CA1065871A

CA1065871A - Process for the production of oxygenated azatetracyclic compounds

Info

Publication number: CA1065871A
Application number: CA220,496A
Authority: CA
Inventors: Hans Blattner
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1974-02-22
Filing date: 1975-02-20
Publication date: 1979-11-06
Also published as: ES434955A1; IE40676L; IL46683A0; FR2261762A1; SE419991B; HU169669B; AU7840075A; DK66175A; JPS50117800A; CH592095A5; ATA132075A; NL7501974A; ZA751092B; SE7501012L; GB1499727A; CS187461B2; DE2506155A1; AT341529B; IL46683A; FR2261762B1

Abstract

ABSTRACT OF THE DISCLOSURE
Process for the production of azatetracyclic compounds of the formula

Description

This invention relates to new azatetracyclic compounds, par-ticularly ~o 5-hydroxy 2,3-dihydro-lH-dibenzo [2J3:6~7~(thiepino and oxe-pino)[4,5-c]pyrrole compounds, substituted in the l-position, of the ~;
formula Rl ~ :
/N\
H2 \ / H2 :' ~ ~ -OH

wherein X represents oxygen or sulphur and Rl stands for lower alkyl or lower alkenyl, and to pharmaceutically acceptable salts of such compounds, as well as to processes for the production thereof.
A lower alkyl group Rl has up to 7, preferably up to ~, carbon atoms and is, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, also straight-chain or oranched-chain pentyl, hexyl or -heptyl bound in any position. ~;
A lower alkenyl group Rl has up to 7, pre~erably up to 4, car-bon atoms and is, e.g., 2-lower-alkenyl such as allyl or methallyl.
5alts o~ compounds of formula I are, in particular, acid addition salts, especially pharmaceutically applicable nontoxic acid addi-tion salts, e.g. with inorganic acids such as hydrochloric acid, hydro-bromic acid, sulphuric acid or phosphoric acid, or with organic acids, such as organic carboxylic and sulphonic acids such as methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, acetic acid, malic . : i . .
acid, tartaric acid, citric acid, lactic acidJ oxalic acid, succinic acid, fumaric acid, maleic acidl benzoic acid, salicylic acid, phenylacetic acidJ mandelic acid or embonic acid.
The new compounds have valuable pharmacological properties, e.g.
properties affecting the central nervous system. They are characterised above all by their central-depressant action and agitation-inhibiting action (amphetamine-antagonistic), which can be demonstrated by pharmacological A `~ :

2 ~

.. . .

10~i5871 tests~ They thus exhibit in the amphetamine-antagonism test ~Niemegeers and Janssen, Arzneimittelforsch., Vol. 24, p. 45 (1974) on the rat an agi-tation-inhibiting action in a dosage range of 3 to 10 mg/kg subcutaneously, or 10 to 40 mg/kg orally. At the same time, in the catalepsy test on the rat (Wirth et al., Arch.Int.Pharmacodyn., Vol. 115, p. 1 (1958)), it is only with oral administration of doses as high as about 20 to 100 mg/kg that the new compounds show cataleptic efects; the relationship between cata-leptic (extrapyramidal) action and amphetamine-antagonistic action is there-fore favourable with respect to the agitation-inhibiting action. The new compounds can thus be used as tranquillising, antipsychotic and agitation-inhibiting compounds for the treatment of conditions of tension and agita-tion.
The invention relates Eore st to compounds of formula I wherein X stands for sulphur, as well as for oxygen, and Rl for lower alkyl having ~
up to 4 carbon atoms~ e.g. methyl or ethyl, as well as allyl; it relates : ;
especially to the compounds given in the examples, or salts thereof, par-ticularly acid addition salts, such as pharmaceutically applicable nontoxic acid addition salts thereof.
The new compounds can be produced in a manner known per se. They are obtained, for example, by a process in which a compound of the formula Xl X2 H2 l l H2 ~ (II), wherein Xl and X2 represent reactive esterified hydroxy groups, is reacted witll an amine of the formula Rl-N~2 (III) and,optionally, in a resulting compound of formula I, and/or, optionally, a resulting salt is converted into the free compound or into another salt, or a free compound obtained )~
~ ~ - 3 -is converted into a salt.

A reac~ive esterified hydroxy group Xl or X2 is a hydroxy group esterified with a strong acid of inorganic or organic character, such as a hydroxy group esterified with a mineral acid, e.g. a hydrohalic acid such as hydrochloric acid, hydrobromic acid or sulphuric acid, or with a strong organic sulphonic acid, e.g. an aliphatic or aromatic sulphonic acid such as methanesulphonic acid, p-toluenesulphonic acid, 4-bromobenzenesulphonic acid or 4-nitrobenzenesulphonic acid. Xl or X2 stands, in particular~ for halogen, especially ~or bromine; it can however also represent organic sulphonyloxy, e~g. p-toluenesulphonyloxy.

The reaction of the star~ing material of formula II
with the amine of formula III is usually performed in the presence of a basic agent, preferably an excess -of the amlne of formula III, but also in the presence of an additional inorganic or organic base, and preferably in the presence of a solvent or diluent, particularly one that is inert to the reactants under the reaction conditions, e.g. an aliphatic, cycloaliphatic or aromatic hydrocarbon such as benzene or toluene, a halogenated aliphatic, cycloaliphatic or aromatic hydrJcarbon such A
` Y

~ ~ ~ 5 ~7 ~

as chloroform, a lower alkanol such as methanol or ethanol, an ether such as diethyl ether or dioxane, a lower alkanone such as acetone, methyl ethyl ketone or diethyl ketone, or a nitrile such as acetonitrile, or a mixture of such solvents, especially a mixture of a lower alkanol and a hydrocarbon, e.g. ben~ene.
The reaction is perfor~ed if necessary with cooling or heating, e.g. in a temperature range of about -10C
to about ~50C, in a closed vessel and/or in an inert gas atmosphere, e.g. in a nitrogen atmosphere.
The starting materials of formula II can be produced in a manner known per se, e.g~ by a process in which a 2-(4-RA-phenyl-X-)-phenylacetic acid, wherein RA
denotes a suitably protected hydroxy group, e.g. a suitably esterified hydroxy group, such as one esterified by the acyl radical of a carbonic acid semi-ester, or an etherified hydroxy group, such as one e~herified by a lower alkyl radical or 2-oxocycloalkyl radical, is converted into an ester such as a lower alkyl ester, e.g.
methyl or ethyl es~er; and this is condensed, in the presence of an alkali metal such as sodium, with a di-lower alkyl carbonate, e.g. diethyl carbonate, to the di-ester of the corresponding 2-(4 RA-phenyl-X-)-phenyl-~, .. . . .. . .. . ... .
.
.
. .

':

;5137~

malonic acid This is methylated in the a-position in the usual manner, e.g. by treatment with a metallising reagent such as an alkali metal lower alkanolate, alkali metal amide or alkali metal hydride, and reaction with a reactive ester of methanol, such as with a methyl halide, e.g. methyl iodide. The malonic es~er compound is then converted, with simultaneous decarboxylation, into the corresponding 2-~4-RA-phenyl-X-)-hydratropic acid. This yields, with the action oI a suitable acid reagent such as hydrofluoric acid, an ll-methyl-10-oxo-10,11-dihydro-dibenzo[b,flthiepin or an ll-methyl-10-oxo-10,11-dihydro-dibenzo[b,f]oxeping which contains in the 8-position, depending on the meaning of the group RA
present in the starting material, the group RA or a hydroxy group liberated under the reaction conditions;
the last-mentioned is converted back, in a manner known per se, into a suitably protected hydroxy group RA. The keto compound obtained in this manner is subsequently treated with a suitable methyl Grignard's reagent such as methyl magnesium iodide; water is then split off from the resulting 8-RA-10,11-dimethyl-10-hydroxy-10,11-dihydro-dibenzolb,f]thiepin or -dibenzo[b,f]oxepin, e.g. by heating in the presence of aqueous mineral acid such as hydro-chloric or sulphuric acid; and the 8-RA-ll-methyl-10-_ ~ _ . .
._, , .

.

:

8t~

methylene-10,11-dihydro-dibenzo~b,f]thiepin compound or -dibenzo[b,f]oxepin compound obtainable as the main product is converted, e.g. by treatment with a suitable base such as an alkali metal hydroxide, e.g. potassium hydroxide, in the presence ~f a lower alkanol, e.g.
ethanol, to the corresponding 8-RA-10,11-dimethyl-dibenzo[b,f]thiepin or -dibenzo[b,~]oxepin. The methyl groups in this are converted into the reactive esterified hydroxymethyl groups of the formula Xl-CH2- or X2-CHz-, e.g. by treatment with a positive halogen-releasing agent such as an N-halogen-imide, e.g. bromosuccinimide. In an 8-RA-lO,ll-bis-halomethyl-dibenzoIb,f]~hiepin or -dibenzo[b,f]oxepin ob~ainable in this manner, halogen, especially bromine, can be converted in a manner known per se, e.g. with formation and subsequent esterifying of hydroxyl groups, into another reactive esterified hydroxy; furthermore, the protected hydroxy group RA can be converted in a manner known per se, e.g. as described below, at this preliminary stage or at some other suitable one, into the group R.
- The new compounds can be obtained also by substituting in a compound of the formula i87:1L
H

2 ~ 2 (I~) -the secondary amino group by the group Rl, and, optionally, carrying out the additional stages of ~he process.
.. . .
The substitution o~ the N-unswbstituted star~ing material of formula IV is performed in a manner Icnown per se, e.g. by treatment with a reactive ester of a lower alkanol or lower alkenol, wherein the esterified hydroxy group has, e.g., the above given meaning, and stands, in particular~ for halogen, e.g. chlorine, bromine or iodine, or organic sulphonyloxy, e.g. p-toluene-sulphonyloxy. The reaction is performed preferably in the presence of a suitable base such as a tertiary amine, e.g. in the presence of a preferably sterically hindered tri-lower-alkylamine, such as ethyl-diisopropylamine ~Hunig base). A methyl group Rl can be introduced also by reaction with formaldeIlyde in the presence of formic acid.
The above reaction is performed, depending on the employed reagent, in the presence of a solvent or diluent and, if necessary, with cooling or heating, in a closed vessel and/or under an inert gas, e.g. in a nitrogen .

-, , . , . ,......... , . . .: . . .
- .. . . .... ~

- - , ' - ' ~ '',:. " ' ' . , ~ 06 ~'7 atmosphere.
The starting material of formula IV can be produced in a manner known per se, e.g. by reaction of a compound of formula II with an excess of ammonia. Furthermore, in a 2-(2-lower alkenyl)-, especially 2-allyl-5-R-2,3-dihydro-lH-dibenzoE2,3:6,7]thiepino[4,5-c]pyrrole or -dibenæol2,3:6,7]oxepino[4,5-c]pyrrole, the N-2-lower-alkenyl substituent, particularly the N-allyl substituent, can be replaced by an acyl group that can be split off, especially by a lower alkoxycarbonyl group, e.g. ethoxy-carbonyl group, e.g. by treatment with a suitable acid halide, such as with a haloformic acid lower alkyl ester, e.g. chloroformic acid ethyl ester. In the thus obtainable 2-acyl-, such as 2-lower-alkoxy-carbonyl-, e g. 2-ethoxy-carbonyl-5-R-2,3-dihydro-lH-dibenzo[2,3:6,7~thiepino 14,5-clpyrrole compound or -dibenzo[2,3:6,7]oxepino[4,5-c]
pyrrole compound, the acyl group, such as the lower alkoxy carbonyl group, e.g. ethoxycarbonyl group, is split off hydrolytically, e.g. by treatment with a suitable aqueous acid or basic agent such as aqueous hydrobromic acid or aqueous-ethanolic potassium hydroxide; or alcoholytically, e.g. by treat~ent with a lower alkanol such as ethanol, in the presence of an alkali metal hydroxide, e.gO potassium hydroxide, and thus replaced by hydrogen.
q - . ~ .

' -. . ~ . , , ~ .
- ,~

~i5~
The new compounds of formula I can be produced also by a process in which, in a compound of the formula , 1 . ~ .
/N~
H C CH
2\ 1 2 (V) ~ ~ R

wherein Ro represents alkoxy or alkanoyloxy, the group Ro is converted into the free hydroxy group, and, optionally, the additional steps are carried out.
Such a group Ro can be converted into the free hydroxy group, in a manner known per se, such as by means of solvolysis, e.g. hydrolysis, al- ;
coholysis or acidolysis, or by means of reduction, e.g. hydrogenolytically, or by treatment with a chemical reagent, and also photolytically.
Such etherified alkoxy is especially methoxy, as well as ethoxy, n-propyloxy, isopropyloxy or n-butyloxy, also tert.-lower alkoxy such as tert.-butyloxy or tert.-pentyloxy.
R as alkanoyloxy is especially lower-alkanoyloxy such as acetyl-oxy, propionyloxy or pivaloyloxy.
The splitting off of a group Ro can be performed in a manner known per se3 usually by hydrolysis, if necessary in the presence of acid or basic agents, such as mineral acids, e.g. hydrochloric acid or hydrobromic acid ~whereby the last-mentioned arè suitable in particular for the splitting off of a lower-alkoxy group Ro, such as methoxy), or alkali metal hydroxides or alkali metal carbonates, e.g. sodium hydroxide or potassium hydroxide.
Certain suitable etherified or esterified hydroxy groups can be split off also by means of other methods; thus, e.g., tert.-lower-alkoxy- or tert.-lower-alkoxycarbonyloxy, or diphenyl-methoxycarbonyloxy optionally containing lower alkoxy, by acidolysis (e.g. by treatment of the corresponding 5137~

starting material with a suitable protonic, at most slightly nucleophilic, strong organic carboxylic or sulphonic acid, e.g. formic acid or trifluoroacetic acid), optionally substituted a-phenyl-lower-alkoxy or a-phenyl-lower-alkoxycarbonyloxy by hydrogenolysis ~e.g. by treatment of the corresponding starting material with hydrogen in the presence o a metal catalyst suitable for hydrogenation purposes, such as palladium), 2-nitro-4,5-dimethoxy-benzyloxycarbonyloxy photolytically (e.g~
by irradiation of the corresponding starting material with ultraviolet light, e.g. of a wave-length of above 290 mm), or benzoylmethoxycarbonyloxy optionally containing halogen or 2-halo-lower-alkoxycarbonyloxy by treatment with a chemical reducing agent (i.e. by means of nascent hydrogen, e.g. by treatment of the corresponding starting material with a suitable metal, e.g. zinc, or with a suitable metal salt, e.g. chromium-II-chloride, in the presence of of a hydrogen donor, eOgO aqueous acetic acid, whereby, e.g., a 2-bromoethoxycarbonyloxy is converted, before the treatment with the chemical reducing agent, advantageously, e.g., by treatment with a suitable iodine salt, such as sodium iodide, into the 2-iodoethoxycarbonyloxy group).
The above splitting-off reaction is usually performed "~ .

:'' - ' -, ' , ,' ''' ' ~-' "' ' :'' .':

,. . , ~ : : . .; .

. . -- ~ , .

~36S~37~

in ~he presence o a solvent or diluent or of a mixture thereof; the - -splitting-off reagent used in excess can simultaneously also serve as so~vent or diluent. Furthermore, the reaction is performad, if necessary or if desired, with cooling or heatingJ e.g. in a temperature range of about -10C to about 120C, in a closed vessel u~der pressure and/or in an inert gas atmosphere, e.g. in a nitrogen atmosphere.
.' " ,,','' ' :: :
'`, ~'''~, !o ,`~ I ~ 12 -87~

The starting materials of formula V are kno~n or can be produced in a manner known per se, e.g. by a process in whlch a compound of the formula Il 12 2 ~ CH2 ~ ~ X ~ ~ RB (VI) wherein Xl and X2 have the above-given meanings, and RB represents the radical Ro or a radical convertible into this~ is reacted with an amine of the formula ~l-NH2 (III), and, if necessary or required, in a compound thus obtained, the group RB is converted into ~he radical Ro.

The groups Xl and X2 stand in particular for halogen and especially for bromine, while RB preferably stands for Ro and particularly for lower alkoxy, e.g. methoxy~
but also, e.g., for a protected amino group such as an acylated amino group, wherein the acyl radical represents, e.g., one of the corresponding radicals which occur in an acyloxy radical Ro.

The reaction of a compound of formula ~rI wi~h an - - - . . . . . . . . . .. .

~ ~6 S~ 7 ~

amine of ~ormula III can be carried out, e.g., in the manner described above for the reaction of a compound of formula II with a compound of formula III. If necessary, a group ~ is converted in a resulting 5 compound, e.g. an acylated amino group RB such as a lower-alkanoylamino group, in a mamler Icnown per se, e.g. by hydrolysis in an acid or alkali medium, into a group Ro, e.g. into ~he free amino group.

In a compound of formula I obtainable according to the process, an alkanoyloxy group R can be converted in a ma-nner known per se, e.g. by solvolysis such as hydrolysis or alcoholysis, optionally in the presence o~
a basic or acid agent such as an aqueous alkali metal hydroxide, e.g. sodium or potassium hydroxide, into the free hydroxy group R. Alternatively, it is possible to convert in a compound obtainable by the process the free hydroxy group R into an alkanoyloxy group R by acylation, e.g. by treatment with a symmetrical or mixed anhydride of an alkanecarboxylic acid, such as with an alkane-carboxylic acid halide, e.g. chloride, usually in thepresence of a basic agent such as an inorganic base, e.g.
an agent forming phenolate, such as an alkali metal, e.g.
sodium or potassium, or a suitable alkali metal compound, t e.g. a sodium or potassium compound, such as 2 suitable /~ - - ' '. ' ''' . , - ' ' '~ :~'., ' - .', :' ', ' .:':. :~
.. ~.. ~ ~ , - , .. ..

10~587~

hydride, ~mide or hydroxide, or a suitable organic nitrogen base such as diisopropylethylamine or pyridine3 including a quaternary ammonium base.

' Depending on the conditions of the process and on the starting materials, there are obtained optionally salt-forming final materials in the free form or in the fonm of their salts which can be converted in the usual manner into each other or into other salts. Thus, free compounds of formula I are formed from resulting acid addition salts~ e.g. by treatment with bases or with basic ion exchangers, whereas free bases of formula I
are converted into acid addition salts, e.g. by reaction with organic or inorganic acids, especially with those that are suitable for the formation of pharmaceutically applicable saltsg such as the aforementioned.

Salts of the new compounds can also be used for purification purposes, e.g. by a process wherein the free compounds are converted into their salts, these are isolated and optionally purified, and again converted into the free compounds. In consequence of the close relationship between the new compounds in the free form and in the form of their salts, it is to be taken, in the foregoing and in the following, that by thc term 'free : - -~L06587~ -compounds' is meant, where the case applies and with the appropriate modifications, also the corresponding salts. -The invention relates also to those modifications of the process whereby a compound occurring as an intermediate at some stage is used as the starting material, and the uncompleted steps are performed, or whereby the process is interrupted at some stage, or whereby a starting material is formed under the reaction condi-tions, or whereby a reaction constituent is optionally present in the form of its salts. ~-For the carrying out of the process according to the invention, there are advantageously used such starting materials which yield the initially specially mentioned groups of final pro-ducts, and particularly the specifically described or emphasised final materials.
The new compounds can be used, e.g., in the form of phar-maceutical preparations which contain an effective amount of the ~-active substance, optionally together with inorganic or organlc, solid or liquid, pharmaceutically usable carrier substances suitable for enteral, e.g. oral, or parenteral administration. There are thus used tablets or gelatine capsules containing the active substance together with extenders, e.g. lactose, dextrose, ,:

- 15a -6SE~

sucrose~ mannitol, sorbltol, cellulose and/or glycin, and lubricants, e.g. diatomaceous earth, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol; tablets contain also binding agents, e.g. magnesium aluminium silicate, starches such as maize, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, optionally, effervecent agents, e.g. s~arches, agar, alginic acid or a salt thereof, such as sodlum alginate, and/or effervescent mixtures, or adsorption agents, colouring agents, flavouring agents and sweetening agents.
Furthermore, the new pharmacologically effective compounds can be used in the form of injectable preparations, e.g.
intravenously administered preparations, or in the form of infusion solutions. Such solutions are preferably isotonic a~ueous solutions or suspensions; these can be prepared before use, e.g. as lyophilised preparations containing the active substance alone or together with a carrier material, e.g. mannitol. The pharmaceutical preparations can be sterilised and/or contain auxiliaries~
e.g. preservatives, stabilising agents, wetting and/or emulsifying agents, solubility-promoting agents, salts for ~6 : : . - ... :. . . .. .

- . . . . . . . . . .
- - i . , .

~L06~;871 regulation of the osmotic pressure, and/or buffers.
The present pharmaceutical preparations, which can optionally contain further pharmacologically valuable substances~ are produced in a manner known per se, S e.g. by means of conventional mixing, granulating, coating, solution or lyophilising processes, and they contain from about 0.1% to 100%, especially from about 1% to 50%, o lyophilisates ~o up to 100% of active substance. The dosage amounts depend on the mode of application, on the species, on the age and on the individual condition.
The daily doses of the free base or of pharmaceutically acceptable salts thereof vary between about 0.05 g and 0.3 g for warm-blooded animals having a weight of about 70 kg.

The following examples serve to illustrate the - ;
invention; temperatures are given in degrees Centigrade.

.' ~'~~ ' . , ~

: ILC3t; i~i~7:~

Example 1 A mixture of 23.0 g of 2-methyl-5-methoxy-2,3-dihydro-lH-dibenzol2,3:6,7]thiepino[4,5-c]pyrrole and 115 ml of 48% aqueous hydrobromic acid is refluxed for 3 hours with stirring, and then cooled to 20. The precipi~ated hydrobromide of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7jthiepino[4,5-c]pyrrole is filtered off and dissolved in 250 ml of 60% aqueous methanol. The solution is rendered alkaline by addition of concentrated aqueous ammonia solution (phenolphthalein), whereupon free 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepino 14,5-c]pyrrole crystallises out. The product melts at 242-245 after recrystallisation from methanol.

Example 2 A suspension of 14.5 g of 2-methyl-5-hydroxy-2~3-dihydro-lH-dibenzol2,3:6,7]thiepino[4,5-c]pyrrole in a mixture of 50 ml of absolute ethanol and 100 ml of acetone is made neutral with 4.95 g of methanesulphonic acid, whereupon the base goes into solution, and after some time the methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-1~-dibenzol2,3:6,7jthiepinol4,5-c]pyrrole crystallises out. The salt melts at 194 - 195 after recrystallisation from absolute ethanol.

- : . :: . .
-,.

. . - .. ~ - , .~ . . -~ID65~7~
Example 3 By boiling 11 g of 2-ethyl-5~methoxy-2a3-dihydro-lH-dibenzo~2,3:6,7]thiepinol4,5-c]pyrrole in 55 ml of 48%
aqueous hydrobromic acid there is obtained, by a process analogous to that described in Example 1, 2-ethyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6~7]thiepino[4,5-c]
pyrrole, which melts at 22~-227 after recrystallisation from ethanol. ~he methanesulphonic acid salt of 2-ethyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepinoL4,5-c]
pyrrole is obtained by a procedure analogous to that of Example 2; it melts at 252-255 after recrystallisation from 80% ethanol.

Example 4 By boiling 14 g of 2-methyl-5-methoxy-2,3-dihydro~
dibenzol2,3:6,7]oxepinol4,5-c]pyrrole in 70 ml of 48%
aqueous hydrobromic acid there is obtained, by a process analogous to that described in Example 1, 2-methyl-S-hydroxy-2,3-dihydro-lH-dibenæo[2,3:6,7]oxepino[4,5-c]
pyrrole, which melts at 244-250 after recrystallisation from methanol. The methanesulphonic acid salt of 2-methyl 5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepinol4,5-c]pyrrole is obtained by a procedure analogous to tha~ of Example 2;
it melts at 235-238 after recrystallisation from methanol.

. .

~3lO6~87~L
Example 5 By boiling 14.7 ~ of 2-ethyl-5-methoxy-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole in 73.5 ml of 48% aqueous hydrobromic acid there is obtained, ~y a method analogous to that described in Example 1, 2-ethyl-S-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]oxepinol4,5-c]
pyrrole, which melts at 172-174 af~er recrystallisation from methanol. The methanesulphonic acicl salt o 2-e~hyl-5-hydroxy-2,3-dihydro-lH-dibenzoE2,3:6,7]oxepino E 4 s 5 - c ]
pyrrole is obtained by a process analogous to that of Example 2: it melts a~ 219-222 after recrystallisation from ethanol.

Example 6 A solution of 4.7 g of acetyl chloride in 20 ml of absolute benzene is added dropwise within one hour, with stirring, to a solution of 8.4 g of 2-methyl-5-hydroxy-2,3-dihydro~ dibenzo[2,3:697~thiepino[4,5-c]pyrrole in 150 ml of absolute pyridine, with the temperature being maintained at between 0 and 5. Stirring is subsequently continued for 2 hours at room temperature, the reaction mixture is then poured on ice water and extracted with ether. The ether solution is separated, washed with water ~0 !~,.. ~ .

' . . ' .' ., . . ' '' ., ' ' ~ . , ' . ~,.

', ,' ' ' ' '. ' ' ''.. '. '. ', ~'. ' '''1 . ., :
. ' . . , ' ., . . ..

iS!37~

and, after drying over sodium sulphate, concentrated by evapora~ion, whereupon 2-methyl-5-acetoxy-2,3-dihydro-lH-dibenzo¦2,3:6,7lthiepino[4,5-c]pyrrole is obtained as oil.
9.5 g of the oily crude base is dissolved in 50 m]
of acetone, and neutralised with a solution of 2.7 g of anhydrous oxalic acid in 10 ml of absolute ethanol, whereupon the oxalate crystallises out; this melts at 117-120 after recrystallisation from abs. ethanol/abs.ether.

Example 7 The following final produc~s are produced analogously to Example 6:
a) from 5.6 g of 2-methyl-5-hydroxy-2,3-dihydro-lH
dibenzo[2,3:6,7}thiepino~4,5-c]pyrrole in 120 ml of absolute pyridine and 5.9 g of heptanoyl chloride in 10 ml of abs. benzene:- 2-methyl-5-heptanoyloxy-2,3 dihydro-lH-dibenzo[2,3:6,7]thiepinol4,5-c~pyrrole, the oxalate of which melts at 195-197 after recrystallisation from abs. ethanol.
b) from 5.6 g of 2-ethyl-5-hydroxy-2,3-dihydro-lH-dibenzo 12,3:6,7]oxepino[4,5-c]pyrrole in 120 ml of absolute pyrridi~e and 3.1 g of acetyl chloride in 10 ml of abs.

~1 :

, :

.

~()6587~
benzene:- 2-ethyl-5-acetoxy-2,3-dihydro-lH-dibenzo l2,3:6,7]oxepinol4 3 5-c]pyrrole, the oxalate of which melts at 152-155 after recrystallisation from abs.
ethanol/acetone.

Example 8 Tablets containing 0.02 g of the methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]
thiepinol4,5-c]pyrrole are produced as ollows:
Composition (for 10000 tablets) methanesulphonic acid salt of 2-methyl-S-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepino[4,5-c]
pyrrole 200.00 g lactose 200.80 g potato starch 354.70 g stearic acid 10.00 g lS talcum 200.00 g magnesi~ stearate 2.50 g colloidal silicon dioxide 32.00 g ethanol q.s.
A mixture of the methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo¦2,3:6,7]thiepino[4,5-c3 pyrrole, the lactose and 194.70 g of potato starch is -- ~B -- .. ......
,~ i, ~ , .
,~,~i .
.

~Q6587~1 moistened with an ethanolic solution of stearic acid and then granulated through a sieve. The granulate is dried and the remaining potato s~arch, the talcum, the magnesium stearate and the colloidal silicon dioxide -are mixed in, and the mixture is pressed to form tablets each weighing 0.1 g, which can optionally be provided with grooves for a finer adjustment of the dosage amount.

Example 9 Dragees containing 0.02 g of the methanesulphonic 10 acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo 12,3:6,7]thiepino[4,5-c]pyrrole are produced as follows:
Composition (for 10,000 dragées) methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepinoL4~5-c3 pyrrole 100.00 g lactose 1i5.90 g stearic acid 10.00 g colloidal silicon dioxide 56.60 g talcum 165.00 g potato starch 20.00 g magnesium stearate 2.50 g saccharose (cryst.) 502~28 g _ ~ _ ~ -.. . . . .

-1~6587~

shellac 6.00 g ~.
gum arabic 10.00 g dyestuff 0.22 g titanium dioxide 1.50 g ethanol q.s.
A granulate is produced from 2-methyl-S-hydroxy-2,3-dihydro-lH-dibenzol2,3:6,7~thiepino[4,5-c]pyrrole, lactose and an ethanolic solution of stearic acid; and, after drying, the granulate is mixed with colloidal silican dioxide, talcum, potato starch and magnesium stearate, and the mixture is pressed to form dragée cores. These are subsequently coated with a concentrated syrup made from saccharose, shellac, gum arabic, dyestuff and titanium dioxide to thus obtain dragées each weighing O.lOS g.

1065873L : ~
Ex~nple_lO

Capsules containing 0.02 g of the methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-diber1zo 12,3:6,7]thiepinol4~5-cJpyrrole are produced as follows:
Composition for lO00 capsules: -S Methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7~thiepinol4,5~cl ~, pyrrole 20.00 g lactose 253.00 g gelatine 2.00 g maize stareh lO.00 g talcum 15.00 g water q.s.

The methanesulphonic acid salt of 2-methyl-5-hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,73thiepinol4,5-clpyrrole is mixed with lactose, the mixture is uniformly moistened with an aqueous solution o~ gelatine, and is then granulated through a suitable sieve (eOg. Sieve III
according to Ph.Helv. V). The granulate is mixed with the dried maize starch and talcum, and the mixture is evenly filled into hard gelatine capsules (size 1).

0~S

. : :

~5~7~

Example 11 An aqueous injection solution containing 0.01 g/ml of the methanesulphonic acid salt of 2-methyl-5-hydroxy-2~3-dihydro-lH-dibenzo[2~3:6~7Jthiepino[4~5-c~pyrrole is produced as follows:

Composition (for 1000 ampoules)-methanesulphonic acid salt of 2-methyl-5-11ydroxy-2,3-dihydro-lH-clibenzo[2,3:6~7]thiepino[4~5-c]
pyrrole 10.00 g water q.s.

A solution of the methanesulphonic acid salt of 2-methyl-5-hydroxy 2,3-dihydro-lH-dibenzo[2~3:G,7]
thiepino[4,5-clpyrrole in 1000 ml of water is illed into ampoules and sterilised. An ampoule con~ains a 1% solution of the active substance.

