is sulfur and the other groups have the meanings given above, with the exception that when both R 1 and R 2 are hydrogen, Y has a meaning other than = CHR? can also be prepared from compounds of the formulas VI or VII using a thiol of the formula VIII.

R

(VI)

45

\

/

NAlk

Rr

50

CHgOH

HS (CH2) mNHCNHR3

(VII)

(VIII)

55

In formula VI above, L represents a leaving group, e.g. Halogen such as bromine or an acyloxy e.g. Acetoxy group. If compounds are to be prepared in which Ri and R2 are hydrogen, then the amino group NR1R2 is protected in compounds of the formulas VI and VII, for example in the case of a primary amine with a phthalimido group. In this case the protecting group may be at an appropriate stage in the reaction using a primary amine or a hydrazine, e.g. of methylamine or hydrazine hydrate.

The reaction between a thiol VIII and a compound of formula VI is preferably carried out in the presence of a

643 238

6

strong base, e.g. Sodium hydride, at room temperature in an organic solvent, e.g. Dimethylformamide made. The reaction between a thiol VIII and a compound of formula VII is preferably carried out at 0 ° C in a mineral acid, e.g. 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 1 have a meaning other than hydrogen, sees the treatment of amine II with carbon disulfide and s the subsequent reaction with a chloroformate ester, e.g. Ethyl chloroformate, to an isothiocyanate of the formula:

NAlk

(CH2) nX (CH2) BKCS

(IX)

in front. If the resulting compound of formula IX is reacted with an amine R3NH2, preferably in a solvent such as acetonitrile, then the product is a compound of formula I in which Y is sulfur and Ri and Rj have a meaning other than hydrogen.

Compounds of the formula I in which Y represents a group = NCN can be prepared from compounds of the formula I in which Y is sulfur by preparing the latter compounds with a heavy metal cyanamide such as that of silver , Lead, cadmium or mercury, preferably in an aqueous solution, heated.

If the groups R 1 and R 2 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, for example, with an alkyl or aralkyl halide. If compounds in which R 1 and / or R 2 are methyl groups are desired, then formic acid and formaldehyde, for example according to the Eschweiler-Clarke reaction, can be used according to an alternative.

In the above discussion of the processes available for the preparation of the compounds according to the invention, primary amines of the formula II were mentioned. These amines are new compounds, as well as their acid addition salts with inorganic and organic acids. These initial products can be made by a number of methods, which will be described below.

Amines of the formula II in which X is oxygen or sulfur can be obtained from compounds of the formula:

and W stands for a group -NH: or a group which can be converted into this group. If W 20 is a protected amino group, e.g. Phthalimido, then the protective group can then be removed by the measures described above.

Groups that can be converted into the RiRnNAlk group are e.g. Aldehyde, nitrite, carboxylic acid or amide groups 25 and phthalimido groups. For example, the -CHO group can be converted by reductive amination using an R1R2NH amine. Likewise, a carboxylic acid group can be converted into the corresponding acid halide or ester group, which is then reacted with an amine R1R2NH, which is followed by a reduction of the amide thus formed with, for example, lithium aluminum hydride to give a group R1R2NCH2-.

Amines of the formula II in which n is 1 and X is 35 oxygen or sulfur can, by reacting a compound of the formulas VI or VII with a compound which is capable of introducing the group -X (CH2) mNH2, where X is oxygen or sulfur and m 40 has the meaning given above, are prepared. If a compound of formula VI is used, the presence of a base is appropriate. If a compound of formula VII is used, the reaction takes place under acidic conditions.

4s amines of the formula II in which n has the value 1, m has the value 2 and X represents oxygen or sulfur can be obtained in such a way that a compound of the formula X in which n has the value 1 and X represents oxygen or sulfur, treated with ethylene amine.

50 amines of the formula II, in which n is 0, m is 3 and X is oxygen, can be obtained from the corresponding nitrii of the formula:

(CH2) nXH

where X is oxygen or sulfur and Rs is the group RiR2NAlk or a group which can be converted into this group and n has the meaning given above, by reaction in the presence of a base, e.g. of sodium hydride, with compounds of the formula:

(CH2) 2CN

(XII)

by catalytic hydrogenation, for example using rhodium on alumina. A compound of formula XII can be derived from a phenol of the formula

L '(CH2) mW

(XI)

where L 'has the meaning given above for L or additionally for a sulfonyloxy group, e.g. Mesyloxy or tosyloxy group, m has the above definition

65

(XIII)

7

643238

wherein R <) is a group which is convertible into R1R2N alk, e.g. an aldehyde, by reaction with acrylonitrile in the presence of a base e.g. methanolic benzyl trimethylammonium hydroxide.

Amines of the formula II, in which X represents a methylene group, can be obtained from compounds of the formula:

(XVIII)

ch2ch2ch2c00h chgchgcooh

(XIV)

where Rs is, for example, a RiRzNAlk group 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 is an amine of the formula II, where X is -CH2-, n is 0 and m is 2. An alternative reduction of a compound of formula XIV, where Rs is, for example, a group RiR: NAlk or a carboxamide or nitrile group, with, for example, lithium aluminum hydride gives an alcohol of the formula:

hydrolyzed, which can then be converted into an amine of formula II, in which X is -CH2- and the sum of m + n = 3, 10, for example by reacting ammonia with the derived acid chloride and subsequent reduction, as above described.

Amines of the formula II, in which n has the value 0 and X represents a group -NH-, can be obtained from starting materials of the formula:

20th

r-,

r,

nal ch2ch2ch2oh into a compound of the formula:

ch2ch2ch2l »

where Rs stands for RiRaNAlk and L 'has the meaning given above, can be converted.

