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Publication numberUS3860606 A
Publication typeGrant
Publication dateJan 14, 1975
Filing dateMar 2, 1973
Priority dateMar 7, 1972
Also published asCA1010032A1, DE2311019A1
Publication numberUS 3860606 A, US 3860606A, US-A-3860606, US3860606 A, US3860606A
InventorsDer Burg Willem Jacob Van
Original AssigneeAkzona Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Tetrahydro-imidazo-dibenzo-oxazepines, thiazepines and-diazepines
US 3860606 A
The invention relates to compounds of the formula:
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Description  (OCR text may contain errors)

United States Patent 1 Van Der Burg 1 Jan. 14, 1975 TETRAHYDRO-IMIDAZO-DIBENZO- OXAZEPINES, THIAZEPINES AND-DIAZEPINES [75] Inventor: Willem Jacob Van Der Burg,

l-leesch, Netherlands [73] Assignee: Akzona Incorporated, Asheville,

[22] Filed: Mar. 2, 1973 [21] Appl. No.: 337,323

[30] Foreign Application Priority Data Mar. 7, 1972 Netherlands 7202963 [52] US. Cl.... 260/309.7, 260/239 DD, 260/327 B, 260/333, 424/273 [51] Int. Cl C0711 57/02 [58] Field Of Search 260/309.7

[56] 3 References Cited UNITED STATES PATENTS 3,435,042 3/l969 Drukker 6t 2117 260/309.6

FOREIGN PATENTS OR APPLICATIONS 1,229,252 4/1971 Great Britain 260/268 PC OTHER PUBLICATIONS The Ring Index Supplement 111 to the second edition, page 256, No. 13084, American Chemical Society, 1965. QD291.P3.

Blattner et al., Chem. Abst., Vol. 76, No. 85721c (1972). QDI.A51

Chemical Abstracts Eighth Collective Index, Volumes 66-75, 1967-1971, Subjects Dibenzobr-Ethanola, page 98798 (1973). QD1.A51.

Chemical Abstracts Eighth Collective Index Volumes 6675 1967-1971, Subjects Glucopelndena, page 156345 (1973). QDLASI. Barton et al., Chem. Abst. Vol. 74, No. 1416342 (1971).OD1.A51.

Primary ExaminerNatalie Trousof Attorney, Agent, or Firm-Francis W. Young; Philip M. Pippenger; Hugo E. Weisberger [57] ABSTRACT The invention relates to compounds of theformula:

in which X represents oxygen, sulphur or the group TETRAHYDRO-IMIDAZO-DIBENZO- OXAZEPINES, THIAZEPINES AND-DIAZEPINES The present invention relates to novel biologically active imidazolidine derivatives. More particularly it relates to tetra-hydro-imidazo-dibenzo-oxazepines, -thiazepines and -diazepines.

From the British Pat. No. 1,229,252 compounds are known differing from the present compounds in that they contain a piperazine instead of an imidazolidine ring. These known piperazine derivatives possess antihistamine and antiserotonine activity.

Surprisingly it has now been found that the present imidazolidine derivatives of the general formula:

in which R, and R hydrogen, hydroxy, halogen, alkyl or alkoxy with 1-6 carbon atoms, acyloxy with l-8 carbon atoms, or a trifluoromethyl group, 7 R hydrogen, an alkyl group with 1-6 carbon atoms, or an aralkyl group with 7-10 carbon atoms, and X oxygen, sulphur or the group NR in which R, is hydrogen or a lower alkyl group with 1-6 carbon atoms, as well as the pharmaceutically acceptable acid addition salts and pharmaceutically acceptable quaternary ammonium compounds thereof, have a complete other therapeutical pattern. The compounds according to this invention show, fully contrary to the compounds described in the said British patent, a positive effect in the reserpine antagonism test, which means that they possess antidepressant activity, whereas the antihistamine and antiserotonine activity of the present compounds may, in general, be disregarded in comparison with the strong antihistamine and/or antiserotonine activity of the compounds described in the British patent. The compounds according to the invention can be prepared by any method commonly used for this type of compounds. They are, however, prepared most conveniently starting from a substance with the general formula:

or an acid addition salt thereof, in which X, R,, R and R have the meaning indicated above.