~6 ~j, ,,,~ \ ' 587~

Example 12 Also the following compounds can be used as active substance for tablets, dragées, capsules, suppositories, ampoules, etc.:

2-ethyl-5-hydroxy-2 ? 3-dihydro-lH-dibenzo[2,3:6~7]thiepino [4,5-~]pyrrole or a salt, e.g. the methanesulphonic acid salt thereof;

2-methyl-S-acetoxy-2,3-dihydro-lH-dibenzo[2~3:6~7]thiepino 14,5-clpyrrole or a salt thereof; and 2-methyl-5-heptanoyloxy-2,3-dihydro-lH-dibenzo[2,3:6~7]
thiepinol4,5-c]pyrrole o-r a salt thereof.

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.~ -- ~ .
, .... - , -' .
': . ' . `

' . ~ :

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the production of azatetracyclic compounds of the formula (I) wherein X represents oxygen or sulphur, and r1 stands for a lower alkyl or lower alkenyl, or pharmaceutically acceptable salts thereof, in which pro-cess a compound of the formula (II) wherein Xl and X2 represent reactive esterified hydroxy groups, is reacted with an amine of the formula R1-NH2 (III) or in a compound of the formula (IV) the secondary amino group is substituted by the group Rl by reaction with a reactive ester of a compound of the formula R1-OH (IVa) or in a compound of the formula (V) wherein Ro represents alkoxy or alkanoyloxy, the group Ro is converted into the free hydroxy group, and where required, in a resulting compound of formula I, the group R1 is converted into another group R1, where required, a result-ing salt is converted into the free compound or into a pharmaceutically accept-able salt, or a free compound obtained is converted into a pharmaceutically acceptable salt.

2. Process according to claim 1, wherein a reactive esterified hydroxy group X1 or X2 is a hydroxy group esterified with a strong acid.

3. Process according to claim 2, wherein a reactive esterified hydroxy group X1 or X2 is a hydroxy group esterified with a mineral acid, or with a strong organic sulphonic acid.

4. Process according to claim 1, wherein the N-unsubstituted starting material of formula IV is reacted with an ester of a lower alkanol or a lower alkenol and a hydrohalic acid.

5. Process according to claim 4, wherein the esterified hydroxy group stands for halogen.

6. Process according to claim 4 or 5, wherein the reaction is per-formed in the presence of a base.

7. Process according to claim 1, wherein the N-unsubstituted starting material of formula IV is treated with formaldehyde in the presence of formic acid.

8. Process according to claim 1, wherein Ro represents in a starting material of formula V an alkoxy or an alkanoyloxy group, which is converted into the free hydroxy group by means of solvolysis, or by means of reduction, and also photolytically.

9. Process according to claim 8, wherein Ro represents lower alkoxy, and is converted by hydrolysis, in the presence of a mineral acid, into the hydroxy group.

10. Process according to claim 1, wherein in the starting materials R
stands for lower alkyl having up to 4 carbon atoms, or for allyl.

11. Process according to claim 1, wherein in the starting materials X
stands for sulphur, and R1 for lower alkyl having up to 4 carbon atoms.

12. Process according to claim 11, wherein in the starting materials R
stands for methyl or ethyl.

13. Process according to claim 1, wherein in the starting materials X
stands for oxygen, and R1 for lower alkyl having up to 4 carbon atoms.

14. Process according to claim 13, wherein in the starting materials R
stands for methyl or ethyl.

15. Process according to claim 12, wherein in the starting materials R1 stands for methyl, whereby there is produced 2-methyl-5-hydroxy-2,3-di-hydro-1H-dibenzo[2,3:6,7]thiepino[4,5-c]pyrrole or a pharmaceutically accept-able salt thereof.

16. Process according to claim 12, wherein in the starting materials R1 stands for ethyl, whereby there is produced 2-ethyl-5-hydroxy-2,3-dihydro-1H-dibenzo[2,3:6,7]thiepino[4,5-c]pyrrole or a pharmaceutically acceptable salt thereof.

17. Process according to claim 14, wherein in the starting materials R1 stands for methyl, whereby there is produced 2-methyl-5-hydroxy-2,3-di-hydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole or a pharmaceutically accept-able salt thereof.

18. Process according to claim 14, wherein in the starting materials R1 stands for ethyl, whereby there is produced 2-ethyl-5-hydroxy-2,3-dihydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole or a pharmaceutically acceptable salt thereof.

19. 5-Hydroxy-2,3-dihydro-lH-dibenzo[2,3:6,7]thiepino and oxepino[4,5-c]pyrrole compounds substituted in the 1-position which correspond to formula (I) defined in claim 1, and the pharmaceutically acceptable satls thereof, whenever prepared by a process as claimed in claim 1 or by an obvious chem-ical equivalent thereof.