DD220307A5 - METHOD FOR THE PRODUCTION OF POLYCYCLIC CARBONIC ACID COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of polycarboxylic carboxylic acid compounds for use as a medicament. OBJECTIVE OF THE INVENTION IS TO PROVIDE NEW COMPOUNDS WITH VALUABLE PHARMACOLOGICAL PROPERTIES, IN PARTICULAR WITH NEUROLEPTIC EFFECT FOR THE TREATMENT OF SCHIZOPHRENIA. ERFINDUNGSGEMAESS, compounds of formula (I) is prepared in which R represents an optionally esterified or amidated CARBOXYGRPPE, R LOW 1 is hydrogen or an optionally substituted aliphatic or cycloaliphatic hydrocarbon radical, X is epoxy or epithio, and n is 1 or 2, or salts thereof, neuroleptic CONNECTIONS.

Description

Berlin »30 · 7. 1984 63 '819 18

Process for the preparation of polycyclic carboxylic acid compounds

Field of application of the invention

The invention relates to a process for the preparation of polycyclic carboxylic acid compounds, as well as pharmaceutical preparations containing such carboxylic acid compounds and, I the use of the latter as pharmacologically active compounds.

C:; , , / ""';.. The compounds according to the invention are used as medicaments, especially as neuroleptics, for example, to treat schizophrenia ·

Characteristic of the known technical solutions

No information is available on which compounds have been used to treat schizophrenia. "" There is also no information available about methods for preparing polycyclic carboxylic acid compounds. *** "

Z iel the Erfindun g

  i

The aim of the invention is to provide novel compounds with valuable pharmacological properties, in particular with a neuroleptic effect and a favorable relationship between the desired action and toxicity and / or undesired side effects.

-3. 8: H-O1SS7u9

Explanation of the essence of the invention

  '.-)

The invention has for its object to find new compounds with the desired properties and process for their preparation ·

  '' .- '.' '', -.- · '

According to the invention, compounds of the formula

^R 1

H (OBj) _n (0H ₂ ) _n

i μ i 4

in which R is an optionally esterified or amidated carboxy group, R is hydrogen or an optionally substituted aliphatic or cycloaliphatic-aliphatic hydrocarbon radical, X is epoxy or epithio, and η is 1 or 2, or salts of such compounds

An esterified carboxy group R is primarily lower alkoxycarbonyl, while an amidated carboxy group R is in particular carbamoyl or mono- or di-lower alkyl-carbamoyl, furthermore lower. ,

alkyleneaminocarbonyl, oxyanilkalkyleneaminocarbonyl, thianethanalkyleneaminocarbonyl or azanoweralkyleneaminocarbonyl, wherein alkylenarienino, oxaalkyleneamino, thiaalkyleneamino and azaalkyleneamino are e.g. Have 4 to 8 ring atoms, and the azole nitrogen optionally, e.g. optionally substituted, optionally etherified or esterified hydroxy, e.g. Hydroxy, lower alkoxy or lower alkanoyloxy, containing lower alkyl may be substituted.

An aliphatic hydrocarbon radical is primarily lower alkyl, but may also be lower alkenyl or lower alkynyl, wherein in the unsaturated radicals the double or triple bond is in a higher than the 1-position. A cycloaliphatic-aliphatic hydrocarbon radical is especially cycloalkyl-lower alkyl, wherein cycloalkyl may contain, for example, up to and with 8 ring carbon atoms. Residues substituents of such hydrocarbon, which are preferably located in a higher than the 1-position are in the first line ¹ optionally etherified or esterified hydroxy groups, such as hydroxy, lower alkoxy, lower alkanoyloxy or halogen.

The symbols η each have the same meaning and stand

'. ^: '. '' (.

neither for 1 or for 2. *

Unless expressly stated otherwise, the general definitions used above and below have preferably the following meanings:

The groups and compounds designated "lower" are primarily up to and including 7, preferably to and having 4 carbon atoms. I '

Γ.

Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl, furthermore n-propyloxycarbony1, isopropyloxycarbonyl, n-butyloxycarbonyl,

Isobutyloxycarbonyl or tert-butyloxycarbonyl, and n-pentyloxycarbonyl, n-hexyloxycarbonyl or n-heptyloxycarbonyl.

Mono- and di-lower alkylcarbamoyl are e.g. Methylcarbamoyl, ethylcarbamoyl, isopropylearbamoyl, dimethylcarbamoyl or diethylcarbamoyl, while alkyleneaminocarbonyl, preferably of 4 to 8, e.g. with 5 or 6 ring atoms, e.g. Pyrrolidinocarbonyl or piperidinocarbonyl, oxaalkyleneaminocarbonyl, preferably with 6 ring atoms, e.g. Morpholinocarbonyl, thiaalkyleneaminocarbonyl, preferably with 6 ring atoms, e.g. Thiomorpholinocarbonyl, and azaalkyleneaminocarbonyl, preferably having 6 to 8 ring atoms, and optionally substituted, e.g. Lower alkyl, hydroxy lower alkyl or lower alkanoyloxy lower alkyl containing azole nitrogen, e.g. Piperazinocarbonyl or 4-methyl-piperazinocarbonyl mean.

Lower alkyl is e.g. in particular methyl or ethyl, furthermore n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl, as well as n-pentyl, neopentyl, n-hexyl or N-heptyl, while lower alkenyl e.g. Allyl, 2-methylallyl, 3,3-dimethylallyl or 2-butenyl, and lower alkynyl e.g. Propargyl mean.

Cycloalkyl-lower alkyl is e.g. Cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl or cyclooctylmethyl.

Lower alkoxy is e.g. in particular methoxy or ethoxy, furthermore n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy.

Lower alkanoyloxy is e.g. Acetyloxy, propionyloxy or butyryloxy. Halogen preferably has an atomic number up to 35 and is e.g.

especially chlorine, but may also be fluorine or bromine.

Salts of compounds of formula I are salts which are primarily pharmaceutically useful and may be primarily acid addition salts, e.g. with inorganic acids, such as hydrogen halides, e.g. Hydrochloric or hydrobromic acid, furthermore nitric acid, sulfuric acid or phosphoric acid, or with organic acids such as corresponding carboxylic acids, e.g. Acetic, propionic, glycolic, succinic, maleic, hydroxymaleic, methylic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-amino-salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic or isonicotinic acid, furthermore amino acids or sulfonic acids, such as optionally hydroxy-containing lower alkanesulfonic acids, eg Methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or ethane-1, 2-disulfonic acid, or arenesulfonic acid, e.g. Benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid, or with other acidic organic substances, such as ascorbic acid. Compounds of formula I wherein R is free carboxy may also contain salts with bases such as salts with metals 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 Triniederalkylaminen such as diethylamine or triethylamine, or mono-, di- or Trihydroxyniederalkylaminen such as di- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) ~ amine, or form inner salts.

Compounds of formula I with asymmetric carbon atoms, e.g. in a radical R, can, also in the form of isomers, such as racemates

or optically active. Antipodes present.

The novel compounds of the formula I and their salts have pharmaceutical

^. .. · _

ecological, especially neuroleptic, effects. These are based i.a. on a strong inhibition of the alpha-1-adrenergic receptor

- C ._

ren, the e.g. By means of a radioreceptor assay, inhibition of (H) WB 4101 binding in the rat brain under in vitro conditions, e.g. according to the U'Prichard et al. in Molec. Pharmacol., Vol. 13, p. 454 (1977), and under in vivo conditions, among the latter at doses above about 0.01 mg / kg upon intraperitoneal administration to rats. The new compounds also show the characteristic of neuroleptic compounds

    ''. '. 3 Inhibition of dopamine receptors, e.g. by inhibition of (H) spiperone binding according to the method of Bischoff et al. in Europ. J. Pharmacol.,

'' \ ''

Vol. 68, p. 305 (1980), at doses above about 1 mg / kg upon intraperitoneal administration to rats. It turns out that the inhibition of the compounds according to the invention has a pronounced selective effect on the hippocampal dopamine receptors; it is e.g. at least three times stronger than that on the striatal dopamine receptors.

