JPH0471075B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to novel benzazepines and benzoxyazepine derivatives having anthelmintic action, pharmaceutical preparations containing them, and their use in medicine or veterinary medicine. [Prior art] Compound praziquantel, 2-
Cyclohexycarbonyl [1,2,3,6,7,
11b] Hexahydro-4H-pyrazino[2,1-
a] Isoquinolin-4-one is a well-known compound with anthelmintic activity. Praziquantel has structure (A). [Problems to be Solved by the Present Invention] An object of the present invention is to provide a novel compound having a useful anthelmintic effect, in particular a useful anthelmintic effect against tapeworms. [Means for Solving the Problems] The present invention has discovered a group of compounds that have useful anthelmintic activity, particularly against tapeworms, and have a structure different from that of praziquantel. According to the invention, the formula (): (In the formula, R is optionally substituted phenyl,
C _3-8 cycloalkyl, C _5-8 cycloalkenyl, C 1-8 alkyl, which may be straight-chain or branched, C _1-8 alkyl, which may be straight-chain or branched C _2-8 alkenyl, 5- or 6-membered heterocyclic group, or optionally substituted phenyl C _1-4
alkyl, each of Y and Z may be the same or different, is oxygen or sulfur, X is _-CH2oxygen- , and the symbol * represents an asymmetric carbon atom) A compound is provided. Compounds of formula () have an asymmetric carbon atom marked by an asterisk in formula () and therefore exist in at least two stereoisomeric forms. The present invention encompasses all isomers of the compounds of formula (), either pure or mixed with other isomers in any proportion. When R is optionally substituted phenyl, it is halogen, C _1-6 alkyl, C _1-6 alkoxy, nitro, amino, mono- or di-C _1-6
It can be substituted with one or more moieties selected from alkylamino and hydroxy. When R is a heterocyclic group, it contains one or more heteroatoms selected from oxygen, sulfur and nitrogen.
or a 6-membered saturated or unsaturated group. A preferred R group is cyclohexyl. A compound of formula () is a compound of formula () [Wherein, X is as defined in formula (), and R ¹ is hydrogen, a protecting group, or a group

[Formula] (wherein R and Y are as defined in formula ()), R ² is C _1-3 alkyl or hydrogen] is refluxed, and R ¹ is a protecting group. If you remove the protecting group and replace it with

[Formula], and if R ¹ is hydrogen, use it as the base.

[Formula] and optionally thereafter, the compound of formula () thus produced, where Z is oxygen, is treated with a sulfur binding reagent (thionation
It can be produced by converting Z into a compound in which Z is sulfur by treatment with a sulfur reagent). A preferred sulfur binding reagent is Lawessons reagent. In the above method, a group in which Y is sulfur

Replacement of [formula] is formula

This can be accomplished by treatment with a dithionate ester of formula ##STR2## where R is as previously defined and ^R.sup.4 is _C.sub.1-6 alkyl. As used herein, the term "protecting group" refers to a group that is stable under the reduction reaction conditions, but can be easily removed after reduction is complete. A typical example of such a protecting group is benzyl, which can be removed, for example, by catalytic hydrogenation using a palladium catalyst in a suitable solvent. Examples of R ² are C _1-3 alkyl and hydrogen, preferably hydrogen. Compounds of formula () can be refluxed by treatment with acid catalysts and acids such as polyphosphoric acids may be conveniently used. The reaction is
At high temperatures such as 100℃ or higher, e.g.
It can be carried out at 180℃. Alternatively, concentrated sulfuric acid can be used, in which case the reaction is carried out at a lower temperature, for example -10<0>C to 40<0>C. Compounds of formula () where R ² is hydrogen are of formula () (wherein X and R ¹ are as defined above)
can be produced by reducing the corresponding imide. The reduction is carried out using a suitable hydride reducing agent such as sodium borohydride in a suitable solvent such as a lower alkanol, preferably ethanol. Compounds of formula () where R ² is alkyl are Dubrieux. Papers by W. Speckamp et al. (e.g. Tetrahedron 31 ,
1437, 1975). Compounds of formula () can be prepared according to this reaction scheme using conventional reagents as shown in the reaction scheme below. In the reaction route, R ³ is a protecting group or

