SK77693A3 - 1,4-benzodioxan derivatives, process for their preparation and their pharmaceutical compositions - Google Patents

Abstract

1,4-Benzodioxane derivatives of the formula I <IMAGE> in which R<1> denotes H or A, Ar denotes an unsubstituted phenyl radical or one mono- or disubstituted by A, F, Cl, Br, I, CN, OH and/or OA or by a methylenedioxy group, A denotes alkyl having 1-6 C atoms and m and n in each case independently of one another denote 1 or 2 and their salts exhibit effects on the central nervous system.

Description

The present invention provides 1,4-benzodioxane derivatives of formula (I)

where

R ¹ represents a hydrogen atom or A,

Ar represents an unsubstituted phenyl radical or a phenyl radical which is substituted one or two times with A, fluorine, chlorine, bromine, iodine, cyano, hydroxy and / or OA, or substituted with methylenedioxy,

A is C 1 -C 6 alkyl and each of m and n is independently 1 or 2, as well as their salts and metabolites.

It has now been found in the context of the invention that the compounds of the formula I and their physiologically acceptable acid addition salts exhibit valuable pharmacological properties. In particular, they have an effect on the central nervous system, in particular a serotonin agonist and a serotonin antagonist effect. They block the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol 140 (1987) 143-155). In addition, they induce changes in dopa accumulation in the striatum and 5-HTP accumulation in N.rapha (Seyfried et al. European J. Pharmacol. 160 (1989), 31-41). They also exhibit an analgesic effect and a blood pressure lowering effect; for example, by oral administration of these compounds to awake, spontaneously hypertonic catheter-induced rats (SHR / Okamoto / NIH-MO-CHBKisslegg; method see Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-). 648) cause a decrease in directly measured blood pressure. Furthermore, these compounds are useful for the prophylaxis and remedy of stroke (Apoplexia cerebri), such as stroke and cerebral ischemia.

The compounds of the formula I and their physiologically acceptable acid addition salts can therefore be used as active substances for the manufacture of medicaments of the type anxiolytics, antidepressants, neuroleptics and / or antihypertensives and as intermediates in the manufacture of other active substances for pharmaceuticals.

The radical A represents an alkyl group having 1, 2, 3, 4, 5, or 6, in particular 1 or 2 carbon atoms, preferably a methyl group, then also ethyl-, η-propyl-, isopropyl-, η-butyl-, isobutyl- , sec-butyl or tert-butyl. The radical OA is preferably methoxy, then also ethoxy, η-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The radical Ar preferably represents an unsubstituted phenyl group, but also a phenyl group which is substituted one or two times. Where the phenyl group is substituted two times, the substituents may be the same or different. Preferred phenyl substituents are fluoro, chloro, methoxy, cyano or methyl. The substituents are in the-, m- and / or p-position, wherein the two-substituted phenyl groups are preferably substituted in the o- and p-position. Preferred individual meanings of Ar include phenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-methoxyphenyl, o-, male- or p-fluorophenyl, o-, m-, or p-methylphenyl; -, m- or p-cyanophenyl or 2,4-dimethoxyphenyl, but also o-, m- or p-ethoxyphenyl, o-, m- or p-bromophenyl, 2,3-, 2,5-, 2- , 6-, 3,4- or 3,5-dimethoxyphenyl, 2,3- or 3,4-methylenedioxyphenyl.

M and n independently represent 1 or 2, but preferably 1.

R ¹ is preferably methyl, but could also be ethyl, propyl, isopropyl, η-butyl, sec-butyl or tert-butyl.

