NO841443L - POLYCYCLIC CARBON ACID COMPOUNDS, PROCEDURES FOR THEIR PREPARATION AND PREPARATIONS CONTAINING SUCH CARBON ACID COMPOUNDS, AND THEIR USE - Google Patents

Description

The invention relates to methods for the production of new polycyclic carboxylic acid compounds.

The invention primarily relates to the production of compounds

with formula

where R means an optionally esterified. or amidated carboxy group, R-^ means hydrogen or an optionally substituted aliphatic or cycloaliphatic-aliphatic hydrocarbon residue, X means epoxy or epithio and n means 1 or 2 as well as salts of such compounds.

An esterified carboxy group is primarily lower alkoxycarbonyl, while an amidated carboxy group here in particular means carbamoyl or mono- or dilower alkylcarbamoyl, further lower alkyleneaminocarbonyl, oxa lower alkyleneaminocarbonyl, tia lower alkyleneaminocarbonyl or aza lower alkyleneaminocarbonyl in the alkyleneamino, oxaalkyleneamino, tiaalkyleneamino and azaalkyleneamino f .ex. has 4 threaded ring atoms and the azanite nitrogen atom optionally e.g. may be optionally substituted as optionally etherified or esterified hydroxy, e.g. lower alkoxy, lower alkanoyloxy-containing lower alkyl.

An aliphatic hydrocarbon residue is primarily lower alkyl,

however, can also be lower alkenyl or lower alkynyl in that in the unsaturated residues the double or triple bond is found in a position higher than 1. A cycloaliphatic-aliphatic hydrocarbon residue is especially cycloalkyl lower alkyl, in which cycloalkyl e.g. may contain up to 8 ring carbon atoms. Substituents of such hydrocarbon residues which preferably be-

found in a higher than I position are primarily optionally etherified or esterified hydroxy groups such as hydroxy lower alkoxy, lower alkanoyloxy or halogen.

The symbols n each time have the same meaning and mean either 1 or 2.

The general definitions mentioned above and used below have, if nothing else is explicitly stated, preferably the following meaning: The groups and compounds designated "lower" primarily have up to and including 7, preferably up to 4 carbon atoms.

Lower alkoxycarbonyl is e.g. methoxycarbonyl or ethoxycarbonyl, further n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl or tert-butyloxycarbonyl, as well as n-pentyloxycarbonyl, n-hexyloxycarbonyl or n-heptyloxycarbonyl.

Mono- and di-lower alkylcarbamoyl are e.g. methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl or diethylcarbamoyl, while alkyleneaminocarbonyl, preferably 4

to 8, e.g. with 5 or 6 ring atoms, e.g. pyrrolidinocarbonyl or piperidinocarbonyl, oxaalkyleneaminocarbonyl, preferably with 6 ring atoms, e.g. means morpholinocarbonyl, thiaalkyleneaminocarbonyl, preferably with 6 ring atoms, e.g. means thiomorpholinocarbonyl and azaalkyleneaminocarbonyl, preferably with 6 to 8 ring atoms and optionally with substituted e.g. lower alkyl, hydroxy lower alkyl or lower alkanoyloxy lower alkyl containing azanitrogen, e.g. means piperazinocarbonyl or 4-methyl-piperazinocarbonyl.

Lower alkyl is e.g. especially methyl or ethyl, further n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, as well as n-pentyl, neopentyl, n-hexyl or N-heptyl, while lower alkenyl e.g. means allyl, 2-methylallyl, 3,3-dimethylallyl or 2-butenyl, and lower alkenyl means e.g. propargyl. Cycloalkyl lower alkyl is e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl or cyclooctylmethyl.

Lower alkoxy is e.g. especially methoxy or ethoxy, further n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy.

Lower alkanoyloxy is e.g. acetyloxy, propionyloxy or butyryloxy.

Halogen preferably has an atomic number of up to 35 and is e.g. especially chlorine, may however also be fluorine or bromine.

Salts of compounds of formula I are primarily pharmaceutically usable salts and may primarily be acid addition salts, e.g. with inorganic acids such as hydrohalic acid, e.g. hydrochloric acid or hydrobromic acid, further hydrochloric acid, sulfuric acid or phosphoric acid, or with organic acids such as corresponding carboxylic acids, e.g. acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, further amino acid or sulphonic acids such as optionally hydroxy-containing lower alkanesulphonic acid, e.g. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or ethane-1,2-disulfonic acid, or arylsulfonic acid, e.g. benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid, or with other acidic organic substances such as ascorbic acid. The compounds of formula I, where R means free carboxy, can also form salts with bases, such as salts with metal, such as alkali or alkaline earth metal, e.g. sodium, potassium or calcium salts, or with organic bases, such as aliphatic amines, e.g. mono-, di- or tri lower alkylamines, such as diethylamine or triethylamine, or mono-, di or trihydroxy lower alkylamines, such as di-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, or inner salts.

Compounds of formula I with asymmetric carbon atoms,

e.g. in a residue R^, it can also exist in the form of isomers, such as racemates or optically active antipodes.

The new compounds of formula I and their salts have pharmacological, especially neurolytic effects. These base, among other things, on a strong inhibition of alpha-l-adrenergic receptors,

like for example. can be detected by means of a radioreceptor test, by means of inhibition of (^H) WB 410L binding in rat brain under in vitro conditions, e.g. according to that of U'Prichard et al. in Molecular Pharmacology, Volume 13, page 454 (1977), mentioned method, and under in vivo conditions under the latter in doses from approx. 0.01 mg/kg by intraperitoneal administration in rats. The new compounds also show the characteristic inhibition of dopamine receptors for neuroleptically active compounds, such as e.g. can be determined by inhibition of (^H)Spiperone binding according to that of Bischoff et al. in Europe. J. Pharmacol., volume 68, page 305 (1980), mentioned method in doses from approx. 1 mg/kg by intraperitoneal administration in rats. Thereby shows

it turns out that the inhibition of the compound according to the invention acts distinctly selectively on the hippocampal dopamine receptors, it is e.g. at least three times stronger than this on striatal dopamine receptors.

The new compounds formula I and their salts can therefore be used as neuroleptics, e.g. for the treatment of schizophrenia with significantly less extrapyramidal side effects and a more favorable ratio between the desired effect and toxicity and/or unwanted side effects.

The invention primarily relates to compounds of formula I, where R means carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, dilower alkylcarbamoyl, lower alkyleneaminocarbonyl with 5 to 8 ring atoms, oxa lower alkyleneaminocarbonyl with 6 ring atoms, tia lower alkyleneaminocarbonyl with 6 ring atoms or aza lower alkyleneaminocarbonyl with 6 to 8 ring atoms, in which the azanitrogen can optionally be substituted with lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, or lower alkanoyloxy lower alkyl, in that in such substituted alkyl residues a substituent is separated by at least 2 carbon atoms from the azanitrogen atom. R-^means hydrogen, lower alkylhydroxy lower alkyl, lower alkoxy lower alkyl, lower alkanoyloxy lower alkyl, halogen lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl lower alkyl, in that in substituted lower alkyl residues a substituent is preferably separated by at least 2 carbon atoms from the ring nitrogen atom, in unsaturated residues there is a double or triple bond in the higher than 1-position, and cycloalkyl contains 3 to 8 ring atoms, in the "lower" labeled residues e.g. contains up to 7 preferably up to 4 carbon atoms, X means epoxy or epithio, and n means 1 or 2, or salts, especially pharmaceutically usable salts primarily acid addition salts of such compounds.