Compounds of formula XVI can then be converted with ammonia to give an amine of formula II in which X is -CH2-, n is 0 and m is 2. The reaction of a compound of formula XVI with an alkali metal cyanide, e.g. Potassium cyanide, gives a compound of the formula:

(XVII)

CHgCHgCHgCN

which can then be reduced with, for example, lithium aluminum hydride, whereby an amine of the formula II is obtained in which X is -CH2- and the sum of m + n = 3. Alternatively, a compound of formula XVII can be a compound of formula:

(XXX)

where R9 is a group which is part of a group RiR2NAlk, e.g.

25th

O

(xv)

R1R2NC-,

30 is convertible, can be prepared by reaction with a compound of formula XI and subsequent removal of any protective groups and reduction of the amide function.

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

och

(xvi)

40

ch = ciicooh

(xx)

45

For example, if the reduction is carried out in the presence of an amine R1R2NH, the aldehyde can be converted to a group R1R2NCH2.

In the reactions described above for the preparation of amines of the formula II, it is usually preferable to use intermediates which contain the desired RiR2NAlk group or a protected form thereof, e.g. Phthalimido. However, intermediates can be used which contain a group which is convertible to the group RiR2NAlk 55 mentioned, and this group can be converted to RiR2NAlk at any suitable stage in the overall preparation.

If both substituents R 1 and R 2 in intermediates to amines of formula II are hydrogen, then the primary amino function can be protected at any stage in the above reaction, for example as a phthalimido group, and the protective group can be removed in a suitable stage by the measures described above .

65 When R 1 and / or R 2 in intermediates to amines of formula II are hydrogen, they can be converted to alkyl or aralkyl groups if necessary, e.g. an alkyl or aralkyl halide

643238

is applied. If R 1 and / or R 2 are methyl, a reaction with formaldehyde and formic acid according to the Eschweiler-Clarke reaction can be suitable.

The derivatives and the manufacturing processes are explained in the examples. Production examples 1 to 6 describe the production of the starting materials. Examples A to F describe the preparation of the starting products 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 carried out on silica gel plates with a thickness of 0.25 mm, 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 hours 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 a gray-white solid (21.4 g), mp 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) 3- (N, N-Dimethyaminocarbonyl) benzoic acid methyl ester

A mixture of thionyl chloride (88 g) and benzene-1,3-dicarboxylic acid monomethyl ester (33 g) was heated at 100 ° C for 1.5 hours. 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. The organic phase was dried and evaporated to give an oil (36 g). TLC silica; Ethyl acetate, Rf 0.8. NMR (CDCb) 1.8 m (2H); 2.2 to 2.7 m (2H); 6.1 s (3H); 6.95 s (6H).

(1) (b) The above example was repeated using the ester (70 g) and 25% aqueous methylamine (118 ml). Methyl 3- (N-methylaminocarbonyl) -benzoate (54 g), mp 128 to 130 ° C., was obtained. TLC silica; Ethyl acetate, Rf 0.57.

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

3- (N, N-Dimethylaminocarbonyl) benzoic acid methyl

ester (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 to give an oil (16 g), bp 95-100 ° C (0.1 mm). TLC silica / methanol, Rf 0.57.

(2) (b) The above example was repeated using 25 g of the ester from (b) above, with 3- (N, -methyl-

aminomethyl) benzene-methanol (9.2 g), bp 110 to 115 ° C (0.02 mm), was obtained. TLC silica; Methanol, RfO, 36.

5 Production example 3

(a) 2- [3- [3- (N, N-Dimethylaminomethyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) -dione

A mixture of 80% sodium hydride (2.2 g) and 3- (N, N-dimethylaminomethyl) phenol (6.95 g) in dry dime-10-thylformamide 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. Evaporation of the dried organic extracts provided the compound as 15 yellow oil (13 g). TLC silica; Ethyl acetate, Rf 0.35, m.p. (oxalate salt) 204 to 207 ° C.

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

(b) A (14g) + B (21.5g) provided 2- [3- [3- (l-pyrrolidinylmethyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) dione (21.4 g). TLC silica; Methanol: 0.880 ammonia (80: 1),

25 Rf0.46. Mp (oxalate salt) 167-169 ° C.

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

3o (d) A (5 g) + B (8.1 g) provided 2- [3- [3- (N, N-dimethylaminoethyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) -dione (5 g), mp 59-60 ° 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) provided 2- [4- [3- (N, N-dimethylamino-35 noethyl) phenoxy] butyl] -1 H-isoindole-1, 3- (2H) -dione (2.8g),

Mp 52-53 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2) Rf 0.55.

(f) A (2.2 g) + B (3.2 g) provided 2- [3- [3- (N, N-dimethylaminopropyl) phenoxy] propyl] -1 H-isoindole-1, 3- (2H) dione

40 (2.5 g), bp 250 ° 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) provided 2- [4- [3- (N, N-dimethylaminopropyl) phenoxy] butyl] -1 H-isoindole-1, 3- (2H) dione

(2.6 g), bp 225 ° C (0.04 mm), TLC silica; Ethyl 45 acetate: isopropanol: water: 0.88 ammonia, Rf 0.5.

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

50 (i) A (5 g) + B (9.7 g) provided 2- [3- [4- (N, N-dimethylaminomomethyl) phenoxy] -1 H-isoindole-1,3, (2H ) -dione (7.1 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf0.5, mp (oxalate salt) 166 to 170 ° C.