These starting compounds are depicted by formula V in the drawings of said British Pat. No. 1,229,252 and their use is described in the specification thereof at page 2, lines 39-59, disclosing the preparation of piperazine compounds therefrom. The British patent in Sheet 1 of the drawings discloses the formula of intermediate V to be:


in which R, and R each represent hydrogen, halogen, hydroxyl, acyloxy, lower alkyl, lower alkoxy, or trifluoromethyl; R represents hydrogen, lower alkyl, lower aralkyl, aminoethyl or aminopropyl; and X represents oxygen, sulfur or NR in which R, is lower alkyl. The preparation of specific compounds of formula V of said British patent is given in the several Examples thereof, and involves starting with ortho-amino-diphenyl ether, which is converted to ortho-chloracetamido-diphenyl ether by treatment with chloracetyl chloride (Example in which Y represents hydrogen (H oxygen or sulphur and i Z, and Z represent the same or different reactive or leaving groups, or may be together a bivalent reactive group, capable'of splitting off together with the hydrogen atoms attached to both nitrogens of the diamine 11, so forming a compound of the formula:

in which X, Y, R,, R and R have the aforesaid meanings.

In general,- the groups Z, and Z may represent halogen, a substituted or unsubstituted amino group, the group CR or SR in which R represents hydrogen, a hydrocarbon radical that may be substituted by hetero atoms or halogen, a R -sulfonyl group, in which R represents a hydrocarbon radical, or Z, and Z together may represent sulphur or oxygen.

If Y represents hydrogen H 2, and Z stand preferably for halogen or hydroxy groups. Reagents III belonging to this type of compounds are, for example, methylenechloride, methylenebromide or methylene diol formaldehyde solution in water or a water containing solvent).

If Y represents oxygen or sulphur the most suitable moieties for Z and Z are halogen, substituted or unsubstituted amino groups, R or SR in which R represents a hydrocarbon radical that may be substituted by hetero atoms or halogen, or Z and Z together are sulphur (in combination with Y sulphur).

Suitable reagents III belonging to this type of compounds are, for example, phosgene, thiophosgene, haloformic esters, such as ethylchloroformate, esters of carbonic acid such as diethylcarbonate, urea and urea derivatives such as thiourea or N,N'-carbonyl-diimidazole, and carbondisulphide.

Preferably methylene halide or formaldehyde (in water) is used as the reagent III in the present condensation reaction because they yield the desired final product according to the invention in a direct way.

If a reagent according to the formula III, in which Y represents oxygen or sulphur, is used, the resulting compound must be reduced additionally to obtain the desired final product. For such a reduction any suitable reducing agent can be used, for example, metal hydrides such as sodium hydride, lithium aluminium hydride or diborane. Said reduction can also be performed catalytically by hydrogenation in the presence of a metal or a metal compound.

If Z and/or Z represent halogen, an agent capable of binding the hydrohalide released in the condensation reaction, such as pyridine, triethylamine, etc., is usually added to the reaction mixture.

The condensation reaction can be performed in any suitable solvent. Where methylene halide is used as the reagent III, special preference is given to an aprotic polar solvent such as dimethylsulfoxide, sulfolane or acetonitril. It is also possible, however, to perform the condensation exclusively in the reagent, for example, methylenechloride or a formaldehyde solution, so in the absence of an (additional) solvent. In certain cases, e.g., where urea is used as the reagent III, the condensation can be carried out in a melt.

The acid addition salts of the compounds according to the invention are prepared in the conventional manner by reacting the free base with a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycollic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or benzoic acid.

The pharmaceutically acceptable quaternary ammonium compounds, in particular the lower (1-4 C) alkyl quaternary ammonium compounds, are obtained by reacting the compounds of the general formula I with an alkyl halide, for example methyl iodide or methyl bromide.

From the above general formula I it appears that the compounds according to the invention possess an asymmetrical carbon. Consequently optical antipodes are possible, also forming part of this invention. Said optical antipodes can be isolated from the racemic mixture in a conventional manner. It is also possible to resolve the racemic starting product II into its optical antipodes and to perform the condensation reaction after that, or to resolve an intermediate product obtained in the synthesis into its optical antipodes.

