IL29571A - 11-substituted dibenzo(b,f)-1,4-oxazepines,dibenzo(b,f)-1,4-thiazepines and dibenzo(b,e)-1,4-diazepines and their preparation - Google Patents
11-substituted dibenzo(b,f)-1,4-oxazepines,dibenzo(b,f)-1,4-thiazepines and dibenzo(b,e)-1,4-diazepines and their preparationInfo
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- IL29571A IL29571A IL2957168A IL2957168A IL29571A IL 29571 A IL29571 A IL 29571A IL 2957168 A IL2957168 A IL 2957168A IL 2957168 A IL2957168 A IL 2957168A IL 29571 A IL29571 A IL 29571A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D267/20—[b, f]-condensed
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Electromagnets (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
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DRe A. WAJfDES S,A
This invention is generally concerned with new heterocyclic compounds, and more specifically with new 11-basically substituted dibenz[b,f]-l,4-oxazepines , dibenzo[b,f]-l,4-thiazepines and dibenzo[b , e ]-l , 4-diazepines of the formula:
and acid addition salts thereof. In formula I, Z denotes oxygen, sulphur, sulphinyl (-SO-) or imino (- H-). represents hydrogen allyl , alkyl containing not more than carbon atoms , hydroxy-alkyl containing not more than 3 carbon atoms, alkoxyalkyl con-taining not more than 6 carbon atoms or alk^yloxyalkyl containing not more than 6 carbon atoms. ^ represents nitro; amino ? aminosulphonyl of the formula are
the same or different and represent hydrogen or methyl; alkyl-sulphinyl of the formula -SOR^ in which R-- denotes alkyl with not more than 3 carbon atoms; or alkylsulphonyl of the formula
-SC-.R,- in which c denotes alkyl with not more than 3 carbon
D
atoms.
Compounds of formula I are obtained when a compound of the formula:
(II),
a residue capable of being split off with the hydrogen of amines, is reacted with piperazine or a piperazine derivatives, respectively, of the formula:
3.
H
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, thiomethyi or p-nitrobenzylthio, or by tosyl.
Starting materials of the formula II are obtained by con-verting lactams of the formula:
wherein Z and 2 have the meaning given above, into the thio-lactams which may be followed by alkylation, or by reaction of the lactams with a halogenating agent such as phosphorus oxychloride or phosphorus pentachloride , most suitably in the presence of a catalytic amount of dimethylaniline or dimethylformamide. lactams of formula IV are themselves obtained by ring closure of compounds of the formula:
OR,
(V),
hydrogen or lower alkyl. For products wherein Z represents or -S-, lactams of formula IV may also he obtained by ring closure of compounds of the formula:
or OSH HalAJ ->· wherein Hal stands for halogen, or of isocyanates of the formula:
Lactams of formula IV in which represents amino are most suitably obtained by reduction of the corresponding nitrolactams.
Compounds of formula I may further be obtained by ring closure through intramolecular condensation of acid amides or acid thioamides of the formula:
wherein Z, and It, have the above-mentioned meaning and Y represents oxygen or sulphur. 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 there- of, 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 di- methylformamide or dimethylaniline.
11-Basically substituted dibenz[b,f]-l,4-oxazepines and dibenzo[b,f]-l,4-thiazepines (formula I ; Z = -0- or -S-)can
also be obtained by dehydration of urea derivatives of the
formula:
wherein has the above-mentioned meaning and Rrj means R^ or de- notes 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 oxy-
chloride and phosphorus pentoxide, if desired in an inert solvent of suitable boiling point such as benzene or toluene etc. Accord- ing to the chosen reaction conditions the starting materials of formula IX with a hydrolytically removable group R,-,, e.g. carb- alkoxy, especially carbethoxy, are cyclicized directly to the 11- (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 2 does not denote amino, the products (I) can also be obtained when amidines of the formula:
wherein Z has the above-mentioned meaning and R'2 represents with exclusion of amino, are treated with a reactive ester of an alcohol of the formula:
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 X are in turn obtained by treating compounds of formula II with ammonia.
On the other hand, compounds of formula I, wherein 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 I, wherein Z denotes sulphinyl, are also obtained by oxidation, e.g. with periodates, of the corresponding compounds in which Z represents sulphur.
Compounds of formula I, wherein represents alkyl- sulphinyl 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 thio-alkyl compounds. Products wherein £ represents alkylsulphonyl are also obtainable by strong oxidation of the corresponding alkylsulphinyl compounds. If the oxidation is carried out on the dibenzo[b,f]-l,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 I, wherein 2 denotes aminosulphonyl of the formula are obtained when the
corresponding compounds containing the group -SO^ 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 HM^ ^, wherein R-, and ^ have the above defined meaning. Starting materials containing a sulphochloride group (-SO2CI) are obtained by diazotization of the corresponding amino compounds followed by the Meerwein re-action.