The invention relates in particular to compounds of formula I, where

R means carboxy or lower alkoxycarbonyl, primarily carbamoyl, further lower alkylcarbamoyl or lower alkylcarbamoyl, further lower alkyleneaminocarbonyl, in which lower alkyleneamino contains 5 or 6 ring atoms in which a residue R in connection with formula I in which n means 1 is preferably located in the 5-position, and in connection with formula I, in which n means 2, is preferably in the 7-position, R^ means hydrogen, lower alkyl, hydroxy lower alkyl or lower alkoxy lower alkyl, in which hydroxy or lower alkoxy are separated by at least 2 carbon atoms from the ring nitrogen atom, lower alkenyl or lower alkynyl in which the double-respectively triple bond is in a higher position than the 1-position, or cycloalkyl lower alkyl, in which cycloalkyl contains 3 to 8 ring carbon atoms, in which the "lower" designated residues contain up to 4 carbon atoms, X means epoxy or epithio, and n means 1 or 2, or salts, especially pharmaceutically usable salts, primarily acid addition salts.

The invention relates in particular to compounds of formula

in which R' means carboxyl or lower alkoxycarbonyl, primarily, however, carbamoyl, lower alkylcarbamoyl or dilower alkylcarbamoyl, further lower alkyleneaminocarbonyl, in which lower alkyleneamino contains 5 or 6 ring atoms, R| means hydrogen, lower alkyl or cycloalkyl lower alkyl, in which cycloalkyl has 3 to 6 ring atoms, in the "lower" designated residues contain up to 4 carbon atoms, X means epoxy or epithio,

n means 1 or 2, or salts, especially pharmaceutically usable salts, primarily acid addition salts of such compounds.

The invention primarily relates to compounds of formula Ia, in which R<1>in particular means carbamoyl, further lower alkylcarbamoyl, in which lower alkyl has up to 4, preferably 1 or 2 carbon atoms, e.g. methylcarbamoyl, or lower alkylcarbamoyl, in which lower alkyl has up to 4, preferably 1 or 2 carbon atoms, e.g. dimethylcarbamoyl, further alkyleneaminocarbonyl, in which alkyleneamino contains 5 or 6 ring atoms, e.g. pyrrolidinocarbonyl, R^ means lower alkyl, with up to 4, preferably with 1 or 2 carbon atoms, e.g. methyl, ethyl or n-propyl, or cycloalkyl lower alkyl, wherein cycloalkyl has 3 to 6, preferably 5 or 6 ring carbon atoms, and lower alkyl has up to 4, preferably 1 or 2 carbon atoms, e.g. cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl, X means epoxy, or preferably epithio and n means preferably 1, further 2, or salts, especially pharmaceutically usable salts, primarily acid addition salts of such compounds.

The invention relates in particular to the examples mentioned for

bonds.

The new compounds of formula I are prepared according to methods known per se, e.g. in it

a) in a connection with formula

where Rq means one to the optionally esterified or amidated

boksy group R transferable residue, or in a salt thereof, RQ is transferred to the group R, or

b) a compound of formula

wherein one of the groups and X 2 means the residue of formula -NH-R 2

(Illa) and the other means a reactive esterified hydroxy group, is ring-closed, if desired, an obtained compound of formula I is transferred to another compound of formula I, and/or if desired, a formed salt is transferred to the free compound or to another salt , and/or if desired, a formed free compound is transferred to a salt, and/or if desired, a formed isomer mixture is divided into the individual isomers.

Salts of starting substances with formula II are primarily acid addition salts as corresponding salts, strong mineral and organic sulphonic acids as the corresponding salts with chlorohydrogen, sulphur, methanesulphonic and p-toluenesulphonic acid.

A residue Rq is in particular the acyl residue of a carboxylic acid, including

sive a corresponding residue of a carboxylic acid derivative. A residue Rq is primarily a functionally modified carboxy group different from the group R, such as e.g. an anhydride form present carboxy group, a thiocarbamoyl group, an optionally o-substituted formimidoyl group or especially cyano group. The corresponding starting substances of formula II can be transferred in a manner known per se into the desired compounds of formula I.

A starting substance of formula II with an anhydridized carboxyl group can be the corresponding symmetrical anhydride, but is preferably an asymmetric anhydride in which the residue RQ again means an inorganic or organic acid anhydridized carboxyl group,

as halocarbonyl, especially chlorocarbonyl or cyanocarbonyl, furthermore, preferably in salt form, e.g. in the form of the lithium salt, present sulfoxycarbonyl, as well as acyloxycarbonyl, in which acyl e.g. means the residue of an aliphatic or aromatic carboxylic acid and which in particular means lower alkoxycarbonyloxycarbonyl, e.g. ethoxycarbonyloxycarbonyl or isobutyloxycarbonyloxycarbonyl.

The starting material of formula II with an anhydrated carboxyl group

RQ can by means of hydrolysis e.g. by treatment with water,

in an acidic or basic medium, are transferred to the corresponding free carboxylic acids or by means of alcoholysis, e.g. by treatment with an alcohol such as a lower alkanol, in the presence of a base such as an alkali metal hydroxide, e.g. sodium hydroxide, is transferred to the corresponding ester. By means of ammonolysis or amino-lysis, e.g. by treatment with ammonia (possibly in derivatized form, e.g. as urea, urethane, formamide or ammonium salts, such as ammonium acetate) or with amines (possibly in derivatized form, e.g. as N-substituted urethane) one can of the starting material of formula II with an anhydrided carboxy-

group especially chlorocarbonyl or lower alkoxycarbonyloxy-carbonyl as residue RQ and corresponding compound of formula I, with an amidated carboxy group R. Thereby one can possibly work in the presence of an acid-binding agent such as an inorganic or organic base, e.g. an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, a tertiary amine, e.g. triethylamine, or a heteroaromatic base, e.g. pyridine, or an excess of the ammonolysis or aminolysis agent.

An anhydridized carboxy group is also a trihalomethyl group, in which halogen is preferably chlorine, or can also be bromine, especially trichloromethyl. A compound of formula II with such a group RQ is the mixed anhydride of an orthocarboxylic acid compound corresponding to the carboxylic acid compound of formula II with a halogen, especially hydrochloric acid. A corresponding starting material can be obtained by means of hydrolysis which is preferably carried out in an aqueous medium in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, e.g. calcium hydroxide, (possibly in the presence of iron), or in the presence of a suitable heavy metal salt, such as iron III chloride, is transferred into the corresponding carboxyl compound of formula I. It can also be converted by treatment with mono- or disubstituted amine, further also with ammonia, possibly in derivatized form, e.g. as formamide or hexamethylenetetramine, to a compound of formula I, wherein R represents an amidated carboxyl group.