55 Production example 4

(a) 2- [2- [3- (N, N-Dimethylaminomethyl) phenoxy] ethyl] -1 H-isoindole-1,3, (2H) -dione

3- (N, N-dimethylaminomethyl) phenol (5.0 g), 80% sodium hydride (1.2 g) and 2- [2- (4-methylbenzenesulfonyl) -60 ethyl] -lH-isoindole-l, 3- (2H) -dione (13 g) was heated to 90 ° C in dimethylformamide. After 12 h, the reaction mixture is cooled and poured into ice water and extracted with ether. Evaporation of the organic solvent gave the product as a viscous yellow oil (5.2 g), it TLC silica; Methanol: ethyl acetate (1: 1), Rf 0.37. Mp (oxalate salt) 166 to 167 ° C.

The following compounds were made in a similar manner

prepared from the corresponding phenol (A) and 2- [2- (4-methylbenzenesulfonyl) ethyl] -1H-isoindole-1,3- (2H) -dione (C):

(b) A (5 g) + C (11.7 g) provided 2- [2- [3- (N, N-dimethylaminoethyl) phenoxy] ethyl] -1 H-isoindole-1,3- (2H) -dione (2.4 g), mp 84-85 ° C. TLC silica; Ethylacetafclsopro-panol: water: 0.88 ammonia, Rf 0.45.

(c) A (2.2 g) + C (4.2 g) provided 2- [2- [3- (N, N-dimethylamino-nopropyi) phenoxy] ethyl] -1 H-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- [3- [3- (N, N-Dimethylaminomethyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) -dione

(1) 2- [3- [3- (Formyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) dione

3-Hydroxybenzaldehyde (0.61 g), 3-bromopropylphthalimide (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, Rp 102 to 104 ° C. TLC silica: methanol: toluene (1: 9), Rf 0.65.

The following connections were made in a similar manner:

(l) (b) 4-Hydroxybenzaldehyde (5 g) and the corresponding phthalimide (10.4 g) provided 2- [2- [4- (formyl) phenoxy] ethyl-1H-isoindole-1,3- 2H) -dione (1.3 g), mp 131.5 to 133.5 ° C TLC methanol: chloroform (1: 100), Rf0.5.

(1) (c) 2-Hydroxybenzaldehyde (6.1 g) and the corresponding phthalimide (12 g) provided 2- [4- [2- (formyl) phenoxy] butyl] -1 H-isoindole-1,3 - (2H) -dione (12.2 g), mp 99.5 to 101 ° C. TLC silica; Methanol: 0.88 ammonia (80: 1), Rf0.8.

(2) 2- [3- [3- (N, N-Dimethylaminomethyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) -dione

2- [3- [3- (formyl) phenoxy] propyl] -1 H-isoindole-1,3- (2H) -dione (132 g) and 33% ethanolic dimethylamine (300 ml) were at room temperature and Atmospheric pressure in ethanol hydrogenated 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, mp (oxalate salt) 204 to 207 ° C.

The following compounds were similarly prepared from 33% ethanolic dimethylamine and the corresponding phthalimide (P):

(2) (b) P (1,2g) + 33% ethanolic dimethylamine (20 ml) provided 2- [2- [4- (N, N-dimethylaminomethyl) -phenoxy] ethyl] -1 H- 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) phe-noxy] butyl] -1 H-isoindole -1.3- (2H) -dione (7 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.55, mp (oxalate salt) 162 to 163 ° C.

Production Example 6

2- [3 - [[3- (N, N-Dimethylaminomethyl) phenyl] thio] propyl] -1 H-isoindole-1,3- (2H) -dione

(1) Dithio-bis-3,3'-N, N-dimethylbenzene carboxamide

Dimethylamine (57 ml) in toluene was added to 3,3'-dithio- (chlorocarbonyl) benzene (46 g) in toluene at 5 ° C.

After 4 h water was added and the solution was mixed with

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Extracted ethyl acetate. Evaporation of the extracts gave the product as an orange oil (49 g). NMR (CDCb) 2.4 to 2.8 m (8H); 7.05 br (12H).

(2) Dithio-bis-3,3'-N, N-dimethylbenzenemethanamine

3,3'-Dithio-N, N-dimethylbenzene carboxamide (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), bp 250 ° C (0.1 mm). NMR (CDCb) 2.5 to 2.9 m (8H); 6.66 s (4H); 7.8 s (6H).

(3) 2- [3 - [[3- (N, N-Dimethylaminomethyl) phenyl] thio] propyl] -1 H-isoindole-1,3- (2H) -dione

80% sodium hydride (2.3 g) and dithio-bis-3,3'-N, N-dimethylbenzomethanamine (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 h 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 gel with ethyl acetate / methanol to give the title compound as a light orange oil (11.3 g). NMR (CDCb) 2.0 to 2.4 m (4H); 2.6 to 2.9 m (4H); 6.151 (2H); 6.59 s (2H); 7.021 (2H); 7.75 s (6H); 7.98 m (2H).

Example A

3- (3-Amiïiopropoxy) -N-methylbenzene methanamine dio-xalate

(1) 3 - [3 - (Formyl) phenoxy] 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 washed 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- [3- (formyl) phenoxy] propionitrile (8.75 g) in a mixture of 33% ethanolic methylamine (50 ml) and ethanol (200 ml) was at room temperature with 5% palladium oxide on charcoal (0.8 g) stirred under 1 atm hydrogen. After the uptake of hydrogen has ended, the mixture is filtered and the residue is washed with ethanol. The ethanolic filtrate and washings were combined, concentrated and treated with excess ethereal hydrogen chloride. The precipitated hydrochloride was recrystallized from a mixture of ethanol and ether in the form of colorless plates (7.9 g), mp 125 to 128 ° C.

Analysis found: theoretical values for CnHisClNiO:

C 58.1; H 6.5; N 12.3;

C 58.3; H 6.5; N 12.35%.

