JPS6178773A - O-trisubstituted 1,4-benzodiazepine and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel C-3 substituted 1,4-pen acyazepines and their pharmaceutical uses. More specifically, the present invention relates to N-substituted amino acid esters of monohydroxy-1,4-benzodiazepine derivatives having the general formula and optically active isomers thereof.

Description of the Prior Art 1. 4-Benzodiazepines are a group of therapeutically active compounds that have found many uses in the treatment of various diseases of the nervous system (2003).
s The Pharmacologic (11 Ba5
is of Therapeutics, (5th edition.

Page 539, McMillan, New York.
N.Y.

1980).

Many substitutions at various positions in the ring system are known and used in human therapy. C1, F.

It is well known to those skilled in the art that replacing H by halogeno such as Br or even N02 yields therapeutically active compounds. The same is true for substitution on the ortho position of the 5-phenyl ring, where H is substituted advantageously by CL, F, Br. H for N at position 1 is CH3 or -CH2CH2N (C2) (,,).

Substitution with is also known to maintain the therapeutically useful properties of the compounds. 7. The N at the 1-position and the carbonyl group at the 2-position can be linked to form a triazole ring. Substitution on carbon 6 is known in that it replaces H with OH. Esterification of this C3-hydroxy group can be carried out, for example, by trichloroacetic acid (T).

Kovac et al., J.Me.d.Chem., 22.109
3 (1979)), but the high toxicity of the resulting ester precludes its use as a therapeutic agent.

These known esthetics A/((), Maksay et al.
J, Chromatography 174. 447
．． 1979), regardless of the compounds of the present invention, the specificity and novelty of which is characterized by the presence of a suitably positioned substituted nitrogen atom on the acyl moiety of the ester.

Summary of the Invention In the general formula (I) of the present invention, R represents a lower alkyl group having up to 5 carbon atoms. R represents an alkoxy substituent having up to 4 carbon atoms. R engineering is H, CI (3, -
CH2CH2N (C2H5). R2 is HlCl
, F, Br, trichloromethyl, N02, and the preferred position of R2 is the 7-position of the ring system. R3 is Hl(J,F
XBr is shown and the preferred position is the ortho position. n is 1
Desired compounds are those in which n is equal to 6, corresponding to an N-substituted amino acid with the structure of the neurotransmitter C) ABA (γ-aminobutyric acid);
is equal to 1 corresponds to an N-substituted amino acid having the structure of neurotransmitter glycine.

The method for producing the compound of the present invention involves adding a small amount of the N-substituted amino acid having the general formula (6) to 1°4-penzodiaze having the general formula (1) in the presence of an equivalent amount of base/an appropriate solvent at an appropriate temperature. It is reacted with the 03-(J derivative of Japanese ginseng).

Preparation of C3-CL substituted derivatives was performed by T. Kovac et al. J.M.
ed.

Chem, 17, 766 (1974). In the general formula (6), R and n are the general formula (I
) has the same meaning as in the case of In general formula (e),
R50, R2, and R3 have the same meanings as in general formula (I).

Suitable bases are organic bases selected from triethylamine, tributylamine, pyridine, 4-dimethylamino-giridine. The solvent may be an aprotic solvent, such as acetonitrile, acetone, ethyl acetate, etc., or the base itself may also serve as a solvent. The temperature that affects the reaction rate varies from 20° to 100° depending on the boiling point of the chosen solvent.
There is a gap between C ().

Another method for synthesizing compounds of general formula (I) is the synthesis of compounds of general formula (IV)
The 03-hydroxy compound is reacted with the compound of general formula (e) in a suitable solvent in the presence of a suitable condensing agent.

(In the formula, R, R2, and R3 have the same meanings as in general formula (I).) Desirable condensing agents include a catalytic amount of an organic base such as pyridine or
-N,N'-dicyclohexylcarbodiimide in the presence of ginorizine. The solvent is an aprotic solvent such as methylene chloride, benzene, toluene or tetrahydrofuran.

