JPH0214350B2 - - Google Patents

Description

Claim 1 General formula: (wherein, X represents oxygen, sulfur or a group _NR5 ,
R ₅ is hydrogen or alkyl (1-4C), R ₁ ,
R ₂ , R ₃ and R ₄ each represent hydrogen, hydroxy group, halogen, alkyl group, alkoxy group or hydroxyalkyl group, R represents hydrogen, alkyl, alkenyl or aralkyl, hydroxyalkyl or acyloxyalkyl, and n Represents the number 0, 1 or 2; however, R, R ₁ , R ₂ , R ₃
and the alkyl moiety in each group of R ₄ has 1 to 4 carbon atoms) or their pharmaceutically acceptable acid addition salts or nitrogen oxides. 2 X represents oxygen, n has the value 1, and/
or R represents alkyl (1-4C). 3. A compound according to claim 2, wherein 3R is methyl. Description The present invention provides novel dibenzoxazonine derivatives,
Dibenz-oxazecin derivatives or dibenzo-
The present invention relates to oxaazacycloundecane derivatives and their corresponding thia and aza derivatives, processes for their production, and pharmaceutical formulations containing these derivatives. In particular, the present invention relates to the general formula: (wherein, X represents oxygen, sulfur or a group _NR5 ,
R ₅ is hydrogen or alkyl (1-4C), R ₁ ,
R ₂ , R ₃ , and R ₄ are each hydrogen, hydroxy group, halogen, cyano group, alkyl group, alkoxy group,
represents an aralkoxy group, alkylthio group, methylenedioxy group, CF ₃ group, NO ₂ group, NH ₂ group, hydroxyalkyl group, or acyloxy group, and R represents hydrogen, alkyl, alkenyl, aralkyl, hydroxyalkyl or acyloxyalkyl; , n represents the number 0, 1 or 2), or their pharmaceutically acceptable acid addition salts, or their nitrogen oxides. The compounds of the invention are important CNS (central nervous system) active compounds, in particular they have strong antipsychotic properties. The compounds are manufactured by methods commonly used for such compounds. A suitable method is the formula: (wherein X, R ₁ , R ₂ , R ₃ , R ₄ and n have the same meanings as specified above and Y ₁ and Y ₂ are both “leaving groups” or both are either represents an oxo(aldehyde) group, or one represents a "leaving group" and the other represents a group -NHR, where R has the meaning already given above. Consists of cyclization. When both Y ₁ and Y ₂ represent leaving groups such as halogen or sulfonyloxy groups, the cyclization to give compounds of formula is ammonia or amine ():H ₂ NR, where R is (with the meaning given above).
When both Y ₁ and Y ₂ represent an oxo group, the desired product can be reacted with said amine H ₂ NR in the presence of a reducing agent such as LiAlH ₄ , di-isobutylaluminum hydride or NaBH ₄ . You can get it by twisting it. The second method commonly used is the general formula: [wherein X, R ₁ , R ₂ , R ₃ , R ₄ and n have the meanings already specified above and Q ₁ and Q ₂ represent hydrogen (2H) or oxygen. provided that at least one of the groups Q ₁ and Q ₂ represents oxygen]. This reduction is carried out by methods commonly used for the reduction of amides, preferably using a metal hydride complex such as lithium aluminum hydride in dimethyl sulfide and tetrahydrofuran, or using diborane or borohydride. The compounds of formula used as starting products are prepared by methods commonly used for the preparation of such compounds. For the sake of completeness, reference will be made to the reaction routes below, in which some commonly used preparation methods are presented in formula form. Apparently after carrying out one of the aforementioned manufacturing methods,
It is possible to convert compounds of the invention into other compounds of the invention. Thus, for example, unsubstituted (on the nitrogen atom) amines of the formula (R=H) can be reacted with conventional methods, for example with alkyl halides, alkenyl halides, or aralkyl halides or acylated at the appropriate nitrogen atom. , which can then be alkylated by reducing the N-acyl compound thus formed. via the Eschweiler-Clarke reaction (reaction with formaldehyde and formic acid) or with a suitable solvent,
Preference is given to introducing a methyl group onto the nitrogen atom, for example via reaction with formaldehyde and sodium cyanoboron hydride in acetonitrile. Another common method involves the de-(ara)alkylation of amines I substituted at the nitrogen atom (R=aralkyl, alkenyl or alkyl).