Compounds of formula I, obtained according to one of the above 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 suit- able 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
, ith
out by treating^^a corresponding alkylene oxide.
Compounds of formula I in which R^ denotes a hydroxy- alkyl group can be subsequently treated with an acylating agent to obtain products wherein -^ represents an alkoyloxyalkyl group. Acid chlorides and acid anhydrides are especially suitable as acylating agents.
Subsequent introduction of a group ^, other than hydrogen, and also subsequent acylation of a hydroxyalkyl group R^ can lead o additional substitution in products in which denotes an amino group; this amino group being additionally substituted.
The bases obtained in this manner are in most cases
crystallizable or can otherwise be destilled in high vacuum with-out decomposition and react with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, maleic acid, succinic 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 obtained in the described manner and their
29571/2
acid addition salts are new compounds which can be used as active
Substances in pharmaceuticals or as intermediates for the pro-duction of such substances. They produce a favourable effect on
j he central nervous system and may therefore be used as analgesics, neuroleptics, sedatives and especially as neuroleptic antidepres-san s .....and. as antiemetics.
.The new compounds of formula I and their acid addition salts , are markedly superior for the above mentioned pharmaceutical applications than the known compounds of similar structure described in the Dutch Patent Specificatiors Kos . 6,406,089 and 293,201 (1965); French Patent Specification No. 1,334,944; Helv Ghim acta 50(1), pp. 245-254 (1967); Encephale 54(6), pp. 517-524 (1965); and Arzne!im-Forsch, 16(2), pp!.255-256 (1966).
Especially compounds of formula I in which R2 denotes
nitro show the typical behaviour pattern for neuroleptics. 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 the compounds 2-nitro-ll-(4-methyl-l-piperazin-yl)-dibenz[b,f]-l,4-oxazepine and 2-nitro-ll-(4-methyl-l-piper-azinyl)-dibenzo[b,f]-l,4- hiazepine, obtained according to
Example 1 or 2, respectively, as well as their acid additio
salts. · . '
Other compounds, 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 the compounds 2-nitro-ll-(l-piperazinyl)-dibenz[b,f]-l,4-oxazepine and 2-nitro-ll-(l-piperazinyl)-dibenzo[b,f]-l,4-thiazepine obtained according to
Example 18 or 20, respectively, and their acid addition salts.
29571/2
Compounds of formula I in which represents amino-sulphonyl or alkylsulphonyl exhibit a marked antiemetic activity. This is shown pharmacologically by a strong apomorphine anta-gonising effect in dogs and rats as well as a comparatively weak cataleptic and locomotor activity suppressing effect.
Pronounced antiemetic activity is shown by 2-dimethyXamino™ sulphonyl-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-1, 4-thiazepine , 2-dimethylaminosulphonyl-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-1,4-oxazepine, 2-methyisulphonyl-ll-( -methyl-l-piperazinyl)-dibenz[b,f]-1,4-oxazepine and 2-methylsulphonyl-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-l,4-thiazepine obtained according to Examples 3, 4, 5 or 26, respectively, and their acid additio salts. . '' { . '.
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 pharma-ceutical preparations may be, for example, in the form of tablets, dragees, or solutions for injection, one dosage unit containing from 10 to 25 mg of active substance, depending on its nature, on the" route of administration and on the physician's prescription, the effective* daily dose amounting to from 5 to 400 mg of active substance.
Example 1
4.9 g of 2- tro-10,ll-dihydro-ll-oxo-dibenz[b,f]-l,4- oxazepine (m.p. 263°C) and 2 ml of Ν,Κ-dimethylaniline are heated in 60 ml of phosphorus oxychloride at reflux for 4 hours. The re- action mixture is then evaporated in vacuo to remove the excess phosphorus oxychloride and the residue is decomposed with ice/ water and shaken out immediately with chloroform. The chloroform extracts are washed with dilute hydrochloric acid and water, dried over sodium sulphate and evaporated to dryness in vacuo. The crystalline residue consisting of crude 2-nitro-ll-chloro-dibenz- [b,f]-l , -oxazepine is heated at reflux for 6 hours with 6 ml of ii-methylpiperazine in 200 ml of xylene. The organic phase is then shaken out with water and dilute hydrochloric acid. The acid ex- tracts are made alkaline with concentrated soda lye and the base which separates is extracted with chloroform. The chloroform ex- tracts are washed with water, dried over sodium sulphate and evaporated to dryness. The residue is crystallized from chloro- form/acetone/petroleum ether and gives
4.7 g of 2-nitro-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-l,4- oxazepine in the form of yellow needles of melting point
192-193°C.