The novel compounds of formula I and their salts can therefore be used as neuroleptics, e.g. for the treatment of schizophrenia, with essential

     & '. *

lower extrapyramidal side effects and a favorable ratio between desired effect and toxicity and / or undesirable side effects.

The invention primarily relates to compounds of the formula I in which R is carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkyleneaminocarbonyl having from 5 to 8 ring atoms, oxanoweralkyleneaminocarbyl with 6-ringthylene thiahylalkyleneaminocarbonyl having 6 ring atoms or azanoweralkyleneaminocarbonyl having from 6 to 8 ring atoms wherein the azole nitrogen may be optionally substituted by lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl or lower alkanoyloxy-lower alkyl, wherein in such substituted lower alkyl radicals a substituent is separated from the azine nitrogen atom by at least 2 carbon atoms, R is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkanoyloxy lower alkyl, lower haloalkyl, lower alkenyl, Lower alkynyl or cycloalkyl

means lower alkyl, wherein a substituent is preferably separated by at least 2 carbon atoms from the ring nitrogen atom, in unsaturated radicals the Doppelbzw. Is present in a higher than the 1-position, and cycloalkyl contains 3 to 8 ring atoms, where radicals denoted "lower", for example up to and containing 7, preferably to and containing 4 carbon atoms, X is epoxy or epithio, and η is 1 or , "is 2, or salts, especially pharmaceutically acceptable salts. Säureadditiqnssalze primarily of such compounds.

More particularly, the invention relates to compounds of formula I, wherein R is carboxy or lower alkoxycarbonyl, but primarily carbamoyl, further lower alkylcarbamoyl or di-lower alkylcarbamoyl, further lower alkylene-aminocarbonyl, wherein lower alkylene-amino contains 5 or 6 ring atoms, wherein R is in compounds of formula I in which η is 1, preferably in the 5-position, and i _n compounds of the formula I, wherein η is 2, preferably in the 7-position, R is hydrogen, lower alkyl, Hadroxyniederalkyl or lower alkoxy lower alkyl, wherein hydroxy or lower alkoxy by minder least 2 carbon atoms is separated from the ring nitrogen atom, lower alkenyl or lower alkynyl, wherein the double or triple-V · ^'1 bond in a higher than, is the 1-position, or cycloalkyl group, wherein cycloalkyl contains 3 to 8 ring carbon atoms, where "lower" radicals contain up to and including 4 carbon atoms, X is for Epox y or epithio, and η is 1 or 2, or salts, especially pharmaceutically. , Usable salts in the first place acid addition salts of such ι compounds. , '... ·'

The invention particularly relates to compounds of the formula

(Ia)

wherein R 'is carboxyl or lower alkoxycarbonyl, but primarily carbamoyl, lower alkylcarbamoyl or di-lower alkylcarbamoyl, further lower alkyleneaminocarbonyl, wherein lower alkyleneamino contains 5 or 6 ring atoms, R' is hydrogen, lower alkyl or cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 6 ring carbon atoms, with "lower" radicals to and containing 4 carbon atoms, X is epoxy or epithio, and η is 1 or 2, or salts, especially pharmaceutically acceptable salts, especially acid addition salts such compounds.

The invention relates in the first place to compounds of the formula Ia in which R 'is, in particular, carbamoyl, furthermore lower alkylcarbamoyl, in which lower alkyl has up to and including 4, preferably 1 or 2, carbon atoms, e.g. Methylcarbamoyl, or di-lower alkylcarbamoyl, wherein lower alkyl has up to and preferably 4, 1 or 2 carbon atoms, e.g. Dimethylcarbamoyl, further alkyleneaminocarbonyl, wherein alkyleneamino contains 5 or 6 ring atoms, e.g. Pyrrolidinocarbonyl, R 'is lower alkyl with bis and with 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 and including 4, preferably 1 or 2, carbon atoms, e.g. Cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl, X is epoxy or preferably epithio, and η is preferably 1, furthermore 2, or salts,

_Q

especially pharmaceutically acceptable salts, especially acid addition salts of such compounds.

The invention particularly relates to the compounds described in the examples. , .

The novel compounds of formula I can be prepared by methods known per se, e.g. by

(a) in a compound of the formula -

R.

-MR

in which R represents a radical convertible to the optionally esterified or amidated carboxy group R, or in a salt thereof converts R into the group R, or

(b) a compound of the formula

^X l ^X 2 Il

(CH) (rs.)

V η / 2 η

Γι π. -4-R (πι) / \ / \ ^

wherein one of the groups X ₁ and X "is the radical of the formula -NH-R (IIIa) and the other is a reactive esterified hydroxy group, and if desired, an obtainable compound of the formula I is converted into one, another compound of the formula I. -

and / or, if desired, converting a salt obtained into the free compound or other salt, and / or, if desired, salifying a free compound obtained, and / or, if desired, adding an obtained mixture of isomers to the salt separates individual isomers.

Salts of starting materials of the formula II 'are primarily acid addition salts, such as corresponding salts with strong mineral and organic sulfonic acids, such as the corresponding salts with hydrochloric, sulfuric, methanesulfonic or p-toluenesulfonic acid.

A radical R is in particular the acyl radical of a carboxylic acid, including the corresponding radical of a carbonic acid derivative. A radical R is primarily one different from the group R,

  , o. , ,

functionally modified carboxy group, e.g. an anhydride carboxy group, a thiocarbamoyl group, an optionally O-substituted formimidoyl group, or especially the cyano group. The corresponding starting materials of the formula II can be converted into the desired compounds of the formula I in a manner known per se.

A starting material of formula II having an anhydrided carboxyl group may be the corresponding symmetrical anhydride, but is preferably an asymmetric anhydride wherein R is an carboxy group anhydrided with an inorganic or organic acid, such as halocarbonyl, especially chlorocarbonyl, or cyano carbonyl. furthermore, sulfo-oxycarbonyl present in salt form, for example in the form of the lithium salt, and also acyloxycarbonyl, in which acyl is, for example, the radical of an aliphatic or aromatic carboxylic acid, especially for lower alkoxycarbonyloxycarbonyl, e.g. Aethoxycarbonyloxycarbonyl or isobutyloxycarbonyloxycarbonyl.

Starting materials of formula II having an anhydrided carboxy group R may be obtained by hydrolysis, e.g. by treatment with water in acidic or basic medium, in the corresponding free carboxylic acids or by alcoholysis, e.g. by treating with an alcohol such as lower alkanol in the presence of a base such as an alkali metal hydroxides, e.g. Sodium hydroxide are converted into the corresponding esters. By ammonolysis or amino-ion, e.g. by treatment with ammonia (optionally in derivatized form, for example as urea, urethanes, formamide, or ammonium salts, such as ammonium acetate) or with amines (optionally in derivatized form, for example as N-substituted urethanes) can be prepared from starting materials of the formula II an anhydridediesierten carboxy, in particular chlorocarbonyl or Niederalkoxycarbonyloxycarbonyl, as R corresponding compounds of formula I with an amidated carboxy - R p obtained. If necessary, in the presence of a clean

I.

rebindering 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. Working pyridine, or an excess of the ammonolysis or aminolysis. ,

An anhydrided carboxy group is also a trihalomethyl group in which halogen is preferably chlorine but may also be bromine, especially trichloromethyl. A compound of the formula II with such a group R represents the mixed anhydride of an orthocarboxylic acid compound corresponding to the carboxylic acid compound of the formula II with a halogeno, especially hydrochloric acid. A corresponding starting material may be obtained by hydrolysis, preferably in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, eg Calcium hydroxide (optionally 'in the presence of iron), or in the presence of a suitable heavy metal salt, such as ferric chloride, is carried out in aqueous medium, are converted into the corresponding carboxyl compound of formula I. You can also do it by treating with one

V '. ·,. , , . , .. -. Ii -. , '. '

mono- or disubstituted amine, and also with ammonia, optionally in derivatized. Shape, e.g. as formamide or hexamethylenetetramine, to a compound of formula I, wherein R represents an amidated carboxyl group.