It is of course possible to introduce or modify the substituents at one or both phenyl nuclei after the condensation reaction. Thus, for example, a hydroxy group present can be acylated or converted into an alkoxy group, an amino group into a halogen group, a methoxy group into a hydroxy group, etc.

The substituent (R at the N nitrogen atom can be obtained by alkylating or aralkylating the unsubstituted nitrogen atom (R H) or by acylating the unsubstituted nitrogen atom followed by a reduction of the carbonyl moiety of the N-acyl compound thus obtained.

It is also quite obvious and well-known in the art to convert the alkylor aralkyl substituted N -nitrogen atom (of formula I) into the unsubstituted nitrogen, for example by heating with chloroformic ester, followed by hydrolysis of the compound thus obtained.

The compounds according to the present invention exert as said before, an antidepressant activity. They can be administered both orally and parenterally, preferably in a dosage of between 0.01 and 1 mg per kg body weight. Mixed with suitable auxiliaries the compounds can be compressed into solid dosage units, such as pills, tablets and coated tablets. They can also be processed into capsules, mixed with auxiliaries, if desired. By means of suitable liquids the compounds can be applied as injection preparations in the form of solutions, emulsions or suspensions.

Compounds which are preferably used in the present invention are:

2,6-dimethyl-l ,2,3, l 3b-tetrahydro-imidazo[ 3 ,4d

dibenzo[b,f](1,4)-oxazepine, Z-methyll ,2,3 l 3b-tetrahydro-imidazo[ 3,4-dldibenzo[b,f]( 1,4)-oxazepine, 2,12-dimethyl-l ,2,3,1 3b-tetrahydro-imidazo[3,4-d1- dibenzo[b,f](1,4)-oxazepine.HCl,

Z-methyll 2-chlorol ,2,3, l 3b-tetrahydroimidazo[3,4-d]-dibenzo [b,f]( l ,4)-thiazepine, Z-methyl- I 2-trifluoromethyl-l ,2,3 3b-tetrahydroimidazo[3,4-d] dibenzo[b,f](1,4)-thiazepine, 2,9-dimethyl-2,3,9,l 3b-tetrahydro-9H-imidazo[ 3,4-

d]-dibenzo[b,f]( l ,4)-diazepine. The following examples serve to illustrate the invention further.

In the examples the following nomenclature and numbering have been used:

d N 131; z

1,2,3,13b-tetrahydro-9H-imidaz0[3,4-d]-dibenzo[b, i] (1,4)-diazepine.

1 Laminomethyl-10,11-dihydro-dibenzo[b,f] (1,4)-0xazepine.

s g} 6 2 9 H 1 1 l-aminornethyl-lO,11-dihydrodibenzo[b,fl (1 ,4)-thiazepine.

' 1-aminomethy1-10,11-dihydro-5H-dibenzolb,e] (1,4)-diazepiue.

EXAMPLE I Preparation of 2-methyl-1,2,3,l 3b-tetrahydroimidazo[3,4-d]-dibenzo [b,f](1,4)-oxazepine 2 of 1 1-methy1aminomethy1-10,1l-dihydrodibenzo[b,f]( 1 ,4)-oxazepine are added to a mixture of 40 ml of ethanol and 15 ml of a 40% solution of formaldehyde in water. The mixture is refluxed for 30 minutes, after which it is evaporated in vacuum to a volume of about 25 ml. An extra quantity of 30 ml of water is added, and the precipitate formed is filtered and then recrystallised from ethanol. Obtained .in this manner: 1.6 g of pure product. Melting point lO2-103C. The tartrate of this compound melts at 113l15C.

EXAMPLE II EXAMPLE III Preparation methyliodide salts (quat. ammonium compounds) A. Of the product obtained in example I, 2-methyl- 1,2,3 ,13b-tetrahydro-imida2o[3 ,4d]- dibenzo[b,f](1,4) oxazepine, 300 mg is boiled for 5 minutes in 10 ml of ether and 2 ml of methyl iodide. The mixture is cooled down, after which the precipitate obtained is filtered off and recrystallised from ethanol. Melting point of the CH salt 192l94C.