Accordingly, the present invention particularly relates to those compounds of formula I in which at least one of the abovementioned radicals is as defined above, in particular the above-mentioned preferred meaning. Several preferred groups of these compounds may be characterized by the following sub-formulas Ia to Ig, which correspond to the general formula I and in which the unexplained residues and parameters have the meaning given in the general formula I, but in the sub-formula

la Ar is p-fluorophenyl and m and n 4 is always the number I *) ib Ar is phenyl and m and n are each 1; ic Ar is p-methoxyphenyl and m and n are each 1; Id Ar is phenyl which is attached at the 4-position of the pyridyl residue; Ie Ar is phenyl, p-methoxyphenyl, or p-fluorophenyl which is attached at the 5-position of the pyridyl residue; If * Ar is phenyl, p-methoxyphenyl or p-fluorophenyl, and R ¹ is hydrogen; ig Ar is phenyl, p-methoxyphenyl or p-fluorophenyl, and R ¹ is methyl.

The invention furthermore relates to a process for the preparation of derivatives

1,4-benzodioxane of the formula I and their salts, characterized in that the compound of the formula II

wherein m is as defined above and

X is chlorine, bromine, iodine, hydroxy or a reactive functionally modified hydroxy group, reacted with a compound of formula III

(III) wherein R ¹ , Ar and n are as defined above, or that the compound of formula IV

(IV) wherein R ¹ and m are as defined above, reacted with a compound of formula V

Ar · (V) wherein Ar, on X are as defined above, or that for a corresponding compound which, although conforming to formula I, contains one or more reducible groups and / or one or more additional groups instead of one or more hydrogen atoms links CC and / or CN, a reducing agent, or treating a corresponding compound, which, although has formula I except that one or more hydrogen atoms contains one or more solvolysable group treated with a solvolysing agent, and / or in that ^the optionally secondary an amine of formula I, i.e. a compound in which R ^{@ 1} represents a hydrogen atom, is converted by alkylation to a tertiary amine of formula I, i.e. a compound in which R @ ³ represents A and / or the Ar group is converted to another Ar group and / The process according to claim 1, characterized in that the base of the formula I obtained is converted by treatment with an acid into one of its salts.

The compounds of formula (I) are essentially prepared by known methods known from the literature (e.g. standard publications such as Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New) York; DE-OS 36 09 14 2) under reaction conditions which are known and suitable for said reactions. It is also possible to use variants which are known per se, but not explained here in greater detail.

The starting materials for the process according to the invention can, if desired, be produced in situ so that they are not isolated from the reaction mixture but are further reacted to the compounds of the formula I.

As mentioned above, compounds of formula I can be obtained by reacting a compound of formula II with a compound of formula III.

In the 1,4-benzodioxane derivatives of the formula II, X is preferably chlorine or bromine, but may also be iodine, hydroxy or reactive, functionally modified hydroxy, in particular alkylsulfonyloxy of up to 6 carbon atoms, for example methanesulfonyloxy or arylsulfonyloxy of 6-10 , for example, benzenesulfonyloxy-, p-toluenesulfonyloxy- or 1- or 2-naphthalenesulfonyloxy. Preferably, m is 1.

In the compounds of formula III, R ^{@ 1 is} preferably hydrogen or methyl, n is preferably 1 and Ar is preferably unsubstituted phenyl or phenyl substituted by fluorine, chlorine, bromine, methyl or methoxy.

Some of the compounds of the formulas II and III are known. Those of which are unknown may be readily prepared by methods similar to those of the known compounds of formulas II and III.

For example, it is possible to obtain compounds of formula II by reducing benzodioxanes which in the 2-position carry a group of the formula -COOH, -COOA, -CH ₂ COOH or -CH ₂ COOA.

For example, the compounds of formula (III) may be prepared by methods known in the art for the production of primary and secondary amines.