A thiocarbamoyl group R in a starting material of formula II may be an unsubstituted thiocarbamoyl group, but is primarily an N-substituted, such as N, N-disubstituted thio, carbamoyl, and especially a Ν, Ν-lower alkyleneamino, carbonyl, wherein the lower alkylene chain eg may be interrupted by a heteroatom, preferably by oxygen; such a thiocarbamoyl group R is especially morpholinothiocarbonyl, further. Thiomorpholinothiocarbonyl, as well as piperidinothiocarbonyl. A starting material of formula I having such a thiocarbamoyl group R 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 carbonates or hydroxides, e.g. Sodium or potassium hydroxide are converted into the compound of formula I with a free carboxy group. By treating a thiocarbamoyl starting material of the formula IT, in which thiocarbamoyl R is

substituted or substituted with a heavy metal oxide, e.g. Mercury oxide, or a basic agent such as an alkali metal, e.g. Sodium or potassium hydroxide, in a lower alkanol can be obtained to corresponding compounds of formula I, wherein R is unsubstituted or substituted carbamoyl.

In a starting material of the formula II, an optionally 0-substituted formimidoyl group R is in particular 0-lower-alkyl, such as O-methyl- or O-ethyl-formimidoyl. By means of hydrolysis of an acid addition salt, such as the hydrochloride or sulfate, of the _: carboxyimidate starting material of the formula II, the corresponding esters, in particular lower alkyl esters of the formula I, can be obtained, while the hydrolysis of such starting material gives

materials of formula II in the presence of a base, e.g. Sodium hydroxide, can reach the carboxylic acid compounds of the formula I. By heating the abovementioned addition salts of arboximidate compounds of the formula IL, it is possible to obtain the corresponding compound of the formula I with an amidated carboxy group, where, in the case of compounds of the formula II with an N-substituted formimidoyl group R, to compounds of the formula I. to lead,; the one corresponding. N-substituted carbamoyl group R have.

The conversion of the preferred cyano group as radical R in a starting material of the formula II into an optionally esterified or amidated carboxy group is usually carried out by means of solvolysis,

whereby upon hydrolysis in the presence of a base, e.g. an alkali metal hydroxides, such as sodium or potassium hydroxide, or an acid, e.g. a mineral acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, to give compounds of formula I having a free carboxy group R.

When the hydrolysis of a cyan starting material of formula II is carried out under particular, e.g. milder, conditions and in particular carried out in the presence of hydrogen peroxide, then one arrives by addition of water (hydration) to compounds of formula I with carbamoyl as group R. The reaction with hydrogen peroxide, which is usually present in excess, in the presence of a base, such as an alkali metal, eg 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 for example in the form of

'· -'

Polyphosphoric acid), or a Lewis acid, e.g. Boron trifluoride, optionally in an aqueous or anhydrous medium (e.g., hydrochloric acid in glacial acetic acid). Instead of hydrogen peroxide, it is also possible to use the complex of the cyan starting material of the formula II with a boron trihalide, in particular boron trihalide.

; ': ' *. 13 - · · ..; . · ^{; -::}

trichloride, which can be hydrolytically converted, using formic acid, the cyan starting material of formula II, 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, treat and thus GE compounds of the formula I, where R is carbamoyl.

A cyan starting material of formula II may also be obtained by treatment with an alkali metal, e.g. Potassium hydroxide, preferably in solid form, in a hydroxy-containing solvent, such as a suitable lower alkanol, e.g. tert-butanol, and with heating in 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 j into a compound of formula I with a corresponding to the alcohol, for example, by lower alkyl, N-substituted Carbamoy! get group.

By treating a starting material of formula II, wherein R is cyano, 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 can be obtained under suitable conditions to give compounds of formula I, wherein R is an esterified carboxy group; In this case, one of the abovementioned Carboximidatausgangsstoffe of formula II is formed as an intermediate, wherein R is an O-substituted, in particular a 0-lower alkylated

Formimidoylgruppe stands.

Further, by treating a compound of formula II wherein R is the acyl radical of an organic carboxylic acid, e.g. for lower alkanoyl, such as acetyl, with. Ammonia in the presence of an acidic reagent, e.g. Sulfuric acid or polyphosphoric acid, to give compounds of formula I wherein R is a corresponding N-substituted, e.g. Represents N-alkyl, such as N-methyl-carbamoyl.

In a starting material of the formula II, the radical R can also be used for

a metallic group and e.g. 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, wherein R is carboxy.

The above-mentioned reactions for the conversion of a radical R in an aldehyde material of the formula II into an optionally esterified or amidated carboxy group R can be carried out in the presence or absence of solvents, with a suitable reagent also serving as a solvent at the same time, as well as suitable condensing agents and catalysts can be carried out, depending on the choice of starting material and the other reactants with cooling or .Warming, if necessary, in a closed system, if necessary, under pressure and / or in an inert gas atmosphere.

The starting materials of the formula II are known or can in in; be prepared in a known manner. So you can, for example, obtained according to the process described under (b), if one uses a Ausgapgsmaterial.der formula III, wherein R is represented by a radical Λ ~ - R or another, can be converted into these convertible radical, and the latter then in a conventional manner in this , Furthermore, in a starting material of the formula II in which R

represents a substituent replaceable by this radical, a

replaced by such radical R. Thus, e.g. a connection ...' '. '°. · '

of formula II, wherein R represents a halogen atom, such as bromine, with an alkali metal, e.g. Potassium, or a heavy metal, e.g. Cuprous cyanide, in a suitable solvent such as an amide-type solvent, e.g. Dimethylformamide, N-methyl-pyrrolidin-2-one or hexamethylphosphoric triamide, are reacted to give starting materials of formula II wherein R is cyano. Further

can be converted in the starting materials of formula II radicals R in a conventional manner into other groups R: so may

..,. _"; O ''.

one e.g. 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 compound of the formula II (R is lower alkanoyl,

for example, acetyl), for example, by treatment with Araruoniumpolysulfid or sulfur in the presence of an amine, especially an N, N-disubstituted amine, such as Ν, Ν-lower alkyleneamine, wherein the lower alkylene chain may optionally be interrupted by a heteroatom, in particular an oxygen atom, and in the first place of morpholine at elevated ^temperature: door, into a corresponding O-substituted Carboximidat- or thiocarbamoyl compound of the formula II (R is 0-substituted formimidoyl or thiocarbamoyl) transform.

In a starting material of the formula ItI, a reactive esterified hydroxy group X or X is in particular a hydroxy group esterified with a strong mineral or organic sulfonic acid and is, for example, halogen, such as chlorine or bromine, or organic sulfonyloxy, such as lower alkanesulfonyloxy, eg methanesulfonyloxy, or arenesulfonyloxy , eg p-toluenesulfonyloxy. The ring closure according to the invention can be carried out in the presence or absence of a solvent or solvent mixture, and / or a co-condensation agent; such as a suitable acid-binding agent, eg, a corresponding inorganic base, such as an alkali metal, eg, sodium hydroxide, or organic base, such as a tertiary amine, such as triethylamine, or a heteroaromatic base, eg pyridine, and also an excess of a compound of the formula H. _? NR (V) are performed. This can be carried out under cooling or heating, in a closed vessel optionally under pressure and / or under a

Inertgasatmosphäre work. -

  '' '·

The starting material of the formula III can be prepared in a manner known per se, it being possible to convert it directly into the desired compound of the formula I under the reaction conditions.

