JPH03255080A - Benzene compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> and R<2> are each H, halogen, alkyl, OH, amino, (substituted)phenyl, etc.; R<3> and R<4> are each H, halogen alkyl, OH, amino, (substituted) phenyl, etc.; R<5> and R<6> are each H, alkyl, hydroxyalkyl, acyl, (substituted)aralkyl, etc.; X is O or S; Y is O or S; A is 6-0C alkylene, O, S, etc.]. EXAMPLE:A 6-[2-(2-thenoyl)phenylthio]-N,N-dimethyl-1-hexaneamine oxalate. USE:Having prolyl endopeptidase inhibitory activity, thus useful for amnesia therapy. PREPARATION:For a compound of formula II (Hal<1> is halogen) and a second compound of formula III, the active hydrogens are pref. substituted with alkali metals, and the resulting compounds are mutually reacted in a solvent at 0-150 deg.C.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention exhibits prolyl endopeptidase inhibitory action,
This invention relates to a benzene compound or a salt thereof useful for treating amnesia.

[Conventional technology]

Prolyl endopeptidase is derived from substance P, which is considered to be a neurotransmitter. It is known to act on and inactivate TRH, neurotensin, and habubresocin, which is thought to be related to memory. on the other hand,
Nakajima et al. and Wakagi et al. found that a compound that inhibits prolyl endopeptidase activity prevented experimental amnesia caused by Skovola in rats, and inferred that prolyl endopeptidase inhibitory activity is involved in memory consolidation (Nakajima et al. et al., Japanese Pharmacological Journal Vol. 82, p. 154, 1983 and Wakagi et al., Biochemistry Vol. 55, p. 831, 1983). In addition, Aoyagi et al. have reported that prolyl endopeptidase activity is increased in the brains of Alzheimer's disease patients (T, Aoyagi + Hxpertmentia
, 46, 94-97 (1990)). This suggests that prolyl endopeptidase inhibitors may be used as anti-amnestic drugs.

So far, as prolyl endopeptidase inhibitors, JP-A-63-130579, JP-A-63-1
As reported in Japanese Patent No. 62672, proline R4 bodies having a peptide bond are known.

[Problem to be solved by the invention]

The present inventors conducted extensive studies with the aim of developing a novel non-peptide prolyl endopeptidase inhibitor.

[Means to solve the problem]

Tokuko Showa 64. Publication No. 7995 discloses that benzene compounds represented by 2-[2(3-dimethylaminopropoxy)benzoyl)thiophene have anxiolytic activity, but there is no mention of prolyl endopeptidase inhibitory activity. In fact, the above compounds have almost no activity.

As a result of extensive studies, the present inventors have found that the strength of the prolyl endopeptidase inhibitory activity varies significantly depending on the length between the benzene ring and the amino group, and has completed the present invention.

The present invention refers to a straight or branched alkylene having 5 to 9 carbon atoms in which the general formula or acyl is present. However, [in the formula, R1
, R2 are the same or different and hydrogen, halogen, alkyl, alkoxy, hydroxyl, a), nitro or optionally substituted phenyl, R3 and R4 are the same or different and hydrogen, halogen, alkyl, alkoxy, hydroxyl, amino, nitro or optionally substituted phenyl, R
5 and R6 are the same or different and represent hydrogen, alkyl, hydroxyalkyl, acyl, optionally substituted aralkyl or heteroaralkyl, or do not represent a group that forms a heterocycle by bonding with adjacent nitrogen atoms. X is-
○- or -S-, Y is 1○ or -5-, A is a straight or branched alkylene having 6 to 10 carbon atoms, -o-, -s or -N (R7)- (R7 is a mixture of hydrogen and alkyl.) It relates to a benzene compound or a salt thereof represented by the following.