A thiocarbamoyl group RQi a starting material of formula II

may be an unsubstituted thiocarbamoyl group, however, is primarily an N-substituted, such as N,N-disubstituted thiocarbamoyl group and especially an N,N-lower alkyleneaminocarbonyl group, in which the lower alkylene chain, e.g. may be interrupted by a heteroatom, preferably with oxygen, such a thiocarbamoyl group Rq is above all morpholinothiocarbonyl, further thiomorpholinothiocarbonyl, and piperidinothiocarbonyl. A starting material of formula I with such a thiocarbamoyl group RQ can be hydrolytically preferably in the presence of an acidic agent, such as a mineral acid, e.g. sulfuric acid or a basic reagent, such as an alkali metal carbonate or hydroxide, e.g. sodium or potassium

hydroxide, is transferred in the compound of formula I, with a free carboxy group. When treating a thiocarbamoyl starting substance f with formula II, in which thiocarbamoyl RQ is unsubstituted or substituted, with a heavy metal oxide, e.g. mercuric oxide, or a basic agent, such as an alkali metal, e.g. sodium or potassium hydroxide, in a lower alkanol one can arrive at corresponding compounds of formula I, in which R means unsubstituted or substituted carbamoyl.

In a starting material of formula II, R is an optionally o-substituted formimidoyl group, especially o-lower alkyl-, such as o-methyl- or o-ethyl-formimidoyl. By means of hydrolysis of an acid addition salt, such as of the hydrochloride or the sulphate, of the carboxyimidate starting material of formula II, the corresponding ester, especially lower alkyl ester of formula I can be obtained, while by means of hydrolysis of such a starting material of formula II

in the presence of a base, e.g. sodium hydroxide, can reach the carboxylic acid compounds of formula I. Heating the above-mentioned acid addition salt of the carboxyimidate compounds of formula II can lead to the corresponding compounds of formula I, with an amidated carboxy group in which the compounds of formula II in an N-substituted formimidoyl group Rq leads to compound of formula I, which has a corresponding N-substituted carbamoyl group R.

The transfer of the preferred cyano group as residue RQ to a starting material of formula II in an optionally esterified or amidated carboxyl group usually takes place by means of solvolysis, while the hydrolysis in the presence of a base, e.g. an alkali metal hydroxide such as sodium or potassium hydroxide,

or an acid, e.g. a mineral acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, is added to compounds of formula I with a free carboxy group R.

Carry out the hydrolysis of a cyan starting material with formula

II under special, e.g. under mild conditions and especially in the presence of hydrogen peroxide, by addition of water (hydration) you arrive at compounds of formula I, with carbamoyl as group R. The reaction with hydrogen peroxide, which is usually present in excess, can be carried out in the presence of a base such as an alkali metal, e.g. sodium or potassium hydroxide, usually in an aqueous medium, or an acid, such as a mineral, e.g. hydrochloric, sulfuric and/or phosphoric acid, usually in concentrated form (the latter e.g. in the form of polyphosphoric acid), or a Lewis acid, e.g. boron trifluoride, or optionally in an aqueous or anhydrous medium (e.g. hydrochloric acid in glacial acetic acid). Instead of hydrogen peroxide, one can also use complexes of the cyan starting material of formula II with a boron trihalide, especially boron trichloride, which can be converted hydrolytically, or treat the cyan starting material of formula II with formic acid, either alone at high temperatures under pressure, or in the presence of a mineral acid such as hydrochloric or hydrobromic acid, e.g. at room temperature and thus arrive at a compound of formula I, in which R means carbamoyl.

A cyan starting material of formula II can also, by treatment with an alkali metal, e.g. potassium hydroxide, preferably in solid form, in a solvent containing hydroxy groups such as a suitable lower alkanol, e.g. tert-butanol, under heating to a compound of formula I with carbamoyl as group R, or by treatment with an alcohol, e.g. a lower alkanol, especially a secondary or tertiary lower alkanol,

in the presence of an acid, such as a mineral acid, e.g. aqueous sulfuric acid, arrive at a compound of formula I, with a corresponding to the alcohol, e.g. lower alkyl-N-substituted carbamoyl group.

When treating a starting material of formula II, wherein Rq is cyan, with an alcohol, especially a lower alkanol, in the presence of an acid, such as a mineral acid, e.g. sulfuric acid, and of water, under suitable conditions, compounds of formula I can be obtained in which R means an esterified carboxy group. Thereby, one of the above-mentioned carboximide starting materials of formula II is formed intermediately, in which Rq means an o-substituted, especially an o-lower alkylated formimidoyl group.

Furthermore, when treating compounds of formula II, in which Rq means the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl such as acetyl, in ammonia in the presence of an acidic reagent, e.g. sulfuric acid or polyphosphoric acid, form a compound of formula I, in which R means a corresponding N-substituted, e.g. N-alkyl-, such as N-methyl-carbamoyl group.

In a starting material of formula II, the residue Rq can also mean

a metallic group, and e.g. mean an alkali metal, such as lithium ion, or preferably a halogen, such as chlorine or bromine magnesium ion. A corresponding starting material can be converted by treatment with carbon dioxide into a compound of formula I, in which R means carboxy.

The above-mentioned reactions to convert a residue Rq in a starting material with formula II into an optionally esterified or amidated carboxy group R can be carried out in the presence or absence of solvents in that a suitable reagent can also serve as a solvent at the same time, as well as suitable condensation agents and catalysts, in that, depending on the choice of starting material and the other reaction participants, you can work under cooling or heating, if necessary in a closed system, possibly under pressure, and/or in an inert gas atmosphere.

The starting substances of formula II are known or can be prepared

in a manner known per se. Thus, you can get them e.g. according to a method mentioned under b) when using a starting material of formula III, in which R means one with the residue R o or another to this transferable residue and 3, the latter is then transferred in a manner known per se in this. Furthermore, in a starting material with formula II in which Rq means a substituent that can be replaced in this residue, one can replace such, with the residue R o . Thus, e.g. a compound of formula II,' in which Ro means a halogen atom, such as bromine, is reacted with an alkali metal, e.g. potassium, or a heavy metal, e.g. copper I-cyanide in a suitable solvent such as an amide-like solvent, e.g. dimethylformamide, N-methyl-pyrrolidin-2-one or hexamethylphosphoric acid triamide, and one thus obtains starting materials of formula II, in which RQ stands for cyan. Furthermore, in starting materials

with formula II, the rest of RQ is converted in a manner known per se to other groups R, thus one can e.g. convert cyano compounds of formula II (R is cyano), by treatment with an alcohol in the presence of an acid, or a lower alkanoyl, e.g. acetyl compounds of formula II (R is lower alkanoyl, e.g. acetyl), e.g. by treatment with ammonium polysulphide or sulfur in the presence of an amide, especially an N,N-disubstituted amine, such as N,N-lower alkylene amine, where the lower alkylene chain may optionally be interrupted by a heteroatom. in particular an oxygen atom, and primarily of morpholine, at elevated temperature to the corresponding o-substituted carboximidate, respectively thio-carbamoyl compound of formula II (R is o-substituted formimidoyl, respectively thiocarbamoyl).