So you can, for example a compound of the formula

a D

5]

i 5 ·] f- * _a .civ)

in which R, for the group R, a radical R or a radical R in this

   '. a: - o is a feasible group, and each of the radicals "X and X, for water

 · '· 1. . ; , a D

* - '.' by treating with an N-halo-amide, in particular N-bromo-succinimide, into a compound of the formula IV in which W rin.X and X ^ are halogen, especially bromine (compound IVa). This can, for. by treating with a suitable cyano acid salt, such as an ammonium cyanide or an alkali metal, e.g. Natriunr-

; '' Or potassium cyanide are converted into a compound of formula IV, wherein X and X are cyano (compound IVb). In this, the cyano groups, e.g. by treating with an alcohol such as a lower alkanol, e.g. Methanol or ethanol, in the presence. , an acid, such as hydrochloric acid, into esterified carboxy, such as lower alkoxycarbonyl groups, e.g. Methoxycarbonyl or ethoxycarbonyl, and these by reduction, i. by treating one

Compound of the formula IV in which X and X represent esterified carboxy

·. '..... a b.

groups (compound IVc), eg with a light metal hydride ;, ^: ; such as lithium aluminum hydride, optionally in the presence of aluminum chloride, are converted into carbinol groups (compounds of formula IV wherein X and X are hydroxymethyl, compounds IVd).

  ι. b

In a compound IVd, the hydroxy groups can be converted, for example by treatment with a suitable acid halide, such as thionyl chloride or an organic sulfonic acid chloride, into reactive esterified hydroxy groups, for example halogen or organic sulphonyloxy (compounds of the formula IV in which X and X. X, are reactive esterified hydroxymethyl; compounds IVe). At any stage of the production of a ¹ intermediate of the

Formula IVa or IVe may be a radical R, optionally after it has

.. '. '-.'.-''."' ο ·.;.;.". \

a group convertible into it, in a manner known per se, e.g. according to one, in connection with the procedure. Rea (a) reactions are converted into the desired group R. A compound of the formula IVa or IVe can then be reacted with an amine of the formula H_N-R. (V), if appropriate in the presence of an acid-binding agent, such as one of the abovementioned bases, to obtain a starting material of the formula III, which, without being isolated, under the reaction conditions, if appropriate ring close and directly into the desired compound of formula ί can be converted.

, ' ' Λ, .. · '·. '.. "' .- .- ''''''"

Compounds of the formula I which can be obtained according to the invention can be converted in a manner known per se into other compounds of the formula I; be guided. Thus, in compounds of the formula I in which R is an esterified or amidated carboxy group, such a group R can be obtained, for example, by hydrolysis, for example in the presence of a basic agent, such as an inorganic base, for example an alkali metal or alkaline earth metal, eg. , Potassium or calcium hydroxide, or an acidic agent, such as a mineral acid, into a free carboxy group R transfer. , , / _; ,

Further, compounds of formula I wherein R. represents a carboxy group, e.g. by treatment with an alcohol, such as a nickel, alkanol, in the presence of a suitable esterifying agent, such as an acidic reagent, e.g. an inorganic or organic acid, such as hydrochloric, trifluoroacetic or p-toluenesulfonic

'.'. ' '. , , ... ·: ''. , '''":.''".'' - acid, or a 'Lewis acid, for example zinc chloride, or a water.

binding condensing agent, e.g. a carbodiimide, such as N, N'-dicyclohexylcarbodiimide, or by treatment with its own diazo reagent, such as a diazo-lower alkane, e.g. Diazomethane, in compounds of

Convert formula I, wherein R is an esterified carboxy group. This can also be obtained by reacting compounds of the formula I in which R is a carboxy group in free form or in salt, such as'; Ammonium or metal, eg. Alkali metal, such as sodium or potassium salt form, with a reactive ester of an alcohol, such as lower alkyl halide, ₍ eg methyl or ethyl chloride, bromide or iodide, or an organic sulfonic acid ester, such as an organic sulfonic acid ester, as a corresponding Niederalky! ester, for example, methanesulfonic or p-toluenesulfonic acid methyl ester or ethyl ester, treated.

Compounds of formula I in which is pure esterified carboxy group can be obtained by transesterification, e.g. by treatment with an alcohol, usually higher than that of the esterified carboxy group in the starting material, in the presence of a suitable transesterifying agent, such as a basic agent, e.g. an alkali metal lower alkanoate, lower alkoxide or cyanide, such as sodium acetate, methoxide, ethylate, tert-butoxide or cyanide, or a suitable acidic agent, optionally with removal of the resulting alcohol, e.g. by distillation, into other ester compounds of formula I. It is also possible to start with so-called activated esters of the formula I in which R represents an activated esterified carboxy group (see below) and convert this to another ester by treatment with an alcohol such as a lower alkanol. ·!. · .. '

The preferred amide compounds of the formula I in which R is an amidated carboxy group can advantageously also be obtained from the corresponding acid and ester compounds of the formula I in which R is an optionally esterified carboxy group. So you can, for example Compounds of formula I having a free carboxyl group R with urea at elevated temperatures, e.g. at

2QO - 240 °, with a 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'-dihexylcarbodiimide, furthermore a phosphine, such as triphenylphosphine (eg together with bis-2-pyridyl disulphide), or a silane, such as trichlorosilane (eg together with pyridine), and the corresponding amide compounds of the formula I, wherein R represents an amidated carboxy group. They may also be obtained from compounds of formula I wherein R is a carboxy group in salt form, e.g. by adding a corresponding ammonium salt, e.g. by treatment with a dehydrating agent such as phosphorus pentoxide, dehydrated, or a corresponding alkali metal, e.g. Sodium salt with an amine, preferably in the presence of a suitable condensing agent, such as tPhenylphosphonsäuredichlorid reacted.

Compounds of the formula I in which R is a carboxyl group _; also first in a reactive derivative such as an anhydride , including a mixed anhydride such as an acid halide, eg. chloride (for example by treating the acid compound of the formula I in which R is carboxy with a thionyl halide, for example chloride), or an anhydride with a formic acid ester, for example lower alkyl ester (for example by treating a salt, such as an ammonium buffer Alkali metal salt, the acid compound of formula I, wherein R is carboxy, with a halogen, such as chloroformic ¹ -., Ester, such as -lower alkyl ester), or in an activated ester, such as a cyanomethyl, nitrophenyl, eg 4-nitro and PbIyhalogenphenyl-, for example, Pentachlorphenylester (eg, by treating a compound of formula I, wherein R is carboxy, with ^{s of} a corresponding hydroxy compound in the presence of a suitable Kondensatiönsmittels, such as NjN'-dicyclohexyl-carbodiimide), and a such reactive derivative then with ammonia (according to

    - 20 -. , , ./ .. ..:;

if appropriate in derivatized form) or an amine and to obtain ₁ amide compounds of the formula I, where R is an amidated carboxy group. These can be obtained directly, or ^: via intermediate compounds; Thus, for example, an activated ester such as a 4-nitrophenyl ester, a compound of formula I with a carboxy group R first with an l.-unsubstituted imidazole and bring the resulting 1-Imidazolylcarbonylverbindung with the ammonia or the amine in reaction. It is also possible to react other non-activated esters, such as lower alkyl esters of compounds of the formula I in which R is, for example, lower alkoxycarbonyl, with ammonia or amines and thus form compounds of the formula I with amidated carboxy groups R.