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

A solution of N-methyl- [3- (2-cyanoethoxy) benzene methanamine hydrochloride (5.39 g) in methanol (50 ml) was passed through a column with a basic ion exchanger

9

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643238

(Amberlyst A-26) eluted. 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 with 5% rhodium on alumina (2.5 g) at room temperature under a pressure of 2.81 kg / cm 2 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 off and dried, mp 196 to 198 ° C. TLC silica; Methanol; 0.88 ammonia (99: 1), Rf 0.1.

Example B

3- (3-aminopropoxy) -N-methylbenzenemethanamine dio-xalate

2- [3- [3- (FormyI) phenoxy] propyl] -1 H-isoindole-1,3- (2H) dione (8.5 g) was in 33% ethanolic methylamine (300 ml) 1 Stirred h 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 named compound was obtained in the form of colorless grains (3.9 g), mp 196 to 198 ° C. TLC silica; Methanol: 0.88 ammonia (20: 1) Rf 0.1.

Example C

(a) 3- (3-aminopropoxy) -N, N-dimethylbenzomethane-amine 2- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -1 H-isoindole-l, 3- ( 2H) -dione (25 g) was treated with 30% ethanolic methylamine (150 ml). After 24 h at room temperature, ether (100 ml) was added and a solid was filtered off. The filtrate was distilled to give the title compound as a yellow oil (12.3 g), b.p. 102 to 112 ° C (0.2 mm). TLC silica: ethyl acetate: isopropanol: water: 0.88 ammonia, Rf0.25.

The following compounds were similarly prepared from the corresponding phthalimide (C):

(b) C (5.4 g) provided 3- (2-aminoethoxy) -N, N-dimethyl-benzenemethanamine (0.45 g). TLC silica; Methanol / ammonia (80: 1), Rf 0.04. NMR (CDCb) 2.8 to 3.1 m (4H); 6.051 (2H); 6.55 s (2H); 6.981 (2H); 7.80 s (6H); 8.4 br, s (2H).

(c) C (2.9 g) provided 4- (4-aminobutoxy) -N, N-dimethyl-benzenemethanamine-bis-oxalate salt (0.8 g). TLC silica; Methanol: 0.88 ammonia, Rf 0.17. NMR (D2O) 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-dimethyl-benzenemethanamine-bis-oxalate salt (1.2 g). NMR (D2O) 2.5 to 2.87 m (4H); 5.72 s (2H); 5,751 (2H); 6.71 (2H); 7.13 s (6H); 7.78 m (2H).

Example D

(a) 3- (3-aminopropoxy) -N, N-dimethylbenzenemethane-amine

2- [3- [3- (N, N-Dimethylaminomethyl) phenoxy] propyl] -1 H-isoindole-l, 3- (2H) -dione (90 g) and 30% aqueous methylamine (200 ml) were heated to 80 ° C. After 4 h the reaction mixture is cooled, made alkaline with 5N sodium hydroxide solution and extracted with toluene. The toluene extract was distilled, whereby the compound mentioned 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 were similarly prepared from the corresponding phthalimide (C):

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

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

Example E

(a) 3- (3-aminopropoxy) -N, N-dimethylbenzenemethane-amine

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

The following compounds were similarly prepared from the corresponding phthalimide (C):

(b) C (2.8 g) provided 3- (2-aminoethoxy) -N, N-dimethyl-benzenethanolamine (1.7 g) bp 135 ° C (0.03 mm). TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.3.

(c) C (4.2 g) provided 3- (3-aminopropoxy) -N, N-dimethyl-benzenethanolamine (2 g), bp 95 ° C (0.03 mm). TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.3.

(d) C (2.5 g) provided 3- (4-aminobutoxy) -N, N-dimethyl-benzenethanolamine (0.9 g), bp 150 ° C (0.04 mm). TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia, Rf0.3.

(e) C (0.5 g) provided 3- (2-aminoethoxy) -N, N-dimethyl-benzenepropanamine (0.26 g), bp 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) provided 3- (3-aminopropoxy) -N, N-dimethylbenzene propanamine (0.95 g), bp 160 ° C (0.04 mm). TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf0.3.

(g) C (2 g) provided 3- (4-aminobutoxy) -N, N-dimethylbenzene propanamine (1.05 g), bp 130 ° C (0.04 mm). TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf0.25.

(h) C (11.3 g) gave 3 - [(3-aminopropyl) thio] -N, N-dimethylbenzomethanamine (2.3 g), bp 142 ° C (0.1 mm), NMR (CDCb) 2.5 to 3 m (4H); 6.6 s (2H); 6.991 (3H); 7.17t (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), bp 90 ° C (0.04 mm). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.2.

(j) C (7 g) provided 2- (4-aminobutoxy) -N, N-dimethylbenzenemethanamine (2.7 g), bp 90 ° C (0.07 mm). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.2.

Example F

(a) 2 - [[3- (N, N-Dimethylaminomethyl) phenyl] methyl thio] ethanolamine

3- (N, N-Dimethylaminomethyl) benzene-methanol (17.4 g) and cysteamine hydrochloride (12 g) were heated at 100 ° C in concentrated hydrochloric acid for 4 hours. The cooled Reak10

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tion 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), bp 154-158 ° C (1.5 mm), mp (hydrochloride salt) 180-182 ° C. TLC Kiëselsâure; Ethyl acetate: isopropanol: water .0.88 ammonia (25: 15: 8: 2), Rf0.37.

(b) 3- (N-Methylaminomethyl) benzene methanol (10.1 g) and cysteamine hydrochloride (7.7 g) similarly became 2 - [[3- (N-Methylaminomethyl) phenyl] methyl thioj-ethanolamine (6.5 g), bp 140 to 145 ° C (0.01 mm)

receive. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia, Rf 0.28.

