GB2128996A - 5H-dibenz[b,f]azopine-5- carboxamides - Google Patents

Description

SPECIFICATION Method of treatment of cerebral insufficiency, pharmaceutical preparations suitable for this purpose, novel active ingredients contained in these preparations and processes for the manufacture of the novel active ingredients The present invention relates to a method for the prophylactic and/or therapeutic treatment of cerebral insufficiency, especially impaired memory conditions, pharmaceutical preparations suitable for this purpose, novel active ingredients contained in these preparations and a process for the manufacture of the novel active ingredients. Piracetam (BAN, DCF, chemical designation 2-oxo-1-pyrrolidineacetamide) has attained great medicinal importance as a nootropic drug, for example for the treatment of organo-cerebral psychosyndrome and sequelae of cerebral traumas or apoplexy. Derivatives and further related compounds of piracetam are at the clinical testing stage. One of the most conspicuous activities of nootropic drugs of the piracetam type within the scope of the customary animal tests for selecting such substances (screening) is their ability to protect freshly obtained information from the amnesiogenic action of cerebral electroshock. Piracetam, and all the derivatives which have so far been clinically tested, have this ability. Surprisingly, it has now been found that 5H-dibenz[b,f]azepine-5-carboxamides of the general formula I

in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X1 and X2 and/or the symbol X3 represent(s) lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl ortrifluoromethyl or X3 alternatively represents halogen having an atomic number of up to 35, cyano or

hydrogen, or if X, represents lower alkyl, then X2 may also represent lower alkyl, or, when at least one of the radicals R1 and R2 is other than hydrogen or Y, and Y2 represent hydrogen, Xi, X2 and X3 may each represent hydrogen, X4 represents hydrogen or, if X3 represents halogen or lower alkyl,X4 may instead also represent one of those radicals, and Y, and Y2 together represent an additional bond or, when X1 and/or X2 represent(s)

otherthan hydrogen, X, or X2 may alternatively represent halogen having an atomic number of up to 35 or cyano, X2 or X1 may represent hydrogen and Y, and Y2 may together represent an additional bond, or X, and

and Y2 represent hydrogen and X1 and X2 together represent epoxy or epimethylene, are able, both in doses which effect complete prevention of convulsions induced by electroshock or which effect substantial

lower doses, to diminish the amnesiogenic action of electroshock to at least a similar or even to a greater degree than piracetam. The findings summarized above can be demonstrated in the following one-step learning test with mice: The test equipment consists of a large box (35 x 20 x 10 cm) which is joined by a sliding door to a small box (10 x 10 x 18 cm). Whereas the small box is brightly lit from above by a 100 watt lamp, the large box is dark. The floor of the two compartments consists of an electrifiable grating. For training, the mice are put individually into the brightly lit small box. Since mice have a spontaneous preference for the dark, most of them go into the dark compartment within 30 seconds. As soon as they have crossed completely into this compartment, the sliding door is closed and a shock (1 mA, 5 seconds) is administered to their feet. The animals are then immediately removed from the device. To test the learning effect (retest), the mice are once more put individually into the light compartment after 24 hours, and the latency period until they are completely in the dark is measured. Most of the animals now normally remain in the light compartment for the entire observation period of 150 seconds. The learning effect is substantially erased, orthe memory of the shock to the feet is at least partially extinguished, if, as amnesiogenic treatment, a temporal electroshock treatment directly follows the shock to the feet administered in the training operation. Parameters of the electroshock: 50 mA, 0.4 seconds, 50 Hz, 0.6 msec pulse width. For testing and comparing their protective action against the amnesiogenic action of the electroshock, the test substances are each administered intraperitoneally 30 minutes before training in the form of a suspension in methocel (RTM), and the animals are subjected to the electroshock treatment immediately after training. 24 hours later, the degree of the learning effect still retained is measured with reference to the dwell time in the lit box and is compared with that of the other test substances as well as with that of the control animals receiving methocel alone and training with and without subsequent electroshock treatment.As doses still significantly effective according to the Mann-Whitney U-test, that is to say EDmin, there were ascertained, for example, for 10-methylthio-5H-dibenz[b,f]azepine-5-carboxamide, 0.1 mg/kg intraperitoneally and, for 3-methylsulphonyl-5H-dibenz[b,f]azepine-5-carboxamide, likewise 0.1 mg/kg intraperitoneally. The following literature on similar tests may be mentioned: S.J. Sara and D. Lefevre, Psychopharmacologia 25, 32-40 (1972), Hypoxia-induced amnesia in one-trial learning and pharmacological protection by piracetam; and Boggan, W.O., and Schlesinger, K., in Behavioral Biology 12,127-134 (1974). The compounds of the above-defined general formula I that are novel are those in which Ri and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, lower alkoxy, halogen having an atomic number of up to and including 35 or cyano and the other represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, or both symbols X1 and X2 represent hydrogen, X3 represents lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl or, when at least one of the radicals X,and X2 is other than hydrogen andXi or X2

represent hydrogen, X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals, and the symbols Y1 and Y2 each represent hydrogen when one of the symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl

independently of one another, each represents lower alkyl or together represent lower alkylene or ethyleneoxyethylene, X1 together with X2 represents epoxy or epimethylene and Y, and Y2 each represent hydrogen, X3 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl, and X4 represents hydrogen or, if X3 represents lower alkyl or halogen,X4 may instead also represent one of those radicals.

lower alkyl, X2, X3 and X4 each represent hydrogen and Y1 and Y2 together represent an additional bond, specifically 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide, N-methyl-, N,N-dimethyl-, N-butyl-and N,Ndibutyl-10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide, are described as intermediates in CH Patent Specification No. 500,196. Special mention should be made of pharmaceutical preparations that contain as active ingredients one or more compounds of the two groups within the scope of the general formula I that are defined in more detail above. Further compounds within the general formula I come under the general formulae of certain patent specifications. For example, in CH Patent Specifications Nos. 325,662, 403,767, 500,101 and 501,196, GB Patent Specification No. 906,452, EP-Offenlegungsschrift No. 50,589 and in BE Patent Specification No. 892,882, compounds of the formula I in which R1 and R2 have the meanings given above, X, and X2 represent

represents hydrogen, X3 and X4 represent hydrogen or, when X1 and/or X2 represent(s) hydrogen or lower alkyl, X3 represents halogen, lower alkyl or lower alkoxy and X4 represents halogen or lower alkyl, Y1 and Y2 each representing hydrogen or together representing an additional bond, are described as anti-convulsants. In US.Patent Specification No. 3,842,091 and in JP Patent Application No. 7308631, compounds of the

X3, X4, Y, and Y2 represent hydrogen, are also described as anti-convulsants. Furthermore, in US Patent Specification No. 4,235,895, BE Patent Specification No. 833,852 and in EP Patent Application No. 50,589,

represent hydrogen, and X3 represents cyano, and Y, and Y2 together represent an additional bond or, when X1 represents hydroxy, they represent hydrogen, are described as anti-convulsants and some of them have been proposed as nootropic drugs in BE Patent Specification No. 892,882 which has not been prior-published. Some of these compounds have also been described specifically in these patent specifications, for

dibenz[b,f]azepine-5-carboxamide, 3,7-dibromo-5H-dibenz[b,f]azepine-5-carboxamide, N,N-diethyl-5Hdibenz[b,f]azepine-5-carboxamide, 5-[(1-piperidinyl)-carbonyl]-, 5-[(1-pyrrolidinyl)-carbonyl]- and 5-[(4-

azepine-5-carboxamide, 10-methyl-5h-dibenz[b,f]azepine-5-carboxamide and 10,11-dimethyl-5Hdibenz[b,f]azepine-5-carboxamide (all CH-PS 403,767), N-methyl-, N,N-dimethyl-, N-butyl-and N,N-dibutyl10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (all as end products in CH-PS 500,196), Nmethyl-, N,N-dimethyl-and N-butyl-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]-azepines-5-carboxamide (all