The compounds of the formula I which are preferred according to the invention, in which R represents an amidated carboxy group, can therefore be prepared by process variant (a) by reacting in a compound of the formula II in which R is an acyl group other than an amidated carboxy group R, in particular one of an amidated carboxy group R is different, optionally functionally modified carboxy group, the radical R converted into the group R. In this case, the acyl group may be nitrogen-free or nitrogen-containing, and the preferred, optionally functionally modified carboxy group R is either a nitrogen-free, optionally functionally modified, or a nitrogen-containing, functionally modified carboxy group. In general, the compounds of the formula I with an amidated carboxy group R by solvolysis of these starting materials of formula II, those with a nitrogen-free, optionally functionally modified carboxy group preferably by means of one of the above-described ammonoiytischen or aminolytic and those with a nitrogen-containing, functionally modified carboxy group by means of one of the hydrolytic process ,

- 21 - - '·'

In compounds of formula I wherein R is an unsubstituted or N-monosubstituted carbamoyl group R, such may be substituted, e.g. by treating with a reactive ester of an alcohol: such as a lower alkanol, e.g. with a corresponding halide or a corresponding organic Λ sulfonyloxy compound, such as lower alkyl halide, e.g. chloride, bromide or iodide, or lower alkane or ethene sulfonic acid lower alkyl ester, preferably in the presence of a basic: agent such as an alkali metal, e.g. Sodium or potassium hydroxide is worked. Care must be taken to ensure that a

\. , ,

ternization of the ring nitrogen atom is avoided. .

Depending on the reaction conditions, the compounds of the formula I can be obtained in free form or in the form of salts.

Salts obtainable in accordance with the invention can be converted in a manner known per se into the free compounds, acid addition salts, for example by treatment with a base, such as an alkali metal hydroxide, salts with : bases, for example by treatment with an acid, such as a mineral acid. Salts, in particular Säureadditionssal'ze for example, can be prepared by treatment with suitable derivatives, for example inorganic, African salts of acids ₁ may be converted to other salts. _:

Free compounds can, for example, by treatment with acids or corresponding anion exchangers, or free compounds of formula I, wherein R is carboxyl _; eg by treating with. suitable bases are converted into their salts.

As a result of the close relationship between the compounds of the formula I in free form and in the form of salts, in the preceding and following among the free compounds or their salts, appropriate and appropriate, if appropriate, to understand the corresponding salts or free compounds.

The compounds, including their salts, may also be obtained in the form of their hydrates, or their crystal forms may be e.g. Include the solvent used for crystallization. '

Depending on the substitution, the compounds of formula I may also be in the form of isomers, e.g. of racemates or optical antipodes.

Racemates can be resolved into the optical antipodes by methods known per se, for example by recrystallization from an optically active solvent, with the aid of suitable microorganisms or by reacting a compound of the formula I with an optically active, salt-forming agent, such as an optically active acid, and separating the thus obtained mixtures of salts, eg due to their different solubilities, to the diastereoric salts from which the antipodes, e.g. by treatment with a base, can be released.

Advantageously, e.g. from a racemate the pharmacologically active antipodes.

The invention also relates to those embodiments of the process according to which one starts from an intermediate compound obtainable at any stage of the process and carries out the missing steps or a starting material in the form of a derivative, e.g. Salt, and / or its racemates or antipodes used κ or forms under the reaction conditions.

In the methods of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. New starting materials and processes for their preparation also form an object of the present invention.

The invention also relates to the use of the compounds

of formula I or of pharmaceutically acceptable salts of such compounds, especially as pharmacologically, primarily as neuroleptic usable compounds. They may be used, preferably in the form of pharmaceutical preparations, in a method for the prophylactic and / or therapeutic treatment of the animal or human body, in particular for the treatment of e.g. of schizophrenia and other related disorders. -

The dosage of the active ingredient administered alone or together with the usual carrier and adjunct material will depend on the species to be treated, its age and individual condition, as well as the mode of administration. The daily doses are for mammals with a body weight of about 70 kg, depending on the nature of the disease, individual condition and age, preferably between about 20 and about 300 mg. '';

The invention further relates to pharmaceutical preparations which contain compounds of the formula I or pharmaceutically acceptable salts of such compounds as active ingredients, and to processes

, , , - s

their production. ^

The pharmaceutical preparations according to the invention are those for enteral, such as peroral or rectal administration, for sublingual administration and for parenteral administration to warm-blooded animals. Corresponding dosage forms, in particular for peroral and / or sublingual administration, e.g. Dragees, tablets or capsules preferably contain from about 10 to about 100 mg, more preferably from about 20 to about 250 mg of a compound of formula I or a pharmaceutically acceptable salt thereof together with pharmaceutically acceptable excipients.

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or

- 24 - '·. / .. '.

Calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, furthermore binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or, if desired, disintegrating agents, such as the abovementioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone , Agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores may be provided with suitable, optionally gastric juice-resistant coatings, which include, inter alia, concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the preparation of gastric juice resistants, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, eg for identification or for labeling different doses of active substance. ι ,

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The stick capsules may contain the active ingredient e.g. in the form of granules, e.g. in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or Magnesiumsetearat, and optionally of stabilizers. In soft capsules, the active ingredient is preferred

in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, dissolved or suspended, wherein stabilizers may also be added.

Suitable rectally applicable pharmaceutical preparations are suppositories which consist of a combination of the active ingredient and a suppository base. Suitable suppository bases are ζ · Β. natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkenols. It is also possible to use gelatin rectal capsules which contain a combination of the active substance with a basic mass. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, eg a water-soluble salt, furthermore suspensions of the active ingredient, such as corresponding oily injection suspensions, are suitable, whereby suitable lipophilic solvents or vehicles, such as fatty olefins, are used. Β · _f sesame oil, or synthetic fatty acid ester, · ζ · Β ethyl oleate, or triglycerides, or aqueous injection suspensions that contain viscosity-increasing substances, z * B · sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers ·

The pharmaceutical preparations of the present invention can be prepared in a manner known per se, for example by means of conventional mixing, granulation, coating, solution or lyophilization processes. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, processed into tablets or dragee cores ·

- 25a Ausführiingsbei game

The following examples illustrate the invention described above, but do not limit its scope in any way. Temperatures are given in degrees centigrade.

Example 1: 38.7 g of the methylsulphonic acid salt of 5-cyiin-2-met-ethyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole are added Stir in 250 ml of 85% sulfuric acid at room temperature and then further stirred for 2 hours, with a complete solution is achieved. The reaction mixture is allowed to stand at room temperature for 7 days, then it is carefully added dropwise with stirring to a mixture of 800 ml of a 25% strength aqueous ammonia solution, ice. and about 1000 ml of ethyl acetate; by adding ice, the temperature is kept below 30 °. Then the. separated organic phase, washed with water, dried over sodium sulfate and concentrated to a small volume, the 2-methyl-2,3-dihydrolH-dibenz [2,3: 6,7] thiepino [4,5-c] pyrrole 5-caryboxamide, crystallized; Mp 170-174 °.

A solution of 15.5 g of the product in 750 ml of acetone is added with stirring 4.8 g of pure methanesulfonic acid, whereupon the. Methanesulfonic acid salt of 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole-5-carboxamide crystallized out; Smp * 220-223 °.

The starting material may e.g. according to the method described in European Patent Application 79102146.2 (Publ. No. 7450).