In this specification, halogen refers to chlorine, bromine, fluorine, and iodine, and alkyl refers to linear or branched alkyl having 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, tertiary butyl, pentyl, hexyl, octyl, etc., alkoxy is a straight or branched alkoxy having 1 to 8 carbon atoms,
Phenyl, which may be substituted with methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, octyloxy, etc., refers to phenyl or as a substituent halogen, alkyl, alkoxy, or fluoromethyl,
Phenyl (chlorophenyl, difluorophenyl, methylphenyl, trimethoxyphenyl, I-lifluoromethylphenyl, aminophenyl, nitrophenyl, cyanophenyl, etc.) having 1 to 3 of hydroxyl group, acino, nitro, cyao, Acyl is a straight chain or branched alkanoyl having 2 to 5 carbon atoms, such as acetyl, propionyl, butyl, pivaloyl, valeryl, etc. branched alkyl, hydroxymethyl;
2-hydroxyethyl, 3-hydroxypropyl, 4-
hydroxymethyl, 5-hydroxypentyl, 6-hydroxyhexyl, 8-hydroxyoctyl, etc., optionally substituted aralkyl or heteroaralkyl refers to halogen, alkyl, alkoxy, trifluoromethyl, hydroxyl group, agono group as a substituent. , nitro, cyano 1
~3 benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexyl, 8-phenyloctyl, 2-pyridylmethyl, 3-pyridylmethyl, 4- Heterocycles formed by bonding to adjacent nitrogen atoms, such as pyridylmethyl, 2-(2-pyridyl)ethyl, furfuryl, and 2-thienylmethyl, are 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, piperidino, 1 - Piperazinyl, 1-homopiperazinyl, morpholino, thiomorpholino (which may be substituted with formyl, alkyl, acyl, etc.), etc., are different from linear or branched alkylene having 6 to 10 carbon atoms. xamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene,
Methylhexamethylene, methyloctamethylene, etc.
-〇-, -S- or -N(R7) (R7 represents hydrogen, alkyl or acyl) is present in the straight or branched alkyl chain L/7 having 5 to 9 carbon atoms -( Hz) z
S (Ctlz) 3-, - (Ctlz) 20 (
Hz) b-.

C++3 CHCHJH (CHz) 6-, etc.

The benzene compound of the present invention can be produced by the following method.

Method 1 - A compound represented by the general formula (in the formula, Ha I' represents a halogen, and the other symbols have the same meanings as above) and the general formula (in the formula, each symbol has the same meanings as above). A method of reacting with the indicated compound.

The reaction is preferably carried out by replacing active hydrogen with an alkali metal using sodium hydride, sodium oxide, sodium methoxide, thorium hydroxide, potassium hydroxide, or the like. The reaction can generally be carried out in a solvent; useful solvents include dimethylformamide, dimethyl sulfoxide, toluene, xylene, CI''C
The reaction temperature is not particularly limited, but the reaction can be sufficiently completed at 0 to 150'C.

Method 2 - A compound represented by the general formula (in the formula, each symbol has the same meaning as above) and a compound represented by the general formula (in the formula, Ha 12 represents a halogen, and the other symbols have the same meanings as above) A method of reacting with a compound that is

The reaction is preferably carried out by replacing active hydrogen with an alkali metal using sodium hydride, sodium amide, sodium methoxide, sodium hydroxide, potassium hydroxide, or the like. The reaction can generally be carried out in a solvent; useful solvents include dimethylforma ξl,
Dimethyl sulfoxide, toluene, xylene, CI~C
The reaction temperature is not particularly specified, but the reaction can be sufficiently completed at 0 to 150°C.

Method 3: A compound represented by General 2 (in the formula, each symbol has the same meaning as above) and a compound represented by the general formula (wherein, Ha13 represents a halogen, and the other symbols have the same meanings as above). A method of reacting with a Grignard reagent or an organolithium compound represented by 3 (wherein each symbol has the same meaning as above).

This reaction proceeds in a conventional manner in a nonaqueous solvent, such as ether, te)-rahydrofuran, dioxane, benzene, toluene, or a mixed solvent thereof, and is then hydrolyzed to obtain the desired product.

Method 4: - A compound represented by the formula (in the formula, Z represents halogen, tosyloxy, mesylmethoxy, and other symbols have the same meanings as above) and a general formula (in the formula, each symbol has the same meaning as above) A method of reacting with a compound represented by

The reaction can be carried out in a solvent in the presence of a base.