The reaction of the compounds of the formulas II and III is carried out according to known methods known from the literature for the alkylation of amines. The reactants may be melted together in the absence of a solvent, optionally in a sealed tube or autoclave. However, it is also possible to react these compounds in the presence of an inert solvent. Suitable solvents are, for example, hydrocarbons such as benzene, toluene and xylene; ketones such as acetone and butanone; alcohols such as methanol, ethanol, isopropyl alcohol and n-butanol; ethers such as tetrahydrofuran (THF) or dioxane; amides such as dimethylformamide (DMF) or N-methylpyrrolidone; nitriles such as acetonitrile and optionally also mixtures of these solvents with each other or mixtures thereof with water. The addition of an acid binding agent such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other weak acid salt with an alkali metal or alkaline earth metal such as potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline, or use of an amine component of formula III in excess. The reaction time varies, depending on the conditions used, from a few minutes to 14 days, and the reaction temperature can range from about 0 to about 150 ° C, usually about 20 to about 130 ° C.

As mentioned above, compounds of formula I can be further obtained by reacting a compound of formula IV with a pyridine derivative of formula V.

Some of the compounds of formula IV are known. Those which are not known can be readily prepared by methods similar to those of known compounds. For example, compounds of formula IV in which R ^{@ 1} is hydrogen are readily obtainable by reduction of the corresponding nitriles. Further, it is possible to obtain compounds of formula IV by reacting pyrocatechin or a reactive derivative thereof with a protected 1-amino-2,3-dihalopropane derivative followed by cleavage of the amino protecting group.

Compounds of formula (V) may be obtained by reduction of the corresponding pyridinecarboxylic acids, pyridine carboxylic acid esters, pyridine acetic acids or pyridine acetic acid esters.

The mutual reaction of the compounds of the formulas IV and V is carried out as a rule according to the same methods as described above in connection with the mutual reaction of the compounds of the formulas II and III.

A further possibility for the preparation of the compounds of the formula I consists in reacting a compound which itself corresponds to the formula I, but instead of hydrogen atoms, with one or more reducible groups and / or one or more additional bonds of CC and / or CN. with a reducing agent, preferably at a temperature in the range of -80 to 250 ° C, in the presence of at least one inert solvent.

Reducible (i.e., hydrogen-replaceable) groups include, in particular, oxygen in the carbonyl group, hydroxy, arylsulfonyloxy (e.g. toluenesulfonyloxy), N-benzylsulfonyl, N-benzyl or O-benzyl.

In principle, compounds containing only one of the abovementioned groups, optionally additional bonds or more such groups or side-by-side bonds, can be converted into compounds of formula I by reduction. Preference is given here to using hydrogen at birth or complex metal hydrides, further to a Wolff-Kizner reduction or to a hydrogen gas reduction using a transition metal catalyst.

When hydrogen is used as the reducing agent in the nascent state, this hydrogen can be produced, for example, by treating metals with weak acids or bases. For example, a mixture of zinc and an alkali metal or iron and acetic acid hydroxide may be used. Also suitable is the use of sodium or other alkali metal in an alcohol such as ethanol, isopropyl alcohol, butanol, amylalcohol or isoamylalcohol or phenol. It is also possible to use an aluminum-nickel alloy in an alkaline aqueous solution, optionally with the addition of ethanol. Sodium or aluminum amalgam in aqueous-alcoholic or aqueous solutions are also suitable for producing hydrogen at birth. The reaction can also be carried out in a heterogeneous phase, using an aqueous or benzene or toluene phase expediently.

In particular, complex metal hydrides, such as lithium aluminum hydride, sodium borohydride, diisobutylaluminium hydride, a compound of the formula NaAl2 O4 Cl2 OCH3, and diborane, if desired with the addition of a catalyst such as fluoride, can advantageously be used as reducing agents. boron, aluminum chloride or lithium bromide. Suitable solvents in this case are, in particular, ethers such as diethyl ether, di-n-butyl ether, tetrahydrofuran, dioxane, diglyme or 1,2-dimethoxyethane, as well as hydrocarbons, for example benzene. For the reduction with sodium borohydride, alcohols such as methanol or ethanol, water and aqueous alcohols are primarily suitable as solvents. In these processes, the reduction is preferably carried out at a temperature in the range of -80 to 150 ° C, in particular 0 to 100 ° C.