These compounds also come into consideration as active ingredients for pharmaceutical preparations and for use in the method according to the invention. Especially important as active ingredients according to the invention are the compounds mentioned in the manufacture and preparation Examples, especially the two mentioned above. The present invention relates to a method for the prophylaxis or therapy of cerebral insufficiency, especially impaired memory conditions having various causes, such as senile dementia, multi-infarction dementia or Alzheimer's dementia, and also of sequelae of cerebral traumas or aplopexy, the method being characterised by the oral or rectal administration of a prophylactically or therapeutically effective amount of a compound of the above-defined general formula I. The dosage depends on the type of disorder, individual condition, age and weight of the patient and the period of treatment and is especially from approximately 0.2 to approximately 17 mg/kg per day or from approximately 15 to 1200 mg per day for adults of normal weight, viz. approximately 70 kg. The invention also relates to pharmaceutical preparations that are suitable for the prophylaxis or therapy of cerebral insuffiency and that contain at least one compound of the above-defined general formula I, optionally together with pharmaceutical carriers. In the method of treatment according to the invention and in pharmaceutical preparations suitable

another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, the symbols X1 and X2, independently of one another, each represents hydrogen or lower alkyl, the symbol X3, when X1 and X2 represent hydrogen, represents halogen having an atomic

and/or X2 represent(s) lower alkyl, X3 represents hydrogen, lower alkyl, lower alkoxy or halogen having an atomic number of up to and including 35, also lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl, X4 represents hydrogen or, if X3 represents halogen, X4 may instead also represent halogen or, if X3 represents lower alkyl,X4 may instead also represent halogen or

There are used especially those compounds of the formula I in which R1 and R2, independently of one another, each represent hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents hydrogen or lower alkyl and the other represents lower alkyl or, when at least one of the radicals R, and R2 is other than hydrogen, it represents hydrogen, or X1 and X2 together represent epoxy or epimethylene, X3 represents hydrogen or halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, also lower alkylthio, lower alkylsulphinyl, lower alkysulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals, and Y,and Y2 each represents hydrogen or, when X1 and X2 represent hydrogen and/or lower alkyl, they together

dibenz[b,f]azepine-5-carboxamide, 10-methyl-5H-dibenz[b,f]azepine-5-carboxamide and 10,11-dimethyl-5Hdibenz[b,f]azepine-5-carboxamide, 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, N,N-diethyl-5Hdibenz[b,f]azepine-5-carboxamide and 5-[(1-piperidinyl)-carbonyl]-, 5-[(1-pyrrolidinyl)-carbonyl]- and 5-[(4morpholinyl)-carbonyl]-5H-dibenz[b,f]azepine, N-methyl-1,1a,10b-tetrahydrocyclopropa[d]dibenz[b,f]azepine-6-carboxamide and N-propyl-1a,10b-dihydro-6H-dibenz[b,f]oxiren[d]-azepine-6-carboxamide.There are preferably used compounds of the formula I in which R1 and R2 represent hydrogen, one of the symbols X1 and X2 represents halogen having an atomic number of up to and including 35 or cyano and the other represents hydrogen, X3 represents halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, also lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or

together represent an additional bond, especially 3,7-dichloro- and 3,7-dibromo-5H-dibenz[b,f]azepine-5carboxamide.

represents hydroxy and X2, Y, and Y2 each represent hydrogen, X3 represents halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, also lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl or, when at least one of the radicals R, and R2 is other than hydrogen, X3 represents hydrogen, and X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals, especially N-methyl-,

N-methyl-, N,N-dimethyl-and N-butyl-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide.Furthermore, there are preferably used compounds of the formula I in which R, and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, X1 and X2 represent hydrogen and X3 and X4 represent halogen having an atomic

each case Y1 and Y2 together representing an additional bond, especially 2-cyano- and 3-cyano-5Hdibenz[b,f]azepine-5-carboxamide and 3,7-dichloro- and 3,7-dibromo-5H-dibenz[b,f]azepine-5-carboxamide.The invention relates also to the compounds of the formula I designated above as being novel or as being known as intermediates, for example those in which R, and R2 represent hydrogen or lower alkyl, X1 represents lower alkoxy, X2, X3 and X4 represent hydrogen and Y, and Y2 together represent an additional bond, for use in a method for the therapeutic treatment of the human or animal body, for example in the method of treatment mentioned at the beginning, to their use as the active ingredients of medicaments and to pharmaceutical preparations containing them, preferably nootropic pharmaceutical preparations. Special mention should be made of 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide, N-methyl-, N,N-dimethyl-, N-butyi- and N,N-dibutyl-1 0-methoxy-5H- dibenz[b,f]azepine-5-carboxamide. The invention also relates to the compounds of the formula I themselves that are designated above as novel, processes for their manufacture, pharmaceutical preparations containing them and their use as the active ingredients of medicaments. The invention relates, for example, to compounds of the formula I in which R, and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X1 and X2 and/or the symbol X3 represent(s) lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl or X3 alternatively represents halogen having an atomic number of up to 35, di-lower alkylsulphamoyl, lower alkyl, cyano or lower alkoxy and the (two)

least one of the radicals R1 and R2 is other than hydrogen and lower alkyl or one of the radicals X3 and X4 is other than hydrogen and Y, and Y2 represent an additional bond, may also represent lower alkoxy, and X2 or X1 (as the case may be) may represent hydrogen, X4 represents hydrogen or, if X3 represents halogen or

bond or,if X, and X2 represent hydrogen, they may alternatively each represent hydrogen, or, if at least one of the radicals R, and R2 is other than hydrogen and X3 and X4 represent hydrogen, X1 may alternatively represent halogen having an atomic number of up to 35 or cyano, X2 may represent hydrogen and Y1 and Y2 may together represent an additional bond.

one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X, and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl and the other represents hydrogen, X3 represents hydrogen, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano, halogen having an atomic number of up to 35, di-lower alkylsulphamoyl, lower alkyl or lower alkoxy, X4 represents hydrogen or, if X3

together represent an additional bend or each represents hydrogen. The invention also relates especially to compounds of the formula I in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, X1 and X2 represent hydrogen, X3 represents halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals, and Yi and Y2 each represent hydrogen or, when at least one of the radicals R, and R2 is other than hydrogen or X3 is other than cyano or X4 is other than halogen, they together represent an additional bond. The invention furthermore relates especially to compounds of the formula I in which one of the symbols Ri and R2 represents lower alkyl and the other represents hydrogen, or R1 and r2 both represent lower alkyl or together represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents halogen having an atomic number of up to and including 35 or cyano and the other, as well as X3 and X4, represents hydrogen, Y, and Y2 together representing an additional bond. The invention likewise relates especially to compounds of the formula I in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene

represents lower alkoxy or hydroxy and X2, Y1 and Y2 each represent hydrogen, X3 represents halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, also lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl or, when R1 and R2 together represent lower alkylene or ethyleneoxyethylene, X3 represents hydrogen, and X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals.