[Effect]

The compounds of formula () have anthelmintic action in particular against tapeworms such as Taenia, Taeniaeformis and Dipylidium caninum. The present invention therefore provides for the use of the formula ( ). The present invention also provides pharmaceutical or veterinary compositions comprising a compound of formula () and a pharmaceutically or veterinarily acceptable carrier therefor. [Means for solving the problem] This composition is administered per kg of animal body weight per administration.
Suitably it comprises sufficient material to provide a dosage of 0.01 to 250 mg of active ingredient, more suitably 0.1 to 50 mg/Kg of active ingredient per administration. The present invention provides an effective and non-toxic amount formula (): (In the formula, R is optionally substituted phenyl,
C _3-8 cycloalkyl, C _5-8 cycloalkenyl, C 1-8 alkyl, which may be straight-chain or branched, C _1-8 alkyl, which may be straight-chain or branched C _2-8 alkenyl, 5- or 6-membered heterocyclic group, or optionally substituted phenyl C _1-4
alkyl, each of Y and Z may be the same or different, is oxygen or sulfur, X is _-CH2- , and the symbol * represents an asymmetric carbon atom) Also provided are pharmaceutical or veterinary compositions for use in the treatment or prevention of helminth infections in humans or non-human animals, comprising: and a pharmaceutically or veterinarily acceptable carrier. In certain aspects, the method includes treating or preventing a tapeworm infection. In some cases, it may be desirable to repeatedly administer a compound of formula () to an infected or potentially infected human or non-human animal according to conventional dosing regimens commonly used in anthelmintic drugs. It will be understood. EXAMPLES The following examples illustrate the invention. Reference example X1 to reference example X6 and reference example X7 to reference example
X11 illustrates the preparation of intermediate compounds, while Examples 1 to 35 illustrate the preparation of compounds of the invention. Reference Example X7 illustrates the resolution of compounds of the invention. Example 1 2-(Cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine Cyclohexanoyl chloride ( 0.34 g) of 4-oxo-1,2,3,4,6,7,
8,12b-octahydropyrazino [2,1-a]
[2] Added to a solution of benzazepine [0.5 g] and triethylamine (0.26 g). The mixture was kept at 0°C for 30 minutes and then at room temperature for 5 hours. The solution was washed first with dilute hydrochloric acid and second with sodium bicarbonate solution. The chloroform solution was dried (over _MgSO4 ) and evaporated. Recrystallization of the residue from chloroform/petroleum ether at 40-60°C afforded the title compound (0.48 g, 64
%) of crystals were obtained. Melting point 187-190℃ C ₂₀ H ₂₆ N ₂ O ₂ Theoretical value - C: 73.6, H: 8.0, N: 8.6% Actual value - C: 73.2, H: 7.7, N: 8.4% Reference example X1 1-( 3-phenylpropyl)-4-benzyl-
2,6-piperazinedione 3-phenyl-1-propylamine (3.63g)
and N-pendyliminodiacetic acid (6.0 g) were mixed and heated to 200° C. under nitrogen atmosphere. The mixture was stirred at this temperature for 1 hour, cooled and purified by column chromatography (SiO ₂ , 40-60°C petroleum ether/chloroform) to give the title product as a pale orange liquid (5.53 g, 64%). Obtained substance. Reference example X2 1-(3-phenylpropyl)-4-benzyl-
2-Hydroxy-6-oxopiperazine A saturated aqueous solution of sodium bicarbonate (20 ml) was heated at 50°C.
and hydrogen to the resulting mixture at 50°C for 2 hours. Sodium boronide (1.23 g) was added in portions. The mixture was stirred for an additional hour at 5°C and the solvent was removed under vacuum. Water (50ml) was added and the mixture was extracted with dichloromethane (3 x 50ml), the extracts washed with brine and dried (over _MgSO4 ). Evaporation of solvent gives white solid (4.36g, 81%)
The title compound was obtained as . Reference example X3 2-benzyl-4-oxo-1,2,3,4,
6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine 1-(3-phenylpropyl)-4-benzyl-
2-hydroxy-6-oxopiperazine (2.6g)
and polyphosphoric acid (53 g) were mixed, heated to 180°C and maintained at this temperature for 3/4 hour. mixture 60
Cooled to °C and added water (200ml). The mixture was cooled, basified with sodium hydroxide solution and extracted with chloroform (3 x 50ml). Evaporation of the solvent and crystallization of the product from diethyl ether gave the title compound (0.78g, 32%). Melting point 125-128℃ Reference example X4 4-oxo-1,2,3,4,6,7,8,
12b-octahydropyrazino [2,1-a]
[2]-Benzazepine 45 in the presence of palladium catalyst (0.3 g) on charcoal
2-benzyl- in solution in ethanol (40 ml) by treatment with hydrogen at °C and atmospheric pressure.
4-oxo-1,2,3,4,6,7,8,12b
Hydrogenolysis of octahydropyrazino[2,1-a][2]benzazepine (1.39 g) gave the title compound (0.6 g, 61%). Examples 2 to 26, represented in the following table, can be prepared in a manner analogous to the preparation of Example 1.

