JPH03251586A - Optically active benzothiepinopyridazine compound and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> and R<2> are H, halogen, trifluoromethyl, OH, amino, nitro, cyano, 1-4C alkyl, 1-4C alkoxy or acyl(amino); R<3> is H, 1-8C alkyl, 1-4C hydroxyalkyl, 2-5C alkanoyloxy(1-4C)alkyl, aryl, aryl(1-4 C)alkyl, heteroaryl, etc.; * represents asymmetric sulfur atom]. EXAMPLE:2-(4-Chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-C]-pyridazi n-3(2H)- one-7-oxide. USE:An antianxiety agent. PREPARATION:The compound of formula II is oxidized with tertiary hydroperoxide in the presence of a compound of formula Ti(OR<4>)4 (R<4> is 1-4C alkyl) and a chiral tartaric acid dialkyl ester as an asymmetric source.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an optically active benzothiepinopyridazine compound useful as a medicine such as an anxiolytic agent, and a method for producing the same.

[Prior art and problems to be solved by the invention] According to Japanese Patent Application Laid-Open No. 1-250383, 5,6-sihydro[1]benzothiepino (5,4-
C) Pyridazin-3(2H)one derivatives are known to have useful pharmacological effects such as selective anxiolytic effects and enhancement of biological defenses.

In the above formula, the compound n-1, that is, the 7-oxide compound represented by the formula - has chirality derived from the sulfoxide, so optical isomers may exist, but it can be synthesized by the usual synthesis method described in the above publication. In this publication, only a racemate is produced, and therefore, the publication does not provide any details regarding the optical isomers.

By the way, natural medicines extracted from animals and plants, such as morphine and digitoxin, contain only one of the possible enantiomers or diastereomers. On the other hand, although many synthetic drugs have chirality, they remain racemic in practice due to the technical and economical difficulties in asymmetric synthesis or resolution of both optical isomers. It is often used to treat.

However, among synthetic drugs, the (-) form has a hypnotic effect, while the (+) form has an stimulant effect, such as barbyl drugs, and both the 6- and 1-form drugs have an equivalent sedative effect.
The toxicity, pharmacological action, and mode of metabolism can be completely different between optical isomers, as seen in thalidomide, where only one isomer and its glutamic acid metabolite exhibit strong teratogenic effects;
In addition, there have been many reports in recent years that the pharmacological action is contributed by only one optical isomer, and the other may be inactive.

Therefore, in recent years, optical isomers have been divided and separated to determine their pharmacological effects.
By comparing the toxicity and removing the inactive isomer, it is important to obtain an optically active form that is purer and has stronger activity than the racemic form, in order to develop safe drugs with fewer side effects. , are beginning to be considered essential. As described above, the optically active form is becoming more important as a medicine than the racemic form, so it would be extremely beneficial to obtain the optical isomer of the compound of formula (A) by a simple method. .

Therefore, the present inventors aimed to obtain optical isomers of the compound of general formula (A) by synthesis from chiral synthetic intermediates, optical resolution using chiral binaphthol, and high performance liquid chromatography (HPLC). We investigated various conventional methods such as preparative separation and asymmetric oxidation using microorganisms. However, for example, by a method of oxidizing a compound of the formula obtained from the reaction of a chiral synthetic intermediate represented by the formula (in the formula, * indicates an asymmetric atom; the same applies hereinafter) and 4-chlorophenylhydrazine. The obtained compound of formula I was found to have low optical purity based on the optical rotation ([α) n = 3.4° (c = 1, chloroform)), and there were problems such as racemization easily occurring in each reaction. Therefore, the synthesis from chiral synthetic intermediates was abandoned. Also, R-(+)-1,1゜-B2-naphthol and 2-
(4-chlorophenyl)-5,6-sihydro[1]benzothiepino(5,4-C)pyridazine-3(2H)-
7-oxide was dissolved in benzene, the precipitated crystals were purified using a column, and the optical purity was determined by the optical rotation, but it was found to be a racemate, and optical resolution using chiral binaphthol was also abandoned. I had no choice. Also,
Preparative separation using HPLC is also inefficient, and methods using microorganisms also have problems. As described above, it has been extremely difficult to industrially obtain optically active substances with high optical purity by conventional methods.