X1 and X2 represent hydrogen, X3 represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, such as methylthio or methylsulphonyl, di-lower alkylsulphamoyl having up to and including 4 carbon atoms in each alkyl moiety, such as dimethylsulphamoyl, lower alkyl or lower alkoxy having up to and including 4 carbon atoms, such as methyl or methoxy, halogen having an atomic number of up to and including 35, such as chlorine, trifluorimethyl, X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent lower alkyl, and Y, and Y2 each represent hydrogen or together represent an additional bond, or in which, on the other hand, R1 and R2, independently of one another, each represents hydrogen or lower alkyl that has up to and including 4 carbon atoms and represents, for example,methyl, one of the radicals X1 and X2 represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, such as methylthio or methylsulphonyl, trifluoromethyl or, when at least one of the radicals R1 and R2 represents lower alkyl, it represents halogen having an atomic number of up to and including 35, such as chlorine or bromine, or cyano, and the other, as well as X3 and X4, represents hydrogen and Y1 and Y2 together represent an additional bond.

and X4 represent hydrogen and a radical R1 or Rzthat is other than hydrogen represents lower alkyl having up to and including 4 carbon atoms, such as methyl or butyl, a radical X1 or X2 that is other than hydrogen represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, such as methylthio or methylsulphonyl, or trifluoromethyl, and a radical X3 that is other than hydrogen represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, such as methylthio or methylsulphonyl, di-lower alkylsulphamoyl having up to and including 4 carbon atoms in each alkyl moiety, such as dimethylsulphamoyl, lower alkyl or lower alkoxy having up to and including 4 carbon atoms, such as methyl or methoxy, halogen having an atomic number of up to and including 35,such as chlorine, or trifluoromethyl, and Y1 and Y2 together represent an additional bond. The invention relates specifically to the novel compounds described in the Examples of manufacture. Hereinbefore and hereinafter, lower radicals or compounds are preferably to be understood as meaning those having a maximum of 7, especially a maximum of 4, carbon atoms. In the compounds of the general formula I, the general terms used may be embodied, for example, by the radicals mentioned in the following: lower alkyl is, for example, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and, first and foremost, methyl or, especially as X3, together with hydrogen as X4, ethyl. Lower alkylene is, for example, 4- to 6-membered and accordingly forms together with the adjacent nitrogen atom, for example,

piperidinyl or hexahydro-1 H-azepin-1-yl. Lower alkoxy is, for example, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy and, first and foremost, methoxy.Lower alkylthio is, for example, ethylthio, propylthio, isopropylthio, butylthio or isobutylthio and, first and foremost, methylthio, lower alkylsulphinyl is, for example methylsulphinyl or ethylsulphinyl and lower alkylsulphonyl is, for example, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl or isobutylsulphonyl and, first and foremost, methylsulphonyl. Halogen having an atomic number of up to 35 is fluorine, bromine and, first and foremost, chlorine and di-lower alkylsulphamoyl is, for example, dimethylsulphamoyl or diethylsulphamoyl. A substituent X3 is, for example, in the 2-position or, especially, in the 3-position.If X4 like X3 represents lower alkyl or halogen, X4 is preferably at the same distance from the nitrogen atom of the central ring, that is to say, for example, methyl groups or chlorine atoms X3 and X4 are in the 2,8- or, preferably, in the 3,7-position of the tricycle. Pharmaceutical preparations according to the invention can be medicinal formulations in single dosage unit form, that is to say dosage unit forms for oral administration, such as tablets, dragees or capsules, or for rectal administration, such as suppositories, or may be medicinal formulations for oral administration not in single dosage unit form, such as syrups. Dosage unit forms contain a compound of the general formula I in an amount that is suitable for taking the above-mentioned daily dose in one or several, preferably a maximum of three, especially two, administrations each preferably comprising one or two dosage units, that is to say the whole or a third, or, especially, half, of a daily dose, or half, a sixth or a quarter, corresponding to from approximately 2.5 to approximately 600 mg, preferably from approximately 5 to approximately 300 mg.Instead of a single compound of the general formula together, the total doses and amounts remaining likewise within the range given above for single compounds. Divisible dosage unit forms, such as breakable tablets, and those having delayed release of active ingredient, may also contain larger amounts of active ingredient, whereas dosage unit forms for administration to children may also contain correspondingly smaller amounts of active ingredient. Medicinal formulations for oral administration not in single dosage unit form, such as syrups, contain amounts of active ingredients corresponding to those of single dosage units in suitable amounts or volume units of, for example, 2.5, 5 or 10 ml. Pharmaceutical preparations which may be used in accordance with the invention contain one or, optionally, more compounds of the general formula I, preferably together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for enteral, for example oral, administration. Tablets or dragee cores are manufactured by combining the active ingredients, for example, with solid pulverulent carriers, such as lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or glycine, optionally with the addition of glidants and lubricants, for example silica, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, optionally with the addition of binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrating agents, for example starches once again, agar, alginic acid or salts thereof, such as sodium alginate, and/or effervescent mixtures, or adsorption agents, colouring substances, flavouring substances and sweeteners.Dragee cores are coated, for example, with concentrated sugar solutions, which may additionally contain, for example, gum arabic, talcum and/or titanium dioxide, or with a lacquer which is dissolved in readily volatile organic solvents or solvent mixtures. Colouring substances can be added to these coatings, for example to identify different doses of active ingredient. Further suitable dosage unit forms for oral administration are dry-fill capsules consisting of gelatin and also soft sealed capsules consisting of gelatin and a plasticiser, such as glycerine. The dry-fill capsules contain the active ingredient preferably in the form of a granulate, for example in admixture with fillers, such as corn starch, and/orwith glidants, such as talcum or magnesium stearate, and, optionally, with stabilisers, such as, for example, ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, to which stabilisers can also be added. There come into consideration as medicinal formulations that are not in single dosage unit form especially syrups manufactured in a conventional manner that contain an active ingredient of the general formula I preferably in suspended form. The pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure, and/or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically active substances, are manufactured in a manner known perse, for example by means of conventional mixing, granulating, confectioning or dissolving methods, and contain from approximately 5 % to 100 %, especially from approximately 10 % to approximately 80 %, of one or, optionally, more compounds of the general formula I. The invention also relates to the compounds of the general formula I described above in a general manner as being novel, and to the remainder not specifically mentioned in the above patent specifications as novel substances,and to a process for the manufacture thereof. The process is characterised in that a) a compound of the general formula II

in which Z represents a halogen atom, is reacted with a compound of the general formula III

b) a compound of the general formula IV

c) in a compound of the formula

in which Z1 represents an etherified mercapto group and Z2 represents a group of the formula n = NRi,

X1 or X2 represents lower alkoxy and Y, and Y2 together represent an additional bond is hydrolysed to form the corresponding compound in which X1 represents hydroxy or to form the tautomeric oxo compound and,

and/or X3 represents lower alkylsulphonyl or lower alkylsulphinyl. The reaction according to a) is preferably carried out in an organic solvent, for example in a lower alkanol, such as ethanol, isopropanol or butanol, in an ethereal liquid, such as tetrahydrofuran or dioxane, or in a hydrocarbon, such as benzene or toluene, at room temperature or, preferably, at elevated temperature, for example at the boiling temperature of the solvent used. The ammonia which may be required as starting material and other gaseous starting materials of the general formula III may be introduced at the beginning of the reaction period or over the entire reaction period, or, if a water-miscible solvent is used, it may alternatively be used as a concentrated aqueous solution. It is also possible, however, to use liquid ammonia or methylamine and to carry out the reaction, if necessary, in a closed vessel. Starting materials of the general formula II are obtained, for example, by reacting the corresponding 5-unsubstituted 5H-dibenz[b,f]azepines with phosgene or carbonic acid dibromide in an inert organic solvent, such as, for example, benzene or, especially, toluene, at room temperature or moderately elevated temperature up to at the boiling temperatures of the solvents mentioned. Of the 5H-dibenz[b,f]azepines required for this reaction, some are known and the others can be manufactured in a manner known perse.The hydrolysis of compounds in which X1 or X2 represents lower alkoxy, which may, if desired, follow the reaction according to a), is carried out in accordance with the enol-ether character of these compounds, for example by heating in an aqueous or aqueous-organic mineral acid, for example in dilute, for example 2N, hydrochloric acid, or dilute sulphuric acid at from moderately elevated temperatures up to the boiling temperature, that is to say at from approximately 60 to a little over 100[deg]C. It is, however, also possible to carry out the hydrolysis, for example, in an aqueous-organic medium, for example in a mixture of water with a lower alkanol or dioxane, in the presence of an acidic ion exchanger, for example Amberlite (RTM) IR-100 (brand name of Rohm and Haas, Philadelphia) or Dowex (RTM) (brand name of Dow Chemical Co., Midland, Michigan). The reaction according to b) is preferably carried out in the presence of an alkaline condensation agent, such as an alkali metal-lower alkoxide, or the lower alkyl mercaptan is used in the form of an alkali metal mercaptide, for example sodium mercaptide. The reaction is carried out, for example, in a lower alkanol, such as ethanol, at from room temperature to moderately elevated temperatures, for example up to 100[deg]C or at the boiling temperature of the solvent used. Of the starting materials of the general formula IV, 1a,10b-dihydro-6H-dibenz[b,f]oxireno[d]azepine-6-carboxamide is known and others can be manufactured analogously to this compound. In reaction c), there are used, for example, compounds of the formula V in which the etherified mercapto group Z, is aliphatically etherified mercapto, such as lower alkylthio, for example methylthio, and the acidic anion A is, for example, the anion of a strong protonic acid, for example a hydrohalic acid, such as a halide ion, for example the iodide ion. The hydrolysis is preferably carried out in an alkaline medium, for example in an aqueous alkali solution, such as sodium or potassium hydroxide solution, preferably in a temperature range of from approximately 60[deg] to approximately 100[deg]C, preferably at boiling heat. The hydrolysis of lower alkoxy to form hydroxy is carried out, for example, by treatment with an aqueous mineral acid; the reduction of double bond, which can also be applied to other compounds of the formula I in which Y1 and Y2 represent an additional bond, is carried out, for example, by catalytic hydrogenation, especially in the presence of copper chromite.The oxidation of lower alkylthio to form lower alkylsulphinyl or lower alkylsulphonyl is carried out, for example, by means of hydrogen peroxide in an organic or organic-aqueous solvent that is inert towards the hydrogen peroxide, for example in acetic acid optionally containing water, or in a mixture formed by.glacial acetic acid and aqueous hydrogen peroxide solution, at moderately elevated temperatures of approximately from 60 to 100[deg]C, if a compound substituted by lower alkylsulphonyl is to be obtained as oxidation product.The oxidation of the lower alkylthio group to form the lower alkylsulphinyl group is carried out, for example, either according to the above process in a temperature range of approximately from 20 to 60[deg]c, or, especially, using an alkali metal periodate, especially sodium or potassium periodate, such as sodium metaperiodate, in organic-aqueous medium, for example lower alkanolic-aqueous medium, especially ethanolic-aqueous medium, at reduced temperature, for example at from 0[deg]Cto room temperature, cf. in this connection also GBIPS 1,114,970. The starting materials for these oxidation reactions can be manufactured, for example, according to process a) or, if X, or X2 represents lower alkylthio, also according to process b). The invention relates also to those embodiments of the described process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is formed under the reaction conditions or is used in the form of a derivative. The starting materials preferably used are those that result in the novel compounds given special mention above, the invention also relating to novel starting materials and processes for their manufacture. In the following Examples 1 to 9, the manufacture according to the invention of compounds of the general formula I and, in the other Examples, the manufacture of pharmaceutical preparations according to the invention are described in more detail without limiting the scope of the invention in any way.

Example 1: 27.1 g (0.1 mol) of 3-methylsulphonyl-5H-dibenz-[b,f]azepine are added, while stirring, to a solution of 19.8 g (0.2 mol) of phosgene in 300 ml of absolute toluene. The mixture is boiled under reflux for 20 hours. It is then completely concentrated by evaporation in a rotary evaporator leaving crude 3-methylsulphonyl-5Hdibenz[b,f]azepine-5-carbonyl chloride having a melting point of 160 -162[deg]. The above crude product is dissolved while stirring at 70[deg] in 600 ml of absolute ethanol. Ammonia gas is introduced into this solution over a period of 2 hours, the reaction solution being constantly boiled under reflux. The reaction mixture is then concentrated by evaporation in a rotary evaporator, the residue is washed with water and, after drying, 3-methylsulphonyl-5H-dibenz[b,f]azepine-5-carboxamide is recrystallised from acetonitrile; m.p. 195 -197[deg]. The starting material can be manufactured as follows: a) 9 g (0.115 mol) of acetyl chloride are added dropwise, while stirring, over a period of 30 minutes to a

in 100 ml of toluene, the temperature being maintained at from 20 to 50[deg]. The reaction mixture is then boiled under reflux for 5 hours and afterwards cooled to 5[deg], whereupon-5-acetyl-10,11-dihydro-3-methylsulphonyl5H-dibenz[b,f]azepine crystallises out. This is filtered with suction, washed well with water and dried in a vacuum enclosure at 80[deg], the melting point then being 157 -159[deg]. b) 31.5 g (0.1 mol) of 5-acetyl-10,11-dihydro-3-methylsulphonyl-5H-dibenz[b,f]azepine are dissolved in carbon tetrachloride and 17.8 g (0.1 mol) of N-bromo-succinimide are added to the solution. The mixture is heated to boiling point while stirring in a nitrogen atmosphere and while being illuminated with a UV lamp. Boiling point is maintained until all of the N-bromo-succinimide at the bottom of the vessel has been converted into succinimide floating on the solution, this taking approximately one hour. The reaction mixture is then cooled to 20[deg] and washed in a separating funnel with water. After drying over sodium sulphate, the solvent is distilled off in a rotary evaporator and the oily residue is dissolved in 60 ml of absolute ethanol.A solution of 60 g of potassium hydroxide in 240 ml of absolute ethanol is added to this solution and the whole is boiled under reflux for one hour. After the reaction mixture has been cooled to 20[deg], 2000 ml of water are added and the precipitated crystals of 3-methylsulphonyl-5H-dibenz[b,f]azepine are filtered with suction, washed with water and then with diethyl ether and dried in a vacuum enclosure at 80[deg], the melting point then being 141 -143[deg].

Example 2: Analogously to Example 1, there is manufactured from 23,9 g (0.1 mol) of 3-methylthio-5H-

dibenz[b,f]azepine-5carbonyl chloride as an oily crude product and from this there is manufactured, using ammonia gas in 600 ml of absolute ethanol, 3-methylthio-5H-dibenz[b,f]azepine-5-carboxamide, m.p. 179 180. (from methanol). The starting material is manufactured analogously to Examples 1a) and 1 b):

5H-dibenz[b,f]azepine, m.p. 69 - 74[deg] (from petroleum ether). b) There is obtained from 28.3 g of 5 acetyl-10,11-dihydro-3-methylthio-5H-dibenz[b,f]azepine and 17.8 g (0.1 mol) of N-bromosuccinimide in 2000 ml of carbon tetrachloride, after treatment with 60 g of potassium hydroxide in 300 ml of absolute ethanol, 3-methylthio-5H-diben[b,f]azepine, mp. 167 -169[deg] (from ethanol).

Example 3: Analogously to Example 1, there is obtained from 22.3 g (0.1 mol) of 3-methoxy-5H-dibenz[b,f]azepine and 19.8 g (0.1 mol) of 3-methoxy-5H-dibenz[b,f]azepine and 19.8 g (0.2 mol) of phosgene in 300 ml of absolute toluene, 3-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride as an oily crude product and from this there is obtained, using ammonia gas in 600 ml of absolute ethanol, 3-methoxy-5H-dibenz[b,f]azepine-5carboxamide, m.p. 154-156[deg] (from benzene). The starting material is manufactured analogously to Examples 1 a) and 1 b) from 10,11-dihydro-3-

bromide.

Example 4: Analogously to Example 1, there is obtained from 30 g (0.1 mol) of 3-(dimethylsulphamoyl)-5H-dibenz[b,f]azepine (cf. CH-PS 408,927) and 19.8 g (0.2 mol) of phosgene in 300 ml of absolute toluene, 3-(dimethylsulphamoyl)-5H-dibenz[b,f]azepine-5-carbonyl chloride as an oily crude product and from this there is obtained, using ammonia gas in 600 ml of absolute ethanol, 3-(dimethylsulphamoyl)-5Hdibenz[b,f]azepine-5-carboxamide, m.p. 215 - 217[deg] (from methanol).

Example 5: Analogously to Example 1, there is obtained from 21.8 g (0.1 mol) of 5H-dibenz[b,f]azepine-3-carbonitrile and 19.8 g (0.2 mol) of phosphene in 300 ml of absolute toluene, 3-cyano-5H-dibenz[b,f]azepine-5-carbonyl chloride, m.p. 168-170[deg] (crude product) and from this there is obtained, using ammonia gas in 600 I of absolute ethanol, 3-cyano-5H-dibenz[,bf]-azepine-5-carboxamide, m.p. 269 - 272[deg] (from chloroform). The starting material is manufactured as follows:

dibenz-[b,f]azepine and 9 g (0.115 mol) of acetyl chloride in 300 ml of absolute toluene, 5-acetyl-3-bromo10,11-dihydro-5H-dibenz[b,f]azepine (crude product), (cf. US-PS 3,056,774). b) Analogously to Example 1 b) there is obtained from 31.4 g (0.1 mol) of 5-acetyl-3-bromo-10,11-dihydro5H-dibenz[b,f]azepine (crude product) and 17.8 g (0.1 mol) of N-bromosuccinimide in 350 ml of carbon tetrachloride, after treatment with 60 g of potassium hydroxide in 300 ml of absolute ethanol, 3-bromo-5H-dibenz[b,f]azepine, m.p. 218 - 220[deg] (from toluene). c) 27.2 g (0.1 mol) of 3-bromo-5H-dibenz[b,f]azepine, 10.7 g (0.12 mol) of copper cyanide and 50 ml of dimethylformamide are boiled under reflux for 4 hours while stirring.The reaction mixture is then cooled to 40. and stirred vigorously with 200 ml of a 50 % aqueous ethylenediamine solution and 200 ml of methylene chloride. The organic phase is then separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic solutions are washed with water, dried over sodium sulphate and concentrated to a small volume whereupon, on cooling, 5H-dibenz[b,f[azepine-3-carbonitrile having a melting point of 181 -182[deg] crystallises out.

Example 6 Analogously to Example 1, there is obtained from 21.8 g (0.1 mol) of 5H-dibenz[b,f]azepine-5-carbonyl chloride, m.p. 208 - 209[deg] (crude product) and from this there is obtained, using ammonia gas in 600 ml of absolute ethanol, 2-cyano-5H-dibenz[b,f]-azepine-5-carboxamide, m.p. from 284[deg] with decomposition (from methylene chloride). The starting material is manufactured as follows: a) Analogously to Example 1a),there is obtained from 27.2 g (0.1 mol) of 2-bromo-10,11-dihydro-5Hdibenz[b,f]azepine and 9 g of acetyl chloride in 300 ml of absolute toluene, 5-acetyl-2-bromo-10,11-dihydro5h-dibenz[d,b]azepine, m.p. 136 -142[deg] (crude product). b) Analogously to Example 1 b), there is obtained from 31.4 g (0.1 mol) of 5-acetyl-2-bromo-10.11dihydro-5H-dibenz[b,f]azepine and 17.8 g (0.1 mol) of N-bromo-succinimide in 350 ml of carbon tetrachloride, after treatment with 60 g of potassium hydroxide in 300 ml of absolute ethanol, 2-bromo-5H-dibenz[b,f]azepine, m.p. 111-113[deg] (from hexane). c) Analogously to Example 5c), there is obtained from 27.2 g (0.1 mol) of 2-bromo-5H-dibenz[b,f]azepine, 10.7 g (0.12 mol) of copper cyanide and 50 ml of dimethylformamide, 5H-dibenz[b,f]azepine-2-carbonitrile, m.p.171 -173[deg] (from methylene chloride).

Example 7: 25.6g (0.1 mol) of 5H-dibenz[b,f]azepine-5-carbonyl choride (cf. GB-PS 906,452) are dissolved at 70[deg], while stirring, in 600 ml of absolute ethanol. Gaseous methylamine is introduced into this solution over a period of 2 hours, the reaction solution being boiled constantly under reflux. The reaction mixture is then concentrated by evaporation in a rotary evaporator and the residue is stirred with water. The product is filtered with suction, washed well with water and then dried in a vacuum enclosure at 70[deg]. After recrystallisation from ethanol, N-methyl-5H-dibenz[b,f]azepine-5-carboxamide, m.p. 210 - 212[deg], is obtained. In an analogous manner, N,10-dimethyl-5H-dibenz[b,f]azepine-5-carboxamide is obtained using 27.0 g (0.1 mol) of 10-methyl-5H-dibenz[b,f]azepine-5-carbonyl chloride (cf. CH-PS 403,767).

Example 8: 11.5 g (0.5 mol) of sodium are dissolved in 2000 ml of absolute ethanol while stirring. 24 g (0.5 mol) of gaseous methyl mercaptan are introduced into this solution at 20 -40[deg]. 25.1 g (0.1 mol) of 1 a,10b-dihydro-6Hdibenz[b,f]oxireno[d]azepine-6-carboxamide (cf. DE-OS 2,246,842) are then added and the mixture is boiled under reflux for 12 hours. The reaction mixture is then concentrated by evaporation in vacuo and the residue is stirred with 1500 ml of water and 300 ml of diethyl ether for 3 hours at 2 - 5[deg]. The suspension is filtered with suction and washed with water and diethyl ether. The moist 10-methylthio-5H-dibenz[b,f]azepine-5carboxamide is dried in vacuo at 80[deg] and has a melting point after recrystallisation from methanol of 175 177..