(c) 2- (N, N-Dimethylaminomethyl) -benzoImethanol (0.8 g) and cysteamine hydrochloride (0.57 g) similarly became 2 - [[2- (N, N-Dimethylaminomethyl) -phenyl] - methylthio] ethanolamine (0.38 g), bp 100 to 105 ° C (0.01 mm), obtained. TLC silica; Ethyl acetate: methanol: 0.88 ammonia (10: 10: 1), Rf 0.22.

(d) 4- (N, N-Dimethylaminomethyl) benzene methanol (4 g) and cysteamine hydrochloride (2.8 g) similarly became 2 - [[4- (N, N-Dimethylaminomethyl) phenyl] methyl] thio] ethanolamine (3.6 g), bp 148 to 150 ° C (0.01 mm)

receive.

Analysis found: theoretical values for C12H20N2S:

C 63.8; H 9.2; N 12.1;

C 64.2; H 9.0; N 12.5%.

Example G

3- (N, N-dimethylaminomethyl) benzene butanamine

3- (N. N-Dimethy laminomethyl) -benzenepropanoic acid ethyl ester

3-Formylcinnamic acid (5.5 g) was heated to 60 ° C. in 30% ethanolic dimethylamine (45 ml) for 30 min and then stirred at room temperature with 10% palladium oxide on charcoal (1.5 g) under hydrogen at 1 atom. After the uptake of hydrogen 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), bp 130 ° C. (0.05 mm).

TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf0.75.

3- (N, N-Dimethylaminomethyl) benzene propanol

Ethyl 3- (N, N-dimethylaminomethyI) benzene propanoic acid ester (0.5 g) and lithium aluminum hydride (0.2 g) were stirred at room temperature in dry tetrahydrofuran for 2 h, 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 (CDCb) 2.81 m (4H); 6.33 tr (2H); 6.59 s (2H); 7.28 m (2H); 7.75 s (7H); 7.7 to 8.4 m (2H).

3- (N, N-Dimethylaminomethyl) -benzenebutanenitrile

3- (N, N-Dimethylaminomethyl) -benzoIpropanol (0.9 g) and p-toluenesulfonyl chloride (0.9 g) were stirred in pyridine for 2 h. The solvent was evaporated and the residue was treated with potassium cyanide (0.7 g) in dimethylformamide at 45 ° C for 16 h. Water was added and the mixture was extracted with ethyl acetate. The extract was distilled to give the product as a colorless liquid (0.3 g), bp 110 ° C (0.02 mm).

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

5

3- (N, N-dimethylaminomethyl) benzene butanamine

3- (N, N-Dimethylaminomethyl) -benzenebutanenitrile (0.9 g) and lithium aluminum hydride (0.35 g) in tetrahydrofuran were stirred at room temperature for 2 h. 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 15 ammonia (25: 15: 8: 2), Rf 0.1, mp (oxalate salt) 125 to 127 ° C.

example 1

(a) N-Methyl-N '- [3- [3- (N, N-dimethylaminomethyl) phe-20 noxy] propyl] -2-nitro-1,1-ethylenediamine

A mixture of 3- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine (1 g) and N-methyl-2-nitroimidothioic acid methyl ester (0.78 g) in water (4 ml) was at room temperature for 4 hours touched. The resulting solution was acidified with glacial acetic acid and then 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 to give the compound as a white solid (0.6 g), mp 81-83 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf0.6.

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

(b) Diamine (2 g) and D (1.4 g) provided N-methyl-N '- [2-40 [[3- (N-methylaminomethyl) phenyl] methylthio] ethyl] -2-

nitro-1,1-ethylenediamine (0.8 g). TLC silica; Methanol: ammonia (50: 1) Rf 0.3, mp (fumarate salt) 163 to 165 ° C.

(c) Diamine (1 g) + D (0.73 g) provided N-methyl-N '- [3 - [[3- (N, N-dimethylaminomethyl) phenyl] thio] propyI] -2- nitro

45 1,1-ethane diamine (0.25 g). NMR (CDCb) -0.5 g 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) provided N-methyl-N '- [3- [3- (N-methylaminomethyl) phenoxy] propyl] -2-nitro-1, 1-

50 ethylenediamine (0.35 g). TLC silica; Methanol: 0.88 ammonia (20: 1), Rf 0.35. NMR (CDCb) 2.68 m (2H); 2.9 to 3.4 m (3H); 5.91 (2H); 6.29 s (2H); 6.531 (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 '- [3-55 [3- (1-pyrrolidinylmethyl) phenoxy] propyl] -2-nitro-1 ,1-

ethylenediamine (0.35 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.35. NMR (CDCb) 2.8 m (IH); 2.9 to

3.5 m (4H); 5.901 (2H); 6.4 s (2H); 6.50 m (2H); 7.1 br (4H); 7.5 to 8.3 m (7H).

so (f) diamine (0.8 g) + D (0.78 g) provided N-methyl-N '[2- [3- (N, N-dimethylaminomethyl) phenoxy] ethyl] -2-nitro-l , l-ethylenediamine (0.55 g), mp 130 to 131 ° 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 '- [4-65 [3- (N, N-dimethylaminomethyl) phenoxy] butyl] -2-nitro -l, l-ethylenediamine (0.38 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.34. NMR (CDCb) 0.3 br (1H); 2.821 (1H); 3.0 to 3.5 m (5H); 6.08 br (2H); 6.67 m (4H); 7.15 br

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12

(3H); 7.81 s (6H); 8.2 br (4H).

(h) Diamine (0.6 g) + D (0.46 g) provided N-methyl-N '- [3- [3- (N, N-dimethylaminoethyl) phenoxy] propyl] -2-nitro- 1,1-ethylenediamine (0.58 g), mp 93-94 ° 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) provided N-methyl-N '- [4- [3- (N, N-dimethylaminoethyl) phenoxy] butyl] -2-nitro- 1,1-ethylenediamine (0.12 g), mp 59-63 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25 .: 15: 8: 2), Rf 0.4.