Analogously to the above process, the following compounds can be prepared using the appropriate starting materials:

2- (cyclopentylmethyl) -2,3-d ihydro-1H-dibenz [2,3: 5,7] thie? ino [4,5-c] pyrrole-5-carboxaraid (amorphous crude product) whose methanesulfonic acid salt melts after recrystallization from methanol at 248-251 °: from 45.5 g of the methanesulfonic acid salt of 5-cyano-2- (cyclopentyl)

     - 27 -. , , :

methyl) -2,3-d ihydro-1H-dibenz [2,3: 6,7] thiepino [4,5-c] pyrrole, e.g. can be prepared according to the method described in European Patent Application 79102146.2 (Publication No. 7450), in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution;

2-methyl-2,3-dihydro-1H-dibenzene2,3: 6,7] oxepinot4,5-c] pyrro1-5-carboxamide, m.p. 218 ° after recrystallization from acetone; from 32.9 g of the hydrochloride of 5-cyano-2-methyl-2,3-dihydro-1H-dibenzo [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 are treated with 12.5 ml of a 4N solution of hydrogen chloride in absolute ethanol, whereupon the hydrochloride of 2-methyl-2,3-dihydrolH-dibenzo [ 2,3: 6,7] oxepino [4,5-c] pyrrole-5-carboxamide crystallized out; Mp. 291-293 °. The starting material can be obtained, for example, by treating 40.5 g of 2-cyano-10, 11-bis (bromomethyl) -dibenzo [b, f] oxepine with 62 g of methylamine in 500 ml of methanol. the 5-cyano-2-methyl-2,3-dihydro-1H-dibenz [2,3: 6, 7] oxepino [4,5-c! pyrrole melts after -. ''' Crystallization from acetonitrile at 136-138 °, and its methanesulfonic acid salt after crystallization from absolute ethanol at 220-223 °;

2-ethyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-c] pyrro1-5-carboxamide, mp 205-210 ° after recrystallization from ethyl acetate; from 38.4 g of the methanesulfonic acid salt of 2-ethyl-5-cyano-2,3-dihydrol-1-dibenzo [2,3: 6,7] oxepino [4,5-c] pyrrole, e.g. can be prepared according to the method described in European Patent Application 79102146.2 (Publ. No. 7450), in 250 ml of 85% sulfuric acid and 800 ml of a 25% aqueous ammonia solution; the hydrochloride of the product melts after recrystallization from absolute ethanol at 215-220 °; and .

2-n-Propyl-2,3-d-hydro-1H-dibenzo [2,3: 6,7] thiepino [4,5,1-c] pyrro1-5-ca'fboxamide, m.p. 120 ° -125 ° after crystallization from ethyl acetate; from 41.4 g of the methanesulfonic acid salt of 2-n-propyl-5-cyano-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole in 250 ml 85% iger sulfuric acid and 800 ml of a 25% aqueous ammonia solution; The Methansulfonsäuresalz the product melts after crystallization from absolute ethanol to 252 - 255 °. The starting material may e.g. according to which in the European patent application. 79102146.2 (Publication No. 7450).

Example 2: 41.5 g of the methanesulfonic acid salt of 7-cyan-3-methyl-2,3,4,5-tetrahydro-1H-dibenz [2,3: 6,7] thiepino [4,5-d] azepine added with stirring in 250 ml of 85% sulfuric acid at room temperature and then further stirred for 10 hours, the starting material is completely dissolved. The reaction mixture is allowed to stand for 7 days at room temperature and then added dropwise with stirring carefully into a mixture of 800 ml of a 25% aqueous ammonia solution, ice and about 1000 ml of ethyl acetate; by adding ice, the temperature is kept below 30 °. The organic phase is then separated, washed with water, dried over sodium sulfate and concentrated to a small volume to give the 3-methyl-2,3,4,5-tetrahydro-lH-dibenz [2,3: 6,7] thiepino [4,5-d] azepine-7-carboxamide crystallized out; Mp. 147 -

A solution of 16.8 g of the product in a mixture of 200 ml of acetone and 40 ml of absolute ethanol is treated with 4.8 g of pure methanesulfonic acid, whereupon the Methansulfonsäuresatz of 3-methyl-2,3,4,5-tetrahydro-lH dibenz [2,3: 6,7] thiepino [4,5-d] azepine-7-carboxamide crystallized out; Mp 220-223 °.

- 29 -

The starting material may e.g. are prepared according to the method described in German Patent Application P 27 23 105.6.

Analogously to the process described above, the following compounds can be prepared using the appropriate starting materials:

3-methyl-2,3,4,5-tetrahydro-lH-dibenz [2,3: 6,7] oxepino [4,5-d] azepin-7 - '·.

carboxamide, m.p. 260-264 ° after crystallization from chloroform; from 39.9 g of the methanesulfonic acid salt of 7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine in 250 ml 85% iger 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 is added with stirring with a 'solution of 4.5 g of anhydrous oxalic acid in 30 ml of absolute ethanol, whereupon the oxalic acid crystallized; Mp 240-242 °. The starting material may be e.g. according to the European patent application 8O81O377.4 (Publication no. 30916) are prepared;

3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-lH-dibenz [2,3: 6,7] oxepino

  ''. '. ·.

[4,5-d] azepine-7-carboxamide, m.p. 110-116 ° 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-joxepino [4,5-d] azepine in 250 ml 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 °. The starting material may e.g. also be prepared in the European patent application 8Ö81O377.4 (Publication no. 30916); and

3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-lH-dibenz [2,3: 6,7] thiepino

^ 4 _v , 5 ~ d- / öaepiii - T "-oxa-oxaiaide (amorphous crude product) j from 48.3 g of the methanesulfonic acid salt of 7-cyano-3- (cyclopentylmethyl) -2,3» 4,5-tetrahydro-IH dibenz ^ * 2,3: 6,7_7-thiepinoZ74,5-d_7azepine 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 are combined with 12.times.5 ml of a 4N solution of hydrogen chloride in absolute ethanol, whereupon the hydrochloride crystallizes out, mp 228-232.degree .. The starting material can, for example, be prepared according to the procedure described in CH-PS 624 105 described methods are prepared ·

Example 3: 38.7 g of the ΜβΐΙΐοηΒμΙίοηΒαΛίΓβθαΙζβθ of 5-cyano-2-methyl-2,3-dihydro-1H-dibenzZr2,3: 6,7J ^ thiepino "4,5-c_7-pyrrole are added with stirring in a mixture The solution is saturated at -10 ° to -20 ° with dry hydrogen chloride and then further stirred for 20 hours at 0 to 5 ° C. Then allowed to flow into 700 ml of ice water and heated for 1 hour at 70-75 ° C. After cooling, the aqueous phase is separated off and made alkaline with a concentrated aqueous ammonia solution. The 2-methyl-2,3-dihydro-1H-dibenzel which is precipitated as OeI ['. 7_7-thiepinoZ74i5-c_7pyrrol-5-carboxylic acid methyl ester is extracted with ethyl ether, and the organic extract is washed with water and, after drying over sodium sulfate, evaporated under reduced pressure. A solution of .16.2 g of the crude product in 100 ml of acetone is 5 ml of its own 4-n solution of C hydrochloric acid in absolute ethanol, whereupon the hydrochloride crystallizes, which melts after recrystallization from absolute ethanol at 247-249 °.

- 31 -. .