In a starting material of formula III, a reactive esterified hydroxy group X-^, respectively X2, means in particular a hydroxy group esterified with a strong mineral acid or organic sulfonic acid and means e.g. halogen, such as chlorine or bromine, or organic sulfonyloxy, such as lower alkanesulfonyloxy, e.g. methanesulfonyloxy or arenesulfonyloxy, e.g. p-toluenesulfonyloxy. The cyclization according to the invention can be carried out in the presence or absence of a solvent or a solvent mixture and/or a condensation agent such as a suitable acid binding agent, e.g. a corresponding inorganic base, such as an alkali metal, e.g. sodium hydroxide, or organic base, such as a tert-amine, such as triethylamine or a heteroaromatic base, e.g. pyridine, further an excess of a compound of formula H2N-R^(V). Thereby, one can work during cooling or heating in a closed vessel, possibly under pressure and/or under an inert gas atmosphere.

Starting material with formula III can be prepared on i and for

known manner, in that under the reaction conditions it can be directly transferred into the desired compound of formula I.

Thus, e.g. a compound with formula

•'in which Ra means the group R, a residue RQ or one in this transferable group, and each of the residues Xa and Xfa means hydrogen, on treatment with a halogenamide, especially N-bromosuccinimide, is converted into a compound of formula IV , where Xa and X^ mean halogen, especially bromine (compound IVa). This can, "e.g. <5>by treatment with a suitable cyanic acid salt such as an ammonium cyanide or an alkali metal, e.g. sodium or potassium cyanide, be transferred into a compound of formula IV, wherein X cl and X, O is cyan (compound IVb).In this, the cyano groups, for example by treatment with an alcohol, such as a lower alkanol, for example methanol °or ethanol, and in the presence of an acid, such as hydrochloric acid, can be transferred to esterified carboxy or lower alkoxycarbonyl groups, e.g. methoxycarbonyl or ethoxycarbonyl, and these reduction e.g. by treatment of a compound of formula IV, in which X a and X, v mean esterified carboxyl groups (compound<5>IVc), e.g. with a light metal hydride, such as lithium aluminum hydride, optionally in the presence of aluminum chloride, converted into carbinol groups (compound of formula IV where X cl and X, O means hydroxymethyl, compound IVd). In a compound IVd, the hydroxy groups can e.g. by treatment with a suitable acid halide such as <0>thionyl chloride or an organic sulph onic acid chloride, is converted into reactive esterified hydroxy groups, e.g. halogen or organic sulfonyloxy (compound of formula IV where X cl and X, D means reactive esterified hydroxymethyl, compound IVe). At one or another stage of the production of an intermediate product, formulas IVa and IVe, a residue RQ, optionally after it has been formed in a transferable group in a manner known per se, e.g. after one of the reactions shown in related procedure a), is converted into the desired one

group R. A compound of formula IVa and IVe can then be treated with an amine of formula f^N-R.^ (V), optionally in the presence of an acid binder such as one of the above-mentioned bases,

in that one can obtain a starting material of formula III which, without being isolated under the reaction conditions, can possibly ring-

is terminated and can be directly transferred in the desired connection with formula I.

According to the invention, the obtained compound of formula I can be applied

in a manner known per se is transferred to other compounds of formula I. Thus, in connection with formula I in which R means an esterified or amidated carboxy group, such a group R can be transferred, e.g. by means of hydrolysis, e.g. in the presence of a basic agent such as an inorganic base, e.g. an alkali metal

or alkaline earth metal, e.g. sodium, potassium or calcium hydroxide, or an acidic agent such as a mineral acid to a free carboxy group R.

Furthermore, one can transfer the compound of formula I, where R means

a carboxy group e.g. by treatment with an alcohol such as a lower alkanol, in the presence of a suitable esterifying agent such as an acidic reagent, e.g. an inorganic or organic acid, such as hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid, or a Lewis acid, e.g. zinc chloride or a water-binding condensation agent, e.g. a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treatment with a diazo reagent, such as a diazole lower alkane, e.g. diazomethane, to compounds of formula I, where R means an esterified carboxy group. These can also be obtained when treating compounds of formula I, in which R means a carboxy group in free form or present in salt, such as ammonium or metal, e.g. alkali metal, such as sodium or potassium salt form, with a reactive ester of an alcohol, such as a lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodide, or an organic sulphonic acid ester, such as an organic sulphonic acid ester as a corresponding lower alkyl ester, e.g. methanesulfonic acid or p-toluenesulfonic acid methyl ester or

-ethyl ester.

Compound of formula I, in which R means an esterified carboxy group, can be converted into another ester compound of formula I by transesterification, e.g. by treatment with an alcohol, usually a higher one than that of the esterified carboxy group in the starting material corresponding alcohol, in the presence of a suitable transesterification agent such as a basic agent, e.g. an alkali metal lower alkanoate, -lower alkanolate or -cyanide such as sodium acetate, -methanolate, -ethylate, -tert-butanolate or -cyanide, or a suitable acidic agent, optionally while removing the alcohol formed, e.g. by distillation. One can also start from so-called activated esters of formula I in which R means an activated esterified carboxy group (see below),

and converting this by treatment with an alcohol, as a lower alkanol into another ester.

The preferred amide compounds of formula I, in which R means

an amidated carboxy group, can advantageously also be obtained from the corresponding acid and ester compounds of formula I, where R means an optionally esterified carboxy group. Thus, one can e.g. react compound of formula I with a free carboxy group R with urea at elevated temperatures, e.g. at 200-240°C with formamide e.g. dimethylformamide in the presence of a suitable condensing agent such as phosphorus pentoxide, at elevated temperatures, or with an amine in the presence of a suitable condensing agent such as a carbodiimide, e.g. N,N<1->dihexyl-carbodiimide, further a phosphine, such as triphenylphosphine (e.g. together with bis-2-pyridyl-disulfide), or a silane, such as trichloro-silane (e.g. together with pyridine) , and the corresponding amide compounds of formula I, where R means an amidated carboxy group. They can also be obtained from compounds of formula I where R means one

carboxy group present in salt form, e.g. in which one hydrates a corresponding ammonium salt, e.g. by treatment with a dehydrating agent, such as phosphorus pentoxide, or converts a corresponding alkali metal, e.g. sodium salt with an amine, preferably in the presence of a suitable condensing agent, such as phenylphosphonic acid dichloride.

One can transfer a compound of formula I in which R means a carboxyl group, also first to a reactive derivative such as an anhydride, including a mixed anhydride such as an acid halide, e.g. -chloride (e.g. by treating the acid precursor compound of formula I, wherein R is carboxy, with a thionyl halide, e.g. -chloride), or an anhydride with a formic acid ester, e.g. -lower alkyl ester (e.g. by treating a salt, such as an ammonium or alkali metal salt of the acid compound of formula I, in which R is carboxy, with a halogen-, such as chloroformic acid ester, such as -lower alkyl ester) or an activated ester such as a cyanomethyl-, nitrophenyl-, e.g. 4-nitro-phenyl-, or polyhalophenyl-, e.g. pentachlorophenyl ester (e.g. by treating a compound of formula I, where R is carboxy, with a corresponding hydroxy compound in the presence of a suitable condensing agent, such as N,N'-dicyclohexylcarbodiimide)/ and subsequently reacting such a reactive derivative with ammonia (possibly in derivatized form), or an amine, and then arrive at the amide compounds of formula V, where R means an amidated carboxy group. This means that you can get these directly or via intermediate connections, so you can e.g. reacting an activated ester, such as a 4-nitrophenyl ester of a compound of formula I, with a carboxy group R first with a 1-unsubstituted imidazole and reacting the 1-imidazolylcarbonyl compound thus formed with the ammonia or amines. One can also bring other non-activated esters such as lower alkyl esters of compounds of formula I, in which R, e.g. means lower alkoxycarbonyl to react with ammonia or amines, and thus form compounds of formula I

with amidated carboxyl groups.