As the base, sodium hydroxide, potassium hydroxide,
Examples include sodium hydride, sodium meloxide, potassium carbonate, and sodium carbonate. In addition, as a reaction solvent, dimethyJl/formami[, ethanol,
Examples include methanol and acetone. The reaction temperature is Q
17) What about the solvent? There are two points above the astigmatism point A, 1, and 80°C at O'C-h and 2.

The raw material compound represented by general formula (IX) is - formula (I
V) is reacted with a compound represented by the general formula Ha M -A-OI-T (XI) (wherein i (al' represents a halogen, and A has the same meaning as above); Then, it can be produced by converting it into the corresponding halide, 1- to silo-gishite, etc.

The benzene compound of the general formula (D) produced in this way can be mixed with inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, and tartaric acid, as necessary. It can be an acid addition salt of. It also exists as a solvate such as a hydrate.

When the compound of the present invention has an asymmetric carbon atom, it exists as a racemate or an optical isomer.

When the compound (r) of the present invention and its acid addition salts are used as the above-mentioned medicines, they can be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc., as powders,
It can be administered orally or parenterally in the form of granules, tablets, capsules, injections, and the like. The dosage varies depending on the disease being treated, the symptoms, and the compound used, but in the case of oral administration, it is usually about 1 to 1000 ml per adult molar.

[For production]

The compound of general formula (1) or a salt thereof of the present invention has an excellent prolyl endopeptidase inhibitory effect that is not observed in known compounds, and is therefore useful for the prevention and treatment of amnesia. Furthermore, the compounds of the present invention also exhibit an action of promoting nerve growth factor production.

〔Example〕

EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Example 1 Dissolve 0.45 g of metallic sodium in 10 ml of methanol, and dissolve 3.7 g of 6-dimethylanohexanethiol at room temperature.
Then, a solution of 4 g of 2-(2-thenoyl)fluorobenzene in 140 ml of dimethylformat was added dropwise.
Pj at 45°C for 4 hours! After stirring, pour into ice water.
Added luen. The toluene layer was extracted with dilute hydrochloric acid, made alkaline with potassium carbonate, and the liberated oil was extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was salted with ciproic acid in ethanol and recrystallized from ethanol to yield 6-C2-(2-thenoyl)phenylthio)-N,N-dimethyl-1-hexaneagon oxalate. Melting point 128-130°C Example 2 Dimethylformamide 1. 0.9 g of 60% thorium hydrogenation was suspended in Oml, and 4.5 g of 6-dimethylagonohexanethiol was added thereto under cooling, followed by stirring at room temperature for 30 minutes. Next, a solution of 5 g of 2-(2-thenoyl)-4-nitrochlorobenzene in 10 ml of dimethylformamide was added dropwise, and after stirring at 50°C for 7 hours, the mixture was poured into ice water and toluene was added. The toluene layer was extracted with dilute hydrochloric acid, made alkaline with potassium carbonate, and the liberated oil was extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was salted with dioxylic acid in ethyl acetate and recrystallized from ethanol to give 6-[4nitro-2-(2-tenoyl)phenylthio]N,N-dimethyl-1-hexanamine oxalate. It was done. Melting point 136-14oC Example 3 0.7 g of 60% sodium hydride was suspended in 10 ml of dimethylformamide, and 6-dimethyl ξ was added to this under cooling.
3.5 g of nowhexanethiol was added, and the mixture was stirred at room temperature for 30 minutes. Next, 10 ml of dimethylformamide containing 5 g of 2-(2-thenoyl)-4-chloroiodobenzene? W
After the liquid was added dropwise and stirred at 60°C for 6 hours, it was poured into ice water and toluene was added. Extract the toluene layer with dilute hydrochloric acid, make alkaline with potassium carbonate 6, extract the liberated oil with toluene,
After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was salted with oxalic acid in ethanol and recrystallized from ethanol to yield 6[4-chloro-2-(2-thenoyl]phenylthio)-N,N-dimethyl-1-hexanoyl oxalate. Obtained. Melting point 116-120
°C (Decomposition) Example 4 0.6 g of 60% sodium hydride was suspended in Oml of dimethylformyl i F' I. To this was added 3 g of 6-dimethylaminohexanethiol under cooling, and the mixture was dissolved at room temperature. 30
Stir for a minute. Next, add 4 g of 2-(2-thenoyl)-4-methyliodobenzene to 10 ml of dimethylformoxide.
After the solution was added dropwise and stirred at 55°C for 5 hours, it was poured into ice water and toluene was added. The l.luene layer was extracted with dilute hydrochloric acid, made alkaline with potassium carbonate, and the liberated oil was extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was salted with 4 acids in ethanol and recrystallized from ethanol to give 6-[4methyl-2-(2-thenoyl)phenylthio]NN-dimethyl-1-hexane≦n oxalate. Obtained. Melting point: 114-117°C Example 5 0.5 g of 60% thorium hydride was suspended in 10 ml of dimethylformamide, 2.4 g of 6-dimethyl agonohexanediol was added under cooling, and the mixture was stirred at room temperature for 30 minutes. did. Next, 3.7 g of 2-(2-thenoyl)-45-dimethoxyiodobenzene in dimethylform 7411
After dropping 0 ml of the solution and stirring at 60°C for 4 hours, the mixture was poured into ice water and toluene was added. The toluene layer was extracted with dilute hydrochloric acid, made alkaline with potassium carbonate, and the liberated oil was extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was salted with oxalic acid in ethanol and recrystallized from ethanol to give 6-(4,,5
-dimethoxy-2-(2-thenoyl)phenylthio)-
N,N-dimethyl-1-hexanamine oxalate was obtained. Melting point: 161-163°C Example 6 3.2 g of 60% sodium hydride was suspended in 30 ml of dimethylformamide, 2(2-tenoyl)phenol was added to this under cooling, and the mixture was stirred at 70°C for 2 hours. .