By the way, the Journal of the American Chemical Society
According to Erican Chemical 5ociety, Vol. 106, pp. 8188-8193 (1984), the Sharpless reagent used in asymmetric epoxidation [Journal on the
American Chemical Society (Journal)
of the A+nerican Chemical
5ociety) Volume 102, Page 5974 (198
0 years)] with water, such as tetraisopropyl orthotitanate, diethyl tartrate, water, tertiary butyl hydroperoxide (1: 2: 1:
It is disclosed that optically active alkyl-aryl sulfoxides and dialkyl sulfoxides can be obtained by oxidizing alkyl-aryl sulfides and dialkyl sulfites with the reagent consisting of 1). However, there are problems such as a decrease in optical purity and yield as the alkyl chain becomes longer, and thus it has not been frequently used for the resolution of chiral sulfur atoms.

[Means to solve the problem]

As a result of intensive studies to solve the above problems, the present inventors have found that by oxidizing the compound of the general formula (II) described below with a Sharpless reagent, a ring structure can be obtained with high optical purity and in good yield. The present inventors discovered that each optical isomer of a compound having an asymmetric sulfur atom can be produced, and completed the present invention.

In other words, the present invention can be applied to the general formula (wherein RI and R2 are the same or different and hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4 alkyl, cl-4 alkoxy, acyl or acylamino, R3 is hydrogen, CI-1 alkyl, hydroxy-cl-4'furkyl, C2-, alkanoyloxy-〇,-, chel, aryl, aryl-Cl-a alkyl, heteroaryl or aromatic 1 to 3 substituents selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, Cl-4 alkyl, Cl-4 alkoxy, and acylamino on the ring.
aryl, aryl-CI-4 alkyl or heteroaryl. * indicates an asymmetric sulfur atom.

) An optically active benzothiepinopyridazine compound represented by: and a method for producing the same are provided.

- To explain the symbols in formula (1) by definition, halogen means fluorine, chlorine, bromine, iodine, C1-4 alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc. cl-a alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.
Acyl refers to acetyl, propionyl, butyryl, pivaloyl, etc. Acylamino refers to acetylamino, propionylamino, butyrylamino, pivaloylamino, etc. Hydroxy-C,4 alkyl refers to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc. C2-, alkanoyloxy-CI-4
Alkyl includes acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, propionyloxypropyl, propionyloxybutyl, etc.
1-8 alkyl is straight chain or branched, and includes methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and 2-ethylhexyl. ArylCl-4alkyl refers to benzyl, phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, etc., aryl refers to phenyl, naphthyl, etc., and heteroaryl refers to phenyl, naphthyl, etc. 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, etc., on the aromatic side, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano,
CI-4 alkyl, C1-4 alkoxy and C2-,
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3.4-';';1 lorophenyl, 4-bromophenyl, 4-fluorophenyl, 3
Trifluoromethylphenyl, 4-hydroxyphenyl, 4-aminophenyl, 4-cyanofer, 4-methylphenyl, 4-methoxyphenyl, 4-acetylaminophenyl, 4-propionylaminophenyl, 3.4.
5-) Rimethoxyphenyl, 4-chlorobenzyl, 4-
Methylbenzyl, 23-dichlorobenzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 3.4.5-)
Rimethoxybenzyl, 2-(4-chlorophenyl)ethyl, 4-(4-chlorophenyl)methyl, 5-chloro-2-pyridyl, 4.5-dichloro-2-pyridyl, 5
-methyl-2-thienyl, 5-methyl-3-thienyl,
5-chloro-2-thienyl, 5-chloro-2-furyl, etc.

Preferred compounds of the present invention are R-(-)-2-(4-chlorophenyl)-5,6-sihydro[1]benzothiepino (5,4-C)pyridazin-3(2H)-one 7
-oxide, S-(+) -2(4-chlorophenyl)-5,6-'; hydro[1]benzothiepino [5,
4-Cl pyridazin-3(2H)-one 7-oxide.

- The compound of formula (1) can be prepared using - the compound represented by formula 3 (in the formula, each symbol has the same meaning as above) in a suitable solvent that does not inhibit the reaction (methylene chloride, chloroform, carbon tetrachloride, benzene, etc.). , toluene, etc.) in the presence of a compound represented by the formula % ([) (wherein R4 represents CI-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, etc.), an asymmetric source (A chiral source means a chiral dialkyl ester of tartaric acid, and includes (+) or (-) diethyl tartrate, diisopropyl tartrate, etc.) under a nitrogen atmosphere, in the presence or absence of water. -78℃ with tertiary hydroperoxide (tertiary butyl hydroperoxide, cumene hydroperoxide, tertiary amyl hydroperoxide, tertiary octyl hydroperoxide, etc.)
By oxidizing for 1 hour to several tens of hours at room temperature, approximately 60-80% e, e, (enantiomeri
c excess), 98% e for the most preferred compounds
, e, optical purity.