Example 9:

product is filtered with suction and washed with 2N acetic acid, then with water and finally with acetone. After drying in a vacuum enclosure at 100[deg], the substance has a melting point of 275 -278[deg] with decomposition.

Example 10:

into a solution of 19.8 g (0.2 mol) of phosgene in 350 ml of toluene. The mixture is boiled under reflux for 20 hours while constantly introducing phosgene. It is then concentrated to dryness by evaporation in a rotary evaporator, 50 ml of petroleum ether/ether(2:1) are added and the whole is cooled to 5[deg] while stirring. The crystallized 10-fluoromethyl-10,11-dihydro-5H-dibenz[b,f]azepine-5-carbonyl chloride is then filtered with suction and dried; m.p. 154-158[deg]. The above product is dissolved in 400 ml of 95 % ethanol while stirring at 70[deg]. Ammonia gas is introduced into this solution for 5 hours, the reaction solution being maintained constantly at reflux. The reaction mixture is then concentrated to dryness by evaporation in a rotary evaporator and the residue is stirred with water and a little ice-cold ether. The crystallised 10-fluoromethyl-10,1 1-dihydro-5H-dibenz[b,f]azepine-5carboxamide is filtered with suction, washed with a little water and cold ether and dried; m.p. 172 -174[deg].The starting material can be manufactured,for example, as follows: a) 31.3 g (0.1 mol) of 10-bromo-5-acetyl-5H-dibenz[b,f]azepine are stirred at 150[deg] for 70 hours in an autoclave with 83.2 g (0.42 mol) of trifluoromethyl iodide and 31.6 g (0.5 mol) of copper powder in 250 ml of dimethylformamide. 200 ml of dimethylformamide are then distilled off in a rotary evaporator and the residue is extracted 4 times with 800 ml of ether each time. The combined ether extracts are 3 times washed with water and dried over sodium sulphate. After clearing with diatomaceous earth and carbon, the ether solution is concentrated to 50 ml and cooled to 5[deg].The crystallised 10-fluoromethyl-5-acetyl-5Hdibenz[b,f]azepine is filtered with suction and dried; m.p. 144-147[deg]. b) 30.3 g (0.1 mol) of 10-trifluoromethyl-5-acetyl-5H-dibenz[b,f]azepine are heated under reflux for 21/2 hours, while stirring, in a solution of 30 g of postassium hydroxide pellets (85 %) in 120 ml of ethanol. The reaction mixture is then poured into 900 ml of water and extracted 3 times with 300 ml of ether each time. The combined ether extracts are washed twice with water and then dried over sodium sulphate. The solvent is distilled off in a rotary evaporator.The oily residue is dissolved in 90 ml of hexane and 10 ml of ether. 10-trifluoromethyl-5H-dibenz[b,f]azepine crystallises on cooling to 20[deg] and is filtered with suction and dried; m.p. 123 -126[deg]. c) 26.1 g (0.1 mol) of 10-trifluoromethyl-5H-dibenz[b,f]azepine are hydrogenated for 40 hours at normal pressure in 500 ml of ethyl acetate with 4.4 g of 10 % Pd/C at 20 - 22[deg]. The catalyst is then filtered off and the filtrate is concentrated by evaporation in a rotary evaporator. The oily residue is purified by chromatography

ether/toluene (4: 1), m.p. 57 - 59[deg].

Example 11: Analogously to Example 1, there is manufactured from 26.1 g (0.1 mol) of 10-trifluoromethyl-5Hdibenz[b,f]azepine and 19.8 g (0.2 mol) of phosgene in 350 ml of toluene, 10-trifluoromethyl-5Hdibenz[b,f]azepine-5-carbonyl chloride; m.p. 140 -144[deg]. This is converted likewise according to Example 1,

194-196[deg].

Example 12: 28.2 g (0.1 mol) of 10-methylthio-5H-dibenz[b,f]-azepine-5-carboxamide are heated under reflux for hours with 130 ml of 30 % hydrogen peroxide in 600 ml of ethanol. The reaction mixture is then concentrated to dryness by evaporation in a rotary evaporator. The residue is dissolved in 100 ml of acetone and 500 ml of absolute ether are added. 10-methylsulphinyl-5H-dibenz[b,f]azepine-5-carboxamide is filtered with suction and dried; m.p.242-247[deg].

Example 13 In a manner analogous to that described in Examples 1 -12, it is also possible to manufacture:

Example 14: 10-methoxy-11-methyl-5h-dibenz[b,f]azepine-5-carboxamide, 10-cyano-11-methoxy-5H-dibenz[b,f]azepine-5-carboxamide, 10-bromo-5H-dibenz[b,f]azepine-5-(N-methyl)carboxamide, 10-cyano-5H-dibenz[b,f]azepine-5-(N-methyl)carboxamide, 3,7-dichloro-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, 3,7-dimethyl-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide,

3-methylthio-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, 3-dimethylsulphamoyl-10,11-dihydro-5H-dibenz[b,f]-azepine-5-carboxamide 5-[(1-piperidinyl)-carbonyl]-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine, 5-[(-piperidinyl)-carbonyl]-10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine,

Tablets, each containing 25 mg of 3-methylsulphonyl-5H-dibenz[b,f]azepine-5-carboxamide, can be manufactured as follows: Composition (for 1000 tablets)

The active ingredient is mixed with the lactose and 146 g of the potato starch, the mixture is moistened with an alcoholic solution of the gelatin and granulted through a sieve. After drying, the rest of the potato starch, the talcum, the magnesium stearate and the highly dispersed silica are admixed and the mixture is pressed to form tablets each weighing 73.0 mg and having the above content of active ingredient; if desired, the tablets can be provided with dividing notches for more accurate dosaging. Instead of the above-mentioned active ingredient, it is also possible to use, for example, the same amount of 10-methylthio-5H-dibenz[b,f]azepine-5-carboxamide. In an analogous manner, it is also possible to manufacture tablets containing a different compound of the general formula I selected from those mentioned in the Examples or mentioned specifically in the description.