According to the invention, the preferred compounds of formula I where R means an amidated carboxy group can therefore be prepared according to method a) by using in a compound of formula II where RQ means an acyl group different from an amidated carboxy group R, especially one different from an amidated carboxy group R , optionally functionally modified carboxy group, transfers the residue RQ to the group R. Thereby the acyl group can be nitrogen-free or nitrogen-containing and a preferred optionally functionally modified carboxy group RQ means either a nitro-free, optionally functionally modified, or a nitrogen-containing functionally modified carboxy group. In general, the compound of formula I with an amidated carboxy group R is obtained by solvolysis of these starting substances of formula II, those with a nitrogen-free, optionally functionally modified carboxy group preferably by means of one of the above-mentioned ammonolytic, or aminolytic and those with nitrogen-containing functionally modified carboxy group, using one of the hydrolytic methods.

In connection with formula I, in which R means an unsubstituted or in N-monosubstituted carbamoyl group R, such can be substituted, e.g. by treatment with a reactive ester of an alcohol, such as a lower alkanol, e.g. with a corresponding halide or a corresponding organic sulfonyloxy compound, such as lower alkyl halide, e.g. -chloride, -bromide or -iodide, or lower alkane- or arene-sulphonic acid lower alkyl esters,

while preferably working in the presence of a basic agent,

as an alkali metal, e.g. sodium or potassium hydroxide.

Care must be taken to avoid quaternization of the ring nitrogen atom.

Depending on the reaction conditions, the compound of formula I

are available in free form or in the form of their salts.

Salts obtained according to the invention can be converted in a manner known per se into the acid addition salts of the free compounds, e.g. in that the treatment with a base such as an alkali metal hydroxide, salts with bases, e.g. by treatment with an acid, such as a mineral acid. Salts, especially acid addition salts, can e.g. by treatment with suitable derivatives, e.g. inorganic salts of acids, are converted into other salts.

Free connections can e.g. by treatment with acid or corresponding anion exchangers or free compounds of formula I, where R means carboxyl, e.g. by treatment with suitable bases, are converted into their salts.

Because of the close relationship between the compound with formula

I in free form and in the form of salts, the preceding and following with free compound and their salts, are also possibly to be understood

the corresponding salts, respectively free compounds.

The compounds including their salts can also be obtained in form

of their hydrates or their crystal forms can e.g. contain a solvent used in crystallization.

The compound of formula I can also be obtained in the form of isomers, e.g. of racemates or optical antipodes.

The racemeats can be divided according to methods known in and of themselves

in the optical antipodes, for example by recrystallization from an optically active solvent, by means of suitable micro-organisms or by reacting the compound of formula I,

with an optically active salt-forming agent such as an optically active acid and separating the thus formed mixtures of salts, e.g. due to their different solubilities in the diastereomeric salts, from which the antipodes can be released, e.g. by treatment with a base.

Preferably, one isolates e.g. from a race food the pharmacologically most active antipode.

The invention also relates to the embodiments of the method according to which one starts from one or another step of the method as an intermediate obtained compound and carries out the missing steps, or uses a starting substance in the form of a derivative, e.g. salt and/or its racemate respective antipodes form under the reaction conditions.

In the method according to the invention, such starting materials are preferably used which lead to the compounds mentioned at the outset as particularly valuable. The starting materials and methods for their production are also covered by the invention.

The compounds according to the invention with formula I, or pharmaceutically usable salts of such compounds, are used in particular as pharmacological compounds primarily as neuroleptically usable compounds. Thereby, they can be used preferably in the form of pharmaceutical preparations in a method for prophylactic and/or therapeutic treatment of animal or human organisms, especially in treatment e.g. of Schizophrenia and other similar diseases.

Dosage of the active substance that is administered alone or together with the usual auxiliary and carrier materials depends on the type to be treated, the age and the individual condition, as well as the method of administration. The daily doses are for breast-

animals with a body weight of approx. 70 kg, depending on the type of illness, individual condition and age, preferably between approx. 20 and approx. 300 mg.

The compounds produced according to the invention with formula I,

or pharmaceutically usable salts of such compounds, active substances are used in pharmaceutical preparations.

The pharmaceutical preparations are for enteral, such as peroral or rectal, further sublingual, as well as parenteral administration to warm-blooded animals. Corresponding dosage unit forms, especially peroral and/or sublingual administration, e.g. dragees, tablets or capsules, preferably contain from approx. 10 to approx. 400 mg, especially from approx. 20 to approx. 250 mg of compound of formula I, or a pharmaceutically acceptable salt thereof, together with pharmaceutically usable carriers.

Suitable carriers are especially fillers such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch pastes when using e.g. of corn, wheat, rice or potato starch] gelatin, tragacanth, methyl cellulose and/or, if desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, Agar, Alginic acid or a salt thereof such as sodium alginate. Aids are primarily flow control and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Dragon cores can be equipped with suitable, possibly gastric juice-resistant covers, i.; the one used. p. a. concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents, or solvent mixtures or for the production of an enteric coating, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or dragee coatings, e.g. for the identification or characterization of different active substance doses.

Further orally usable pharmaceutical preparations are injectable capsules of gelatins, as well as soft closed capsules of gelatins and a plasticizer, such as glycerol or sorbitol. The capsules may contain active substances, e.g. in the form of a granule, e.g. in a mixture with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers may also be added.

As rectally applicable pharmaceutical preparations it comes

e.g. in terms of suppositories which consist of a combination of the active substance with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with base material, as base materials there are e.g. namely liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, primarily aqueous solutions of an active substance, in water-soluble form, are suitable,

e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions in which suitable lipophilic solvents or carriers are used, such as fatty oils, e.g. sesame oil or synthetic fatty acid

esters, e.g. ethyl oleate, or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally stabilizers.

The pharmaceutical preparations can be prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving, or lyophilizing methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, possibly granulating a formed mixture, and processing the mixture or the granulate if desired or necessary after adding suitable excipients for tablets or dragee cores.

The invention will be explained in more detail with the help of some examples where the temperature is indicated in degrees Celsius.

EXAMPLE 1

38.7 g of the methanesulfonic acid salt of 5-cyano-2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-cpyrrole are introduced with stirring into 250 ml of 85% sulfuric acid at room temperature, and further re-

is then stirred for 2 hours, during which complete dissolution is achieved. The reaction mixture is allowed to stand for 7 days at room temperature, and is then carefully added dropwise while stirring into a mixture of 800 ml of a 25% aqueous ammonia solution,

ice cream and approx. 1000 ml acetic acid ethyl ester. By adding ice, the temperature is kept below 30°C. The organic phase is then separated, washed with water, dried over sodium sulfate and evaporated to a small volume, during which 2-methyl-2,3-dihydro-1H-dibenz[2,3;6,7]thiepinof4,5-c is crystallized ]pyrrole-5-carboxamide,

melting point 170-174°C.