(j) Diamine (0.26 g) + D (0.22 g) provided N-methyl-N '- [2- [3- (N, N-dimethylaminopropyl) phenoxy] ethyl] -2-nitro- 1,1-ethylenediamine (0.2 g), mp 82-83.5 ° C. TLC silica; Ethyl acetate: water: isopropanol: 0.88 ammonia (25: 8: 15: 2), Rf0.4.

(k) Diamine (0.2 g) + D (0.15 g) provided N-methyl-N '- [3- [3- (N, N-dimethylaminopropyl) phenoxy] propyl] -2-nitro- 1,1-ethylenediamine (0.14g), mp 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), mp 79 to 80.5 ° C. TLC silica; ethyl acetate: water: isopropanol: 0.88 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), mp 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-ethylenediamine (0.12 g), mp 133-136 ° C. TLC silica; Methanol: 0.88 ammonia (19: 1), Rf 0.5.

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

(p) Diamine (2.5 g) + D (2.0 g) provided N-methyl-N '- [4- [2- (N, N-dimethylaminomethyl) phenoxy] butyl] -2-nitro- l, l-ethylenediamine (1.9 g), mp 98.5 to 100 ° C. TLC silica; Methanol: ammonia (80: 1), Rf0.45.

(q) Diamine (0.7 g) + D (0.44 g) provided N-methyl-N '- [4- [3- (N, N-dimethylaminomethyl) phenyl] butyl] -2-nitro- l, 1-ethylenediamine (0.4 g), mp (dihydrochloride) 137 to 139 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf0.5.

Example 2

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

N-nitrocarbamimidothioic acid methyl ester (0.77 g) and 3- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine (1.0 g) were added. Heated to 40 ° C in ethanol for 20 min. The solution was cooled, whereby the named compound was precipitated. This was filtered off and recrystallized from ethyl acetate as a white solid (0.44 g), mp 114 to 115 ° C. TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.48.

Example 3

N- [3- [3- (N, N-Dimethyaminomethyl) phenoxy] propyl] guanidine dinitrate

3- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine (2 g) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.1 g) were heated under reflux in ethanol for 16 h. The solvent was removed and the residue was washed with boiling ethyl acetate before being crystallized from ethanol. In this way, the compound mentioned was obtained as a white solid (1 g), mp 123 ° to 124 ° C.

TLC silica; Ethyl acetate: isopropanol: water: 0.88 5 ammonia (25: 15: 8: 2), Rf 0.34.

. Example 4

(a) N-Cyano-N'-methyl-N "- [3- [3- (N, N-dimethylamino-io methyl) phenoxy] propyl] guanidine

N-cyano-N'-methylcarbamimidothioic acid methyl ester (0.8 g) and 3- [3-aminopropoxy] -N, N-dimethylbenzenemethane-amine (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 to give the title compound as a clear yellow oil (0.54 g). TLC silica; Methanol: 0.88 ammonia (80: 1), Rf 0.51.

20th

Analysis found: theoretical values for C15H23N5O:

C 62.54; C 62.28;

H 8.31; H 7.96;

N 23.93; N 24.22%.

25th

The following compounds were similarly prepared from the corresponding amine (5 g) and methyl N-cyano-N'-methylcarbamimidothioate (2.8 g):

30 (b) N-Cyano-N'-methyl-N "- [2 - [[3- (N, N-dimethylamino-methyl) phenyl] methyIthio] ethyl] guanidine (2.3 g). TLC silica; methanol, Rf 0.47.MMR (CDCb) 2.5 to 3 m (4H); 6.25 s (2H); 6.5 to 6.9 m (4H); 7.18 d (3rd H); 7 to 7.5 m (2H); 7.73 s (6H).

35 (c) amine (1.5 g) and ester (0.86 g) provided N-cyano-N'-methyl-N "- [2 - [[2- (N, N-dimethylaminomethyl) phenyl] - methylthio] ethyl] guanidine (1.1 g), mp 107-108.5 ° C.

40

Example 5

N-Methyl-N '- [3- [3- (N, N-dimethylaminomethyl) phe-noxy] propyl] urea

Methyl isocyanate (0.27 ml) and 3- (3-aminopropoxy) -N, N-45 dimethylbenzenemethanamine (0.97 g) were stirred in acetonitrile at room temperature for 2 hours. The compound mentioned was filtered off, washed with acetonitrile and recrystallized from ethyl acetate in the form of colorless prisms (0.49 g), mp 79.5 to 80 ° C. TLC silica; Methanol: 0.88 50 ammonia (80: 1), Rf 0.45.

Example 6

N-Methyl-N- [2 - [[2- (N, N-dimethylaminomethyl) phenyl] -55 methylthio] ethyl] thiourea

2 - [[2- (N, N-Dimethylaminomethyl) phenyl] methylthio] ethanolamine (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-60 using a mixture of ethyl acetate and methanol as the eluent. In this way, the compound mentioned was obtained as a white solid (1 g), mp 57 to 59 ° C.

65 Analysis found: theoretical values for C14H23N3S:

C 56.2; H 8.1; N 13.8;

C 56.5; H 7.8; N 14.1%.

13

643238

Example 7

N-Methyl-N '- [2 - [[3- (N, N-dimethylaminomethyl) phenyl] methylthio] ethyl] -2-nitro-1,1-ethylenediamine

2 - [[3- (N, N-Dimethylaminomethyl) phenyl] methylthio] ethanolamine (3 g) and 1-nitro-2,2-bis (methylthio) ethylene (2.2 g) were treated for 7 hours heated to reflux in acetonitrile. The solvent was removed and the remaining oil was used without further purification. The oil was treated with ethanolic methylamine (33%, 34 ml) and refluxed for 3 hours. The solvent was removed and the remaining oil was purified by column chromatography on silica with methanol. The resulting orange oil was stirred with ether, whereby the compound mentioned was obtained as a white crystalline solid (0.23 g), mp 62 to 64 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.36.