Example 2
2.0 g of 2- itro-10,ll-dihydro-ll-oxo-dibenzo[b,f]-l,4- thiazepine (m.p. 270-286°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 yacuo. The residue is treated with xylene, once again evaporated i^_y_ac^°_ and then refluxed for 16 hours with 15 ml of N-methyl-piperazine and 10 ml of dioxane. After evaporating to dryness in_yacuo 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 addition of concentrated ammonia solution and taken up in ether. The ether phase is washed four times with water, dried over sodium sulphate and evaporated. The resinous residue obtained is then dissolved in ether, filtered through aluminium oxide and evaporated. The residue is crystallized from acetone/petroleum ether to give 1.7 g of 2-nitro-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-l,4-thiazepine in the form of yellow matted needles of melting point 141-142°C.
Example 5
4.5 g of 2-Dimethylaminosulphonyl-10,ll-dihydro-ll-oxo-dibenzo[b,f]-l, 4-thiazepine (m.p. 283-2S4°C) and 1.3 ml of
Ν,Ν-dimethylaniline are refluxed in 40 ml of phosphorus oxy-chloride for 4.5 hours. The excess phosphorus oxychloride is then distilled off Ϊ2_Υ5.Η2 an(^ "^e residue is dissolved in xylene. The xylene solution is poured onto ice/water, shaken out twice with
sulphate and then concentrated to 100 ml in vacuo. 8 ml of N- methylpiperazine are added and the reaction mixture is refluxed for 4 hours and then treated with dilute soda lye and water. The xylene phase is separated and shaken out with dilute hydrochloric acid. The acid extracts are made alkaline with concentrated ammonia
s,
solution and the base which separates extracted with chloroform. After drying over sodium sulphate the chloroform extracts are evaporated in vacuo. The residue is crystallized from acetone/ petroleum ether whereby 4.9 g of 2-dimethylaminosulphonyl-ll-(4- methyl-l-piperazinyl)-dibenzo[b,f]-l,4-thiazepine are obtained in the form of slightly yellow needles of melting point 192-193°C
Example 4
1.8 g of 2-Dimethylaminosulphonyl-10,ll-dihydro-ll-oxo-dibenz[b,f]-l,4-oxazepine (m.p. 243-245°C) and 0.6 ml of■ N,N-di-methylaniline are refluxed in 20 ml of phosphorus oxychloride for 4 hours. The excess phosphorus oxychloride is removed completely in vacuo and the residue dissolved in xylene and poured onto ice/ water. The xylene solution is shaken out twice with dilute hydro-chloric acid and once with water, then dried over sodium sulphate and concentrated to. 50 ml in_vacuo. 3 ml of N-methylpiperazine are added and the reaction mixture is refluxed for 4 hours and then treated with dilute soda lye and water. The xylene phase is
separated and shaken out with dilute hydrochloric acid. The acid extracts are made alkaline with concentrated ammonia solution and the base which separates is extracted with chloroform. The chloro-form extracts are dried over sodium sulphate and evaporated in vacuo. The residue is crystallized from ether/petroleum ether whereby 1.8 g of 2-dimethylaminooulphonyl-ll-( -me hyl-l-piper-azinyl)-dibenz[b,f]-l,4-oxazepine of melting point 149-150°C are
Example 5
g of 2-Methylsulphonyl-10,ll-dihydro-ll-oxo-dibenz[b,f]- 1,4-oxazepine (m.p. 242-244°C) and 1.8 ml of N,N-dimethylaniline are refluxed in 50 ml of phosphorus oxychloride for 5 hours after which the reaction mixture is evaporated to dryness in_yacuo. The residue is treated with xylene, once again evaporated and then dissolved in xylene and poured onto ice. The aqueous phase is shaken out three times with xylene. The combined xylene . extracts are washed with dilute hydrochloric acid, water and aqueous sodium chloride solution, dried over sodium sulphate, treated with active charcoal and filtered through a small amount of aluminium oxide. The filtrate is concentrated and then refluxed with 12 ml of N-methylpiperazine for 6 hours. The reaction mixture is treated with water and concentrated soda lye and shaken out twice with ether. The ether extracts are washed several times with water and then shaken out with dilute hydrochloric acid. The acid extracts are made alkaline and extracted twice with ether. The ether phase is washed with water and aqueous sodium chloride solution, dried over sodium sulphate, treated with active char-coal and filtered through a small amount of aluminium oxide. The filtrate is concentrated and treated with petroleum ether. The crystals which precipitate are dissolved in acetone and, after concentrating, recrystallized by addition of ether/petroleum ether. 5.8 g of 2-methylsulphonyl-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-1,4-oxazepine in the form of slightly yellow needles of melting point 178-179°C are obtained.