Next, under cooling, 6-dimethyl axi-hexyl chloride 5
．． A solution of 5 g of dimethylformua Ei in 30 ml was added dropwise, stirred at 80°C for 15 hours, poured into ice water, and
~Added ruene. The I.luene layer was extracted with dilute hydrochloric acid, made alkaline with potassium carbonate, and the liberated oil was extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was made into a salt with fumaric acid in ethanol and recrystallized from ethanol to obtain 6-(2-(2-tenoyl)phenoxy)-N,N-dimethyl 1-hexaneamine fumarate.

Melting point: 118-120°C 9 Example 7 3-(2-thenoyl)-4--(6-(+-syloxy)hexyldio)2I-lobenzene 5.4g dimethylformamide To the solution, 3.4 g of jetylamine was added, stirred at 50°C for 2 hours, poured into ice water, extracted with toluene, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.The residue was passed through a silica gel column. Chromatography and elution with chloroform gave 1.0-(4-nitro2-(2'-tenoyl)phenylthio)-N,N diethyl-1-decanamine as an oil.

11-NMR (CDCIz) δ: 1.1.
O(t,6+1), 1.15-1.60 and 1. ．．
65-1. ．． 75 (each m, 1.6H), 2.45 (
t, 21+) 2.60 (q, 4fl), 3.00
(t, 2H), 7.1.5 (m, IIIL 7.50
and 7.80 (dcl, 2H each), 7.50 and 8.30 (d, 211 each), 8.35 (S, 1.
1+) The following compounds are produced in the same manner as in the above examples.