B. In the same manner the CH salt of 2,6-dimethyl- 1,2,3,l3btetrahydro-imidazo[ 3,4-d]-dibenzo[b,f]( l ,4)- oxazepine (example 11.1) is prepared. Melting point of the CH salt l84-186C.

EXAMPLE IV Preparation of 1 2-methyl-6-chloro-1,2,3,13btetrahydro-imidazo[3,4-d]-dibenzo[b,f]( 1 ,4)- thiazepine and other derivatives a. 1.5 g of 8-chloro-ll-methylaminomethyl-l0,l1- dihydro-dibenzo[b,f](1,4)-thiazepine are dissolved in 20 mlof ethanol, after which 10 ml of a formaldehyde solution in water are added. The mixture is heated for 40 minutes at 50C, after which it is evaporated in vacuum to a volume of 15 ml. After the addition of 10 ml of water the precipitate is filtered off and recrystallised at once from methanol. Obtained: 1.1 g of pure product; m.p. 1459147C.

b. In the same manner are prepared the 2-methylcompound (m.p. 147150C), the 2-methyl-12- chloro-compound (m.p. 1 13-1 15C) and the 2- methyl-6-trifluoro-methyl-compound 145-147C).

EXAMPLE V Preparation of 2,9-dimethyl-1 ,2,3,1 3b-tetrahydro-9H- imidazo[3,4-d]-dibenzo[b,f]( l ,4)-diazepine and other derivatives a. 8 g of 5-methyl-11-methylaminomethyl-10,l1- dihydro-5l-I-dibenzo[b,e](l,4)-diazepine are added to a mixture of ml of ethanol and 25 ml of a 40% formaldehyde solution in water. The mixture is left to stand for 30 minutes, after which it is evaporated in vacuum to one-third of the volume. Finally 40 ml of water are added and the mixture is extracted with ether. The 'ether extracts are washed with water, dried on anhydrous sodium-sulphate and evaporated. The resulting yellow oil is chromatographed over silicagel. The methanol eluate yields, after evaporation, 5.6 g of the crystalline substance, that melts at l02C after recrystallisation from ethanol.

b. In the same manner are prepared the 2-ethyl-9- methyl-compound (mp 9 8-100C) and the corresponding l2-methoxy, l2-hydroxy and 12-methyl compounds.

EXAMPLE v1 Resolution of 2-methyl- 1 ,2,3 ,1 3b-tetrahydroimidazo[3 ,4-d]-dibenzo[b,f](1,4)-oxazepine (racemic) 6 g of (racemic) Z-methyl-l,2,3,13b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepine are dissolved in 400 m1 of absolute ethanol. Then a solution of 2.8 g 2(R), 3(R)-tartaric acid (natural tartaric acid) in 100 ml of ethanol are added. The mixture is left 'to stand overnight, after which the crystallisate is sucked off. The crystals are passed into 1N NaOH, after which the mixture is extracted with benzene. Then the benzene layer is washed with water, dried on Na SO and evaporated to dryness. The residue has a rotation of [04] +37.

The extraction process described above is repeated three times resulting into a product with a constant rotation of [01],; +62; m.p. l34135C.

In the same manner the laevorotatory enantiomer is obtained with 2(8), 3(5) tartaric acid (synthetic) from the mother liquors of the dextrarotatory enantiomer. [a] 62.

EXAMPLE VII Preparation of 2-m ethyl-l ,2,3 1 3b-tetrahydroimidazo[3,4-d]-di-benzo[b,f](1,4)-oxazepine A. Two grammes of 1l-methylaminomethyl-l0,lldihydro-dibenzo[b,f](1,4)-oxazepine are dissolved in 12 ml of methylene chloride, after which 12 ml dimethylsulfoxide and 5 ml of triethylamine are added. The mixture is refluxed for 4 hours. The excess of methylenechloride and triethylamine are distilled off in vacuo. The remaining liquid is diluted with 50 ml of water. The mixture is left to stand for one hour, after which the precipitate, obtained after filtration, is crystallised from ethanol. The substance melts at l00102C.