-(ar)alkylation] to the corresponding unsubstituted amine (R=H). In this way, N-benzyl groups can be converted into the corresponding NH groups by catalytic hydrogenation in a simple manner. Another possibility for de-(ara)alkylation is that the (ara)alkyl [(ar)alkyl] of the formula
or consisting of reacting an alkenyl-substituted amine with a chloroformate or BrCN and then hydrolyzing the resulting carbamate. Furthermore, the obtained carbamate may be converted into a methyl group by conventional reduction methods. A compound of the formula (provided that the symbol R ₁ , R ₂ , R ₃ or R ₄
of which at least one is hydroxy), the alkoxy substituents and preferably methoxy substituents of the phenyl group are subjected to conventional hydrolysis to the corresponding hydroxy group with an acid such as _BBr3 or HBr. Good too. If one of the symbols R ₁ to _{R 4} represents a benzyloxy group, the benzyloxy group may be converted into the corresponding hydroxy group by conventional reduction. Additionally, the nitro group (NO ₂ ) on one or both phenyl moieties can be reduced to an amino group in a conventional manner. Next, CuCN after diazotization
This amino moiety can be converted into a cyano moiety by reacting with. The cyano (CN) moieties on one or two phenyl moieties can be hydrolyzed and then reduced to yield the corresponding hydroxymethyl groups. The hydroxy groups in the definitions of R 1 to R 4 or the hydroxy groups of the hydroxy-alkyl moieties in the definition of R can be converted to the corresponding hydroxy groups in the definitions of R ₁ to _{R 4} or the hydroxy groups of the hydroxy-alkyl moieties in the definition of R by reacting with the desired carboxylic acids or their acid halides, anhydrides or reactive esters. It can be converted to an acyloxy group. in the usual manner by reacting the free base I with an acid such as HCl, HBr or HI, phosphoric acid, acetic acid, maleic acid, malonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, ascorbic acid or salicylic acid, An acid salt of the compound of the present invention is produced. Nitrogen oxides I are obtained by oxidizing nitrogen atoms with oxidizing metal oxides such as peracids, H ₂ O ₂ or MnO ₂ . Compound I can be administered either enterally or parenterally. Compound I can be processed into forms suitable for oral administration such as pills, tablets and coated tablets by mixing with a suitable carrier. For injection, the compound of the formula is dissolved, emulsified or suspended in a liquid suitable for injection. Additionally, Compound I can be formulated in the form of suppositories or sprays. Preferably, the compound is used in a dosage of from 0.01 mg to 10 mg per kg body weight per day. For humans,
A dosage of 1 to 500 mg per day is recommended. Alkyl groups in the definition of R ₁ , R ₂ , R ₃ and R ₄ have 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. 1~
Represents a saturated alkyl group having 4 carbon atoms. The alkyl group in the definition of R has the same meaning but can also be a cycloalkyl group or a cycloalkyl-alkyl group having 3 to 6 carbon atoms, such as cyclohexyl, cyclopentyl, cyclobutylmethyl and cyclopropylmethyl. . Alkenyl in the definition of R is understood to be an unsaturated alkyl group having 2 to 6 carbon atoms, preferably an unsaturated alkyl group having 3 or 4 carbon atoms, such as allyl and 2-butenyl. Should. The aralkyl group in the definition of R is substituted with an aromatic group such as a phenyl group or a naphthyl group (R ₁ ,