Analogously to the process described above, the following compounds can be prepared using the appropriate starting materials:

3- (Cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2, J: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid methyl ester, m.p. 148-149 ° after crystallization from ethyl acetate; from 46.7 g of the methanesulfonic acid salt of 7-cyano-3- (cyclopentylniethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-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 after a short time the methanesulfonic acid salt of 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro -lH-dibenz [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid methyl ester. ' , crystallized, mp 229-231 °;

Methyl 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylate, m.p. 130-131 ° after crystallization from acetone ; from 39.9 g of the methanesulfonic acid salt of 7-cyano-3-methyl-r 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine in 310 ml of toluene and 160 ml of methanol and dry hydrogen chloride; the Methansulfonsäuresalz melts after crystallization from absolute ethanol at 230-233 °; and '

3-Methy1-2,3,4,5-tetrahydro-lH-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-7-carboxylic acid methyl ester, mp. 133-134 ° after crystallization from diethyl ether ; from 41.5 g of the methanesulfonic acid salt of 7-cyano-3-methyl-1,2,3,4,5-tetrahydro-1H-dibenz [2 •, 3: 6, 7] thiepino [4,5-d] azepine 310 ml of toluene and 160 ml of methanol and dry hydrogen chloride; the Methansulfonsäuresalz melts after crystallization from absolute ethanol at 224-225 °.

Example 4: 40.4 g of methyl 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepine [4,5-d] azepine-7-carboxylate with a solution of 7 g of sodium hydroxide in 150 ml of 70% aqueous ethanol with stirring for 1 hour at reflux. Subsequently, the hot reaction mixture is diluted with 450 ml of distilled water and treated with 300 ml of 10% methanesulfonic acid; the resulting precipitate is dissolved by heating to 80-90 ° again. By addition of concentrated aqueous ammonia solution to pH 8-9, the S-CCyclopentylmethylJ-ZjS ^ .S-tetrahydro-lH-dibenz [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid precipitates which off. sucked and washed with water and ethanol, mp 260-262 ° after drying under reduced pressure at 100 °; the methanesulfonic acid salt melts at about 215 ° (with decomposition).

In an analogous manner, the following compounds can be obtained when selecting the appropriate starting materials:

2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole-5-carboxylic acid, m.p. 194-198 °; from 32 _; 3 g of 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrro1 -5-carboxylic acid methyl ester and 7 g of sodium hydroxide in 150 ml of 70% aqueous ethanol;

3-methyl-2,3,3,5,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid, m.p. 280-288 °; from 33.5 g of 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid ester and 7 g of sodium hydroxide in 150 ml of 70 % aqueous ethanol; the methanesulfonic acid salt of the product melts upon crystallization from ethanol at 310-314 ° C; and

3-Methy1-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-7-carboxylic acid, m.p. about 295-305 ° (with decomposition ); from 35.1 g

^; '. - 33 -, - ...

3-Methyl-1,2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6 ', 7] thiepino [4,5-d] azepine-7-carboxylic acid methyl ester and 7 g sodium hydroxide in 150 ml 70% aqueous Aethanol; the Methansulfonsäuresalz the product melts after crystallization from a mixture of ethanol and diethyl ether at 200-203 °.

Example 5: A mixture of 38.9 g of 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7 carboxylic acid, 1200 ml of methylene chloride and 15.2 g of triethylamine is refluxed with stirring for 30 minutes, anschliessehd cooled to -10 ° and treated dropwise within 30 minutes with a solution of 16.3 g of ethyl chloroformate in 50 ml of methylene chloride. After completion of the addition, the clear reaction solution is allowed to stir for an hour at -10 to 0 ° and then added dropwise at this temperature, a solution of 6.8 g of dimethylamine in 50 ml of methylene chloride to; by stirring at room temperature for 2 hours

the reaction is completed. The reaction mixture is washed with water and 2-n. washed 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 to give the 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxep ino [4,5-d ] azepine-7-carboxylic acid-Ν, Ν-dimethyl-amide crystallized, which melts after drying under reduced pressure at 80 ° and then recrystallization from acetone at 142-144 °.

A solution of 20.8 g of the product in 200 ml of acetone is added under stirring with 4.8 g of pure methanesulfonic acid, whereupon the Methansulfonsäuresalz crystallized; Mp. 264-268 °.

Analogously to the process described above, the following compounds can be prepared using the appropriate starting materials:

- 34 -

3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid N-methylidene (amorphous); from 38.9. g 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid, 15.2 g of triethylamine and 16 , 3 g of ethyl chloroformate, then 4/7 g of methylamine, with methylene chloride as solvent; the Methansulfonsäuresäl.z the product melts after crystallization from methanol at 296-302 °;

3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine-7-carboxylic acid N, N-dimethylamide, m.p. 128 ° after crystallization from a mixture of diethyl ether and n-pentane; from 32.1 g of 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo2,3: 6,7] oxepino [4,5-d] azepine, 7-carboxylic acid, 15.2 g of triethylamine and 16.3 g of ethyl chloroformate, 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 °;

3-Methy1-2,3,4,5-tetrahydro-1H-dibenzo 2,3: 6,7] thiepino [4,5-d] azepine-7-carboxylic acid N, N-dimethylamide (amorphous); from 33.7 g of 3-methyl-2,3,3,5,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-7-carboxylic acid, 15.2 g of triethylamine and 16 _; 3 g of ethyl chloroformate, then 6 _; 8 g of dimethylamine with methylene chloride as solvent; the fumaric acid salt of the product melts upon crystallization from a mixture of absolute ethanol and acetone at 195-198 °;

3-methyl-7-pyrrolidinocarbonyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine (amorphous); from 33.7 g of 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-7-carboxylic acid, 15.2 g of triethylamine and 16.3 g of ethyl chloroformate, ethyl acetate, then 10.7 g of pyrrolidine, with methylene chloride as a solution. the fumaric acid salt of the product melts after crystallization C from a mixture of absolute ethanol and acetone at 188-190 °; '

- 35 -

2-> ethyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5- c] pyrrole-5-carboxylic acid N, N-dimethylamide (amorphous); from 30.1 g of 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole-5-carboxylic acid, 15.2 g of triethylamine and 16.3 g Ethyl chloroformate, then 6.8 g of dimethylamine, with methylene chloride as the solvent; the methanesulfonic acid salt of the product melts upon crystallization from absolute ethanol at 219-222 ° C; and ,

2-Methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] Jpyrro1-5-carboxylic acid N-methylamide, Srap. 170-175 ° after crystallization from absolute ethanol; from 30.1 g of 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole-7-carboxylic acid, 15.2 g of triethylamine and 16.3 g of ethyl chloroformate, then 4.7 g of methylamine, with methylene chloride as the solvent; the Methansulfonsäuresalz the product melts after crystallization from ethanol at 270-273 °.

Example 6 : 4.39 g of 10, 11-bis-bromomethyl-dibenz [b, f] thiepien-2-carboxamide are dissolved in 400 ml of absolute toluene at 80 ° and added within one hour at 43-45 ° to a solution of 155 g methylamine in 400 ml of methanol. During the addition of methylamine gas is additionally introduced. The reaction mixture is stirred for 1 hour at 50 ° and then distilled off the solvent and the excess methylamine. The residue is treated with water and the suspension obtained is extracted with methylene chloride. The organic phase is separated, washed with water, dried over potassium carbonate and evaporated. The residue is dissolved in 40 ml of acetone. On cooling, the 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino- [4,5c] pyrrole-5-carboxamide crystallizes and is filtered off with suction and dried. Mp 170-174 °.

: - 36 -

1.54 g of the base obtained are dissolved in 60 ml of acetone. Thereafter, 0.48 g Mefhansulfosäure be added. The crystallized Methansulfqnat is filtered off with suction and dried. Mp. 220-223 °.