Claims (1)

1. Novel 5H-dibenz[b,f]azepine-5-carboxamides of the general formula I

in which R1 and R2, independently of one another each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the symbols X, and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl trifluoromethyl, lower alkoxy, halogen having an atomic number of up to and including 35 or cyano and the other represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, or both symbols X1 and X2 represent hydrogen, X3 represents lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or

represents halogen or cyano and X2 or X1 (as the case may be) represents hydrogen, Ri represents hydrogen or lower alkyl and R2 represents lower alkyl, or R, together with R2 represents lower alkylene or ethyleneoxyethylene, or when X1 or X2 represents lower alkoxy and X2 or X, (as the case may be) represents hydrogen and R1 together with R2 represents lower alkylene or ethyleneoxyethylene, X3 may alternatively represent hydrogen, X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals, and the symbols Y, and Y2 each represent hydrogen when one of the symbols X1 and X2 represent lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl

represent lower alkylene or ethyleneoxyethylene and X, together with Y1 represents oxo and X2 and Y2 represent hydrogen, or X, represents hydroxy and X2, Y1 and Y2 represent hydrogen, or R, and R2, independently of one another, each represents lower alkyl or together represent lower alkylene or

hydrogen, X3 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl, and X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals. 2. Novel 5H-dibenz[b,f]azepine-5-carboxamides of the general formula I

another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X1 and X2 and/orthe symbol X3 represent(s) lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl or X3 alternatively represent halogen having an atomic number of up to 35, di-lower alkylsulphamoyl, lower alkyl, cyano or lower alkoxy and the (two) remaining symbol(s) of the symbols Xi, X2 and X3 represent(s) hydrogen, provided that X1 or X2, when at least one of the radicals Ri and R2 is otherthan hydrogen and lower alkyl or one of the radicals X3 and X4 is other than hydrogen and Y, and Y2 represent an additional bond, may also represent lower alkoxy, and X2 or X1 (as the case may be) may represent hydrogen, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those

alternatively each represent hydrogen, or, if at least one of the radicals R1 and R2 is otherthan hydrogen and X3 and X4 represent hydrogen, X1 may alternatively represent halogen having an atomic number of up to 35 or cyano, X2 may represent hydrogen and Y, and Y2 may together represent an additional bond. 3. Compounds according to claim 2, with the proviso that, in compounds of the formula I in which X1 and

R2 represent hydrogen, and X4 is other than halogen if X3 represents halogen.

hydrogen or lower alkyl or, together, represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or

having an atomic number of up to and including 35 or cyano, and the other represents hydrogen, or both represent hydrogen or, independently of one another, each represents lower alkylthio, lower alkylsulphinyl,

R2 represent lower alkylene or ethyleneoxyethylene and X2 or X1 (as the case may be) represents hydrogen, or X1 and X2, independently of one another, each represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, represents hydrogen, or, when one of the symbols X1 and X2 represents hydrogen and the other represents lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, or both symbols X1 and X2 represent hydrogen or, independently of one another, each represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, X3 represents lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, di-lower alkylsulphamoyl or

and X2 is other than hydrogen, X3 represents cyano, and X4 represents hydrogen, or one of the radicals X3 and X4 represents lower alkyl or halogen and the other represents lower alkyl, or, when at least one of the

represent an additional bond or, when X1 and X2 both represent hydrogen, they also each represent hydrogen.

5. Compounds according to claim 1 in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl and the other represents hydrogen, X3 represents hydrogen, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano, halogen having an atomic number of up to 35, di-lower alkylsulphamoyl, lower alkyl or lower alkoxy, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals, and Y, and Y2 together represent an additional bond or each represents hydrogen. 6. Compounds according to any one of claims 1 to 4 in which R, and R2, independently of one another, each represent hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, X1 and X2 represent hydrogen, X3 represents halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals, and Y, and Y2 each represent hydrogen or, when at least one of the radicals R1 and R2 is other than hydrogen or X3 is other than cyano or X4 is other than halogen, they together represent an additional bond. 7. Compounds according to any one of claims 1, 2 and 4 in which one of the symbols R1 and R2 represents lower alkyl and the other represents hydrogen, or R, and R2 both represent lower alkyl or together represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents halogen having an atomic number of up to and including 35 or cyano and the other, as well as X3 and X4, represents hydrogen, Y, and Y2 together representing an additional bond.

hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, X1 and Y1 together represent oxo and X2 and Y2 each represent hydrogen, or Xi represent lower alkoxy or hydroxy and X2, Y, and Y2 each represent hydrogen, X3 represents halogen having an atomic number of up to and including 35, lower alkyl, lower alkoxy, also lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano or di-lower alkylsulphamoyl or, when R1 and R2 together represent lower alkylene or ethyleneoxyethylene, X3 represents hydrogen, and X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals.

X3 represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, di-lower alkylsulphamoyl having up to and including 4 carbon atoms in each alkyl moiety, lower alkyl or lower alkoxy having up to and including 4 carbon atoms, halogen having an atomic number of up to and including 35, ortrifluoromethyl, X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent lower alkyl, and Y1 and Y2 each represent hydrogen or together represent an additional bond. 10. Compounds according to claim 1 in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl that has up to and including 4 carbon atoms, one of the radicals X1 and X2 represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, trifluoromethyl or, when at least one of the radicals R1 and R2 represents lower alkyl, it represents halogen having an atomic number of up to and including 35 or cyano, and the other, as well as X3 and X4, represents hydrogen and Y, and Y2 together represent an additional bond.

X4 represent hydrogen and a radical R1 or R2 that is other than hydrogen represents lower alkyl having up to and including 4 carbon atoms, a radical Xi or X2 that is other than hydrogen represents lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, or trifluoromethyl, and a radical X3 that is other than hydrogen represents loweralkylthio, lower alkylsulphinyl or lower alkylsulphonyl each having up to and including 4 carbon atoms, di-lower alkylsulphamoyl having up to and including 4 carbon atoms in each alkyl moiety, lower alkyl or lower alkoxy having up to and including 4 carbon atoms, halogen having an atomic number of up to and including 35, or trifluoromethyl, and Y, and Y2 together represent an additional bond.

12. 3-Methylsulphonyl-5H-dibenz[b,f]azepine-5-carboxamide.

14. 3-Methoxy-5H-dibenz[b,f]azepine-5-carboxamide.

15. 3-(Dimetylsulphamoyl)-5H-dibenz[b,f]azepine-5-carboxamide.

16. 2-Cyano-5H-dibenz[b,f]azepine-5-carboxamide. 17. N-Methyl-5H-dibenz[b,f]azepine-5-carboxamide.

19. 10-Methylthio-5H-dibenz[b,f]azepine-5-carboxamide.

20. 10-Methylsulphonyl-5H-dibenz[b,f]azepine-5-carboxamide.

21. 10-Trifluoromethyl-5H-dibenz[b,f]azepine-5-carboxamide.

23. 10-Methoxy-11-methyl-5H-dibenz[b,f]azepine-5-carboxamide.

24. 10-Cyano-5H-dibenz[b,f]azepine-5-(N-methyl)carboxamide.

25. 3,7-Dichloro-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

26. 3,7-Dimethyl-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

27. 2,8-Dimethyl-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

28. 3-Methylthio-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

29. 3-Dimethylsulphamoyl-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

31. 3-Chloro-5H-dibenz[b,f]azepine-5-carboxamide.

32. 5-[(1-Piperidinyl)-carbonyl]-10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine. 33. 5-[(1-Piperidinyl)-carbonyl]-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine.

34. 3-Methylsulphonyl-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide.

36. 5H-Dibenz[b,f]azepine-5-carboxamides of the general formula I

another, represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, lower alkoxy, halogen having an atomic number of up to and including 35 or cyano and the other represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, or both symbols X, and X2 represent hydrogen, X3 represents lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl or, when at least one of the radicals X1 and X2 is other than hydrogen and X, or X2 represents halogen or cyano and X2 or X1 (as the case may be) represented hydrogen, R, represents hydrogen or lower alkyl and R2 represents lower alkyl, or R, together with R2 represents lower alkylene or ethyleneoxyethylene, X3 may alternatively represent hydrogen, X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals, and the symbols Y1 and Y2 each represent hydrogen when one of the symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl ortrifluoromethyl and the other represents hydrogen or both represent hydrogen or

is other than cyano or at least one of the radicals X3 and X4 is other than halogen, the symbols Y1 and Y2 together represent an additional bond, or in which R, and R2 together represent lower alkylene or

represents hydroxy and X2, Y, and Y2 represent hydrogen, or R1 and R2, independently of one another, each represents lower alkyl or together represent lower alkylene or ethyleneoxyethylene, X1 together with X2 represents epoxy or epimethylene and Y1 and Y2 each represent hydrogen, X3 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl, and X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals, for use in a method for the therapeutic treatment of the human or animal body. 37. Compounds according to claim 36 in which R, and R2, independently of one another, each represents hydrogen or lower alkyl or, together, represent lower alkylene or ethyleneoxyethylene, one of the symbols X, and X2 represents lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or

having an atomic number of up to and including 35 or cyano, and the other represents hydrogen, or both represent hydrogen or, independently of one another, each represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, the symbol X3, when X1 or X2 represents halogen or cyano and X2 or X1 (as the case may be) represents hydrogen, or X, and X2, independently of one another, each represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, represents hydrogen, or, when one of the symbols X1 and X2 represents hydrogen and the other represents lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, or both symbols X, and X2 represent hydrogen or, independently of one another, each represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, X3 represents lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, di-lower alkylsulphamoyl or halogen having an atomic number of up to and including 35, or,

represents hydrogen, or one of the radicals X3 and X4 represents alkyl or halogen and the other represents lower alkyl, or, when at least one of the radicals X, and X2 is other than hydrogen, both represent halogen, and the symbols Y, and Y2 together represent an additional bond or, when X, and X2 both represent hydrogen, they also each represent hydrogen, for use according to claim 36.

38. Compounds according to claim 36 in which X, represents lower alkoxy, R, and R2 represent hydrogen or lower alkyl, X2, X3 and X4 each represent hydrogen and Y1 and Y2 together represent an additional bond, or a compound according to any one of the claims 1 to 35 for use according to claim 36, for example as a nootropic drug.

39. 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide for use according to claim 36.

40. N-methyl-10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide for use according to claim 36.

41. N,N-dimethyl-1 0-methoxy-5H-diberiz[b,f]azepine-5-carboxamide for use according to claim 36.

42. N-butyl-10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide for use according to claim 36.

43. N,N-dimethyl-1 0-methoxy-5H-dibenz[b,f]azepine-5-carboxamide for use according to claim 36. 44. Pharmaceutical preparations containing a compound according to any one of claims 2 to 4, 6 to 8, 12 to 20 and 37 to 43 in addition to customary pharmaceutical adjuncts and/or carriers.

45. Pharmaceutical preparations containing a compound according to any one of claims 1, 3, 5; 9 to 11 and 21 to 36 in addition to customary pharmaceutical adjuncts and/or carriers. 46. Process forthe manufacture of novel 5H-dibenz-[b,f]azepine-5-carboxamides of the general formula I

in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, lower alkoxy, halogen having an atomic number of up to and including 35 or cyano and the other represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl, or both symbols X1 and X2 represent hydrogen, X3 represents lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl or, when at least one of the radicals X1 and X2 is other than hydrogen and X, or X2

hydrogen and R1 together with R2 represents lower alkylene or ethyleneoxyethylene, X3 may alternatively represent hydrogen, X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals, and the symbols Y1 and Y2 each represent hydrogen when one of the symbols X1 and X2 represent lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl

hydrogen, X3 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, halogen having an atomic number of up to and including 35, cyano or di-lower alkylsulphamoyl, and X4 represents hydrogen or, if X3 represents lower alkyl or halogen, X4 may instead also represent one of those radicals, characterised in that a) a compound of the general formula II

in which Z represents a halogen atom, is reacted with a compound of the general formula III

b) a compound of the general formula IV

in which Ri, R2, X3 and X4 have the meanings given under formula I, is reacted with a lower alkyl mercaptan or an alkali metal-lower alkyl mercaptide to form a compound of the general formula I in which X1 or X2 represents lower alkylthio, X2 or X1 (as the case may be) represents hydrogen and Y, and Y2 together represent an additional bond and Ri, R2, X3 and X4 have the meanings given under formula I, or c) in a compound of the formula

to form the corresponding 0=C(NRiR2) group, and, if desired, a compound of the general formula I in which X1 or X2 represents lower alkoxy and Y, and Y2 together represent an additional bond is hydrolysed to form the corresponding compound in which X, represents hydroxy or to form the tautomeric oxo compound and,

lower alkylthio is oxidised to form the corresponding compound of the general formula I in which X1, X2 and/or X3 represents lower alkylsulphonyl or lower alkylsulphinyl. 47. Process for the manufacture of novel 5H-dibenz[b,f]azepine-5-carboxamides of the general formula I

in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X1 and X2 and/or the symbol X3 represent(s) lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl or X3 alternatively represents halogen having an atomic number of up to 35, di-lower alkylsulphamoyl, lower alkyl, cyano or lower alkoxy and the (two) remaining symbol(s) of the symbols X1, X2 and X3 represent(s)

lower alkyl or one of the radicals X3 and X4 is other than hydrogen and Y1 and Y2 represent an additional bond, may also represent lower alkoxy, and X2 or X1 (as the case may be) may represent hydrogen, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those

alternatively each represent hydrogen, or, if at least one of the radicals R1 and R2 is other than hydrogen and X3 and X4 represent hydrogen, X1 may alternatively represent halogen having an atomic number of up to 35

characterised in that a) a compound of the general formula II

in which Z represents a halogen atom, is reacted with a compound of the general formula III

or b) a compound of the general formula IV

in which R1, R2, X3 and X4 have the meanings given under formula I, is reacted with a lower alkyl mercaptan or an alkali metal-lower alkyl mercaptide to form a compound of the general formula I in which X, or X2 represents lower alkylthio, X2 or X1 (as the case may be) represents hydrogen and Y, and Y2 together represent an additional bond and R1, R2, X3 and X4 have the meanings given under formula I, and, if desired, a compound of the general formula I in which X2, X2 and/or X3 represents lower alkylthio is oxidised to form

alkylsulphonyl or lower alkylsulphinyl.

48. Process according to claim 47, characterised in that compounds of the general formula I are manufactured in which X3 is other than cyano and R1 and/or R2 are (is) other than hydrogen or at least one of

additional bond. 49. Process according to claim 46, characterised in that compounds of the general formula I in which R1 and R2, independently of one another, each represents hydrogen or lower alkyl or, bonded to one another, represent lower alkylene or ethyleneoxyethylene, one of the two symbols X1 and X2 represents lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl or trifluoromethyl and the other represents hydrogen, X3 represents hydrogen, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, trifluoromethyl, cyano, halogen having an atomic number of up to 35, di-lower alkylsulphamoyl, lower alkyl or lower alkoxy, X4 represents hydrogen or, if X3 represents halogen or lower alkyl, X4 may instead also represent one of those radicals, and Y1 and Y2 together represent an additional bond or each represents hydrogen, are manufactured. 50. Process for the prophylaxis and/or treatment of cerebral insufficiency, characterised by the oral or rectal administration of a compound as claimed in anyone of claims 1 to 43.

51. The novel compounds obtainable in accordance with the process of any one of claims 46 to 49, the novel starting materials used and novel intermediates formed.