The third synthesis method uses a compound of general formula (IV) and general formula (1
an acid chloride derived from 10 in the presence of at least an equal amount of an organic base such as pyridine, substituted chlorine, triethylamine, and a water-free aprotic solvent such as methylene chloride, acetone, ethyl acetate, diethyl ether or having the role of solvent. This is done within the base itself.

To illustrate, but not limit, the invention:
The following manufacturing example is shown.

Example 1 1.45 F (10 mmol) of N-acetyl-γ-aminobutyric acid, 2.1i (15 mmol) of triethylamine and 3.05 F (10 mmol) of 6°7-dichloro-1,3- Dihydro-5-phenyl-2H-1,
The solution of 4-benzodiazepin-2-one is stirred at room temperature under nitrogen for about 1 hour. The solvent is removed in vacuo and the residual solid is stirred in ice-cold water for 60 minutes. The resulting slurry is filtered and the collected material is washed several times with water and a small amount of cold acetone. Crystallization of the crude from 25d acetonitrile and after drying yields analytically pure filter-(4-acetamido)phthyryloxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2.
-on, 1.4f with a melting point of 199-201°C was obtained.

Analysis value of C21H2oCIN304: Calculated value: C60,95H4,87N10.15cf8.
57 Actual measurement value: C60, 76H5, 00N10.07Cf8.
53 Example 2 2.37 t (11.6 mmol) of N-tertiary butyloxycarbonyl to γ-aminobutyric acid and 2.639 (12
, 76 mmol) of N,N'-dicyclohexyl-calmediimide in anhydrous methylene chloride was stirred at room temperature under nitrogen with stirring. Then 172η (1,16 mmol) of 4-gylolidinoviridine and 2.22F
(7,73 mmol) of 7-chloro-1,3-dihydro-6- and dolo#'/-5-phenyl-2H-114-benzodiazepin-2-one are added. The mixture is stirred at 40° C. for 1 hour.

The mixture was then diluted sequentially with water (3x100rnt), 5% acetic acid (2x100+n/) and saturated NaMCO3 (100mt).
), washed with water (100 g), the organic phase was washed with anhydrous Mg5O,
Dry with. The solvent was evaporated to dryness to give an amorphous solid of 4.0
Get 6 f. This product was converted into 1202 silica (4,
5X 15 ctn). 50% of the substance methylene chloride/methanol
:1 mixture was eluted. The impure 7-lactones were combined and rechromatographed in the same manner. 5
After drying at 0° C./Q and 1 Torr, a total amount of 1.21 amorphous, analytically pure 7-chloro-1,3-dihydro-5-
Phenyl-6-(4-6th class poxycarginylamino)
Butyryloxy-2H-1,4-pendidiazegino 2
- Got on.

Analysis value of C24H26CLN305: Calculated value: C61,08H5,57N8.90 cJ
7.51 Actual value: C60, 91H5, 60N8.78
cz7.53 Example 6 3.83 f (26.4 mmol) of N-acetyl-
γ-aminobutyric acid and 7.36 m (52,8 mmol)
of triethylamine dissolved in 70-anhydrous acetonitrile was added 6°7 of 8.15 F (24 mmol).
-Dichloro-5-〇-cucrophenyl-1,3-dihydro-2H-1,4-benzodiazepine □-2-one was added.

After stirring for 20 minutes at room temperature under nitrogen, the solvent was evaporated and the residue was
Chromatographed on 70f silica. Elute with a 11:1 mixture of methylene chloride/methanol,
Removal of the solvent and crystallization from methylene chloride/diethyl ether gave an almost pure product. Crystallization from ethyl methyl ketone gave 2.42 of the product. The product obtained from the mother liquor was recrystallized to give an additional 1.21 product.

- The combined product (after dehydration for 3 days at 70°C and 10.2 Torr) has a melting point of 120-121°C. As a result of microanalysis, the obtained 3-(4-acetamido)-butyryloxy-7-chloro-5-o-chlorophenyl-1,3-dihydro-2H-1,4-pendidiazeginol 2-one is half of the solvent molecule. to crystallize.