The starting material can be prepared in the following way:

'29, 4 g of 2-cyano-10, ll-dimethyl-dibenz [b, f] thiepin be presented 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 under reflux for 1 hour. Then distilled on a rotary evaporator 200 ml of tert-butyl alcohol. 100 ml of ether and 800 ml of water are added to the residue with stirring. The precipitated 10, ll-dimethyl-dibenz [b, f] thiepin-2-carboxamide is filtered off, washed with water and recrystallized from 400 ml of absolute alcohol. Mp. 195-200 °.

2.81 g of 10,1-dimethyldibenz [b, f] thiepin-2-carboxamide are dissolved in 900 ml of carbon tetrachloride at 70 ° and then 3.63 g of N-bromosuccinimide are added. While stirring and exposing with a UV lamp, the mixture is refluxed for 10 minutes. The reaction mixture is cooled to 20 ° and filtered off with suction, the crystallized crude 10, H-bis-bromomethyl-dibenz [b, f] thiepin-2-carboxamide from. The above product is dissolved in chloroform, washed twice with 2N sodium hydroxide solution and then three times with water. After drying over sodium sulfate, the solution is concentrated to 30 ml, cooled and sucked

 Mp 202-204 °.

Example 7: Tablets containing 0.020 g of the methanesulfonic acid salt of 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyprole-5-carboxamide eg manufactured as follows:

- 37 -

Composition (for 10 000 tablets): 2-methyl-2,3-dihydro-1H-dibenzene. [2,3: 6,7] thiepino [4,5-c] azepine-5-carboxamide

methanesulfonic acid salt 200.00 g

Lactose. 290.80) g

Potato starch, 274.70 g

Stearic acid 10.00 g

Talc 200.00 g

Magnesium stearate 2.50 g

Colloidal Silica 32.00 g

Ethanol, q.s.

A mixture of the 2-methyl-2,3-dihydro-1H-dibenz [2,3: 6,7] thiepino- [4,5-c] pyrrole-5-carboxamide-methanesulfonic acid salt which becomes lactose and 194s7 g of potato starch moistened with 'an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and colloidal silica are mixed, and the mixture is compressed to 0.1 gram weight tablets, which may optionally be provided with partial grooves for finer dosage adjustment.

Example 8 ,: capsules containing 0.025 g of 2-methyl-2,3-dihydro-lH-Diben _Z [2,3: 6,7] thiepino _[4,5-C] pyrrole-5-carboxamide inethansulfonatsäuresalzes can be prepared as follows;

- 38 -

Composition (for 1 000 "capsules): 2-methyl-2,3-dihydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-c] pyrrole-5-carboxamide

methanesulfonic acid salt 25.00 g

Lactose, - 249.00 g

Gelatin 2.00 g

Corn starch. 10.00 g

Talc · 15.00 g

Water . q "s.

Mixing the 2-methyl-2,3-dihydro-lH ⁱ dibenz [2,3: 6,7] thiepino- [4I5-c] pyrrole-5-carboxamide methanesulfonic acid salt with the lactose, the mixture wetted evenly with an aqueous solution of gelatin and granulated through a sieve with a mesh size of 1.2-1.5 mm. The granules are mixed with the dried corn starch and talc and filled with portions of 300 mg into hard gelatine capsules (size 1).

Claims (7)

- 39 Invention claim 1 · Process for the preparation of compounds of the formula I j I v / \ A wherein R is an optionally esterified or amidated carboxy group, R is hydrogen or an optionally substituted aliphatic or .cycloaliphatischenaliphatisohen hydrocarbon radical, X epoxy or epithio, and η 1 or 2, characterized in that (a) in a compound of the formula (CH ₂ ) _n A / "\ A i »-t- * o or in a salt thereof converts R ₀ into the group R, - 40 - in which R represents a radical which can be converted into the optionally esterified or amidated carboxy group R, or
or (b) a compound of the formula T ¹ I ² (CHg) _n (CH _{2) n} (III) i ii i 4- ^R wherein one of the groups X- and Xg represents the radical of the formula -MH-R _1. (IIa) and the other represents a reactive esterified hydroxy group, and if desired converts an obtainable compound of the formula I into another compound of the formula I. , and / or, if desired, converting a salt obtained into the free compound or other salt, and / or, if desired, salifying a free compound obtained, and / or, if desired, adding a mixture of isomers to the resulting salt separates individual isomers « Method according to item 1, characterized in that one proceeds from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or forms a starting material under the reaction conditions, or   · - 41 -. · · · '. , , '. a reaction component optionally in the form of its derivatives, such as a salt. , 3 · Process according to item 1, characterized in that compounds of the formula I in which R is carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkyleneaminocarbonyl having 5 to 8 ring atoms, oxanoweralkyleneaminocarbonyl having 6 ring atoms, thia-lower alkylaminocarbonyl having 6 ring atoms or azanowercalkyleneaminocarbonyl having 6 optionally substituted by lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl or lower alkanoyloxy lower alkyl, wherein in such substituted lower alkyl groups a substituent is separated by at least 2 carbon atoms from the azachlorite atom, R 1 is hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkanoyloxy lower alkyl, lower haloalkyl , Lower alkenyl, lower alkynyl or cycloalkyl-lower alkyl, wherein in substituted lower alkyl radicals a substituent is preferably substituted by at least 2 carbon atoms of Ring nitrogen atom is separated, in unsaturated radicals the double or triple bond is present in a position higher than the 1-position, and cycloalkyl contains 3 to 8 ring atoms, where radicals denoted "lower" contain up to and including 7 carbon atoms, X is epoxy or epithio, and η is 1 or 2, and salts thereof, 4. The method according to item 1, characterized by reacting compounds of formula I, wherein R is carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkyl ^: .carbonyl, or Ni ede ralkylenamino carbonyl, wherein lower alkyl enamino contains 5 or 6 ring atoms, R _{1 is} hydrogen, lower alkyl, hydroxy lower alkyl or lower - 42 - alkoxy-lower alkyl in which hydroxy or lower-alkoxy is separated from the ring nitrogen atom by at least 2 carbon atoms, fiederalkenyl or lower-alkynyl in which the double or triple bond is in a position higher than the 1-position, or cycloalkyl-lower alkyl in which cycloalkyl contains from 3 to 8 ring carbon atoms, where radicals denoted "lower" contain up to and including 4 carbon atoms, X is epoxy or epithio, and η is 1 or 2, and salts thereof are prepared * 5 · Method according to item 1, characterized in that compounds of the formula (0H ₂ ) _n V / ··· ·
• · · · -R * I Il II Ia) v \ / v x wherein R ^{1 is} carboxy, mederalkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl or lower alkylene-aminocarbonyl, wherein lower alkyleneamino contains 5 or 6 ring atoms, R 1 is hydrogen, lower alkyl or cycloalkyl-lower alkyl, wherein cycloalkyl has 3 to 6 ring carbon atoms, wherein radicals designated "lower" containing up to and including 4 carbon atoms, X is epoxy or epithio, and η is 1 or 2, and salts are daron, A method according to item 1, characterized in that compounds of formula Ia of item 4 wherein R ^{1 is} carbamoyl, lower alkylcarbamoyl wherein lower alkyl has up to and including 4 carbon atoms, di-lower alkylcarbamoyl wherein lower alkyl has up to and including 4 carbon atoms, or alkyleneaminocarbonyl in which alkyleneamino contains 5 or 6 ring atoms, Ri denotes lower alkyl having up to and including 4 carbon atoms, or cycloalkyl-lower alkyl, wherein cycloalkyl has 3 to 6 ring carbon atoms, and lower alkyl has up to 4 carbon atoms, Σ represents epoxy or epithio, and η 1 or 2, and salts thereof, Process according to item 1, characterized in that 2-methyl-2,3-dihydro-IH-dibenzZT 2 »3: 6,7_7thiepino-Zr4,5-c_7pyrrol-5-carboxamide and salts thereof are prepared