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[Table] Reference example X5 2-(triphenylmethyl)-4-oxo-1,
2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]Benzazepine Triphenylmethyl chloride (0.47 g) in chloroform (25 ml, ethanol free) at 0° 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.31 g) and triethylamine (0.25
ml) was added to the mixture. The mixture was maintained at 0° for 30 minutes and then at room temperature for 90 minutes. The solution was washed with saturated sodium bicarbonate solution, dried (over _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , Et ₂ O) to give the title compound (0.66 g, 100%) as a white powder. Reference example X6 4-thioxo-1,2,3,4,6,7,8,
12b-octahydropyrazino [2,1-a]
[2] Benzazepine 2-(triphenylmethyl) in HMPA (10ml)
-4-oxo-1,2,3,4,6,7,8,
12b-octahydropyrazino [2,1-a] [2]
Benzazepine (0.66 g) and Lowessan reagent [2,4-bis(4-methoxyphenyl)-1,3
-dithia-2,4-diphosphethane-2,4-disulfide] (0.29 g) was heated to 80° under nitrogen atmosphere. The mixture was stirred at this temperature for 3 hours, cooled and partitioned between water and diethyl ether. The organic layer was washed with water and evaporated to give a yellow foam. This residue was dissolved in acetone (20
ml), cooled to 0° and dissolved in concentrated hydrochloric acid (0.5 ml).
ml) was added. After stirring for 30 minutes at room temperature, the mixture was evaporated and the residue was partitioned between dilute hydrochloric acid and chloroform. The aqueous portion was made basic with sodium carbonate and extracted with chloroform. The chloroform portion was washed with brine, dried (over _K2CO3 ) and evaporated to give the title compound as _a white solid. Example 27 2-(Cyclohexycarbonyl)-4-thioxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine Cyclohexanoyl chloride (0.16 g) in chloroform (20 ml, ethanol free) at 0°.
Thioxo-1,2,3,4,6,7,8,12b-
Octahydropyrazino[2,1-a][2]benzazepine (0.24g) and triethylamine (0.25ml) were added to a mixture. The mixture was maintained at 0° for 30 minutes and then at room temperature for 5 hours. The solution was washed first with dilute hydrochloric acid and second with sodium bicarbonate solution. The chloroform solution was dried (over _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , Et ₂ O) and dichloromethane/40
Recrystallization from -60°C petroleum ether gave the title compound as white crystals (55 mg, 16%). Melting point 150~
151℃ C ₂₀ H ₂₆ N ₂ As OS Theoretical value: C: 70.1, H: 7.8, N: 8.2, S: 9.3
% Actual value: C: 70.4, H: 7.8, N: 8.1, S: 8.8
% Example 28 2-(cyclohexylcarbonyl)-4-thioxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine HMPA (4ml) 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,
8,12b-octahydropyrazino [2,1-a]
[2] A mixture of benzazepine (0.30 g) and Lowessan reagent (0.19 g) was heated at 80° under a nitrogen atmosphere. Stir the mixture at this temperature for 3 hours,
Cooled and poured into water. This was extracted with diethyl ether. Wash the organic layer with water,
Dry (over _MgSO4 ) and evaporate. The residue was purified by column chromatography (SiO ₂ , Et ₂ O) and recrystallized (CH ₂ Cl ₂ /40-60 petroleum ether) to give white crystals of the title compound (0.13 g, 41%). I got it. melting point 150
~151°C 4-oxo-1,2,3,4,6,7, substituted by using appropriately substituted 3-phenylpropylamine in Reference Examples X1 to X4
8,12b-octahydropyrazino [2,1-a]
[2] Benzazepine is obtained and reacted with cyclohexanoyl chloride according to the method in Example 1 to obtain the following substituted 2-(cyclohexyl)-
4-oxo-1,2,3,4,6,7,8,12b
-Octahydropyrazino[2,1-a][2]benzazepine was obtained.

[Table] Example 31 Nitrogen of 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine 2-(Cyclohexycarbonyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (600 mg, 1.8 mmol) was dissolved in concentrated sulfuric acid (7 ml) and concentrated nitric acid (4 ml) with cooling. The solution was heated to 35° C. for 2 hours, poured into water (100 ml) and extracted with CHCl ₃ (2×50 ml). The combined extracts were dried (over MgSO ₄ ) and concentrated in vacuo to give a mixture of 10- and 11-mononitrogenated products, which was analyzed by preparative HPLC [UltrasilODS 10 micron, 25
cm×10mm, MeOH:H ₂ O (7:3), 1ml/min]
Separated by Residence time 8.3 minutes and 9.2 minutes. Reference example X7 2H-4-oxo-1,2,3,4,6,7,
8,12b-octahydropyrazino [2,1-
a] (2) Resolution of benzazepine (±)2H-4-oxo-1,2,3,4,6,
7,8,12b-octahydropyrazino (2,1-
a)(2) Benzazepine (3.2g, 0.0148mol) was dissolved in methanol (35ml) and a solution of (-)tartaric acid (2.45g, 0.0163mol) in methanol (140ml) was added. The mixture was heated on a steam bath, filtered while hot and allowed to cool. White crystals precipitated, which were filtered and recrystallized from methanol (250 ml) to yield (-)2H-4-oxo-1,2,3,
The (-)tartrate salt of 4,6,7,8,12b-octahydropyrazino(2,1-a)(2)benzazepine was obtained. (α) ²² _D −149° (H ₂ O). A solution of this salt in water is basified with ammonium hydroxide and extracted with chloroform to yield the free base (-)2H-4-oxo-1,2,3,4,6,7,8,12b as a white solid. -octahydropyrazino(2,1-a)(2)benzazepine was obtained. (α) ²² _D −221° (CH ₃ OH). Similarly, using (+)tartaric acid in place of (-)tartaric acid, the following compounds were obtained: (+)2H-4-oxo-1,2,3,4,6,
7,8,12b-octahydropyrazino (2,1-
a) Benzazepine (+) tartrate. (α) ²² _D +
As 153°H ₂ O ₀ C ₁₇ H ₂₂ O ₇ Theoretical value C; 57.7, H; 6.0, N; 7.6% Actual value C; 55.7, H; 6.1, N; 7.4% and (+) 2H-4-oxo -1, 2, 3, 4, 6,
7,8,12b-octahydropyrazino (2,1
-a) Benzazepine (+) tartrate. (α) ²² _D
+212゜(CH ₃ OH) Example 32 (+)2-(Cyclohexylcarbonyl)-4-
Oxo-1,2,3,4,6,7,8,12b-
Octahydropyrazino (2,1-a)(2)benzazepine (+)2H-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino instead of racemic amine (2,1-a)(2) The title compound was obtained by the method of Example 1 using benzazepine. The product was subjected to column chromatography (Si/
CHCl ₃ ). (α) ²² _D +41° (CH ₃ OH). Example 33 (−)2-(cyclohexylcarbonyl)-4-
Oxo-1,2,3,4,6,7,8,12b-
Octahydropyrazino (2,1-a)(2)benzazepine (-)2H-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino instead of racemic amine The title compound was obtained as a white solid by the method outlined in Example 1 using (2,1-a)(2) benzazepine. The product was purified by column chromatography (Si/CHCl ₃ ). (α) ^22D ₋ 42( _CH3OH ). Example 34 2-(cyclohexylthiocarbonyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine cyclohexanecarbodithionate Methyl (0.24
g) of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.3g) in dimethylformamide (5ml). added to the solution. The mixture was refluxed for 4 hours, cooled and poured into water. This was extracted with diethyl ether, the ether solution was dried (over _MgSO4 ) and evaporated. The residue was purified by column chromatography (SiO ₂ , diethyl ether).
C ₂₀ H ₂₆ N ₂ As OS m/e Theoretical value: 342.1766, Actual value: 342.1770 Example 35 2-(Cyclohexylcarbonyl)-4-oxo-1,2,3,6,7,12b-hexahydropyrazino [1,2-d][1,4]benzoxyazepine 4-oxo-1,2,3,6,7,12b-hexahydropyrazino[1,2-d][1,4]benzoxyazepine (0.9g) and triethylamine (1g) were dissolved in dichloromethane (20ml), cooled in ice and cyclohexanoyl chloride (0.7g, 1.1 eq.) was added. The mixture was stirred for 3 hours at room temperature and then washed with dilute aqueous hydrochloric acid followed by dilute aqueous ammonia solution. Evaporation of the dichloromethane gave an oil which was purified by color chromatography (SiO ₂ /chloroform) and crystallized from ether/40°-60° petroleum ether to give white crystals of the title compound. Melting point 92-93゜C ₁₉ H ₂₄ N ₂ O ₃ Theoretical value C, 69.49; H, 7.37; N, 8.3% Actual value C, 69.53; H, 7.40; N, 8.54% Reference example X8 1-(2- (phenoxyethyl)-4-benzyl-
2,6-piperazinedione 2-phenoxyethylamine (1.37g) and N
- mix benzylimidodiacetic acid (2.23 g),
It was heated to 225° and maintained at this temperature for 15 minutes.
After cooling, chloroform was added and the product was purified by column chromatography (SiO ₂ /CHCl ₃ ) to give the title compound (2.1 g) as a reddish oil. Reference example X9 1-(2-phenoxyethyl)-4-benzyl-
2-Hydroxy-6-oxopiperazine 1-(2-phenoxyethyl)- in ethanol (60 ml) and saturated sodium bicarbonate solution (15 ml)
4-benzyl-2,6-piperazinedione (2.24
g) was cooled to 5° and sodium borohydride (0.4g) was added. The mixture was stirred for 1 hour at 5°, water (150ml) was added and the mixture was extracted with chloroform (3x75ml). Evaporation of the chloroform gave the title compound (2.1g) as an off-white solid. Reference example X10 2-benzyl-4-oxo-1,2,3,6,
7,12b-hexahydropyrazino [1,2-
d] [1,4]Benzoxyazepine 1-(2-phenoxyethyl)-4-benzyl-
2-hydroxy-6-oxopiperazine (4g)
was added to concentrated sulfuric acid (50ml) at 0-10° and the mixture was stirred for 30 minutes. The resulting solution was poured onto ice, made basic with _NH4OH and extracted with chloroform to give the title compound as a pale blue oil (2g). ^Reference _example 2-Benzyl-4-oxo-1,2,3,6,7,12b- in 90% acetic acid over palladium catalyst (5%) on charcoal at pressure.
Hexahydropyrazino [1,2-d] [1,4]
Hydrogenation of the benzoxyazepine gave the title compound after basification and extraction. Pharmacological data Taenia Taeniaformis (Taenia
Cats infected with Taeniaeformis and Dipylidium caninum were treated for 30 days.
2-(cyclohexylcarbonyl)-4- in mg/Kg
Oxo-1,2,3,4,6,7,8,12b-octahydropyrazino-[2,1-a][2]benzazepine was used orally for treatment. This treatment completely eliminated the tapeworm infection. The following compounds were administered orally to cats infected with Dipyridium caninum and/or Taenia tenieformis and exhibited the following activities:

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Claims (1)

[Claims] 1 Formula (): (In the formula, R is optionally substituted phenyl,
C _3-8 cycloalkyl, C _5-8 cycloalkenyl, C 1-8 alkyl, which may be straight-chain or branched, C _1-8 alkyl, which may be straight-chain or branched C _2-8 alkenyl, 5- or 6-membered heterocyclic group, or optionally substituted phenyl C _1-4
alkyl, each of Y and Z may be the same or different, are oxygen or sulfur, X is _-CH2- , and the symbol * represents an asymmetric carbon atom). Compound. 2 When R is an optionally substituted phenyl, the phenyl is halogen, C _1-6 alkyl,
The compound according to claim 1, which is substituted with one or more atoms or groups selected from C _1-6 alkoxy, nitro, amino, mono- or di-C _1-6 alkylamino and hydroxy. 3 When R is a heterocyclic group, the heterocyclic group may be a 5- or 6-membered saturated or unsaturated group having one or more heteroatoms selected from oxygen, sulfur and nitrogen. A compound according to claim 1. 4. The compound according to claim 1, wherein R is cyclohexyl. 5 The compound is 2-(cyclohexylcarbonyl)-
4-oxo-1,2,3,4,6,7,8,12b
The compound according to claim 1, which is -octahydropyrazino[2,1-a][2]benzazepine. 6 Formula (I): (In the formula, R is optionally substituted phenyl,
C _3-8 cycloalkyl, C _5-8 cycloalkenyl, C 1-8 alkyl, which may be straight-chain or branched, C _1-8 alkyl, which may be straight-chain or branched C _2-8 alkenyl, 5- or 6-membered heterocyclic group, or optionally substituted phenyl C _1-4
alkyl, each of Y and Z may be the same or different, are oxygen or sulfur, X is _-CH2- , and the symbol * represents an asymmetric carbon atom). In a method of producing a compound, the formula (): [In the formula, X is as defined in formula (),
R ¹ is hydrogen, a protecting group or a group (where R and Y are as defined in formula ()) and R ² is C _1-3 alkyl or hydrogen. and when R ¹ is a protecting group, remove the protecting group and replace it with a group [formula], and when R ¹ is hydrogen, substitute it with a group [formula], and Thereafter, the compound of formula (), in which Z is oxygen, produced in this way may be converted into a compound of formula (), in which Z is sulfur, by treatment with a vulcanizing reagent. Method for producing the compound (). 7. The method according to claim 6, wherein the vulcanizing reagent is a Lowessan reagent. 8 Substitution of the group [formula] in which Y is sulfur with a dithionate ester of the formula [formula], where R is as defined in formula () and R ⁴ is C _1-6 alkyl. The method according to claim 6 or 7, which is carried out by. 9. A method according to any one of claims 6 to 8, wherein ^R2 is hydrogen. 10 Effective and non-toxic amount formula (): (In the formula, R is optionally substituted phenyl,
C _3-8 cycloalkyl, C _5-8 cycloalkenyl, C 1-8 alkyl, which may be straight-chain or branched, C _1-8 alkyl, which may be straight-chain or branched C _2-8 alkenyl, 5- or 6-membered heterocyclic group, or optionally substituted phenyl C _1-4
alkyl, each of Y and Z may be the same or different, are oxygen or sulfur, X is _-CH2- , and the symbol * represents an asymmetric carbon atom). A pharmaceutical or veterinary composition for use in the treatment or prevention of helminth infections in humans or non-human animals, comprising a compound and a pharmaceutically or veterinarily acceptable carrier.