0 ◎ 8-(2-(2-Thenoyl)phenylthio]NN-
Dimethyl-1-octanamine ◎ 8- (2-(5-methyl-2-thenoyl)phenylthio]-N,N-dimethyl-1-octanamine ◎ 6-[5-chloro-2-(2-tenoyl) phenylthio)-N,N-dimethyl-1-hexaneamine ◎ 8-[4-di-2-(2-tenoyl)phenylthio)-N,N-dimethyl-1-octaneamine◎ 6-[5- Isopropyl-2-(2-tenoyl)phenylthio)-N,N-dimethyl-1-hexanoane ◎ To 6-[6-methyl-2-(2-tenoyl)phenylthio)-N,N-dimethyl-1- Xanamine◎ 6-[4-methoxy-2-(2-thenoyl)phenylthio)-N,N-dimethyl-]-hexaneamine◎ 6- (2-(2-thenoyl〉phenylthio)N-
Benzyl-N-methyl-1-hexaneagone ◎ 1-medyl-4-phenylthio] ◎ 6-(2-(2 N,N-dimethyl◎ 3- (2-C2 thio)ethylthio) Ropyruagone ◎ 6- ( 2-[2-thio]ethylthio] 6-C2-(2-thio]ethoxy) Zanagon Preparation Example Compound of Example 1 (6-(2-(2-tenohexylcopiperazinfuroyl)phenylthio) 1-hexaneakun(2-thenoyl)phenyl N, N-dimethyl-1-p(2-thenoyl)phenyl N, N-dimethyl-1-h(2-thenoyl)phenyl N, N-dimethyl-1-hexyl 10.0 ■ Lactose 50.0 ■ Cornstarch 15.5 ■ Microcrystalline cellulose 20.0 ■ Talc
4,0■Magnesium stearate
- Q, 5 ri 100.0 mg The compound of Example 1, lactose, corn starch and microcrystalline cellulose are mixed in a kneader, then 5% corn starch paste is added, granulated and dried.

The mixture is sieved through a 24 sieve sieve, mixed with talc and magnesium stearate, and made into 100 square tablets using a pestle with a diameter of 7 mm.

〔Effect of the invention〕

Test Example (Measurement of P P CE inhibitory activity) The prolyl endopeptidase inhibitory activity was measured using a rat cerebral soluble fraction as *■enzyme, as described by Wakagi et al. (Biochem, B
iophys, Acta, + 569 + 184.
(1979) and Kato et al. (J, Neurochem,
, 35, 527.1.980). 30.25mM succinyl-glycyl-prolyl-methylcoumarinamide, 1.15ml of 0.1M Na/phosphate buffer (pH 47,0), 0.1ml of crude enzyme and 0.1n+] of 0.25mM succinyl-glycyl-prolyl-methylcoumarinamide; 1 ml of a solution containing the compound of the present invention [a mixed solution containing the final dimethyl sulfoxide concentration (0.25%) was added at 30°C.
After heating for 5 minutes, 1.5 ml of 0.1M 1% l' acid buffer (pH 4,2) was added to stop the reaction. The fluorescence intensity (a) of the liberated methylcoumarin agode was measured using a fluorophotometer (E
x, 370nm, E+n, 440r+m). At the same time, the fluorescence intensity (b) of a control group using a dimethyl sulfoxide solution (final concentration 0.25%) not containing the compound of the present invention was measured, and the prolyl endopeptidase inhibition rate was calculated using the following formula, and 50% inhibition was obtained. Concentration required for (ICso)
was calculated.

Inhibition (%) −< (ba-a) /b) X 1. O
O Pharmacology Deku 4 Compound (r) or a salt thereof exhibits an excellent prolyl endopeptidase inhibitory effect, and therefore can be used for the treatment of amnesia. Furthermore, the compounds of the present invention also exhibit an action of promoting nerve growth factor production.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Good phenyl, R^3, R^
4 are the same or different and are hydrogen, halogen, alkyl, alkoxy, hydroxyl group, amino, nitro, or optionally substituted phenyl; R^5 and R^6 are the same or different and are hydrogen, alkyl, hydroxyalkyl, acyl, It represents an optionally substituted aralkyl or heteroaralkyl, or a group bonded to an adjacent nitrogen atom to form a heterocycle. X is -O- or -S-, Y is -
O- or -S-, A is a straight chain or branched alkylene having 6 to 10 carbon atoms, or -O-, -S- or -N
(R^7)-(R^7 represents hydrogen, alkyl or acyl) represents a straight or branched alkylene having 5 to 9 carbon atoms. However, X and ▲There are mathematical formulas, chemical formulas, tables, etc.▼ are connected by a straight chain part with 6 or more atoms. ] A benzene compound or its salt represented by: