US3539573A - 11-basic substituted dibenzodiazepines and dibenzothiazepines - Google Patents

Description

United States Patent 3,539,573 ll-BASIC SUBSTITUTED DIBENZODIAZEPINES AND DIBENZOTHIAZEPINES Jean Schmntz, Pourtalesstrasse 36, Muri, near Bern, Switzerland, and Fritz Hunziker, Wabernstrasse 53, Bern, Switzerland N 0 Drawing. Continuation-impart of applications Ser. No. 532,856, Mar. 3, 1966, and Ser. No. 712,956, Mar. 14, 1968; said Ser. No. 532,856 is a continuation-in-part of applications Ser. No. 282,561, May 23, 1963, and Ser. No. 347,986, Dec. 12, 1963, which are continuationsin-part of application Ser. No. 130,755, Aug. 11, 1961. This application Oct. 21, 1968, Ser. No. 769,373

Claims priority, application Switzerland, Aug. 16, 1960, 9,276/60; Dec. 2, 1960, 13,542/ 60; July 20, 1961, 8,529/61; May 25, 1962, 6,350/62; Dec. 5, 1962, 14,251/62, 14,252/62, 14,253/62; Feb. 15, 1963, 1,902/63; Mar. 22, 1967, 4,103/ 67; July 11, 1967, 10,115/ 67; Nov. 3, 1967, 15,453/67 Int. Cl. C07d 93/42, 53/06 U.S. Cl. 260-268 8 Claims ABSTRACT OF THE DISCLOSURE (A) ll-basic substituted dibenzodiazepines and dibenzothiazepines having the general Formula A:

wherein Z denotes a member of the class consisting of bivalent sulfur, imino, and lower alkyl imino; R is a member of the class consisting of hydrogen and alkyl with l to carbon atoms, and R is a member of the class consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, phenyl, R -substituted phenyl, aminoalkyl having from 1 to 5 carbon atoms, lower alkylated aminoalkyl having from 2 to 8 carbon atoms, amino, and lower alkylated amino; or R and R together with N form a member of the class consisting of l-pyrrolidinyl, piperidino, morpholino, thiomorpholino, l-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower hydroxyalkyl)-1-piperazinyl and 4-(lower alkoxy-lower alkyl)-1-piperazinyl; and R R and R are members of the class consisting of hydrogen, halogen, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, and lower alkylthio; and (B) ll-basic substituted dibenzodiazepines and dibenzothiazepines having the general Formula B:

wherein Z denotes a member of the group consisting of sulfur, sulphinyl and imino; R' represents a member of the group consisting of hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxyalkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms and alkoyloXyalkyl containing not more than 6 carbon atoms; and R is a member of the group consisting of nitro, amino, aminosulphonyl of the formula SO NR R' wherein R' and R, are the same or different members of the group con sisting of hydrogen and methyl, alkylsulphinyl of the formula SOR' wherein R denotes alkyl with not more than 3 carbon atoms, and alkylsulphonyl of the formula SO R wherein R' denotes alkyl with not more than 3 carbon atoms; and (C) the nontoxic pharmaceutically acceptable acid-addition salts of (A) and (B).

These compounds are particularly active as neuroplegics, neuroleptics, neuroleptic antidepressants, anticmetics, analgesics, sedatives, parasympathicolytics and antihistaminics.

This is a continuation-in-part application of our copending patent applications Ser. No. 532,856, filed Mar. 3, 1966, and Ser. No. 712,956, filed Mar. 14, 1968, the former being in turn a continuation-in-part application of our copending applications Ser. No. 282,561, filed May 23, 1963, and Ser. No. 347,986, filed Dec. 12, 1963, which were copending with application Ser. No. 130,755, filed Aug. 11, 1961; each of the above mentioned applications now abandoned.

The object of the present invention is to provide 11- basic-substituted dibenzo[b,e][l,4]diazepines and dibenzo[b,f][l,4]thiazepines useful for producing such pharmacologically signficant action in standardtest animals as analgesic action, sedative and motility depressing action, parasympatholytic action, antihistaminic action, antitetrabenazine action and apomorphinantagonistic action. These compounds can also be embodied in therapeutically useful forms for use as analgesics, antihistaminics, sedative and motility depressing agents, parasympatholytic agents, antiallergics, adrenolytics, neuroplegics, neuroleptics, neuroleptic antidepressants and antiemetics.

A further object of the invention is to provide ll-basic substituted dibenzo[b,e] [1,4]diazepines and dibenzo[b,f] [1,4]thiazepines having the above-mentioned actions of the general formula:

and acid addition salts thereof. In Formula I, Z denotes bivalent sulfur, imino, or lower alkyl imino; R represents hydrogen or alkyl with l to 5 carbon atoms; R denotes hydrogen, alkyl with '1 to 5 carbon atoms, phenyl, R substituted phenyl, aminoalkyl with 1 to 5 carbon atoms, lower alkylated aminoalkyl with 2 to 8 carbon atoms, amino, or lower alkylated amino; or R and R together with N form l-pyrrolidinyl, piperidino, morpholino, thiomorpholino, l-piperazi-nyl, 4-(lower alkyl)-l-piperazinyl, 4-(lower hydroxyalkyl)-1-piperazinyl and 4-(lower alkoxy-lower alkyl)-l-piperazinyl; and R R and R are the same or different and denote hydrogen, halogen, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio; the term lower meaning that the corresponding alkyl, alkoxy, etc., residues contain from 1 to 3 carbon atoms.

A further object of the invention is to provide ll-basic substituted dibenzo[b,e][1,4]diazepines and dibenzo 3 [b,f] [1,4] thiazepines having the above-mentioned actions of the general formula:

and acid addition salts thereof. In Formula II, Z denotes sulfur, sulphinyl (SO) or imino (NH--), R represents hydrogen, allyl, alkyl containing not more than 3 carbon atoms, hydroxyalkyl containing not more than 3 carbon atoms, alkoxyalkyl containing not more than 6 carbon atoms or alkoyloxyalkyl containing not more than 6 carbon atoms. R denotes nitro; amino; aminosulphonyl of the formula -SO NR' R' wherein R;.; and R' are the same or different and represent hydrogen or methyl; alkylsulphinyl of the formula -SOR' wherein R' denotes alkyl with not more than 3 carbon atoms; or alkylsulphonyl of the formula -SO R' in which R' represents alkyl with not more than 3 carbon atoms.

The compounds of Formula I are obtained by treating a reaction mixture containing nitrilium of irnonium cations of the general formulae:

R3 R4 R3 wherein Y denotes bivalent sulfur, lower alkyl imino, or acyl imino, and R and R have the meaning stated above; with ammonia or an amine of the formula HNR R wherein R and R have the meaning stated above, and subsequently splitting off a protecting acyl residue.

The starting reaction mixture containing the cations of Formula III is, for instance, obtained from compounds of the formula:

wherein Y, R and R have the meaning stated above, and wherein A represents halogen, lower alkoxy, lower alkylthio or p-nitrobenzylthio. The latter compounds, in turn, can be prepared by thermal cyclization of o-aminodiphenylamino-o-carboxy1ic acids to form lactams of the formula:

NHC O and by treatment thereof with a halogenizing agent, such as phosphoroxychloride, phosphorus pentachloride or a mixture thereof, preferably in the presence of a catalytic amount of dimethylaniline or dimethylformamide, or by treatment of the lactams (V) with phosphorus pentasulfide to build the corresponding thiolactams, whose tautomeric form can be alkylated to build the imido thio ethers. In accordance with this finding, it is not necessary to isolate the imido compounds of Formula IV, which in part are not stable, as intermediate compounds, but the reaction with the amine having the formula HNR R can directly be performed using the reaction mixture which contains the nitrilium or imoni-um cations of Formula III.

The cations of Formula III can further be prepared, for example, by intramolecular Ritter reaction (reaction of the nitrile radical with a phenyl cation) from ocyanodiphenyla-mines or o-cyanodiphenylsulfides, by Beckmanns rearrangement of acridone oxime or thioxanthone oxime, which may be suitably substituted, or by Schmidt reaction of acridone or thioxanthone, which may be substituted, with hydrazoic acid. Starting with unsymmetrically substituted oximes or -ketones, Beckmanns rearrangement and the Schmidt reaction, however, yield mixtures of isomers, which subsequently must be separated, if necessary.

The compounds of Formula I are also obtained by exposing a urea derivative corresponding to the formula:

wherein Y, R R R and R have the meaning stated above, to dehydrating conditions, e.g., through several hours action by dehydrating agents, such as zinc dichloride, aluminium chloride, tin tetrachloride, phosphoric acid and the like, if required in the presence of an inert solvent of suitable boiling point, such as benzene, toluene, etc., but preferably through heating with phosphoroxychloride in toluene in accordance with the Bischler- Napieralski reaction. Those products (I) in which Z is imino are obtained by this process, setting out from corresponding compounds wherein Y is acyl imino, by splitting off the acyl residue after successful ring closure.

Products of Formula I are further obtained by ring closure by intramolecular condensation of acid amides or acid thio amides having the formula.

wherein R denotes oxygen or sulfur, and Z, R R R and R have the meaning stated above. A purely thermal condensation is, in general, not possible with the acid amides-which, in turn, are obtainable, for instance, by reduction of the corresponding nitro eompoundsbut rather with the acid thio amides, which can, for instance, be prepared by treatment of the acid amides with phosphorus pentasulfide, and which must not necessarily be isolated in order to be used in the subsequent condensation step. Especially when starting with the acid amides, the reaction will suitably be performed in the presence of condensation agents, such as phosphorus pentachloride, phosphoroxychloride, phosgene, polyphosphoric acid and so on. It is to be assumed that ring closure occurs over intermediate compounds, such as i'mide chlorides, amide chlorides, imido phosphates, amido phosphates and salt-like derivatives thereof, which in general cannot be isolated. The condensation of the acid thio amides may be favored by the presence of mercury salts or by formation of intermediate imido thio ethers, which may be activated. Heating and use of an inert diluent are indicated, and, when working with phosphoroxychloride and phosphorus pentachloride, also addition of catalytic amounts of dimethylaniline or dimethylformamide.

Insofar as, by these reactions, compounds of Formula I are obtained, wherein R and/or R denote hydrogen, radicals R and/or R other than hydrogen may subse quently be introduced, if desired, by reaction of the amines obtained with reactive esters of alcohols having the formulae R OH or R OH, respectively, preferably with esters of halohydric acids, sulfuric acid or toluene su1- phonic acid, if desired after previous or with simultaneous action of a basic catalyst of metallizing agent, such as sodium amide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate, or potassium tbutylate.

In the same way, a lower alkyl residue may be subsequently introduced in the 5-position of reaction products wherein Z denotes imino by reacting them with a reactive ester of lower alkanols, preferably after previous or with simultaneous action of a basic catalyst or metallizing agent.

On the other hand, in order to obtain products of Formula I, wherein Z denotes imino, a cleavable protecting residue occurring in the Y unit of the starting ma terial, can be split off after ring closure in known manner, for instance, by subjecting a S-acetyl or S-benzoyl derivative to selective hydrolysis, or by subjecting a S-carbobenzoxy derivative to hydrogenolysis.

Compounds of Formula II are obtained when a compound of the formula:

wherein Z and R' have the meaning defined above and X denotes a residue capable of being split off with the hydrogen of amines, is reacted with piperazine or a piperazine derivative, respectively, of the formula:

H (IX) wherein R, has the above-mentioned meaning.

A residue capable of being split off with the hydrogen of amines, which can be bound ionically or covalently to the carbon atom, can most conveniently be represented by halogen, sulphydryl, or alkoxy and alkylthio which may be activated e.g., methoxy, thiomethyl or p-nitrobenzylthio, or by tosyl.

Starting materials of the Formula VIII are obtained by converting lactams of the formula:

wherein Z and R have the above-mentioned meaning and R' denotes hydrogen or lower alkyl. For products wherein Z represents --S, lactams of Formula X may also be obtained by ring closure of a compound of the formula:

NHC o R2 SH Hal- (XII) 6 wherein Hal stands for halogen, or of isocyanates of the formula:

NCO Rz (XIII) Lactams of Formula X in which R' represents amino are most suitably obtained by reduction of the corresponding nitrolactams.

Compounds of Formula II may further be obtained by ring closure through intramolecular condensation of acid amides or acid thioamides of the formula:

wherein Z, R' and R' have the above-mentioned meaning and R represents oxygen or sulfur. A purely thermal condensation rarely succeeds with the acid amides but rather with the thioamides which are, for example, obtained from the acid amides by treatment with phosphorus pentasulphide and need not be isolated before the following condensation. Especially in the case of the acid amides it is desirable to perform the ring closure in the presence of condensing agents, such as phosphorus pentachloride, phosphorus oxychloride, phosgene, polyphosphoric acid, and the like. It is assumed that the ring closure proceeds by way of intermediate steps such as imidochlorides, amidochlorides, imidophosphates, amidophosphates or salt-like derivatives thereof, which, in general, are not isolatable. The condensation of the thioamides is favoured by the presence of mercury(II) salts or by intermediate formation of imidothioethers which may be activated. Heating and, if required, the use of a suitable inert solvent are desirable, and when using phosphorus oxychloride and phosphorus pentachloride addition of catalytic amounts of dimethylformamide or dimethylaniline.

ll-basic substituted dibenzo[b,f] [1,4]thiazepines (Formula I; Z=S) can also be obtained by dehydration of urea derivatives of the formula:

wherein R has the above-mentioned meaning and R-; means R' or denotes a removable group, especially a hydrolytically removable group. The ring closure is preferably carried out by heating in the presence of dehydrating agents such as Zinc chloride, aluminium chloride, stannic chloride, phosphoric acid, polyphosphoric acid and the like, especially phosphorus oxychloride or phosphorus oxychloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene, etc. According to the chosen reaction conditions the starting materials of Formula XV with a hydrolytically removable group R e.g., carbalkoxy, especially carbethoxy, are cyclicized directly to the ll-(l-piperazinyl) compounds by hydrolysis of the removable group. Other removable groups can be split off after ring closure in a way known per se, e.g., by hydrogenolysis.

As long as R does not denote amino, the compounds of Formula II can also be obtained when amidines of the formula:

(XVI) wherein Z' has the above-mentioned meaning and R";,, represents R' with exclusion of amino, are treated with a reactive ester of an alcohol of the formula:

HO-CHz-CHz (XVII) wherein R has the above-mentioned meaning. The reaction is carried out following or by simultaneous treatment with a basic catalyst or metallization agent such as sodamide, lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate or potassium-t-butoxide. Suitable esters are those of inorganic or organic acids, e.g. hydrohalic acid, sulphonic acid or carbonic acid esters. The required amidines XVI are in turn obtained by treating compounds of Formula VIII with ammonia.

On the other hand, compounds of Formula II, wherein R' is amino, may be obtained by reduction of the corresponding nitro compounds. The reduction is most suitably carried out by treatment with hydrogen in the presence of a catalyst such as palladium charcoal or Raney nickel or by treatment with stannous chloride and hydrochloric acid.

Compounds of Formula II, wherein Z denotes sulphinyl, are also obtained by oxidation, e.g., with periodates, of the corresponding compounds in which Z represents sulfur.

Compounds of Formula II, wherein R' represents alkylsulphinyl or alkylsulphonyl, respectively, can also be obtained by mild (e.g., with periodates) or strong (e.g., with hydrogen peroxide or peracetic acid) oxidation of the corresponding alkylthio compounds. Products wherein R';,, represents alkylsulphonyl are also obtainable by strong oxidation of the corresponding alkylsulphinyl compounds. If the oxidation is carried out on the dibenzo[b,f] [1,4] thiazepines (Z'=-S-) then, according to the type of oxidizing agent used, the corresponding thiazepine sulphoxides (Z'=SO) are obtained.

Finally, compounds of Formula II, wherein R' denotes aminosulphonyl of the formula SO NR' R' are obtained when the corresponding compounds containing the group SO X instead of aminosulphonyl, wherein X denotes a residue which is removable with the hydrogen of amines, especially halogen, are reacted with ammonia or an amine of the formula HNR' R wherein R' and R'.; have the above defined meaning. Starting materials containing a sulphochloride group (SO Cl) are obtained by diazotization of the corresponding amino compounds followed by the Meerwein reaction.

Compounds of Formula II, obtained according to one of these methods, wherein R represents hydrogen can be converted to such compounds wherein R does not represent hydrogen, e.g., by treatment with reactive esters of alcohols of the formula R' --OH. Hydrohalic acid or toluenesulphonic acid esters are suitable for this purpose. An alkyl group R' can also be introduced by the method of reductive alkylation, i.e., by reaction with corresponding aldehydes either with hydrogen in the presence of a catalyst or with a reducing agent such as formic acid. The introduction of a hydroxyalkyl group R' can also be carried out by treating with a corresponding alkylene oxide.

Compounds of Formula II in which R' denotes a hydroxyalkyl group can be subsequently treated with an acylating agent to obtain products wherein R' represents an alkoyloxyalkyl group. Acid chlorides and acid anhydrides are especially suitable as acylating agents.

Subsequent introduction of a group R' other than hydrogen, and also subsequent acylation of a hydroxyalkyl group R, can lead to additional substitution in products in which R' denotes an amino group; this amino group being additionally substituted.

The bases I or II obtained in this manner are in most cases crystallizable or can otherwise be distilled in high vacuum without decomposition and react with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, snccinic acid, tartaric acid, toluene sulphonic acid and the like to form addition salts which are stable in water, in which form the products may also be used.

The bases I and II as well as their acid addition salts are new compounds which can be used as active substances in pharmaceuticals.

The 8-chloro-l1-(4-methyl 1 piperazinyl)-5H-dibenzo[b,e][1,4]diazepine obtained according to Example 13 shows in animal experimentation the properties of a neuroplegic with intense analgesic sedative, parasympatholytic action. The analgesic action is determined by measuring the pain threshold during electrical stimulation of the dental pulp in the rabbit. It is compared in Table I below with the action of known analgesics.

The sedative and motility depressing effect may be seen from the moving activity test according to Caviezel and Baillod [Pharm. Acta Helv. 33, 469 (1958)] in the mouse. In this test, the EDSO in mg./kg. p.o. amounts to 2.5. Comparative figures will be seen in Table II below.

The 2-chloro-l1-(4-methyl-l-piperazinyl-dibenzo [b,f]- [1,4]thiazepine obtained according to Example 14 shows in animal experimentation, the properties of a neuroleptic agent with intense motility depressing action and antagonistic effect to apomorphine. The motility depressing action was determined by measuring the moving activity in the mouse in acordance with the method of Caviezel and Baillod [Pharm. Acta Helv. 33, 469 (1958)], as well as by the open-field test in the rat according to the method of Ianssen et al. [Psychopharmacologia 1, 389 (1960)], using 10 animals in each test. In Table II below, the average values obtained are compared with the corresponding data of known neuroleptics. Furthermore, Table II shows comparative data for the acute toxicity in the mouse as well as for cataleptic action. The latter was tested in rats, which, in several intervals after s.c. injection of divers amounts of active substance, were put with both front paws on a column of 7 cm. in altitude, measuring the duration of persistence of the animal in this unnatural 1 1 7-chloro-1 1- B-dimethylarnino-ethylamino -H-dibenzo [b,e] [1,41thiazepine, 5 -methyl-8-methoxy-1 1- (4-methyl-1-piperazinyl) -5H- dibenzo [b,e] [1,4] diazepine, 8-methyl-11-(fi-dimethylamino-ethylamino)-5H-dibenzo [b,e] [1,4] diazepine,

, 8-methyl-11-(4-methyl-1-piperazinyl)-dibenzo[b,f] [1,4]

thiazepine,

S-methoxy-l 1- (4-methyl-1piperazinyl)-dibenzo [b,f]

[l, 4]thiazepine, and 5 -methyl-1 1-(4-methy1-1-piperazinyl) -5H-dibenzo[b,e]

[1,4] diazepine.

Compounds which are representative of the compounds defined by Formula I and which exhibit pharmacologically significant antihistamine action in standard test animals are:

8-chloro-1 1-(4-methyl-1-piperazinyl) -5H-dibenzo [b,e]

[1,4] diazepine,

3-methyl-1 1- (4-methyl-1-piperazinyl) -dibenzo[b,f]

[ 1,4] thiazepine,

5-methyl-8-chloro-1 1-(4-methyl-1-piperazinyl) -5H- dibenzo [b,e] [1,4] diazepine,

11- 4-methyll-piperazinyl -5I-I-dib enzo [b,e] [1,4]

diazepine,

5 -n1ethyl-1 1- 4-methyll-piperazinyl -5H-dibenzo [b,e]

[1,4] diazepine,

3-methyl-1 1-(4-methyl-1-piperazinyl) -5H-dibenzo [b,e]

[1,4] diazepine,

8-methyl-1 1- (4-methyl-1-piperazinyl) -5H-dibenzo [b,e]

[1,4]diazepine,

3-chloro-1 1-(4-methyl-1-piperazinyl) -5H-dibenzo [b,e]

[1,4] diazepine,

3-methoxy-11-(4-methyl-1-piperazinyl)-5H-dibcnzo[b,e]

[1,4] diazepine,

8-chloro-11-(4-methyl-1-piperaziny1)-dibenzo[b,f]

[1,4] thiazepine,

8-methoxy-l 1- (4-methyll -piperazinyl) dibenzo [b,f]

[1,4] thiazepine,

2-chloro1 1-(fl-dimethylamino-ethylamino -dibenzo [b,f]

[1,4] thiazepine, and

2-methyl-1 1- (4-methyl-1-piperazinyl) -dibenzo [b,f]

[1,4] thiazepine.

Compounds of Formula II in which R denotes nitro show also the typical behaviour pattern for neuroleptics. As mentioned above, this manifests pharmacologically, e.g., in a suppression of locomotor activity, a cataleptic and/or an apomorphine antagonising effect in mice or rats, respectively. The most effective compounds in this respect are 2-nitro-11-(4-methyl-l-piperazinyD-dibenzo [b,f] [1,4]thiazepine, obtained according to Example 95, as well as its acid addition salts.

Certain compounds of Formulas I and II, especially those with ll-(l-piperazinyl) residues show simultaneously the behaviour pattern for neuroleptics and antidepressants whereby the antidepressant action is shown pharmacologically by a tetrabenazine antagonism observed in rats. Especially active in this respect are 2-nitro-11-(1-piperazinyl)-dibenzo[b,f][1,4]thiazepine obtained according to Example 101 and its acid addition salts.

Compounds of Formula II in which R represents aminosulphonyl or alkylsulphonyl exhibit a marked antiemetic activity. This is shown pharmacologically by a strong apomorphine antogonising eifect in dogs and rats as well as a comparatively weak cataleptic and locomotor activity suppressing effect.

Pronounced antiemetic activity is shown by 2-dimethylaminosulphonyl 11 (4 methyl 1 piperazinyl) dibenzo[b,f] [1,4]thiazepine and 2-methylsulphony1-11-(4- methyl 1 piperaziny1)-dibenzo [b,f] [1,4]thiazepine obtained according to Examples 96 or 105, respectively, and their acid addition salts.

To further illustrate the pharmacological activity and the dosage levels in which the compounds of the present invention are used to provide an indicated pharmacological analgesic activity, the following data are given in Table III:

TABLE III Toxicity (mouse) LD5 Dose mgJkg mg./kg. Threshold i.v. i.v. current 1 1 In percent of the control values.

Table IV gives data on compounds which exhibit seda- Table V gives data on compounds which exihibit parasympatholytic action. This action is determined by the property of such substances to reduce or annul the hypotensive action which is otherwise observed in the narcotized cat upon electric stimulation of the Vagus nerve or upon administration of acetylcholine (ACH). In Table V those doses of inventive products are shown which cause reduction of the hypotensive action of Vaigus stimulation and ACH, respectively:

TABLE V Toxicity (mouse) Parasympatholytic action LD ED 5, mg./kg. i.v. lL/

i.v. Vagus stim. Upon ACH r Parasympatholytic product of Example No.2

rs swwws" Table VI gives data on compounds which exhibit antihistaminic action. The antihistaminic action is determined by the standard histamine asthma-test in the guinea pig. Upon p.o. administration of the test compound, the animals are put in an atmosphere containing histamine areosol. In the following Table VI those doses of inventive products are shown which protect 50% of the animals completely against histamine asthma during at least 10 minutes (ED The compounds of this invention can be administered in the form of pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration. The pharmaceutical preparations may be, for example, in the form of tablets, dragees, or solutions for injection.

EXAMPLE 1 A 10.0 g. quantity of methyl 7 methylthio-l0,11- dihydro 11 oxo 5H dibenzo[b,e][1,4]diazepine is heated under reflux conditions during 1 hour with g. of phosphor-us pentachloride in 350 ml. of dry chloroform. The yellow-red solution is concentrated to dryness in vacuo. The residue is heated under reflux for 3 hours with 38 ml. of N-methylpiperazine in 160 ml. of absolute dioxane. Upon concentration in vacuo of the dioxane solution as far as possibe, the residue is distributed between diluted soda lye and benzene. The biphasic solution is separated from undissolved substance by filtration. After washing of the benzenic phase with water, the alkaline material is extracted by shaking with diluted acetic acid, freed by addition of ammonia and dissolved in benzene. The benzenic phase is Washed with water, dried over sodium sulfate and concentrated. After clarifying with alumina, the residual solvent is evaporated. The residue crystallizes spontaneously from ether and, after recrystallization from acetone/petroleum ether, yields 6.9 g. (52% of the theoretical amount) of 5 methyl 7-methylthio-11-(4-methyl- 1 piperazinyl) 5H dibenzo [b,e] [l,4]diazepine in the form of yellow prisms, having a melting point of 171- 173 C.

EXAMPLE 2 8.4 g. of 3 methyl 10,11-dihydro-11-oxo-dibenzo [b,f] [1,4]thiazepine are heated for 2 hours under reflux with 9 g. of phosphorus pentachloride in 120 ml. of dry chloroform. Upon evaporation to dryness in vacuo, 30 ml. of N-methylpiperazine are slowly added; then heating under reflux is continued for further 3 hours. The reaction mixture is worked up as in Example 1, with the exception that ether is used in place of benzene in the extraction step. The 3 methyl 11 (4-methyl-1-piperazinyl)-dibenzo [b,f] [1,4] thiazepine distills at 178 C./0.02 mm. Hg. and can be crystallized from ether/ petroleum ether. The yield is 6.9 g. (61% of the theoretical) of faint yellow prisms having a melting point of 92-95 C.

EPQAMPIJE 3 A solution of 9.6 g. of 5 methyl 8 chloro-l0,11-dihydro 11 oxo 5H-dibenzo[b,e] [1,4] diazepine in ml. of phosphoroxychloride, containing 3 ml. of dimethylaniline, is heated for 2 hours under reflux. The dry residue obtained upon evaporation of the reaction mixture in vacuo, is mixed with 50 ml. of N-methylpiperazine in 40 ml. of dioxane and heated under reflux for 4 hours. Working up of the reaction mixture as in Example 2 yields 8.1 g. (66% of the theoretical amount) of S-methyl-S- chloro 11 (4 methyl-l-piperazinyl)-5H-dibenzo[b,e] [l,4]diazepine in the form of reddish-yellow plates of melting point 164-165 C. (from ether/ petroleum ether).

EXAMPLE 4 11.8 g. of 10,11 dihydro 11 oxo-5H-dibenzo[b,e] [l,4]diazepine, 0.4 ml. of dimethylformamide and 8.6 g. of phosphoroxychloride in ml. of dry chloroform are agitated during 2 hours under reflux conditions. Upon concentration of the reaction mixture to dryness in vacuo, the residue is heated under reflux for 4 hours with 30 ml. of absolute dioxane and 30 ml. of piperidine. The reaction mixture is worked up in the same manner as in Example 2, with the exception that diluted hydrochloric acid is used in place of acetic acid for isolating the base. 6.1 g. (39% of the theoretical yield) of 11 piperid-ino 5H dibenzo [b,e][1,4]diazepine are obtained in the form of yellow plates of melting point 129-131" C. (from ether/petroleum ether).

EXAMPLE 5 The reaction mixture obtained from 0.7 g. of potassium and 15 ml. of tertiary butanol is mixed with 4.4 g. of 7-chloro-1l-mercapto-5H. dibenzo[b,e] [l,4]diazepine in 50 ml. of dioxane and heated for 1 hour under reflux. Upon cooling, a solution of 3.5 g. of p-nitrobenzylchloride in 10 ml. of dioxane is added drop by drop with agitation, and the mixture is again refluxed during 2 hours and then concentrated to dryness in vacuo. The residue is distributed between Water and chloroform. The chloroformic solution is washed with diluted soda lye and water, dried over sodium sulfate and concentrated. Upon addition of petroleum ether, 7-chloro-l1-p-nitrobenzylmercapto-5I-I-dibenzo[b,e] [l,4]diazepine crystallizes in an amount corresponding to 79% of the theoretical yield. After recrystallization from acetone/petroleum ether the product has a melting point of l78182 C.

A solution of 4.6 g. of this product in 10 ml. of N- methylpiperazine, containing 3 drops of glacial acetic acid, is heated during 24 hours under reflux. The reaction mixture is concentrated to dryness in vacuo. The residue is distributed between ether and ammonia/water. The etheral solution is washed with water and extracted with 1 N acetic acid. The acid extract is clarified with charcoal, mixed with concentrated ammonia solution and saturated with sodium chloride. The alkaline precipitate is separated by filtration and recrystallized from acetone/ petroleum ether. 3.2. g. (85% of the theoretical yield) of 7-chloro-l1- (4-methyl-1-piperazinyl)-5H dibenzo[b,e] [l,4]diazepine are obtained, having a melting point of 179-181 C.

EXAMPLE 6 A 7.05 g. quantity of N-methyl-o-ureido-diphenylarnine is boiled under reflux conditions for 3 hours with 15 ml. of phosphoroxychloride in ml. of absolute toluene, whereupon a yellowish-red, syrupy product separates out. After evaporating the solvent, the residue is decomposed With dilute ammonia solution, the organic substance which forms as a vicous oil is dissolved in chloroform, and the chloroform extract is Washed with Water, dried over sodium sulfate and evaporated. As residue, there are obtained 6.58 g. of a yellow resinous product which solidifies with foam in vacuum and most of which on distribution between ether and diluted hydrochloric acid passes into the acid layer. From the hydrochloric acid extract, the base is liberated with ammonia, separated by suction and washed with water. After drying, the product is recrystallized from acetone/petroleum ether to provide a yield 1 5 of 4.2 g. (61% of the theoretical) of yellow S-methyl-llamino5H-diben zo-[b,e][1,41diazepine having a melting point of 167-168 C.

The N-rnethyl-o-ureido-diphenylamine used as the starting material can be obtained in the form of needles having a melting point of 180-183 C., in a yield of 90%, by introducing, while cooling, potassium cyanate in slight excess into an acetic solution of N-methyl-o-arnino-diphenylamine and by aspirating the precipitate which forms after diluting with water and allowing the whole to stand, by washing with diluted hydrochloric acid and water and by recrystallizing from acetone/water.

Identical products as is Example 6 are obtained, in some cases however in poor yields, by using phosphoric acid, aluminium chloride or zinc chloride as condensing agents.

EXAMPLE 7 By proceeding in the same way as in Example 6, but using o-piperidylamido-diphenylsulfide as the starting material and leaving out the toluene solvent, there is obtained 1l-piperidino-dibenzo[b,f][1,4] thiazepine, melting point 133-134 C., in a yield of 12% of the theoretical.

EXAMPLE 8 A yield of 3.4 g. of 11-piperidino-dibenzo[b,f] [1,4]thiazepine is obtained having a melting point of 133134 C., which is identical with the product of Example 7.

EXAMPLE 9 By proceeding as in Example 8 but setting out from imido thio ether and N-methyl-piperazine and using a trace of glacial acetic acid as the catalyst, there is obtained 11- (4-rnethyl-1-piperazinyl) 5H-dibenzo [b,e] [1,4] diazepine having a melting point of 184-185" C. (from acetone/ petroleum ether) in a yield of 87% of the theoretical.

EXAMPLE A mixture of 6.2 g. of N-methyl-2-aminodiphenylamine- 2'-carboxylic acid piperidide, 6.0 g. of phosphorus pentasulfide and 60 ml. of pyridine is heated during 4 hours under reflux. The reaction mixture is evaporated to dryness in vacuo. 15 0 ml. of 2 N aqueous soda solution are added to the residue, and after a certain time the yellow crystalline precipitate is taken into benzene. The benzenic solution is extracted with 2 N hydrochloric acid. The acid extract is clarified with charcoal and treated with concentrated ammonia water to precipitate the alkaline substance, which is dissolved in ether. The ethereal solution is washed with water and dried over sodium sulfate. The residue obtained yields, after recrystallization from ether/petroleum ether, 3.4 g. (57%) of the theoretical amount) of S-methyl-ll-piperidine-SH-dibenzo[b,e][1,4]

diazepine in theform of lemon-colored grains having a melting point of 162-163 C.

EXAMPLE 1 1 6.2 g. of N-methyl-Z-aminodiphenylarnine-2-carboxylic acid (,B-dimethylamino)ethylamide and 6 g. of phosphorus pentasulfide in 6O ml. of pyridine are heated during 4 hours under reflux. The reaction mixture is Worked up as in Example 10, however, the extraction is performed using diluted acetic acid in place of hydrochloric acid. 3.5 g. (59% of the theoretical yield) of S-methyl-ll-(B- dimethylamino-ethylamino) 5H-dibenz0[b,e] [1,4]diazepine are obtained in the form of yellow plates having a melting point of 167-170 C. (from acetone/petroleum ether).

EXAMPLE 12 EXAMPLE 13 7.4 g. of 2-amino-4-ch1orodiphenylamine-2'-carboxylic acid (4"-methyl)piperazide and ml. of phosphoroxychloride are heated for 3 hours under reflux in the presence of 1.4 ml. of N,N-dimethylaniline. Upon concentration of the reaction mixture in vacuo as far as possible, the residue is distributed between benzene and ammonia/ice water. The separation and purification of the basic component is performed as in Example 11. 2.9 g. (41% of the theoretical yield) of 8-chloro-11-(4-methyll-piperazinyl) 5H dibenzo[b,e] [1,4] diazepine are obtained in the form of yellow grains of melting point 182-184 C. (from acetone/petroleum ether).

EXAMPLE 14 6.8 g. of 2-amiuo-4'-chlorodiphenylsulfide-2-carboxylic acid(4-methyl)piperazide are heated for 1 hour under reflux with 7 g. of phosphorus pentachloride in 35 ml. of phosphoroxychloride, in the presence of 10 drops of dimethylformamide. The residue obtained by evaporation of the reaction mixture in vacuo is worked up as in Example 12. 2.7 g. (42% of the theoretical yield) of 2-chloro-1l-(4-methyl-1-piperazinyl) dibenzo[b,f][1,4] thiazepine are obtained in the form of faint yellow grains of melting point 118-120 C. (from ether/petroleum ether).

In like manner as in Examples 1 to 14, there are obtained from the corresponding starting materials the products listed in the following Table VII. Therein R R R R and Z denote the corresponding residues of Formula I. In the last column, e means ether, pe petroleum ether, and ac acetone.

TABLE VII Example Z R; or R4 Rz M.P. or B.P.* of the base, C.

15 -N H -N(C2Hs 2 16 -IT If m 201-203 (from ac/pe).

EXAMPLE 95 2.0 g. of 2-nitro-l0,l1-dihydro-1l-oxo-dibenzo[b,f] '[1,4]thiazepine (M.P. 270286 C. dec. and 1 ml. of N,N-dimethylaniline are refluxed with 15 ml. of phosphorus oxychloride for 5 hours after which the reaction mixture is evaporated to dryness in vacuo. The residue is treated with xylene, once again evaporated in vacuo and then refluxed for 16 hours with 15 ml. of N-methylpiperazine and ml. of dioxane. After evaporating to dryness in vacuo the residue is distributed between ether and dilute aqueous ammonia solution. The ether phase is Washed twice with water and then shaken out with dilute acetic acid. The base is set free from the acid extracts by benzene solution is exhaustively extracted with dilute acetic acid and the acetic acid extracts are treated with active charcoal. The basic fraction is set free, under icecooling, with concentrated ammonia solution and taken up in chloroform. The chloroform extracts are washed with water, dried over sodium sulphate and evaporated. The residue is dissolved in ether and filtered through aluminum oxide. The residue obtained after evaporation of the solvent is systematically crystallized from acetone/ ether/ petroleum ether. The first fraction to crystallize is 0.6 g. of starting material. 0.72 g. of 2-nitro-ll-(4-methyll piperazinyl) dibenzo[b,f] [1,4]thiazepine of melting point l38141 C. are obtained from the more soluble portion. This compound is identical to the product obaddition of concentrated ammonia solution and taken tained according to Example 95. up in ether. The ether phase is washed four times with water, dried over sodium sulphate and evaporated. The EXAMPLE 98 resinous residue obtained is then dissolved in ether, gof 2 nltrO 11 (ly -p p y filtered through aluminum oxide and evaporated. The l il[L lf p Obtained according to ExamRle residue is crystallized from acetone/petroleum ether to are miXed Wlth of stannous chlofide a Whlle give 1.7 g. of 2-nitro-1l-(4-methyl-1-piperazinyl)-dibenz stirring and cooling with ice, treated dropwlse with dilute [b f] [l,4]thiazepine i h f m f yellow matted dl hydrochloric acid (238 ml. of concentrated hydrochloric f melting Point 141 142 Q acid and 100 ml. of water). The reaction mixture becomes lighter in colour and a white precipitate is formed. After EXAMPLE 96 25 the addition is complete the reaction mixture is stirred 4.5 g. of 2-dimethylaminosulphonyl-10,ll-dihydro-l1- for a further 20 minutes while cooling, then for 15 minoxo-dibenzo[b,f] [1,4]thiazepine (M.P. 283284 C.) and utes at 40 C. The reaction mixture is thereupon made 1.3 ml. of N,N-dimethylaniline are refluxed in 40 m1. of strongly alkaline with concentrated soda lye and the phosphorus oxychloride for 4.5 hours. The excess phosprecipitate taken up in ether. The ether phase is exphorus oxychloride is then distilled off in vacuo and the haustively shaken out with dilute acetic acid and the residue is dissolved in xylene. The xylene solution is base liberated from the acetic acid extracts by addition poured onto ice/water, shaken out twice with dilute hyof concentrated ammonia solution and taken up in ether. drochloric acid and once with water, dried over sodium The ether phase is washed with water, dried over sodium sulphate and then concentrated to 100 ml. in vacuo. 8 ml. sulphate and evaporated. The residue is dissolved in of N-methylpiperazine are added and the reaction mixether, filtered through aluminum oxide and evaporated. ture is refluxed for 4 hours a d th treat d ith dilute After crystallization of the residue from ether/petroleum soda lye and water The xylene phase is separated @3161 10-05 gof y -P P Y and shaken out with dilute hydrochloric acid. The acid i nzo[b,f][1,4]thiazepine are obtained as colourless extracts are made alkaline with concentrated ammonia P i m mB ti gP i t165167 C- solution and the base which separates is extracted with chloroform. After drying over sodium sulphate the EXAMPLI? 99 chloroform extracts are evaporated in vacuo. The residue A of Sodlum metapenodate in 40 is crystallized from acetone/petroleum ether whereby 4.9 of Water 15 added in one lot to a Solution of g. of 2 dimethylaminosulphonyl 1l-(4-methyl-1-piper- 9 2 Intro j 11 (4 Y 1 pipel'azinyl) dibenzo azinly)-dibenzo[b,f][l,4]thiazepine are obtained in the fl if r Pbtamed according to Example 95, f f li yellow needles f melting paint while stirring under ice-cooling. The reaction mixture is 193 C then stirred at room temperature for 5 hours and left to EXAMPLE97 stand overnight. After diluting with water and treating r with active charcoal the basic fraction is set free under 3.72 of 2 amrno-2 -(4 -methyl-l-p1peraz1nyl-carice-cooling with concentrated soda lye and taken up in bony1)-4 -n1tro-d1ph enylsulph ide (M.P. l84187 C.) benzene. The benzene solution is washed with Water, dried 1 1111- Of 1methy1an1l1ne are refluxed for 3 hours over sodium sulphate and concentrated. The solution is in 20 ml. of phosphorus oxychlorlde after which the refiltered through aluminum oxide and evaporated to dryaction mixture is evaporated to dryness. The residue is ness. The residue is crystallized from acetone and acetreated with xylene, once again evaporated and then tone/petroleum ether to give 4.3 g. of 2-nitro-1l-(4- partitioned between benzene and dilute hydrochloric acid. methyl 1 piperaziny1)-dihenzo [b,f] [l,4]thiazepine-5- The base is set free from the acid extracts with concenoxide in the form of yellow matted needles of melting trated ammonia solution and taken up in benzene. The point 182185 C.

TABLE VIII Example Z i R: Melting point 101 -S H N0r Base: 153155 C. (from ac/pe).

102 -S- -CHzCHz-OH -N0r Base: 130134 C. (from ac/pe).

103 -S H -S02N(CH )z Base: 186-188" C. (from ch/e).

104 NH CH SO2N(CH )r Base: 193-195 O. (from ac/pe).

105 S OH; --SO2CH3 Base: 219223 C. (from ac/pe).

106 S H SO2GH3 Base: 180-183 C. (from ch/pe).

107 S -CH SO2C2H Base: 169-170 C. (from ch/pe).

108 S H SO2C2H5 Maleate:180185 C. (from me/ac/e).

109 NH CH3 -N0r Base: 110112 C. (from ac/pe).

TABLE VIII Cntiuued Example Z R; R'z Melting point.

110 --NH II -SOzN(CH3)z Base: 147-150 C. (from ac/pe).

111 NH CH SO2CH Dihydrobromide: 225-230 C. (dec.; from Ins/ethyl acetate).

112 -NH H SO2OH Dihydrobromide: 233-248" C. (from Inc/ethyl acetate).

113 S H SO2NHCH3 Base: 218-222 C. (from ac/pe).

114 S --GH -SOzNI-ICH; Base: 168170 C. (from ac/pe).

115 S 0 H N02 Base: 174176 C. (from ac/pe).

EXAMPLE 100 A solution of 3.42 g. of sodium metaperiodate in ml. of water is given in 3 portions to a stirred solution of 6.24 of 2 dimethylaminosulphonyl-11-(4-methyl-1- piperazinyl) dibenzo[b,f][l,4]thiazepine obtained according to Example 96, in 40 ml. of water and 10 ml. of glacial acetic acid at 0 C. A precipitate which appears is brought into solution by adding ml. of 2 N acetic acid. The reaction mixture is kept at room temperature for 24 hours, then made alkaline with concentrated soda lye and shaken out with chloroform. The chloroform extracts are Washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue is crystallized from acetone/petroleum ether to give 5.9 g. of 2 dimethylaminosulphonyl-l -(4-methyl-l-piperazinyl)- dibenzo[b,f] [l,4]thiazepine-5-oxide of melting point 208- 210 C.

By analogous procedures as in Examples 95-97, e.g., the products given in the following Table VIII are obtained. In the table Z, R and R' have the above defined meaning. In the column on the right hand side ac means acetone, e=ether, ch chloroform, me methanol and pe=petroleum ether.

We claim:

1. A compound selected from the class consisting of (A) ll-basic substituted dibenzo[b,c] [l,4]diazepines and elibenzo[b,f] [1,4]thiazepines of the formula:

a l l a W\2 4 wherein Z denotes a member of the class consisting of bivalent sulfur, imino, and lower alkyl imino; R is a member of the class consisting of hydrogen and alkyl with 1 to 5 carbon atoms, and R is a member of the class consisting of hydrogen, alkyl having from 1 to 5 carbon atoms, phenyl, R monosubstituted phenyl, aminoalkyl having from 1 to 5 carbon atoms, lower alkylated aminoalkyl having from 2 to 8 carbon atoms, amino, and lower alkylated amino; or R and R together with N form a member of the class consisting of l-pyrrolidinyl, pipeidino, morpholino, thiomorpholino, l-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower hydroxyalkyl)-1-piper azinyl and 4-(lower alkoxy-lower alkyl)-1-piperazinyl; and R R and R are members of the class consisting of hydrogen, halogen, hydroxy, trifiuoromethyl, lower alkyl, lower alkoxy, and lower alkylthio; and (B) the nontoxic pharmaceutically acceptable acid-addition salts of (A).

2. 8 chloro 11-(4-rnethyl-l-piperazinyl)-5H-dibenzo [b,e][1,4]-diazepin and its non-toxic pharmaceutically acceptable acid-addition salts.

(A) ll-basic substituted dibenzo[b,e] [1,4]-diazepines and dibenzo[b,f][1,4Jthiazepines of the formula:

RH (.11 N

wherein Z denotes a member of the class consisting of bivalent sulfur, imino, and lower alkylimino; R, is a member of the group consisting of hydrogen, allyl, alkyl having not more than 3 carbon atoms, hydroxyalkyl having not more than 3 carbon atoms, alkoxyalkyl having not more than 6 carbon atoms and alkoyloxyalkyl having not more than 6 carbon atoms; and R is a member of the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy and lower alkylthio, and (B) the nontoxic pharamaceutically acceptable acidaddition salts of (A).

References Cited UNITED STATES PATENTS 3,107,261 10/1963 Gerber et a] 260453 3,347,849 10/1967 Schmutz 260239 3,417,193 11/1968 Coppolk 260-268 X DONALD G. DAUS, Primary Examiner US. Cl. X.R.