C2□H Engineering, CJL2N304-1/2 (Analysis value of 14H80: Calculated value C'57.03 H4, 78N8.
67 (J14.63 actual value C57,01) 14.
60 N8.78 (J14.78 Example 4 5.13 t (21,56 mmol) of N-acetyl-γ-aminobutyric acid and 4.1 d (29,42 mmol) of anhydrous triethylamine in 60-anhydrous acetonitrile 6.27 f (19,6 mmol) of 3,7-dichloro-1,3-dihydro-1-methyl-5 were added to the solution.
- Add phenyl-2H-1,4-benzodiazepin-2-one.

The solution is stirred under nitrogen and the temperature is kept at 600°C for 12 hours, followed by a further 7 hours at 80°C. The dark brown solution is concentrated to an oil and filtered through a 150t silica column.

The fraction eluted with methylene chloride/methanol 15:1 is evaporated to dryness and the solid residue (42) is crystallized from methylene chloride/-7 ethyl ether. Reconsolidated from acetonitrile/diisozologyl ether, 40
After dehydration for 90 hours at 10,5 Torr °C, analytically pure 6-(4-acetamido)butyryloxy-2chloro-1,6-dihydro1-methyl-5-phenyl-2H-1,4-benzodiazepine-2 -on, m, p
.

Obtain 2.84 f for 131-162°.

Analysis value of C22H22CfN304: Theoretical value: C61,65N5.18 N9.82 C
J8.28 actual measurement value: C (51,81N5.09N
10.02 (J8.26 Example 5) In a solution of 3.70 rnt (31,66 mmol) of N-acetylglycine and 4.40 rnt (31,66 mmol) of triethylamine in 80-anhydrous acetonitrile, 1
2? (31,66 mmol) of solid 6,7-cyclo-1,3-dihydro-5-7m=Rhu2H-1,
Add 4-pendiazeginor 2-one.

The resulting suspension is stirred under a nitrogen source.

After a further '50 and 120 minutes, 2.2d (15.83 mmol) of triethylamine are added.

After 6 hours, the solvent was completely removed in vacuo and the residue was dissolved in 25-methylene chloride/methanol 9:1 and dissolved at room temperature.
Stir the sealed solution for an hour to allow crystallization. 27. nt
Recrystallization from methyl ethyl ketone gave 6.55f analytically pure 3-acetamido-acetoxy-7-chloro-
1,5-cyhero 5-phenyl-2H-1,4-pendecyacecen-2-one, m, p, 210-211°C is obtained.

C engineering, H engineering. Analysis value of CJ, N304: Calculated value: C59
, 15H4, 18N10.89 cz9.19 Actual value: c5B, 96 1 (4,33N10.73 ci,
05 Example 6 4.65 t (32,06 mmol) of N-acetyl-γ-aminobutyric acid, 4.46 d (32,00 mmol) of triethylamine and 10.3 f (29
, 15 mmol) of 7-chloro-5-0-chlorophenyl-1,3-dihydro-6-hydroxy-2H-1,4
-A solution of benzodiazepine-2-one in 90-anhydrous acetonitrile was refluxed for 125 hours. The dark brown mixture was concentrated and the residue was chromatographed on 4502 silica gel in ether/methanol 9:1 followed by 200f Florisil in methylene chloride/ethanol 25:1. The resulting material was dissolved in acetone, filtered, the filtrate was concentrated and the residue was heated at 50 o/min for 50 hours.
Dehydrated at 0.5 Torr and amorphous 6-(4
-acetamido)butyryloxy-7-chloro-5-o
-chlorophenyl-1,3-dihydro-1-methyl-2
-1°4-benzodiazepin-2-one was obtained.

C22H2□ (Analysis value of J2N304: Calculated value: C57
,16H4,58N9.08 (J15.33 actual value: C57,38H4,92N8.87 (414,2
5. Toxicity Test As shown in Table 1, the compounds of the present invention have low toxicity.

Table 1 Oxavipam >1500 Example 1 1 5002
>1500 6 >1000 Pharmacological Tests The pharmacological activity of the compounds of the invention was evaluated by the following traditional tests known to exhibit useful therapeutic activity.

Monoantipentylenetetraday/l/ (L, O, Ran
d(11l, W.