A solution of 15.5 g of the product in 750 ml of acetone is mixed with stirring with 4.8 g of pure methanesulfonic acid, whereupon the methanesulfonic acid salt of 2-methyl-2,3-dihydro-1H-dibenz[2,3;6,7 Jtiepino[4,5-c]pyrrole-5-carboxamide, melting point 220-223°C.

The starting material can e.g. can be obtained according to the procedure described in European application no. 79102146.2 (Publication no. 7450).

Analogously to the above-mentioned method, the following compounds can be prepared using the corresponding starting materials: 2-(cyclopentylmethyl)-2,3-dihydro-1H-dibenz [2,3:6,7]thiepino[4,5-c]pyrrole- 5-carboxamide' (amorphous crude product), whose methanesulfonic acid salt after recrystallization from methanol melts at 248-251°C, from 45.5 g of the methanesulfonic acid salt of 5-cyano-2-(cyclopentylmethyl)-2,3-dihydro-lH -dibenz[2,3:6,7]thiepino[4,5-cjpyrrole, such as e.g. can be produced according to the method described in the European application no. 79102146.2 (Publ. no. 7450) in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution;

2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole-5-carboxamide, mp 218°C after recrystallization from acetone; from 23.9 g of the hydrochloride of 5-cyano-2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole.in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution, a solution of 14.6 g of the product in a mixture of 140 ml of acetone and 140 ml of absolute ethanol is mixed with 12.5 ml of a 4-n solution of hydrogen chloride in absolute ethanol, whereupon it crystallizes out the hydrochloride of 2-methyl-2,3-dihydro-1H-dibenz [2,3:6,7]okepino[4,5-c]pyrrole-5-carboxamide, melting point of 291-293°C. The starting material can e.g. obtained by treating 40.5 g of 2-cyano-10,11-bis-(bromomethyl)-dibenz b,f oxepino with 62 g of methylamine in 500 ml of methanol, 5-cyano-2-methyl-2,3-dihydro- 1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, melts after crystallization

separation from acetonitrile at 136-138°C and its methanesulfonic acid salt after; crystallization from absolute ethanol at 220-223°C.

2-ethyl-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole-5-carboxamide, melting point 205-210°C, after recrystallization from ethyl acetate, from 38 .4 g of the methanesulfonic acid salt of 2-ethyl-5-cyano-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, which e.g. can be produced according to a method mentioned in European application no. 79102146.2 (Publ. no. 7450), in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution, the product's hydrochloride melts after recrystallization from absolute ethanol at 215-220°C , and

2-n-propyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxamide, melting point 120-125°C after crystallization from acetic acid ethyl ester from 41 .4 g of the methanesulfonic acid salt of 2-n-propyl-5-cyano-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c] pyrrole in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution. The product's methanesulfonic acid salt melts after crystallization from absolute ethanol at 252-255°C. Starting material can e.g. is produced according to the method described in the European application no. 79102146.2 (Publication no. 7450).

EXAMPLE 2

41.5 g of the methanesulfonic acid salt of 7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d]azepine are introduced with stirring into 250 ml 85% sulfuric acid at room temperature

and further stirred for 10 hours, during which the starting material completely dissolves. The reaction mixture is allowed to stand for 7 days at room temperature, and is then carefully dripped with stirring into a mixture of 800 ml of a 25% aqueous ammonia solution, ice and approx. 1000 ml acetic acid ethyl ester.

By adding ice, the temperature is kept below 30°C. The organic phase is then separated, washed with water, dried over sodium sulfate and evaporated to a small volume in which 3-methyl-2,3,4,5-tetrahydro-1H-dibenz[ 2,3:6,7] crystallizes out. tie-pino[4,5-d]azepine-7-carboxamide, mp 147-150°C.

A solution of 16.8 g of the product in a mixture of 200 ml of acetone and 40 ml of absolute ethanol is mixed with 4.8 g of pure methanesulfonic acid, whereupon the methanesulfonic acid salt of 3-methyl-2,3,4,5-tetrahydro-lH- dibenz[ 2,3:6,7]thiepino[4,5-d]azepine-7-carboxamide, crystallizes with melting point 220-223°C.

The starting material can e.g. produced according to the method described in German application P 27 23 105.6.

Analogous to the above-mentioned method, the following compounds can be prepared using corresponding starting materials: 3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepinof 4,5-d]azepin-7 -carboxamide, melting point 260-264°C after crystallization from chloroform; of 39.9 g of the methanesulfonic acid salt of 7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine in 250 ml 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution, a solution of 16 g of the product in 1500 ml of absolute ethanol, are mixed with stirring with a solution of 4.5 g of anhydrous oxalic acid in 30 ml of absolute ethanol, after which the oxalic acid salt is crystallized, melting point 240-242°C. The starting material can e.g. is produced according to the procedure specified in European application 80810377.4 (Publication no. 30916).

3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxamide, melting point 110-116°C, after crystallization from acetone, of 46.7 g of the methanesulfonic acid salt of 7-cyano-3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5- d]azepine in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution. The methanesulfonic acid salt of the product melts after crystallization from a mixture of absolute ethanol and acetone at 176-180°C. The starting material can e.g. also produced according to the method described in European application 80810377.4 (Publication no. 30916), and

3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d]azepine-7-carboxamide (amorphous crude product) of 48.3 g of the methanesulfonic acid salt of 7-cyano-3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d]azepine in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution.

A solution of 20.2 g of the product in a mixture of 200 ml of acetone and 50 ml of absolute ethanol is mixed with 12.5 ml of a 4-n solution of hydrogen chloride in absolute ethanol, after which the hydrochloride crystallizes out, melting point 228-232°C . The starting material can e.g. is produced according to the method described in Swiss patent no. 624105.

EXAMPLE 3

38.7 g of the methanesulfonic acid salt of 5-cyano-2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrrole are dissolved with stirring in a mixture of 310 ml of toluene and 160 ml of methanol. The solution is saturated at -M0° to -i- 20°C with dry hydrogen chloride and is then further stirred for 20 hours at 0-5°C. It is then allowed to flow to 700 ml of ice water and heated for 1 hour at 70-75°C. After cooling, the aqueous phase is separated and made alkaline with a concentrated aqueous ammonia solution. The 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepion[4,5-c]pyrro1-5-carboxylic acid methyl ester which precipitates as an oil is extracted with diethyl ether and the organic extract is washed with water and evaporated after drying over sodium sulfate under reduced pressure. A solution of 16.2 g of the crude product in 100 ml of acetone is mixed with 12.5 ml of a 4-n solution of hydrogen chloride in absolute ethanol, whereupon the hydrochloride crystallizes out, which after recrystallization from absolute ethanol melts at 247-249°C .