Furthermore, one or more carbonyl groups can be reduced to methylene groups by the Wolff-Kižner method. For example, anhydrous hydrazine in absolute ethanol is used under pressure at a temperature in the range of from 150 to 250 ° C. The alkali metal alkoxide is preferably used as the catalyst. The reduction can also be modified according to the Huang-Minlon method by reacting the hydrazine hydrate in a high boiling, water miscible solvent such as diethylene glycol or triethylene glycol in the presence of an alkali such as sodium hydroxide. The reaction mixture is generally boiled for 3-4 hours. Thereafter, the water is distilled off and the resulting hydrazone is decomposed at a temperature of up to about 200 ° C. The Wolff Kuzner reduction can also be carried out at room temperature in dimethyl sulfoxide with hydrazine.

In addition, it is possible to carry out reductions using hydrogen gas under the catalytic action of transition metals such as Raney nickel or palladium. In this way, for example, chlorine, bromine, iodine, sulfhydryl or also hydroxy can be replaced by hydrogen.

Compounds which otherwise correspond to the general formula I but contain one or more solvolyzable groups instead of one or more hydrogen atoms can be solvolyzed, in particular hydrolyzed, to the compounds of general formula I.

The starting materials for solvolysis are, for example, compounds which correspond to the general formula I, but instead of a hydrogen atom on the secondary nitrogen atom they contain a solvolyzable group. For example, the particular acyl derivatives (which have formula I except that, instead of R ¹ include an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group having up to 10 carbon atoms, such as methane-, benzene- or p-toluenesulfonyl ) to hydrolyze to the corresponding compounds of formula I in which R ^{@ 1} represents a hydrogen atom, for example in an acidic, preferably neutral or alkaline medium, at a temperature in the range of 0 to 200 ° C. Suitable bases are, in particular, sodium, potassium or calcium hydroxide, sodium carbonate or potassium carbonate or ammonia. As a rule, water is chosen as the solvent; lower alcohols such as methanol or ethanol; ethers such as THF or dioxane; sulfones such as tetramethylenesulfone; or mixtures thereof, in particular mixtures containing water. Hydrolysis can also be carried out using water alone, especially at boiling point.

Furthermore, the compounds of the formula I can also be converted into other compounds of the formula I by known methods.

For example, compounds of formula I wherein R ¹ is hydrogen can be alkylated by reaction with alkyl halides. The conditions for such reactions are generally known and are described in standard chemical publications (e.g., J. March, Adv. Org. Chem. 3rd edition, J. Wiley & Sons (1985)).

Furthermore, it is also possible to convert the radical Ar to another radical Ar.

On the other hand, the hydroxy group can be converted to groups of formula OA by known alkylation methods.

Compounds of formula I which contain a group of formula A0 can be converted to the corresponding hydroxy derivatives by cleavage of the ether moiety. For example, ether cleavage can be carried out using diisobutylaluminum hydride (DIBAH) or dimethylsulfide / boron tribromide complex, for example in toluene, ethers such as THF or dimethylsulfoxide, or by melting with pyridine or aniline hydrohalide, for example about 150 to 250 ° pyridine hydrochloride. C.

The base of the formula I obtained can be converted into the corresponding acid addition salt by treatment with an acid.

Acids which provide physiologically acceptable salts are suitable for this reaction. Inorganic acids such as sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, amidosulfonic acid, organic acids, e.g. aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic acids, sulfonic acids or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid , 2-hydroxyethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, naphthalene mono and naphthalenedisulfonic acids, and lauryl sulfuric acid.

The free bases of the formula I can, if desired, be liberated from their salts by treatment with strong bases such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate.

The compounds of formula I may contain one or more asymmetric centers. Therefore, they can be obtained in the form of racemates or, if optically active starting materials are used, also in optically active form. When the compounds contain two or more centers of asymmetry, they generally fall off in the form of mixtures of racemates from which the individual racemates can be isolated; in pure form, for example, by recrystallization from inert solvents. The racemates obtained can, if desired, be mechanically or chemically resolved into optical antipodes by known methods. Preferably, the diastereomer is formed from the racemate by reaction with an optically active resolving agent. For example, optically active acids such as the D- and L-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid ^, camphorsulfonic acid, mandelic acid, malic acid or lactic acid are suitable as resolving agents. The various forms of diastereomers can be separated in a known manner, for example by traction crystallization, and the optically active compounds of the formula I can be released from the diastereomers in a known manner.

The invention furthermore relates to the use of the compounds of the formula I and their physiologically acceptable salts for the production of pharmaceutical preparations, which is carried out in particular by a non-chemical process. In this case, they can be carried out together with at least one carrier or excipient or, optionally, in combination with one or more other active substances, in a suitable dosage form.

The invention furthermore relates to compositions, in particular pharmaceutical preparations, containing at least one compound of the formula I and / or one of their physiologically acceptable salts. These preparations can be used as medicaments in human or veterinary medicine. Suitable carrier materials are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with novel compounds such as water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. In particular, tablets, dragees, capsules, syrups, juices, drops or suppositories are used for enteral administration, and solutions, preferably oily or aqueous solutions, suspensions, emulsions or implants for parenteral administration, and ointments, creams or powders for topical administration. The novel compounds can also be lyophilized and the resulting lyophilisates used, for example, for the production of injectables.

The above compositions may be sterilized and / or comprise assistants, such as ⁱⁿ lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colorants, flavorings and / or aroma substances. If desired, they may contain one or more other active ingredients, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used in the therapeutic treatment of human or animal bodies and in the control of diseases. They are useful for the treatment of central nervous system diseases such as tension, depression and / or psychosis and for the elimination of side effects in the treatment of hypertonia (for example using α-methyldopa). Furthermore, these compounds may find use in endocrinology and gynecology, for example in the treatment of acronegaly, hypogonadism, secondary ameno'rhoe, premenstrual syndrome, undesirable puerpelar lactation, and in the prophylaxis and treatment of cerebral disorders (e.g. migraine), particularly in geriatrics -alkaloids and in the treatment of sequelae of cerebral infarction (Apoplexia cerebri), such as stroke or cerebral ischemia.

In this connection, the substances according to the invention are generally administered in a manner similar to known commercially available preparations (e.g. bromocriptine, dihydroergocornine), preferably in a dosage of from about 0.2 to about 500 mg, in particular 0.2 to 50 mg, per dosage unit. The daily dosage is preferably in the range of about 0.001 to about 10 mg / kg body weight.

Lower dosages (about 0.2 to 1 mg per dosage unit and about 0.001 to 0.005 mg / kg body weight) are particularly suitable for use as anti-migraine agents. For other indications, a dosage of from about 10 to about 50 mg per dosage unit is preferred. However, the specific dose for each particular patient will depend on a variety of factors, such as the efficacy of the particular compound administered, age, body weight, general health, sex and diet of the patient, time and route of administration and elimination rate, combination of drugs used and severity of the particular disease. to which the treatment is aimed. Oral administration is preferred.

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the invention in any way. Usual processing and the like. If necessary, water is added to the mixture, the resulting mixture is extracted with dichloromethane, the organic phase is separated, dried over sodium sulphate, filtered and evaporated and the residue is purified by silica gel chromatography and / or crystallization. All temperatures are in degrees Celsius. The Rf values are determined by thin layer chromatography on silica gel. The mobile phase used is also listed for each value.

Examples of the invention

Example 1

A solution of 0.9 mol of 2-chloromethyl-4-phenylpyridine hydrochloride (compound A) [m.p. 174-176 ° C, obtainable by reduction of 4-phenylpyridine-2-carboxylic acid with lithium aluminum hydride to give 2-hydroxymethyl-4-phenylpyridine m.p. 183-184 ° C followed by reaction with thionyl chloride], 1 mol of 2-amino-methyl-1,4-benzodioxane and 5 ml of triethylamine are boiled in 100 ml of acetonitrile for 12 hours. N- (1,4-benzodioxan-2-ylmethyl) -N- (4-phenyl-2-pyridyl) amine (dihydrochloride), m.p. 237-238 ° C.

Similarly, reacting compound A with N- (1,4-benzodioxan-2-yl) methyl-N-methylamine gives N- (2,4-benzodioxan-2-yl) methyl-N- (4-phenyl-2- pyridyl) -N-methylamino;

with N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-amine;

N- (4-phenyl-2-pyridyl) methyl) -N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-methylamine;

with N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-methylamine

N- (4-phenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-methylamine;

with N- (1,4-benzodioxan-2-yl) methyl-N-ethylamine gives N- (4-phenyl-2-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine ;

with N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-propylamine gives N- (4-phenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxan-2- yl) ethyl] -N-propylamine;

with N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-isopropylamine gives N- (4-phenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxane- 2-yl) ethyl] -N-isopropylamine.

Example 2

A mixture of 2.1 g of 3-p-fluorophenyl-5-aminomethylpyridine [which is obtained by reduction of lithium aluminum hydride-3-p-fluorophenyl-5-cyanopyridine] and 1.6 g of 2-chloromethyl-1,4-benzodioxane (compound B), dissolved in 40 ml of water and 40 ml of acetone is boiled for 16 hours and then worked up in the usual manner. There was thus obtained N- (3-p-fluorophenyl-5-pyridylmethyl) -N (1,4-benzodioxan-2-ylmethyl) amine; hydrochloride, m.p. 221-222 ° C.

In a similar manner, reaction of compound B with 3-p-methoxyphenyl-5-aminomethylpyridine is obtained

N- (3-p-methoxyphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine dihydrochloride; mp 228-230 ° C with 3-phenyl-5-aminomethylpyridine

N- (3-phenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine, dihydrochloride, m.p. 230-233 ° C.

with 3-p-cyanophenyl-5-aminomethylpyridine

N- (3-p-cyanophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine;

with 3-p-chlorophenyl-5-aminomethylpyridine

N- (3-p-chlorophenyl) -5-pyridylmethyl) -N- (1,4-be.nzodioxán2-ylmethyl) amine;

with 3-p-bromophenyl-5-aminomethylpyridine

N- (3-p-bromophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine;

with 3- (2,4-dimethoxyphenyl) -5-aminomethylpyridine

N- [3- (2,4-dimethoxyphenyl) -5-pyridylmethyl] -N- (1,4benzodioxan-2-ylmethyl) amine;

with 3- (2,4-dichlorophenyl) -5-aminomethylpyridine

N- [3- (2,4-Dichlorophenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) amine;

with 3-p-methylphenyl-5-aminomethylpyridine

N- (3-p-methylphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine;

with 3-m-methylphenyl-5-aminomethylpyridine

N- (3-m-methylphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine;

with 3-p-ethoxyphenyl-5-aminomethylpyridine

N- (3-p-ethoxyphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine;

with 3- (3,4-dimethoxyphenyl) -5-aminomethylpyridine

N- [3- (3,4-dimethoxyphenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) amine

Example 3

To a suspension of 0.6 g of diisobutylaluminium hydride (DIBAH) in 20 ml of tetrahydrofuran was added dropwise a solution of N- (3-p-methoxyphenyl-5-pyridylmethyl) -N- (1,4-benzodioxane) under stirring at 20 ° C under nitrogen. -ylmethyl) amine in 40 mL of tetrahydrofuran. The mixture was stirred at 20 ° C for 1 hour, quenched with dilute sodium hydroxide, filtered and the filtrate worked up in the usual manner. N- (3-p-hydroxyphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine is obtained.