B. According to the above method (reagent 111 methylenechloride) the following substances are prepared:

2-methyl-12-chloro-l,2,3,13b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-thiazepine; m.p. ll2114C. 2-methyl-1,2,3,13b-tetrahydro-imidazo[3,4-d]- dibenzo[b,f](1,4)-thiazepine; m.p. 147-149C. 2,9-dimethyl-l ,2,3 ,l 3b-tetrahydro-9l-I-imidazo[3,4-

d]-dibenzo[b,f](1,4)-diazepine; m.p. 102C.

EXAMPLE VIII 2-methyl-1,2,3,13b-tetrahydro-imidazo[3,4-d]- dibenzo[b,f](1,4)-oxazepine 2 g of the diamine 1l-methylaminomethyl-l0,l1- dihydro-dibenzo[b,f](1,4)-oxazepine is dissolved in CS and the solution is refluxed for 6 hours. During this refluxing process a residue is precipitated, that is isolated by filtration. This residue, thio-l ,2,3 ,13b-tetrahydro-imidazo[3,4-d]- dibenzo[b,f]( 1,4) oxazepine, is immediately dissolved in THF, after which 1.5 g LiAlI-L, is added. The mixture is refluxed for 3 hours while stirring. The mixture is then cooled down to 0C, after which 6 ml water is 50 added dropwise. The mixture is stirred for one additional hour and then filtered. The filtrate is evaporated to dry in vacuo. After recrystallisation of the residue obtained from ethanol the pure compound is obtained: m.p. 102-l03C.

The same product is obtained, if instead of CS phosgene or ethylchloroformate in a suitable solvent or urea (in a melt) is used.

EXAMPLE IX l,2,3,13b-tetrahydro-imidazo[3,4-d]- dibenzo[b,f](1,4)-oxazepine In the same manner as described in example 1 1,2,3 ,1 3b-tetrahydroimidazo[3,4-d]-dibenzo[b,f](1,4)-oxazepine is obtaining starting from 5 dibenzo[b,f](1,4)-oxazepine.

What is claimed is: l. A compound of the formula:

in which X is oxygen, sulfur or NR in which R, is hydrogen or alkyl of 1-6 carbon atoms; R and R are 20 each hydrogen, halogen, hydroxy, alkyl of l-6 carbon atoms, alkoxy of 1-6 carbon atoms or trifluoromethyl; R is hydrogen, alkyl of l-6 carbon atoms or phenylalkyl of 7-10 carbon atoms; or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable quaternary ammonium compound thereof.

2. A compound according to claim 1 of the formula:

claim 1, or a pharmaceutically acceptable-acid addition salt or a pharmaceutically acceptable quaternary ammonium compound thereof.

3. A compound according to claim 1 of the formula:

2-methyl-3- QN l.

ll-aminomethyl-10,l l-dihydro-

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3435042 *Mar 30, 1965Mar 25, 1969Colgate Palmolive CoNovel morphanthridine derivatives
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4002632 *Jan 22, 1975Jan 11, 1977Akzona IncorporatedTetracyclic piperidino derivatives
US4039558 *Oct 20, 1975Aug 2, 1977Akzona IncorporatedAntihistamine, sedatives
US4313931 *Feb 23, 1981Feb 2, 1982Boehringer Ingelheim KgFused dibenzo imidazolo compounds, compositions and use
US4503060 *Aug 20, 1982Mar 5, 1985Boehringer Ingelheim Kg3-Imino-3H-dibenzo-[c,f]-imidazo-[1,5-a]azepine pharmaceuticals
US4728735 *Nov 10, 1986Mar 1, 1988Merck & Co., Inc.Lipoxygenase inhibitors
US5478934 *Nov 23, 1994Dec 26, 1995Yuan; JunCertain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands
DE2614406A1 *Apr 2, 1976Oct 14, 1976Akzo NvTetracyclische verbindungen, verfahren zu deren herstellung und arzneimittel, enthaltend diese verbindungen
U.S. Classification540/546, 540/557, 540/555, 540/547
International ClassificationC07D498/04, C07D513/04, C07D487/04
Cooperative ClassificationC07D513/04, C07D487/04
European ClassificationC07D487/04, C07D513/04