Analogous to the method mentioned above, the following compounds can be prepared using corresponding starting materials: 3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino^ , 5-d ] azepine-7-carboxylic acid methyl ester , melting point at 148-149°C, after crystallization from acetic acid ethyl ester of 46.7 g of the methanesulfonic acid salt of 7-cyano-3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz [2,3:6,7]oxepinot4,5-d]azepine in 310 ml of toluene and 160 ml of methanol and dry hydrogen chloride. A suspension of 20.8 g of the product in 250 ml of boiling acetone is carefully mixed with 4.8 g of pure methanesulfonic acid, resulting in a complete solution from which the methanesulfonic acid salt of 3-(cyclopentylmethyl)-2,3,4 crystallizes out after a short time ,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid methyl ester, mp 229-231°C;

3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid methyl ester, melting point 13C-131°C, after crystallization from acetone, of 39.9 g of methanesulfonic acid

the salt of 7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7] oxepino[4,5-d]azepine in 310 ml of toluene and 160 ml of methanol and dry hydrogen chloride, the methanesulfonic acid salt melts after crystallization from absolute ethanol at 230-233°C; and

3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d] azepine-7-carboxylic acid methyl ester, melting point 133-134°C, after crystallization of diethyl ether of 41.5 g of the methanesulfonic acid salt of 7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7] thiepino[4,5-d]azepine in 310 ml of toluene and 160 ml of methanol and dry hydrogen chloride, the methanesulfonic acid salt melts after crystallization from absolute ethanol, at 224-225°C.

EXAMPLE 4

40.4 g of 3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid methyl ester is boiled with a solution of 7 g of sodium hydroxide in 150 ml of 70% aqueous ethanol with stirring for 1 hour under reflux. The hot reaction mixture is then diluted with 450 ml of distilled water and mixed with 300 ml of 10% methanesulfonic acid. The formed precipitate goes back into solution when heated at 80-90°C. On addition of concentrated aqueous ammonia solution to pH 8-9, 3-(cyclopentylmethyl-2,3,4,5-tetrahydro-1H-dibenz) precipitates

[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid which is filtered off and washed with water and ethanol, melting point 260-262°C after drying under reduced pressure at 100°C. The methanesulfonic acid salt melts at approx. 215°C during decomposition.

Analogously, by choosing suitable starting materials, the following compounds can be obtained: 2-methyl-2,3-dihydro-1H-dibenzyl[2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxylic acid, melting point 194-198°C, of 32.3 g of 2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxylic acid methyl ester and 7 g of sodium hydroxide in 150 ml of 70% aqueous ethanol;

3- methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid, melting point 280-288°Cf of 33.5 g 3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid ester and 7 g sodium hydroxide in 150 ml 70% aqueous ethanol. The product's methanesulfonic acid salt melts after crystallization from ethanol at 310-314°C, and

3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d] azepine-7-carboxylic acid, melting point 295-305°C (under decomposition) ,

of 35.1 g of 3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d]azepine-7-carboxylic acid methyl ester and 7 g of sodium hydroxide in 150 ml 70% aqueous ethanol. The product's methanesulfonic acid salt melts after crystallization from a mixture of ethanol and diethyl ether at 200-203°C.

EXAMPLE 5

A mixture of 38.9 g of 3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepinot4,5-d]azepine-7-carboxylic acid, 1200 ml of methylene chloride and 15.2 g of triethylamine are boiled with stirring for 30 minutes under reflux, then cooled to -M0°C, and mixed dropwise over 30 minutes with a solution of 16.3 g of chloroformate ethyl ester in 50 ml of methylene chloride. After completion of the addition, the clear reaction solvent is allowed to

stirring for 1 hour at -MO to 0°C, and adding dropwise

at this temperature, a solution of 6.8 g of dimethylamine in 50 ml of methylene chloride, with stirring for 2 hours at room temperature, the reaction is brought to completion. The reaction mixture is washed with water and 2-n aqueous sodium hydroxide solution, and extracted with a 5% solution of methanesulfonic acid in water. The acidic extract is made alkaline with concentrated aqueous sodium hydroxide solution,! it crystallizes 3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid-N,N-dimethylamide , as a drying under reduced pressure at 80°C and subsequent recrystallization from acetone, melts at 142-144°C.

A solution of 20.8 g of the product in 200 ml of acetone is mixed with stirring with 4.8 g of pure methanesulfonic acid, after which the methanesulfonic acid salt crystallizes out, melting point 264-268°C.

Analogous to the above-mentioned method, it can be used

from corresponding starting materials the following compound is prepared: 3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid-N -methylamide (amorphous), of 38.9 g of 3-(cyclopentylmethyl)-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7 -carbonic acid, 15.2 g of triethylamine and 16.3 g of chloroformate ethyl ester, then 4.7 g of methylamine with methylene chloride as solvent. The methanesulfonic acid salt of the product melts after crystallization from methanol at 296-302°C;

3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-d]azepine-7-carboxylic acid-N,N-dimethylamide, melting point 126-128 °C, after crystallization from a mixture of diethyl ether and n-pentane of 32.1 g of 3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]oxepino [4,5 -d]azepine-7-carboxylic acid, 15.2 g of triethylamine and 16.3 g of chloroformate ethyl ester, then 6.8 g of dimethylamine with methylene chloride as solvent. The methanesulfonic acid salt of the product melts after crystallization from acetone at 154-158°C;

3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d]

azepine-7-carboxylic acid-N,N-dimethylamide (amorphous), from 33.7 g of 3-methyl-2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4, 5-dazepine-7-carboxylic acid, 15.2 g of triethylamine and 16.3 g of chloroformic acid ethyl ester, then 6.8 g of dimethylamine with methylene chloride as solvent. The fumaric acid salt of the product melts after crystallization from a mixture of absolute ethanol and acetone at 195-198°C;

3-methyl-7-pyrrolidinocarbonyl-2,3,4,5-tetrahydro-1H-dibenz [2,3:6,7]thiepino[4,5-dJazepine (amorphous), from 33.7 g of 3-methyl- 2,3,4,5-tetrahydro-1H-dibenz[2,3:6,7]thiepino[4,5-d]azepine-7-carboxylic acid, 15.2 g of triethylamine and 16.3 g of chloroformate ethyl ester, then 10 .7 g of pyrrolidine, with methylene chloride as solvent. The fumaric acid salt of the product melts after crystallization from a mixture of absolute ethanol and acetone at 188-190°C;

2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxylic acid-N,N-dimethylamide (amorphous), of 30.1 g 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxylic acid, 15.2 g of triethylamine and 16.3 g of chloroformate ethyl ester, then

6.8 g of dimethylamine with methylene chloride as solvent. The methanesulfonic acid salt of the product melts after crystallization

from absolute ethanol at 219-222°C; and

2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxylic acid-N-methylamide, melting point 170-175°C after crystallization from absolute ethanol, of 30.1 g of 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrrole-7-carboxylic acid, 15.2 g of triethylamine and 16 .3 g of chloroformic acid ethyl ester, then 4.7 g of methylamine with methylene chloride as solvent. The methanesulfonic acid salt of the product melts after crystallization with ethanol at 270-273°C.

EXAMPLE 6

4.39 g of 10,11-bis-bromomethyl-dibenz[b,f]thiepiene-2-carboxamide are dissolved in 400 ml of absolute toluene at 80°C and dripped into the

of 1 hour at 43-45°C to a solution of 155 methylamine in 400 ml methanol. During the dripping, further methylamine gas is introduced. The reaction mixture is stirred for a further 1 hour at 50°C, then the solvent and excess methylamine are distilled off. The remainder is mixed with water and the resulting suspension is extracted with methylene chloride. The organic phase is separated, washed with water, dried over potassium carbonate and evaporated. The remainder is dissolved in 40 ml of acetone. On cooling, 2-methyl-2,3-dihydro-1H-dibenzo[2,3:6,7] thiepino-[4,5c]pyrrole-5-carboxamide crystallizes and is suctioned off and dried. Melting point 170-174°C.