represents an alkyl group (as defined above for R ₂ , R ₃ and R ₄ ); The aromatic group may be substituted with one or more alkyl (1-4C), halogen, hydroxy or alkoxy groups. Preferably, it represents a substituted or unsubstituted phenyl alkyl group having 7 to 12 carbon atoms, such as phenylmethyl, phenylethyl, mp dihydroxyphenylethyl, mp dimethoxyphenylethyl and phenylpropyl. “Hydroxyalkyl” group, “alkylthio”
Alkyl moieties present in groups and “alkoxy” groups (see definitions of R ₁ , R ₂ , R ₃ and R ₄ )
has the same meaning as defined for "alkyl" in the definitions of _R1 to _R4 . The alkyl moieties (see definition of R) present in "hydroxyalkyl" and "acyloxyalkyl" groups have the same meanings as defined for the alkyl group in the definition of R. Acyloxy groups in the definition of R ₁ to _{R 4} are carboxylic acids having 1 to 18 carbon atoms, especially aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, phenylacetic acid and phenylpropionic acid, or phenyl- It is derived from aliphatic carboxylic acids. More specifically, acyloxy groups with "relatively long" aliphatic chains or phenyl-aliphatic chains are preferred. Particularly preferred are acyloxy groups having 8 to 18 carbon atoms such as octanoyloxy, decanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, stearoyloxy and cinnamoyloxy. The acyloxy components of the acyloxyalkyl group (definition R) have the same meaning. “Halogen” in the definition of R ₁ to _{R 4} refers to fluorine, chlorine,
Bromine or iodine is to be understood; chlorine is preferred. The following numbering and nomenclature was used in the examples:

[Formula] X=O, S5,6,7,8-tetrahydro-dibenz(b,h)(1,5)oxazonine, or thiazonine
-dibenzo-(b,h)(1,5)diazonine

[Formula] X=O, S6,7,8,9-tetrahydro-5H-
Dibenz(b,i)(1,6)oxazecin or thiazecin

[Formula] 8,9,10,15-hexahydro-5H-dibenzo(b,j)(1,6)diazacyclo-undecine Preferred compounds of the invention are those compounds of the formula. In this case (whether in combination or not), X represents oxygen, n has a value of 1,
R represents alkyl (1-4C), preferably methyl, and either both phenyl groups are unsubstituted or one or both phenyl groups are mono-substituted. Example 1 7-Benzyl-6,7,8,9-tetrahydro-5H-dibenz-(b,i)(1,6)oxazecin a 12 g of 2,2'-oxybisbenzeneacetic acid with stirring under nitrogen A solution of 300 ml of dry tetrahydrofuran (THF) was added to a suspension of 12 g of LiAlH ₄ in 750 ml of dry ether. After this addition, the mixture was refluxed for about 1 hour, after which 48 ml of water was added dropwise while the mixture was cooled on ice. Next, remove the formed white inorganic precipitate,
Washed with THF. The liquid was evaporated to dryness to give an oily residue. Yield: 10.7g. in toluene:ethyl acetate (1:1)
R _f = 0.45 on _SiO2 . b 5.5 g of 2,2'-oxybisbenzene-ethanol from a and 100 ml of 48% hydrogen bromide were heated to 130°C for 4 hours with vigorous stirring. After cooling the reaction mixture, add 500ml of water to this mixture.
and the resulting mixture was extracted with ether. The ether extract was washed with water, dried,
Evaporated under vacuum. The residue was then purified on a silica gel column. Yield: 5.7g (oil). R _f in hexane:toluene (8:2)
= 0.50 on _SiO2 . c 9.7 g of 1,1'-oxybis[2(β-bromoethyl)benzene] from b and dry xylene
A mixture of 13 ml of benzylamine dissolved in 970 ml was refluxed for 16 hours. After cooling the mixture, 1n
NaOH was added and the organic layer was separated and then evaporated to dryness. The residue was purified on a silica gel column. Yield: 6.25g (oil). in methanol:acetone (9:1)
R _f = 0.75 on _SiO2 . Example 2 6,7,8,9-tetrahydro-5H-dibenz(b,i)(1,6)oxazecin 7-benzyl-6,7,8,9-tetrahydro-5H-dibenz(b,i)( 1,6) 6.5 g of oxazecin was dissolved in 450 ml of glacial acetic acid. in this solution
1 g of Pd/c (10%) was added, after which hydrogen was introduced into the reaction mixture for 2 hours. Then remove the catalyst and
The liquid was evaporated in vacuo. The residue was dissolved in dilute ammonia and the mixture was extracted with ether. The ether extracts were washed, dried and evaporated. Yield 4.3g (oil), melting point (HCl salt): 246°C. R _f in methanol:acetone (9:1)
= 0.10 on _SiO2 . Example 3 (a) 6,7,8,9-tetrahydro-7-methyl-5H-dibenz(b,i)(1,6)oxazecin 6,7,8,9-tetrahydro-5H-dibenz(b, i) 1 g of (1,6) oxazecin was mixed with 4 ml of formic acid and 3.8 ml of 37% formalin.
This mixture was heated at 100°C for 1 hour. After cooling,
0.5 ml of concentrated hydrochloric acid was added and the reaction mixture was evaporated.
The residue was then dissolved in dilute NaOH and the mixture was extracted with ether. The ether extracts were washed, dried and evaporated to dryness. Yield: 1.05g (oil). in methanol:acetone (9:1)
R _f = 0.25 on _SiO2 . (b) 6,7,8,9-tetrahydro-7-methyl-5H-dibenz(b,i)(1,6)oxazecin(Z)-2-butenedioate (1:1) 6,7,8 ,9-Tetrahydro-7-methyl-5H-dibenz(b,i)(1,6)oxazecin (1.05 g) was dissolved in 6 ml of ethanol.
A solution of 0.6 g maleic acid in 3 ml ethanol was added to this solution. The formed crystals were removed and then washed with ether. Yield: 1.3g; melting point 158°C. Example 4 The following compound was prepared in a manner similar to that described in Examples 1, 2 and 3: 3-chloro-6,7,8,9-tetrahydro-
5H-dibenz(b,i)(1,6)oxazecine HCl, mp156℃; 3-chloro-6,7,8,9-tetrahydro-
7-Methyl-5H-dibenz(b,i)(1,6)
Oxazecin, mp (maleate): 145°C; 6,7,8,9-tetrahydro-3,7-dimethyl-5H-dibenz(b,i)(1,6)oxazecin, mp (maleate): 165℃; 6,7,8,9-tetrahydro-7-methyl-
1,2-dimethoxy-5H-dibenz (b,i)
(1,6) Oxazecin; 5,6,7,8,9,14-hexahydro-7-
Benzyl-14-methyldibenzo(b,i)(1,
6) Diazecin, meruene: ethanol (8:
R _f in 2) = 0.38 on SiO ₂ ; 6,7,8,9-tetrahydro-7-methyl-
5H-dibenzo(b,i)(1,6)thiazecin,
mp (maleate): 176℃; 5,6,7,8,9,10-hexahydro-7-
Methyldibenzo(b,j)(1,6)oxazacycloundecine HCl, mp216℃; 5,6,7,8,9,10-hexahydro-dibenzo(b,j)(1,6)oxaza Cycloundesine HCl, mp249℃; 3-chloro-6,7,8,9-tetrahydro-
7-cyclopropylmethyl-5H-dibenz (b,
i) (1,6) Oxazesin/HCl, mp225~
226℃; 3-chloro-6,7,8,9-tetrahydro-
7-Benzyl-5H-dibenzo(b,i)(1,
6) Thiazecin, toluene:ethyl acetate (8:
R _f in 2) = 0.81 on SiO ₂ ; 3-chloro-6,7,8,9-tetrahydro-
7-Methyl-5H-dibenzo(b,i)(1,6)
Thiazecin, mp (maleate): 182°C; 2-methoxy-6,7,8,9-tetrahydro-7-benzyl-5H-dibenz (b,i) (1,
6) Oxazecin, toluene:ethanol (8:
R _f in 2) = 0.61 on SiO ₂ ; 2-methoxy-6,7,8,9-tetrahydro-7-methyl-5H-dibenz(b,i) (1,
6) Oxazecin, toluene:ethanol (8:
R _f in 2) = 0.34 on SiO ₂ ; 3-nitro-6,7,8,9-tetrahydro-
7-Methyl-5H-dibenz(b,i)(1,6)
Oxazecin; 3-amino-6,7,8,9-tetrahydro-
7-Methyl-5H-dibenz(b,i)(1,6)
Oxazecin; 5,6,7,8-tetrahydro-6-methyl-
Dibenzo (b, h) (1,5) thiazonine HCl,
mp245℃; 5,6,7,8-tetrahydro-6-methyl-
Dibenz(b,h)(1,5)oxazonine
HCl, mp235℃; 1,2-methylenedioxy-6,7,8,9-
Tetrahydro-7-methyl-5H-dibenz (b,
i) (1,6)oxazecin. Example 5 5,6,7,8-tetrahydro-6-methyldibenz(b,h)(1,5)oxazonine(a) 8.5 g of 2-(2'-hydroxymethylphenoxy)benzene-ethanol and 48 % hydrogen bromide 40
ml of the mixture was heated at boiling point for 6 hours with vigorous stirring. After the mixture has cooled, pour the mixture into water.
It was diluted with 200ml and extracted with ethyl acetate. The extracts were washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified on a silica gel column. Yield: 40g (oil). R _f in toluene = 0.85 on silica gel. (b) With vigorous stirring, dimethyl sulfoxide
4 g in 30 ml and 100 ml of 96% ethanol1-
(2′-bromo-methylphenoxy)-2-(β
-bromoethyl)benzene (from a) above)
A solution of 100 ml of 22% methylamine in ethanol was added dropwise to the solution. This mixture was then poured into 50 ml of water and extracted with ether. Dry the ether extract in vacuo for 20 min.
Evaporated at °C. Yield: 2.5g (oil). in methanol:acetone (9:1)
R _f = 0.3 on silica gel. (c) Add 2.5 g of 2-[2'-(β-bromoethyl)phenoxy]-N-methyl-benzenemethanamine obtained from (b) to 50 ml of THF and 100 ml of ether.
and refluxed for 2 x 24 hours. After cooling, it was evaporated and the resulting residue was purified on a silica gel column. Yield: 0.2g (oil); Melting point (HCl salt): 233
~235℃. in methanol:acetone (9:1)
R _f = 0.6 on _SiO2 . Example 6 5,6,7,8,9,10-hexahydro-7-
Methyldibenz(b,j)(1,6)oxaazacycloundecine. 1-[2'- in 20ml EtOH and 20ml dry DMSO
(β-bromoethyl)phenoxy]-2-(γ-
Bromopropyl) benzene 1.34 g (3.3 mmol)
was introduced into the ampoule. Then 1 ml of triethylamine and 0.64 g of 16.3% by weight methylamine in DMSO were added. The ampoule was sealed and then heated in an oil bath at 80°C for 4 hours. The reaction mixture was then poured into water and extracted with ether. The ether extract was then washed with dilute HCl. The aqueous layer was then made alkaline and extracted again with ether, and the collected ether layers were washed with water, dried and evaporated. The yield is
410 mg (oil); R _f in methanol:acetone (9:1)
= 0.25 on _SiO2 . Melting point (HCl salt): 215-216℃.

[Table] Explanation of reaction formula a Reaction with salicylic acid. b Reaction with O-hydroxyphenylacetic acid. c Reaction of O-iodine with phenylacetonitrile. d Reduction with _LiAlH4 . e After reaction with HBr and then reaction of this bromide with KCN, the nitrile is hydrolyzed. f HBr and then react the bromide with 1 equivalent of RNH ₂ . g Reduction with hydrogen and Pd/c followed by cyclization. h Reaction with O-hydroxyphenylacetonitrile. i Reduction with di-isobutylaluminum hydride (DIBAH).