Preferably - a compound of formula (n) in methylene chloride;
In the presence of tetraisopropyl orthotitanate, chiral diethyl tartrate was used as the chiral source, and 15% was obtained at 20°C to 0°C with tertiary butyl hydroperoxide in the presence or absence of water under a nitrogen atmosphere. By reacting for ~20 hours, an optically active compound of formula (1) can be produced.

The compound of general formula (1) thus obtained can be purified to an optically pure compound by a conventional purification method such as recrystallization or column chromatography.

[Action and effect of the invention]

According to the method of the present invention, optical isomers of benzothiepinopyridazine compounds, which could not be easily obtained by conventional methods such as optical resolution and asymmetric synthesis, can be easily produced with high optical purity.

Furthermore, the obtained optically active compound of general formula (I) exhibits high affinity for benzodiazepine receptors, has an antagonistic effect on chemical proconvulsants such as bicuculline and pentylentitrazole, and Although it shows strong anxiolytic effects in anti-conflict tests in rats, it has weak muscle relaxant, anesthesia-enhancing, and alcohol-enhancing effects, and low toxicity, making it highly safe and useful as a selective anxiolytic drug. be. Examples of useful target diseases for the compounds of the present invention include autonomic nervous system imbalance, neurogenic emesis, neurogenic dermatitis, neurogenic angina, and neurogenic dyspnea, as well as anxiety and tension induced by various diseases. These include psychosomatic diseases such as, anxiety neurosis, etc., and can be used for the prevention, improvement, or treatment of these diseases. It is also useful as a neutralizer for overdosing or poisoning of existing anxiolytics such as diazepam.

Furthermore, certain compounds of formula (1) have pharmacological effects such as enhancing the phagocytic ability of leukocytes, enhancing the phagocytic ability of macrophages, and preventing infection, and are useful as agents for promoting biological defense. be.

When the compound of the present invention is used as a medicine, it is mixed with appropriate pharmaceutically acceptable excipients, carriers, diluents, and other additives, and prepared into tablets, capsules, granules, syrups, injections, suppositories, or It can be administered in the form of a powder, etc. For example, in the case of oral administration, the dosage is usually about 5 to 500 ml per day for adults, and this can be administered once or in divided doses.

The following margin [Examples] The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these in any way.

Example 1 8.6 ml of tetraisopropyl orthotitanate and (+)
- 12 g of diethyl tartrate was placed in a four-necked flask through which nitrogen was passed at room temperature, and the mixture was stirred for 10 minutes. To this, 2-(4-chlorophenyl)-5,6-sihydro[1]benzothiepino (5,4-c)pyridazin-3(2H)-one 1
0g and methylene chloride 3001 were added, and the mixture was stirred at room temperature for 15 minutes. After cooling this to -20°C, 19ml of tertiary butyl hydroperoxide was added,
It was left at ℃ for 17.5 hours. After washing the reaction solution with sodium bisulfite and concentrating the methylene chloride layer, 2-(4-chlorophenyl)-5,6-dihydro(1) pentthiepinol having an optical purity of 53.6% e,e immediately after the reaction was obtained. (5,4-C)pyridazin-3(2H)-one
7-oxide was obtained. Then, it was purified by silica gel column chromatography using chloroform as a mobile phase. This 2-(4-chlorophenyl)-5,6-sihydro[1]benzothiepino(5,4-C)pyridazine-3
The operation of dissolving (2H)-one 7-oxide in acetonitrile, leaving it to stand, filtering off the precipitated crystals, and concentrating the filtrate was repeated. The crystals obtained by concentrating the filtrate were dissolved in methanol and allowed to stand, then the precipitated crystals were filtered off and the filtrate was concentrated. The obtained crystals were recrystallized from ethanol, with a melting point of 217.4°C and an optical purity of 98.2%e, e,
, (α:lD=38.2° (c=1, chloroform) R-(-)-2-(4-chlorophenyl)-5,6
-Sihi) -Rho (1) Beni/Zochepino (5,4-c
) Pyridazin-3(2H)-one 7-oxide was obtained.

Optical purity was determined using ethanol as the mobile phase and a flow rate of 0.8 μl/
minutes), Chiralcel OD column (Daicel Chemical, 25C1
It was quantified by high performance liquid chromatography (Shimadzu, LC-6AD) using 1×0.46 CI1).

The temperature was room temperature, the detection wavelength was 254 nm, and the area percentage method was used for quantitative determination. Moreover, the absolute configuration was confirmed by XNIA analysis.

Also, during the same operation as above, cumene hydroperoxide was used instead of tertiary butyl hydroperoxide,
When oxidation and treatment are carried out in the same manner using tertiary amyl hydroperoxide and tertiary octyl hydroperoxide, the optical purity immediately after the reaction is 89% e, e, , When using tertiary amyl hydroperoxide 51.48
% e, e, 2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino C5,4-C) which is 63.26% e, e when using tertiary octyl hydroperoxide. Pyridazin-3(2H)-one 7-oxide was obtained. The method for quantifying optical purity is the same as above. However, as a mobile phase, ethanol (0.5ml/
minutes) was used.

Example 2 The same operations and treatments as in Example 1 were carried out using (-)-diethyl tartrate instead of (+)-diethyl tartrate.
Melting point: 217.8°C, optical purity: 97.3% e, e, [α
]. = + 38.8° (c=1, chloroform) S
-(+)-1-(4-chlorophenyl)-5,6-sihydro[1]benzothiepino (5,4-cl) Pyridazin-3(2H)-one 7-oxide was obtained.

It was confirmed to be S-(+) by X-ray structural analysis, and the method for quantifying optical purity was the same as in Example 1.

Example 3 9-chloro-2-(4-chlorophenyl)- as a raw material
5,6-sihydro[1]benzothiepino (5,4-
c) By using pyridazin-3(2H)-one and performing the same operations and treatments as in Example 1, the optical purity immediately after the reaction was 60.76% e, e, and the optical purity after purification by column chromatography. 65.20%e, e, [α]
. = -32,1° (C-1, chloroform) 9-
Chloro-2-(4-chlorophenyl)-5,6-';
Hydro-(1)benzothiepino (5,4-c)pyridazin-3(2H)-one 7-oxide was obtained. The method for quantifying optical purity is the same as in Example 1. However, the mobile phase is isopropyl alcohol:ethanol (5:1).
(flow rate 0.4 ml/min).

Example 4 10-chloro-2-(4-chlorophenyl) as a raw material
-5,6-sihydro[1]henzothiepino (5,4
-c) Example 1 using pyridazin-3(2H)-one
By performing the same operations and treatments, the optical purity immediately after the reaction was 79.54% e, e, and the optical purity after purification by column chromatography was 79.14% e, e, C.
10-chloro-2-(4chlorophenyl)-5,6 at tx”J o =-74,6° (c=1, chloroform)
-Sihydro(1)benzothiepino (5,4-c)pyridazin-3(2H)-one 7-oxide was obtained.

The method for quantifying optical purity is the same as in Example 1. however,
Isopropyl alcohol: ethanol (5
: 1) was used (flow rate 0.4 ml/min).

Example 5 2-(4-chlorophenyl)-10fluoro-5,6-sihydro[1]benzothiepino (5,4
-c) By using pyridazin-3(2H)one and performing the same operations and treatments as in Example 1, the optical purity immediately after the reaction? 1.69% e, e, Optical purity after purification by column chromatography 73.60% e, e, [α]
. = -9,16° (c = 1, chloroform) 2-(4
-chlorophenyl)-10-fluoro-5,6-dihydro[1]benzothiepino[5,4-C]pyridazine-
3(2H)-one 7-oxide was obtained. The method for quantifying optical purity is the same as in Example 1. However, isopropyl alcohol:ethanol (5:1) was used as the mobile phase (flow rate 0.4+nl/min).

Example 6 2-(4-chlorophenyl)-10-methyl-5,6-sihydro[1]benzothiepino(5,4-
c) By using pyridazin-3(2H)-one and performing the same operations and treatments as in Example 1, the optical purity immediately after the reaction was 73.93% e, e, and the optical purity after purification by column chromatography. 73.12%e, e, , [α)
, = -46,1° (C=1, chloroform) 2-(4
-chlorophenyl)-10-methyl-5,6-sihydro[1]benzothiepino (5,4-c)pyridazine-
3(2H)-one 7-oxide was obtained. The method for quantifying optical purity is the same as in Example 1. However, ethanol (flow rate 0.6 N1/min) was used as the mobile phase.