In a similar manner, the corresponding amine (3 g) and l-nitro-2,2-bis (methylthio) ethylene (2.2 g) were converted into N-methyl-N '- [2 - [[4- (N , N-dimethylaminomethyl) phenyl] methylthio] ethyl] -2-nitro-1,1-ethylenediamine (2.5 g), mp 98.5 to 100 ° C.

Analysis found: theoretical values for C15H24N4O2S:

C 55.45; H 7.40; C 55.50; H 7.45;

N 17.1% N 17.3%.

Example 8

(a) N- [3- [3-N, N-Dimethylaminomethyl) phenoxy] propyl] -N '- (2-methoxyethyl) -2-nitro-1,1-ethylenediamine hydrochloride

(1) N- [3- [3- (N, N-Dimethylaminomethyl) phenoxy] propyl] -2-nitroimidothioic acid methyl ester

3- (3-aminopropoxy) -N, N-dimethylbenzenemethanamine (10 g) and l-nitro-2,2-bis (methylthio) ethylene (16 g) were refluxed in tetrahydrofuran for 19 h. Oxalic acid dihydrate (1.3 g) was added and the resulting precipitate was discarded. The solvent was removed, leaving the compound as a crystalline solid (10 g), mp 59-63 ° C.

Analysis found: theoretical values for C15H23N3O3S:

C 54.95; C 55.35;

H 7.15; H 7.05;

N 12.95; N 12.90%.

C 52.1; H 7.70; N 14.0;

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 (0.8 g) and 70% aqueous ethylamine (3 ml) provided N-ethyl-N '- [3- [3- (N, N-dimethylamino-

methyl l) -phenoxy] -propyl-2-nitro-1,1-ethylenediamine hydrochloride (0.69 g), mp 144 to 145 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf 0.55.

(2) (c) Esters (0.8 g) and 0.88 ammonia (0.5 ml) provided N- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] -2-nitro -l, l-ethylenediamine hydrochloride (0.6 g), mp 100 to 102 ° C. TLC silica; Ethyl acetate: isopropanol: water: 0.88 ammonia (25: 15: 8: 2), Rf0.65.

Example 9

N-methanesulfonyl-N'-methyl-N "- [3- [3- (N, N-dimethylaminomethyl) phenoxy] propyl] guanidine is N-methanesulfonylcarbonimidodithioic acid dimethyl ester (3 g) and 3- [3 -Aminopropoxy] -N, N-dimethylbenzenemethane-amine (2.5 g) was refluxed in ethanol for 4 h, then methylamine was added and refluxed for a further 1 h. The solvent was removed and the The residue was purified by column chromatography on silica with methanol, whereby the compound mentioned was obtained as a yellow gum (1.9 g). TLC methanol: 0.88 ammonia (80: 1), Rf 0.65. NMR (CDCb) 2, 85 m (IH); 2.9 to 3.3 m (3H); 3.0 to 4.3 brs (2H); 25 5.901 (2H); 6.5 q (2H) i 6.6 s (2H ); 7.1 s (6H); 7.75 s (6H); 7.9 m (2H).

Example 10 Pharmaceutical Compositions

30th

(a) Tablets for oral administration, 50 mg for 10,000 tablets

Active ingredient

500 g anhydrous lactose U.S.P.

2.17 kg

Sta-Rx-1500 strength *

300 g

Magnesium stearate BP

30 g

(2) N- [3- [3- (N, N-Dimethylaminomethyl) phenoxy] propyl] -N '- (2-methoxyethyl) -2-nitro-1,1-ethylenediamine hydrochloride

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

Analysis found: theoretical values for C17H28N4O4:

40 * A form of a directly compressible starch from A .. E. Staley Mfg. Co. (London) Limited, Orpington, Kent.

The active ingredient is sieved through a sieve with a mesh size of 250 (im. Then the four 45 powders are intimately mixed in a mixer and compressed in a tablet machine by a punch with a diameter of 8.5 mm.

see (b) Injectable preparation for intravenous administration

% Weight / weight

Active ingredient

2.5

Water for injection BP

to 100.0

dilute hydrochloric acid BP

to pH 5.0

60 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 µm. It is filled 65 in 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.

643 238

14

(c) Oral delayed release tablets, 150 mg for 10,000 tablets

Active ingredient 1.500 kg

Cutina HR ** 0.400 kg anhydrous lactose U.S.P. 2.060 kg

Magnesium stearate 40 g

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

The active ingredient, the anhydrous lactose and most of the Cutina HR are intimately mixed together. The mixture is then moistened by mixing with a 10% solution of the rest of the Cutina HR in technical methylated fuel OP 74. The moistened mass is granulated through a sieve with an opening of 1.2 mm and dried at 50 ° C. in a fluid bed dryer. The granules are 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.

(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 .mu.m and then mixed with the other powders. The powder is filled into No. 3 hard gelatin capsules on a suitable filling machine.

The compounds of formula I have been shown to be inhibitors of gastric acid secretion induced by histamine. This has been shown in rats using a modified method described by M. N. Ghosh and H. O. Schild in "British Journal of Pharmacology", 1958, volume 13, page 54.

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

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

A midline incision is made in the abdominal wall to expose the stomach, which is separated from the liver and spleen by cutting the connective tissue. A small opening is made in the fundus area 5 of the stomach and the stomach is washed with 5% dextrose solution. The esophagus is cannulated with a rubber tube and the esophagus and vagus nerves are cut off above the cannula.