1.54 g of the formed base is dissolved in 60 ml of acetone. 0.48 g of methanesulfonic acid is then added. The crystallized methane sulphonate is suctioned off and dried. Melting point 220-223°C.

The starting material can be produced in the following way:

29.4 g of 2-cyano-10,11-dimethyl-dibenz[b,f]thiepine are taken in 400 ml of tert-butyl alcohol. 28 g of powdered potassium hydroxide are introduced into this suspension while stirring and the mixture is boiled for 1 hour under reflux. 200 ml of tert-butyl alcohol is then distilled off on a rotary evaporator. 100 ml of ether and 800 ml of water are added to the residue while stirring. The precipitated 10,11-dibutyl-dLbenz[ b , f ] thiepine-2-carbocamide is filtered off with suction, washed with water and recrystallized from 400 ml of absolute alcohol. Melting point 195-200°C.

2.81 g of 10,11-dimethyl-dibenz[b,f]thiepine-2-carbamide are dissolved in 900 ml of carbon tetrachloride at 70°C and then 3.63 g of N-bromosuccinimide are added. While stirring and under illumination with a UV lamp, the mixture is boiled for 10 minutes under reflux. The reaction mixture is cooled to 20°C and the crystallized crude 10,11-bis-bromomethyl-dibenz[b,f]thiepine-2-carboxamide is filtered off with suction. The above product is dissolved in chloroform, washed twice with 2-n caustic soda and then three times with water. After drying over sodium sulphate, the solution is evaporated to 30 ml, cooled and aspirated. Melting point 202-204°C.

EXAMPLE 7

Tablets containing 0.020 g of the methanesulfonic acid salt of 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino[4,5-c]pyrroic-5-carboxamide are prepared, e.g. as follows:

Composition (for 10,000 tablets):

A mixture of 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]thiepino-[4,5-c]pyrrole-5-carboxamide methanesulfonic acid salt, the lactose

and 194.70 g of potato starch are moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate and the colloidal silicon dioxide are mixed in and the mixture is pressed into tablets of 0.1 g weight each, which, if desired, can be equipped with break instructions for finer adjustment of the dosage.

EXAMPLE 8

Capsules, containing 0.25 g of the 2-methyl-2,3-dihydro-1H-dibenz [2,3:6,7]thiepino[4,5-c]pyrrole-5-carboxamide methanesulfonic acid salt, can be prepared as follows :

Composition (for 1,000 capsules)

The 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,1]thiepini-[4,5-c]pyrrole-5-carboxamide sulfonic acid salt is mixed with the lactose, the mixture is evenly moistened with an aqueous solution of gelatin and granulate it through a sieve, with a mesh size of 1.2-1.5 mm. The granulate is mixed with the dried corn starch and talc and portions of 300 mg are filled into hair gelatin capsules (size 1).

Claims (7)

1. Process for the preparation of compounds of formula in which R means an optionally esterified or amidated carboxy group, R-^ means hydrogen or an optionally substituted aliphatic or cycloaliphatic aliphatic hydrocarbon residue, X means epoxy or epithio, n means 1 or 2, characterized in that a) in a compound of formula in which R denotes a residue transferable to the optionally esterified or amidated carboxy group R, or in a salt thereof, RQ is transferred to group R, or b) a compound of formula in which one of the groups X-^ and X,, means the residue of formula -NH -R^(Illa) and the other a reactive esterified hydroxy group are ring-closed. And if desired, an obtained compound of formula I is transferred into another compound of formula I, and/or if desired another salt is transferred to the free compound or to another salt, and/or if desired a formed free compound is transferred to a salt , and/or if desired, a formed isomer mixture is divided into the individual isomers. 2. Method according to claim 1, characterized in that it starts from one or other step of the method as an intermediate obtained compound and the. missing process steps are carried out or the process is interrupted at one or another step, or a starting material is formed under the reaction conditions, or a reaction component is optionally used in the form of its derivatives as a salt. 3. Method according to claim 1, characterized in that a compound of formula I is prepared, where R means carboxy lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, dilower alkylcarbamoyl, lower alkyleneaminocarbonyl with 5 to 8 ring atoms, oxalolower alkyleneaminocarbonyl with 6 ring atoms, or lower alkyleneaminocarbonyl with 6 ring atoms or azalower alkyleneaminocarbonyl with 6 to 8 ring atoms, in which the azanitrogen can optionally be substituted with lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, or lower alkanoyloxy lower alkyl, in that in such substituted lower alkyl residues a substituent is separated by at least 2 carbon atoms from the azanite nitrogen atom, R, means hydrogen lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkanoyloxy lower alkyl, halogen lower alkyl, lower alkenyl lower alkynyl or cycloalkyl lower alkyl, in that in substituted lower alkyl residues a substituent is preferably separated by at least 2 carbon atoms from the ring nitrogen atom, in unsaturated residues there is a double or triple bond in a higher position than 1, and cycloalkyl contains 3 to 8 ring atoms, in that with "lower" designated residues contain empty. 7 carbon atoms, X means epoxy or epithio, and n means 1 or 2 and salts thereof. 4. Method according to claim 1, characterized in that compounds are produced where R means carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbonyl or lower alkyleneaminocarbonyl, in which lower alkyleneamino contains 5 or 6 ring atoms, R-^means hydrogen, lower alkyl, hydroxy lower alkyl or lower alkoxy lower alkyl, in which hydroxy or lower alkoxy is separated by at least 2 carbon atoms from the ring nitrogen atom, lower alkenyl or lower alkynyl, in which the double or triple bond is in a higher than 1 position, or cycloalkyl lower alkyl in which cycloalkyl contains 3 to 8 ring carbon atoms, in the "lower" designated residues contain up to 4 carbon atoms, X means epoxy or epithio, and n means 1 or 2 and salts thereof. 5. Process according to claim 1, characterized in that compounds of the formula are prepared where R' means carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, dilower alkylcarbamoyl or lower alkyleneaminocarbonyl, in which lower alkyleneamino contains 5 or 6 ring atoms, R| means hydrogen, lower alkyl or cycloalkyl lower alkyl, in which cycloalkyl has 3 to 6 ring carbon atoms, in the "lower" designated residues contain up to 4 carbon atoms, X means epoxy or epithio and n means 1 or 2, as well as salts thereof. 6. Method according to claim 1, characterized in that compounds of formula Ia are prepared, according to claim 4, in which R' means carbamoyl, lower alkylcarbamoyl, in which lower alkyl has up to 4 carbon atoms, dilower alkylcarbamoyl, in which lower alkyl has up to 4 carbon atoms, or alkyleneaminocarbonyl, in which alkyleneamino contains 5 or 6 ring atoms, R| means lower alkyl with up to 4 carbon atoms or cycloalkyl lower alkyl, in which cycloalkyl has 3 to 6 ring carbon atoms and lower alkyl has up to 4 carbon atoms, X means epoxy or epithio, and n means 1 or 2, as well as salts thereof. 7. Process according to claim 1, characterized in that 2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7] thiepino[4,5-c]pyrrole-5-carbamide and salts thereof are produced.