Example 4

In a similar manner to Example 3, starting from N- [3- (2,4-dimethoxyphenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) amine by reaction with 1.1 g of DIBAH after common workup gave N- [3- (2,4-dihydroxyphenyl) -5-pyridylmethyl] N- (1,4-benzodioxan-2-ylmethyl) amine.

Example 5

A solution of 2.8 g of N- [3- (p-methoxyphenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) amine (m.p. 228-230 ° C) in 40 ml of DMF with ice-cooling, 0.3 g of sodium hydride is added and the mixture is stirred for one hour. Then, 1.5 ml of ethyl iodide is added thereto, the mixture is stirred for a further 2 hours and, after usual work-up,

N- [3- (p-methoxyphenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine.

In a similar manner, alkylation of the corresponding secondary amines of formula I gives the following compounds:

N- (4-phenyl-2-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine;

N- (4-p-methylphenyl-2-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine;

N- (4-phenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxan-2-yl) ethyl] N-ethylamine;

N- (4-p-methylphenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-methylamine;

WITH

N- (4-m-methoxyphenyl-2-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine;

N- (4-p-methylphenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-propylamine;

N- (4-p-methoxyphenyl-2-pyridylmethyl) -N- [2- (1,4-benzodioxan-2-yl) ethyl] -N-isopropylamine;

N- (3-p-methoxyphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-isopropylamine;

N- (3-phenyl-5-pyridyl) methyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-methylamine;

N- (3-p-cyanophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine;

N- (3-p-chlorophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine;

N- (3-p-brómfeny1-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-methylamine;

N- [3- (2,4-dimethoxyphenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) -N-ethylamine;

N- (3-p-fluorophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-methylamine, Rf = 0.3 (ethyl acetate);

N- [3- (2,4-Dichlorophenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) -N-propylamine;

N- (3-p-methylphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-isopropylamine;

N- (3-m-methylphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-isopropylamine;

N- (3-p-ethoxyphenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) -N-isopropylamine;

N- [3- (3,4-dimethoxyphenyl) -5-pyridylmethyl] -N- (1,4-benzodioxan-2-ylmethyl) -N-butylamine;

N- [3- (2,4-hydroxyphenyl) -5-pyridylmethyl] -N- (1,4benzodioxan-2-ylmethyl) -N-butylamine.

Example 6

Dissolve 0.1 mol of (±) -N- (3-p-fluorophenyl-5-pyridylmethyl) N- (1,4-benzodioxan-2-ylmethyl) amine in a mixture of ethyl acetate and ethanol (400 mL; 3: 1) at 50 ° C and 0.05 mol of L - (+) - mandelic acid dissolved in

350 ml of the same solvent mixture. The reaction mixture was then cooled to room temperature and allowed to stand for 64 hours to crystallize. The resulting crystals were collected and purified by recrystallization from a 3: 1 mixture of ethyl acetate and ethanol.

There was obtained (-) - N- (3-p-fluorophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine L - (+) - mandelate. Subsequent work-up with triethylamine gives R - (+) - N- (3-fluorophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine, Rf 0.29 (acetone); [.alpha.] _D @ ²⁰ = + 33.3 DEG (methanol).

Example 7

The mother liquors obtained in the crystallization procedure of Example 6 are concentrated, the concentrate is mixed with 25 ml of methanol and the mixture is heated to 50 ° C. 0.27 mol of D - (-) - dibenzoyltartaric acid, dissolved in 40 ml of methanol, is added and the mixture is cooled to 0 ° C to crystallize. The crystals formed are separated and purified by recrystallization from methanol. D - (-) - dibenzoyltartrate is obtained. (-) - N- (3-p-fluorophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine. Further treatment with triethylamine gave S - (-) - N- (3-p-fluorophenyl-5-pyridylmethyl) -N- (1,4-benzodioxan-2-ylmethyl) amine, Rf 0.29 (acetone) ; [α] ²⁰ _D = -28.6 ⁰ (methanol).

The following examples relate to pharmaceutical compositions comprising a 1,4-benzodioxane derivative of the Formula I or an acid addition salt thereof.

Example A

tablets

A mixture of 1 kg of N- (3-phenyl-5-pyridylmethyl) -Nl, 4-benzodioxan-2-ylmethyl) amine, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium searate. is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example B

dragee

In a similar manner to Example A, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example C

Capsules of N- (3-p-methoxyphenyl-5-pyridylmethyl) -N-1,4-benzodioxan-2-ylmethyl) amine are normally filled with hard gelatin capsules so that each capsule contains 20 mg of the active ingredient.

Example D

ampoules

A solution of 1 kg of N- (4-phenyl-2-pyridylmethyl) -N-1,4-benzodioxan-2-ylmethyl) amine dihydrochloride in 60 liters of distilled water is sterilized by filtration and then filled with ampoules which are lyophilized and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Similarly, it is possible to obtain tablets, dragees, capsules and ampoules containing one or more of the other active compounds of the formula I and / or their physiologically acceptable acid addition salts.

Claims (7)

PATENT CLAIMS CLAIMS 1. 1,4-Benzodioxane derivatives of general formula (I) EMI2.0 [0009] wherein: EMI2.0 [0000] R ¹ represents a hydrogen atom or A, Ar represents an unsubstituted phenyl radical or a phenyl radical which is substituted one or two times with A, fluorine, chlorine, bromine, iodine, cyano, hydroxy and / or OA or substituted with methylenedioxy, A is C 1 -C 6 alkyl and each of m and n is independently 1 or 2, and salts thereof. 2. (a) N- (1,4-Benzodioxan-2-ylmethyl) -N- (4-phenyl- 2-pyridylmethyl) amine and its acid addition salts; b) N- (1,4-benzodioxan-2-ylmethyl) -N- (5-phenyl- 3-pyridylmethyl) amine and its acid addition salts; c) N- (1,4-benzodioxan-2-ylmethyl) -N- (5-p-fluoro-phenyl-3-pyridylmethyl) amine and its acid addition salts; d) N- (1,4-benzodioxan-2-ylmethyl) -N- (5-pmethoxyphenyl-3-pyridylmethyl) amine and its acid addition salts. A process for the preparation of 1,4-benzodioxane derivatives of formula I and their salts, characterized in that the compound of formula II (II) wherein m is as defined above and X is chlorine, bromine, iodine, hydroxy or a reactive functionally modified hydroxy group, reacted with a compound of formula III (III) wherein R ¹ , Ar and n are as defined above, or that a compound of formula IV (IV) (CH ₂ ) _b -NR ¹ H wherein R ¹ and m are as defined above, reacted with a compound of formula V (V) wherein Ar, on X are as defined above, or that to a corresponding compound which, although corresponding to formula I, instead of one or a plurality of hydrogen atoms contain one or more reducible groups, and / or one or more additional bonds of CC and / or CN are treated with a reducing agent, or that the corresponding compound, although corresponding to formula I, contains but instead of one or more hydrogen atoms one or more solvolyzable groups act with a solvolytic agent, and / or optionally a secondary amine of the formula and I, the compound, by alkylation of the compound, is converted to the formula I by treatment with an acid from its salts. in which R ¹ represents a hydrogen atom, to a tertiary amine of the general formula in which R ¹ represents A and / or that another Ar group and / or that i turns I, i. with the group Ar base on some A process for the manufacture of pharmaceutical preparations, characterized in that the compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts is converted together with at least one solid, liquid or semi-liquid carrier or excipient into a suitable dosage form. A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts. Use of the compounds of the formula I according to claim 1 or their physiologically acceptable salts for the manufacture of medicaments. Compounds of formula I according to claim 1 or their physiologically acceptable salts for controlling diseases.