A small opening is then made in the pyloric area of the io stomach. A large Perspex cannula is then inserted into the stomach through the opening in the fundus area in such a way that the inlet end of the cannula protrudes from the stomach through the opening in the pyloric area. The cannula is designed in such a way that the effective volume of the stomach is reduced and that a turbulent flow of the perfusion fluid is generated across the mucosal surface. A drainage cannula is then inserted through the opening in the fundic region of the stomach. Both cannulas are tied in place by 20 bandages around the stomach. They are arranged so that the main blood vessels are avoided. Puncture wounds are made in the delivery wall and the cannulas are passed through. The stomach is passed through the esophageal and pyloric cannulas with 5% Dex-25 troublesolution of 39 ° C at a rate of

1.5 ml / min flow through each cannula. The effluent is passed through a microflow pH electrode and recorded using a pH meter and a flatbed recorder.

30 The basal release of gastric acid secretion is monitored by measuring the pH value of the outflow. Increased acid secretion is then induced by continuous intravenous infusion of a submaximal dose of histamine. This creates a stable plateau of acid secretion. The flow effluent pH is determined when this condition is reached.

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

The difference in acid secretion between the basal release and the histamine-stimulated plateau value 45 is calculated as the hydrogen ion concentration in mol / 1 from the change in the pH value of the flow-through effluent. The decrease in acid secretion caused by administration of the test compound is also calculated as a change in the hydrogen ion concentration in mol / 1 based on the difference in the pH value of the flow-through liquid. The percentage decrease in acid secretion caused by administration of the residual compound can then be calculated from the two values obtained.

B

Claims (10)

643238 PATENT CLAIMS 1. Aminoalkylbenzene derivatives with therapeutic efficacy of the general formula: NAXlcs Y il co > - (CH2) nX (CH2) mNHcNH! Î3 in which R 1 and R 2, which may be the same or different, represent hydrogen or lower alkyl, cycloalkyl, aralkyl or lower alkenyl groups or lower alkyl groups through an oxygen atom or a group -N-, I. R4 in which R4 has the meaning hydrogen or lower alkyl, is interrupted, or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring which has the hetero functions -O- and -N- I. R4 may contain, R3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl, X represents -O-, or -CH2- or -N-, I. Rs where Rs is hydrogen or lower alkyl, Y is = S, = 0, = NRe or = CHR7, where Rs is hydrogen, nitro, cyano, lower alkyl, aryl, arylsulfonyl or lower alkylsulfonyl, R7 is nitro, Lower alkylsulfonyl or arylsulfonyl, m is an integer from 2 to 4, n has the value 0.1 or 2 and alk represents a straight-chain or branched alkylene chain having 1 to 6 carbon atoms, as well as the physiologically acceptable salts and hydrates thereof, in which the substituents which are attached to the benzene ring are ortho, meta, or para to one another. stand. 2. Compounds according to claim 1, characterized in that the Ri and R2 are independently hydrogen or lower alkyl or together with the stick 20 atom to which they are attached form a 5- or o-membered heterocyclic ring, Alk stands for a straight-chain alkylene chain with 1 to 3 carbon atoms, n has the value 0 or 1, Y stands for = S, = 0, = CHNCh or NRE , where R & stands for hydrogen, nitro, cyano or lower alkylsulfonyl 25 and R3 stands for hydrogen, lower alkyl or alkoxyalkyl. 3. Compounds according to claim 1 or 2, characterized in that the substituents attached to the benzene ring are mutually in the meta position. 30th 4. Compounds according to any one of claims 1 to 3, characterized in that R 1 and R 2 independently of one another represent hydrogen or methyl or, together with the nitrogen atom to which they are attached, form a pyrrolidine ring, Alk represents a methylene group, n has the value 0, Y stands for = CHNCh or = NRô, where Ró stands for nitro, cyano or methylsulfonyl, R3 stands for hydrogen or methyl, m has the value 3 and X stands for oxygen. 5. A compound according to claim 1, characterized in that it contains the N-methyl-N '- [3- [3- (N, N-dimethylamino- methyl) phenoxy] propyl] -2-nitro-1,1-ethylenediamine. 6. A compound according to claim 1, characterized in that it is the N-methyl-N '- [3- [3- (l-pyrrolidinylmethyl) phenoxy] propyl] -2-nitro-1,1-ethylenediamine . 45 7. A process for the preparation of aminoalkylbenzene derivatives according to claim 1, characterized in that a primary amine of the formula II: NAlk (CH2) nX (CH2) mNH2 (II) wherein R 1, R 2, Alk, X, n and m have the meanings given in claim 1, with a compound capable of reacting a group -CNHRB II Y wherein R3 and Y have the meanings given in claim 1, the compound of formula I being isolated as a base or in the form of a physiologically acceptable salt or as a hydrate thereof. 65 8. A process for the preparation of aminoalkylbenzene derivatives according to claim 1, wherein Y = NR6 or = CHR7, characterized in that a compound of the formula V: 643 238 ; NAlk X) (CHa) nX (CH2) ^ 0-P Q (V) wherein Ri, R2, Alk, X, n and m have the meanings given in claim 1 and Q for the group = NRó or = CHR? (where Rf> and R? have those specified in claim 1) and P represents a leaving group, with an amine of the formula R3NH2, where R3 has the meaning given in claim 1, reacting the compound of formula I as Base or isolated in the form of a physiologically acceptable salt or as a hydrate thereof. 9. As a means for carrying out the method according to claim 7, the compound of formula II (II) wherein Ri, R2, Alk, X, n and m have the meanings given in claim 1. 10. Medicament, characterized in that it contains at least one compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.