Example 6
3.72 g of 2-Amino-2l-(4"-methyl-l"-piperazinyl-carbonyl)-4'-nitro-diphenylsulphide (m.p. 184-187°C) and 1 ml of N,N-di-
oxychloride after which the reaction mixture is evaporated to dry- ness. The residue is treated with xylene, once again evaporated and then partitioned between benzene and dilute hydrochloric acid. The base is set free from the acid extracts with concentrated ammonia solution and taken up in benzene. The 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 ice-cooling, 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 aluminium oxide. The residue obtained after evaporation of the solvent is systematic-ally 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-methyl-l-piperazinyl) -dibenzo[b , f]-1 , -thiazepine of melting point 138-141°C are obtained from the more soluble portion. This compound is indentical to the product obtained according to Example 2.
Example 7
3 g of 2-(4M-Methyl-l"-piperazinyl-carbonylamino)-4'-methylsulphonyl-diphenyloxide (m.p. 145-146°C) and a mixture of 2 g of phosphorus pentoxide and 10 ml of phosphorus oxychloride are refluxed for 24 hours. The excess phosphorus oxychloride is then distilled off in vacuo and the residue decomposed with ice/ water. The solution obtained is made alkaline with concentrated soda lye and shaken out with ether. The ether extracts are washed with water and shaken out thoroughly with dilute hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and shaken out with chloroform. The chloroform extracts are washed
in vacuo. The residue is crystallized from acetone/petroleum ether and gives 1.5 g of 2-methylsulphonyl-ll-(4-methyl-l-piper-azinyl)-dibenz[b,f]-l,4-oxazepine of melting point 178-179°C identical to the product obtained according to Example 5.
Example 8
7.9 g of 2- tro-ll-amino-dibenz[b,f]-l,4-oxazepine
(m.p. 238-240°C) and potassium-t-butoxide (from 4.0 g of potassium) are stirred together in 40 ml of dimethylsulphoxide for 30 minutes. After addition of 7.5 g of bis-(p-chloroethyl)methylamine hydro- chloride, 1.3 g of potassium iodide and a further 20 ml of dimethyl- sulphoxide the mixture is stirred for a further 14 hours at 80°C. The reaction mixture is then partitioned between benzene and a large volume of water. The benzene layer is washed with water, then exhaustively extracted with dilute acetic acid. The acetic acid ex-tracts are treated with active charcoal, cooled with ice and made alkaline with concentrated soda lye. The base which is set free is taken up in chloroform. The chloroform solution is washed with water, dried with sodium sulphate and evaporated. The residue is dissolved in benzene and filtered through aluminium oxide. After concentration and dilution with petroleum ether, crystals precipi-tate which are then recrystallized from chloroform/acetone/
petroleum ether to give 4.3 g of 2-nitro-ll-(4-methyl-l-piper-azinyl)-dibenz[b,f.]-l,4-oxazepine of melting point 192-194°C
which is identical to the product obtained according to Example 1. Example 9
.2 g of 2-Nitro-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-1,4-oxazepine obtained according to Example 1 are hydrogenated with hydrogen in the presence of 1 g of 5 "/° palladium-charcoal in 450 ml of methanol at normal pressure. After take-up of 3.05 1
mixture filtered to remove the catalyst. The filtrate is evaporated in vacuo and the residue taken up in chloroform, filtered through aluminium oxide and concentrated. On addition of petroleum ether crystals are formed which are separated and recrystallized from chloroform/ether/petroleum ether. 14.1 g of 2-amino-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-l,4-oxazepine of melting point 153-156°C are obtained.
Example 10
11.5 g of 2-Nitro-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-1,4-thiazepine obtained according to Example 2 are mixed with
24.5 g of stannous chloride and while stirring and colling with ice, treated dropwise with dilute hydrochloric acid (238 ml of concentrated hydrochloric acid and 100 ml of water). The reaction mixture becomes lighter in colour and a white precipitate is formed. After the addition is complete the reaction mixture is stirred for a further 20 minutes while cooling, then for 15 minutes at 40°C. The reaction mixture is thereupon made strongly alkaline with concentrated soda lye and the precipitate taken up in ether. The ether phase is exhaustively shaken out with dilute acetic acid and the base liberated from the acetic acid extracts by addition of concentrated ammonia solution and taken up in ether. The ether phase is washed with water, dried over sodium sulphate and eva-porated. The residue is dissolved in ether, filtered through aluminium oxide and evaporated. After crystallization of the residue from ether/petroleum ether 10.05 g of 2-amino-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-1,4-thiazepine are obtained as colourless prisms of melting point 165-167°C.
Example 11
A solution of 3.4 g of sodium metaperiodate in 40 ml of
( 4-methyl-l-piperazinyl)-dibenzo[b,f]-1,4-thiazepine , obtained according to Example 2, while stirring under ice-cooling. The reaction mixture is then stirred at room temperature for 5 hours and left to stand overnight. After diluting with water and treat ing with active charcoal the basic fraction is set free under ice-cooling with concentrated soda lye and taken up in benzene. The benzene solution is washed with water, dried over sodium sulphate and concentrated. The solution is filtered through aluminium oxide and evaporated to dryness. The residue is crystallized from acetone and acetone/petroleum ether to give 4.3 g of 2-nitro-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-l,4- thiazepine-5-oxide in the form of yellow matted needles of melt- ing point 182-185°C
Example 12
A solution of 3.42 g of sodium metaperiodate in 10 ml of water is given in 3 portions to a stirred solution of 6.24 g of 2-dimethylaminosulphonyl-ll-(4-methyl-l-piperazinyl)-dibenzo- [b,f]-l,4-thiazepine obtained according to Example 3, 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 20 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 ΐϊ-:_Ζ¾2ΰ · Tiie residue is crystallized from acetone/petroleum ether to give 5.9 g of 2-dimethylaminosulphonyl-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-l,4-thiazepine-5-oxide of melting point 208-210°C.
Example 13
(4-methyl-l-piperazinyl)-dibenz[b,f]-1, 4-oxazepine maleate (m.p. 198-201°C) ia dissolved in 40 ml of water and 10 ml of glacial acetic acid. This solution is treated dropwise while stirring at 0°C with a solution of 3.42 g of sodium metaperiodate in
ml of water. After the addition is complete the reaction
mixture is left to stand at room temperature for 24 hours, then made alkaline with concentrated soda lye and shaken out with ether. The ether extracts are washed with water and then ex- haustively shaken out with dilute hydrochloric acid. The acid extracts are 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 i£_yacuo. The residue is dissolved in acetone and treated with 1.8 g of maleic acid. After concentration and addition of ether crystals preci-pitate which are recrystallized from methanol/acetone/ether to give 6.0 g of 2-methylsulphinyl-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-l,4-oxazepine maleate of melting point 206-207°C.
Example 14
A solution of 5.2 g of crude 2-chlorosulphonyl-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-l, -oxazepine, obtained as described below, in 80 ml of chloroform is treated dropwise at room temperature with 50 ml of a 10 o dimethylamine solution in toluene. The reaction mixture is stirred for a further 2 hours at room temperature, then for 1 hour at 40°C and finally eva-porated to dryness in_vacuo. The residue is taken up in dilute acetic acid, treated with active charcoal and made alkaline with concentrated ammonia solution. The base which separates is taken up in benzene, the benzene solution washed three times with water, dried over sodium sulphate and evaporated. The residue is taken
residue obtained after evaporation of the solvent is crystallized from acetone/petroleum ether to give 3.2 g of 2-dimethylamino- sulphonyl-ll-( -methyl-l-piperazinyl)-dibenz[b,f]-1,4-oxazepine of melting point 148-150°C which is identical to the product ob- tained according to Example 4.
2-Chlorosulphonyl-ll-(4-methyl-l-piperazinyl)-dibenz- [b,f]-l,4-oxazepine used as starting material is obtained as follows :
.4 g of 2-Amino-ll-( -methyl-l-piperazinyl)-dibenz- [b,f]-l,4-oxazepine (m.p. 153-156°C) are dissolved in 50 ml of glacial acetic acid and 15 ml of 38 hydrochloric acid and diazotized in the usual manner at 0°-5°C with a solution of 3.6 g of sodium nitrite i 6 ml of .water. The diazonium solution ob-tained is added within a few minutes while stirring at 10°C to 40 ml of a 30 solution of sulphur dioxide in glacial acetic acid containing 2 g of cuprous chloride. After the development of nitrogen subsides at room temperature the reaction mixture is warmed for 15 minutes at 40°C. The reaction mixture is then diluted to l with water and treated with active charcoal. While stirring and cooling carefully, the basic fraction is precipitated with concentrated soda lye and taken up in chloroform. The chloro-form extracts are washed once with dilute soda lye and once wit water, dried over sodium sulphate and evaporated. Crude 2-chloro-sulphonyl-ll-(4-methyl-l-piperazinyl)-dibenz[b,f1-1, -oxazepine is obtained as residue.
Example 15
.4 g of 2-Dimethylaminosulphonyl-ll-(l-piperazinyl)-dibenz[b,f]-l,4-oxazepine obtained according to Example 42 are dissolved in 50 ml of acetone and treated with 1 g of anhydrous
acetone and refluxed for 3 hours while stirring. The reaction mixture is then evaporated in_vacuo and the residue distributed between dilute soda lye and ether. The ether extracts are washed with water and exhaustively shaken out with dilute aqueous hydro- chloric acid. The acid extracts are made alkaline with concen- trated 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 4.9 g of 2-dimethylaminosulphonyl-ll-(4-ethyl-l-piperazinyl)-dibenz[b,f]-l,4-oxazepine of melting point 160-161°C.
Example 16
4.63 g of the same starting material as in Example 15 are dissolved in 80 ml of isopropanol and treated with 1.6 g of anhydrous potassium carbonate, then, while stirring and heating, treated dropwise with 3 g of β-methoxyethyl-p-toluene sulphonic acid ester in 10 ml of isopropanol. After the addition is complete the mixture is refluxed for 1.5 hours, then evaporated in vacuo. The residue is partitioned between dilute soda lye and ether and the ether extracts exhaustively shaken out with dilute hydrochloric acid. The acid extracts are made alkaline with concentrated soda lye and shaken out with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The oily residue is dissolved in warm acetone together with 1.2 g of maleic acid and crystallized by addition of ether. 4.9 g of 2-di-methylaminosulphonyl-ll-(4-β-met ox eth l-l-piperazin l)-dibenz-[b,f]-l,4-oxazepine maleate of melting point 124-140°C (decompos-ition) are obtained.
Example 17
piperazinyl)-dibenz[b,f]-l, 4-oxazepine obtained according to Example 39 are mixed with 30 ml of absolute pyridine and 15 ml of acetic anhydride, left to stand for one hour at room temper- ature and then warmed for a short time on the steam bath. The reaction mixture is evaporated i _vacuo and the residue diluted with water. The basic fraction is precipitated in the cold with concentrated soda lye and exhaustively extracted with ether. The ether phase is washed with water, dried over sodium sulphate and evaporated. The residue is dissolved in acetone and treated with 1.8 g of maleic acid. After concentration of the solution and addition of ether crystals precipitate which are recrystallized from acetone/ether to give 3 g of 2-diniethylaminosulphonyl-ll- (4-p-acetoxyethyl-l-piperazinyl)-dibenz[b,f]-l, 4-oxazepine maleate of melting point 155-158°C.
Further products correspondin to formula I given in the following table are obtained by analogous procedures to those given above. In the table Z, and 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.
T a b l e
-CH5 -Ν02 base: 110-112°C
(from ac/pe)
Η -S02 (CH5)2 base: 147-150°C
(from ac/pe)
-CH5 -S02CH5 dihydrobromide :
225-230°C
(dec. ; from me/
ethyl acetate)
Η -S02CH5 dihydrobromide :
233-248°C (from
me/ethyl acetate)
Η base: 218-222°C
(from ac/pe)
s -CH^ -S02 HCH5 base: 168-170°C
(from ac/pe)
V Η >S02C2H5 base:
(from ac/pe)
Ν>' -CH2-CH2-OCH5 -N02 ■ base: 102-104°C
(from e/pe)
\>' -CI^-CH2-0H -S02N(CH3)2 base: 164-166°C
(from ac/e/pe)
Η -N02 base: 174-176°C
(from ac/pe)
\> -CH2-CH=CH2 -S02N(CH3)2 base: 150-151°C
(from ac/pe)
Η -S02N(CH5)2 base: 181-182°C
(from ac/pe)
Production of tablets
For the manufacture of tablets, the products of this in- vention can be mixed with lactose and granulated with water,
0.59¾ sodium alginate or 1 gelatine solution. The dried
granulate is compressed into tablets in the presence of about 5 ?° of talcum, 5 % of corn starch and 0.1 o of magnesium stearate. In this way, there are obtained, e.g. tablets of the following composition:
A) 2- tro-ll-(4-methyl-l-piperazinyl)-dibenz- [b ,f]-l,4-oxazepine 25 mg
Lactose 115 mg
Corn starch 7.5 mg
Talcum 7.5 mg
Magnesium stearate 0.15 mg
These 155 mg tablets, which are provided with a crack- line, can be administered orally in a dosage of one half to two tablets two to four times per day in the treatment of
subjects suffering from any form of schizophrenia, any form of mania, severe psychotic and non-psychotic states of excite- ment, chorea, athetosis, and extrapyramidal movement dis- orders.
B) 2-Nitro-ll-(l-piperazinyl)-dibenz[b,f]- 1,4-oxazepine 20 mg
Lactose 120 mg
Corn starch 7.5 mg
Talcum 7.5 mg
Magnesium stearate 0.15 m
These 155 mg tablets, which are provided with a crack-
to two tablets two to five times, in some cases up to
times 4 tablets per day in the treatment of subjects
suffering from states of mental depression and especially agitated forms of depression.