8ch (11lek, G, A, He1se, E
, F. Keith and R6 Bagdon: J.
, Pharmacol, Exp, Therap
eutics.

129.163-171.1960).

-gcs (E,, A, 8wlnyard, W,
C, Brown and Ri.

S. Goodman: J., Pharmaco.
l, Exp, Therapeutics.

-Analgesia (N, B, Eddy Tori, Leimbac
h: J, Pharma-col, gxp, Th
erapeutics, 107, 385-39
3, 1953).

Muscle relaxation (N, W, Dunham and T, S, M
iya: J, Am.

Pharm, Ass,, 46. A3. 208-
209+1957).

locomotor activity (W, J, Kinnard and C,
J, Carr: J, Pharmacol, Exp, T
herapeutics, 121, 354-361
．． 1957).

These activities are shown in Table 2.

According to the data in Table 2, the compounds of the present invention have between 0.5 and 40
At low doses of +q/kp, it has remarkable activity as an anti-sedative, analgesic, muscle relaxant, sedative, hypnotic, and anxiolytic. These activities, combined with its low level of toxicity, make tenocan particularly useful for treating human and animal diseases such as pain, anxiety, aggression, insomnia, and myalgia due to infection.

Additionally, the compounds of the invention have one or more useful pharmacological effects on the mammalian central nervous system.

It can be included in pharmaceutical compositions as active agents useful in the drug treatment of the above-mentioned diseases in the field of psychosomatic and psychopharmaceuticals.

The compounds of the present invention can be administered orally, in conventional dosage forms such as tablets, capsules, solutions, suspensions, injections, herbal medicines, together with pharmaceutically compatible non-toxic diluents and adjuvants.
It can be administered parenterally or rectally.

Claims (17)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I
) (wherein R is lower alkyl of up to 5 carbon atoms, alkoxy of up to 4 carbon atoms, straight or branched chain, R_
1 is H, -CH_3, or -CH_2-CH_2N (C
_2H_5)_2, and R_2 and R_3 are each independently H, Br, Cl, F, trifluoromethyl or NO_
2 and n is the whole number from 1 to 5)
Benzodiazepines. (2) The compound according to claim 1, wherein R_2 is located at the 7-position of the ring system. (3) The compound according to claim 1, wherein R_1 is chlorine. (4) The compound according to claim 1, wherein R_3 is in the ortho position. (5) The compound according to claim 1, wherein R_3 is chlorine. (6) The compound according to claim 1, wherein R is -CH_3. (7) The compound according to claim 1, wherein R is tertiary butyloxy. (8) The compound according to claim 1, wherein n is 3. (9) The compound according to claim 1, wherein n is 1. (10) 3-(4-acetamido)butyryloxy-7
-chloro-1,3-dihydro-5-phenyl-2H-1
, 4-benzodiazepin-2-one. (11) 3-(4-tert-butyloxycarbonylamino)-butyryloxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2
The compound according to claim 1, which is -one. (12) 3-(4-acetamido)butyryloxy-7
-chloro-5-o-chlorophenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one,
A compound according to claim 1. (13) 3-(4-acetamido)butyryloxy-7
-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. (14) 3-acetamido-acetoxy-7-chloro-
The compound according to claim 1, which is 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one. (15) 3-(4-acetamido)-butyryloxy-
7-chloro-5-o-chlorophenyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2
The compound according to claim 1, which is -one. (16) A 1,4-benzodiazepine compound having the formula according to claim 1, which is used as a sedative-hypnotic, an anxiolytic, an anxiolytic, and an analgesic. (17) As a sedative-hypnotic, anxiolytic, anti-sedative, and analgesic, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (I) (wherein R is a lower alkyl group having up to 5 carbon atoms) , an alkoxy group having up to 4 carbon atoms, straight or branched, R_1 is H, -CH_3, -CH_2CH
_2N(C_2H_5)_2, R_2 and R_3 are each independently H, Br, Cl, F, trifluoromethyl, NO_2, and n is a whole number from 1 to 5). Psychosomatic and psychopharmaceutical compositions, characterized in that they contain a therapeutically effective amount of and pharmaceutically compatible diluents and suppositories.