Example 7 10-acetyl-2-(4-chlorophenyl)-5,6-sihydro[1]benzothiepino (5,
t-c) By using pyridazin-3(2H)-one and performing the same treatment and operation as in Example 1, the optical purity immediately after the reaction was 61.37% e, e, and after purification by column chromatography. Optical purity 65.89% e, e, (
α) o = 1 of 90.5° (c = 1, chloroform)
0-acetyl-2-(4-chlorophenyl)-5,6-
Cyhydro[1]benzothiepino (5,4-c)pyridazin-3(2H)-one 7-oxide was obtained. The method for quantifying optical purity is the same as in Example 1. However, ethanol (flow rate 0.6 ml/min) was used as the mobile phase.

Example 8 2-(4-chlorophenyl)-10-methoxy-5,6-sihydro[1] pentthiepino(5,4
-C) Example 1 using pyridazin-3(2H)-one
By performing the same operations and treatments as above, the optical purity immediately after the reaction was 58.79% e, e, and the optical purity after purification by column chromatography was 61.09% e, e, [α
) b”19.7° (c = 1.chloroform) 2-(4
-chlorophenyl)-10-methoxy-5,6-dihiF
[1] Benzothiepino (5,4-c) pyridazine 3
(2H)-one 7-oxide was obtained. The method for quantifying optical purity is the same as in Example 1. However, ethanol (flow rate 0.6+nl/min) was used as the mobile phase.

Example 9 8-chloro-2-(4-chlorophenyl)- as a raw material
5,6-sihydro[1]benzothiepino (5,4-
c) By using pyridazin-3(2H)-one and performing the same operations and treatments as in Example 1, the optical purity after purification by column chromatography was 50.03% e, e
,, [α]. =-41,0'' (C=1.rioo form) 8-rio.

2-(4-chlorophenyl)-5,6-sihydro[1
]Benzothiepino(5,4-c)pyridazine-3(2H
)-one 7-oxide was obtained.

The method for quantifying optical purity is the same as in Example 1. however,
Ethanol (flow rate 0.6+I/min) was used as the mobile phase.

Example 10 Using 2-(4-methoxyphenyl)5,6-sihydro[1]benzothiepino[5,4-c)pyridazin-3(2H)-one as a raw material, the operations and treatments were carried out in the same manner as in Example 1. By performing this process, the optical purity after purification by column chromatography is 68.5% e, e, , l:α]
. = -30,5° (c=0.9, chloroform) 2
-(4-methoxyphenyl)-5,6-sihydro[1
] Henzothiepino(5,4-c)pyridazine-3(2H
)-one 7-oxide was obtained. The method for quantifying optical purity is the same as in Example 1. However, acetonitrile:water:acetic acid (400:600:0.1) was used as the mobile phase (flow rate: 0.6ml/min).

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 are the same or different, hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C_1_-_4 Alkyl, C_1_-_
4 alkoxy, acyl or acylamino, R^3 is hydrogen, C_1_-_8 alkyl, hydroxy-C_1_
-_4 alkyl, C_2_-_5 alkanoyloxy-
C_1_-_4 alkyl, aryl, aryl-C_1
_-_4 alkyl, heteroaryl or aromatic ring with halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C_1_-_4 alkyl, C_1_-_
It represents aryl, aryl-C_1_-_4 alkyl, or heteroaryl having 1 to 3 substituents selected from 4-alkoxy and acylamino. * indicates an asymmetric sulfur atom. ) An optically active benzothiepinopyridazine compound represented by: (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 are the same or different, hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C_1_-_4 Alkyl, C_1_-_
4 alkoxy, acyl or acylamino, R^3 is hydrogen, C_1_-_8 alkyl, hydroxy-C_1_
-_4 alkyl, C_2_-_5 alkanoyloxy-
C_1_-_4 alkyl, aryl, aryl-C_1
_-_4 alkyl, heteroaryl or aromatic ring with halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C_1_-_4 alkyl, C_1_-_
It represents aryl, aryl-C_1_-_4 alkyl, or heteroaryl having 1 to 3 substituents selected from 4-alkoxy and acylamino. ) in the presence of a compound represented by the general formula Ti(OR^4)_4 (wherein R^4 represents C_1_-_4 alkyl) and a chiral tartrate dialkyl ester as an asymmetric source. There are general formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by oxidation using tertiary hydroperoxide. ) A method for producing an optically active benzothiepinopyridazine compound represented by