C) 2-Dimethylaminosulphonyl-ll-(4-methyl-l- piperazinyl}-dibenz[b,f]-1,4-0xazepine 10 mg
Lactose 70 mg
Corn starch ' 5 mg
Talcum 5 mg
Magnesium stearate 0.1 mg
These 90 mg tablets, which are provided with a crack- line, can be administered orally in a dosage of one half to two tablets one to three times per day in the treatment of subjects suffering from nausea and vomiting following oper- ations or ray treatment o,r due to stomach or metabolism dis- orders, intoxications, drug incompatability, pressure on the brain or pregnancy. These tablets may also be used prophyl- actically against post operative vomiting.
Claims (10)
1. A compound selected from the class consisting of (A): 11-basically substituted dibenz[b,f]-l,4-oxazepines, dibenzo[b,f]-l,4-thiazepines and dibenzo[b,e]-l,4-diazepines of the formula: wherein Z denotes a member of the group consisting of oxygen, sulphur, 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 alkjbyloxyalkyl containing not more than 6 carbon atoms; and ^ is a member of the group consisting of nitro, amino, aminosulphonyl of the formula -SC^ R-j ^ wherein R^ and ^ are the same or different members of the group consisting of hydrogen and methyl, alkylsulphinyl of the formula -SO ^ wherein R-. denotes alkyl with not more than 3 carbon atoms, and alkyl-sulphonyl of the formula -SC^ ^ wherein R^ denotes alkyl with not more than 3 carbon atoms; and (B) acid addition salts of (A).
2. 2-Nitro-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-1,4-oxazepine and its acid addition salts.
3. 2-Nitro-ll-(4-methyl-l-piperazinyl)-dibenzo[b,f]-l,4-
4. 2-Nitro-ll-(1-piperazinyl ) -dibenz[ b , f]-1 , 4-oxazepine and its acid addition salts.
5. 2-Nitro-ll-(1-piperazinyl ) -dibenzo[ ,f]-1 , 4-thiazepine and its acid addition salts.
6. 2-Dimethylaminosulphonyl-ll-(4-methyl-l-piperazin-yl)-dibenzo[b,f]-l,4-thiazepine and its acid addition salts.
7. 2-Dimethylaminosulphonyl-ll-(4-methyl-1-piperazinyl )-dibenz[b,f]-l,4-oxazepine and its acid addition salts.
8. 2-Methylsulphonyl-ll-(4-methyl-l-piperazinyl)-dibenz[b,f]-l,4-oxazepine and its acid addition salts.
9. 2-Methylsulphonyl-11-( 4-methyl-1-piperazinyl)-dibenzo[b,f]-l,4-thiazepine and its acid addition salts.
10. A process for the preparation of 11-basically substituted dibenz[b,f]-l,4-oxazepines, dibenzo[b,f]-l,4-thiazepines and dibenzo[b,e]-l,4-diazepines of the formula: wherein Z denotes oxygen, sulphur, sulphinyl or imino; 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 alkoyl-oxyalkyl containing not more than 6 carbon atoms; and R2 denotes nitro, amino, aminosulphonyl of the formula -SO^ R^ wherein R^ and ^ are the same or different and represent hydrogen or methyl, alkylsulphinyl of the formula -S0R.. wherein R.- denotes alkyl with not more than 3 carbon atoms, or alkylsulphonyl of the formula -SC^R^ wherein R^ denotes alkyl with not more than 3 carbon atoms; as well as acid addition salts thereof comprising either: a) reacting a compound of the formula: wherein Z and nave "the meaning defined above and X denotes a residue capable of being split off with hydrogen of amines, with piperazine or a piperazine derivative, respectively, of the formula: H wherein R, has the above-mentioned meaning, or b) subjecting acid amides or thioamides of the formula: wherein Z, R^ and have the above defined meaning and Y represents oxygen or sulphur, to intramolecular condensation, or c) for the preparation of compounds in which Z is oxygen or sulphur, subjecting urea derivatives of the formula: wherein has the above-mentioned meaning and ^ means R^ or denotes a removable group, to dehydration, if necessary with subsequent splitting off of the removable group, or for the preparation of the desired compounds where R, not denote amino, treating amidines of the formula; wherein Z has the above defined meaning and R' represents R2 with exclusion of amino, with a reactive ester of an alcohol of' the formula: wherein R, has the above-mentioned meaning, or for the preparation of compounds in which 2 denotes amino, reducing corresponding nitro compounds, or for the preparation of compounds in which Z denotes sulphinyl, oxidizing corresponding compounds in which Z denotes sulphur, or for the preparation of compounds in which 2 denotes alkyl-sulphinyl or alkylsulphonyl, respectively, treating correspond ing thioalkyl compounds with a mild or strong oxidizing agent, respectively, or for the preparation of compounds in which R2 denotes alkylsulphonyl, treating corresponding alkylsulphinyl compounds with a strong oxidizing agent, or for the preparation of compounds in which 2 denotes amino-sulphonyl, reacting corresponding compounds containing the group -SC X instead of aminosulphonyl, wherein X denotes a * residue which is removable with the hydrogen of amines, with ammonia or an amine of the formula H R,R, , wherein R, and R. have the above defined meaning, if desired with subsequent introduction of a residue R^ other than hydrogen in products in which R1 denotes hydrogen and/or with subsequent acylation of products in which R^ is hydroxyalkyl, the reaction product being isolated in the form of the free base or in the form of an acid addition salt with an appropriate inorganic or organic acid. Dated this 3rd March 1968 For the Applicants: DR. REIKHOLD COM AND PARTNERS
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH358267 | 1967-03-13 | ||
CH410367A CH481133A (en) | 1967-03-22 | 1967-03-22 | Process for the preparation of basic substituted heterocycles |
CH655767A CH484924A (en) | 1967-05-09 | 1967-05-09 | Process for the preparation of basic substituted heterocycles |
CH1011567A CH485752A (en) | 1967-07-14 | 1967-07-14 | Process for the preparation of basic substituted heterocycles |
CH1545367 | 1967-11-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
IL29571A true IL29571A (en) | 1972-04-27 |
Family
ID=27509145
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL2957168A IL29571A (en) | 1967-03-13 | 1968-03-04 | 11-substituted dibenzo(b,f)-1,4-oxazepines,dibenzo(b,f)-1,4-thiazepines and dibenzo(b,e)-1,4-diazepines and their preparation |
Country Status (9)
Country | Link |
---|---|
AT (3) | AT292716B (en) |
BE (1) | BE712114A (en) |
DE (1) | DE1720007A1 (en) |
FR (1) | FR8046M (en) |
GB (1) | GB1216523A (en) |
IL (1) | IL29571A (en) |
NL (1) | NL6803570A (en) |
NO (1) | NO123459B (en) |
SE (1) | SE364277B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9500998D0 (en) * | 1995-03-19 | 1995-03-19 | Haakan Wilhelm Wikstroem | New sulfone ester analogues of iso-clozapine and related structures: atypical neuroleptics |
EP2088147A1 (en) | 2003-12-22 | 2009-08-12 | Arcadia Pharmaceuticals Inc. | Dibenzo-condensed azepine, diazepine, oxazepine and thiazepine derivatives as muscarinic agonists and methods of treatment of neuropsychiatric disorders |
WO2007053618A1 (en) * | 2005-10-31 | 2007-05-10 | Acadia Pharmaceuticals Inc. | Prodrugs of muscarinic agonists and methods of treatment of neuropsychiatric disorders |
EP1951694A4 (en) * | 2005-11-18 | 2010-09-22 | Astrazeneca Ab | Salt forms |
WO2013070107A1 (en) * | 2011-11-09 | 2013-05-16 | Общество С Ограниченной Ответственностью "Валентек" | 5h-dibenzo[b,e][1,4]diazepine derivatives and use thereof |
-
1968
- 1968-03-04 IL IL2957168A patent/IL29571A/en unknown
- 1968-03-04 DE DE19681720007 patent/DE1720007A1/en active Pending
- 1968-03-05 GB GB00561/68A patent/GB1216523A/en not_active Expired
- 1968-03-05 AT AT00204/70A patent/AT292716B/en not_active IP Right Cessation
- 1968-03-05 AT AT00206/70A patent/AT292718B/en not_active IP Right Cessation
- 1968-03-05 AT AT215368A patent/AT292707B/en not_active IP Right Cessation
- 1968-03-08 SE SE03129/68A patent/SE364277B/xx unknown
- 1968-03-12 FR FR143389A patent/FR8046M/fr not_active Expired
- 1968-03-12 NO NO94668A patent/NO123459B/no unknown
- 1968-03-13 BE BE712114D patent/BE712114A/xx unknown
- 1968-03-13 NL NL6803570A patent/NL6803570A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
NO123459B (en) | 1971-11-22 |
SE364277B (en) | 1974-02-18 |
AT292716B (en) | 1971-08-15 |
AT292718B (en) | 1971-08-15 |
FR8046M (en) | 1970-08-10 |
DE1720007A1 (en) | 1971-05-19 |
GB1216523A (en) | 1970-12-23 |
BE712114A (en) | 1968-09-13 |
NL6803570A (en) | 1968-09-16 |
AT292707B (en) | 1971-09-10 |
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