JPH0315637B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 5-(aminoalkyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazepines. Wander, A. is a British patent
No. 907,646 discloses the preparation of certain of the dibenzodiazepines used in the present invention, such as the active ingredient of the compound of Example 1 in the form of the maleate salt. Wander, A. is a British patent
No. 959994 discloses the use of the reduced product.
For example, 5-
(Aminoalkyl)-11-phenyl-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine. Greig, M.E. et al., J.
Med.Chem. 14 , No. 2, p. 153 (1971) describes specific dibenzodiazepine congeners [especially 2-
The anaphylactic activity of chloro-5-(dimethylaminoethyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazepine is disclosed. Compounds useful as a therapeutic agent for depression according to the present invention are those represented by the following general formula and pharmaceutically acceptable acid addition salts thereof. (X is selected from the group consisting of H, Cl, Br, F; R ¹ , R ² are both H, or when R ² is methyl, R ¹ is H) Pharmaceutically acceptable acid addition Salts are physiologically compatible salts, such as those formed with strong or weak acids. Typical examples of strong acids are hydrochloric acid, sulfuric acid, and phosphoric acid.
Representative examples of weak acids include fumaric acid, maleic acid, succinic acid, oxalic acid, and cyclohexanoic acid. In order to demonstrate the antidepressant use of the compound represented by the general formula, Englehardt, EL et al. J.Med.Chem.11(2):325
(1968), a conventional method for demonstrating the utility of compounds for the treatment of depression in humans, was used as follows. 20 mg/Kg of the test compound was administered to five adult female mice (ICR-DUB species) to reduce eyelid ptosis (32 mg/Kg, I.
P.) Tetrabenazocine (Methanesulfonate)
The drug was administered intraperitoneally 30 minutes before administration. Thirty minutes later, each animal was examined for complete eyelid closure (blepharoptosis). Litchfield et al.
Pharmacol.Exp.The rap.96, pp. 99-113 (1949)
The ED ₅₀ (median effective dose) for each test compound that inhibits tetrabenazine-induced depression in mice can be established using the method described in . Among the dibenzodiazepines useful as a treatment for depression, preferred are the active agents of Example 1 (Reference Example), namely 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[b,e][1,4 ] Diazepine. The first object of the present invention is to develop novel 5-(aminoalkyl)-11-phenyl-5-H-dibenzo[b,
e] [1,4] diazepines. Other objective advantages of the present invention will be apparent to those skilled in the art, including:
In addition, other objects and advantages will become apparent from the description of this specification. A therapeutic agent for depression using the compound of the present invention comprises an active ingredient represented by the general formula and a suitable pharmaceutical carrier as an optional ingredient, and is in the form of a solution, syrup, elixir, tablet, capsule, suppository, powder, etc. used in For compounds in which the 5-position in the general formula is substituted with 3-dimethylaminopropyl, a dehydration condensation catalyst such as phosphorus pentoxide or phosphorus oxyhalide (the latter is preferred) is used in a suitable solvent such as 1,1,2,2-
It is prepared by cyclodehydration of N-(3-dimethylaminopropyl)-O-benzamido-diphenylamine using tetrachloroethane as described in GB 907,646. The reaction formula is as follows. (X is defined the same as in the general formula) A new compound in which the 5th position in the general formula is substituted with 3-aminopropyl is a new N-[3-(1-phthalimido)propyl]-O-benzamide. Diphenylamine (b) is cyclodehydrated, then the phthalimide moiety is converted to amino (NH ₂ ) with hydrazine and acid.
Manufactured by changing to The reaction formula is as follows. The compounds represented by the general formula (where X is defined as in the general formula) are also new. A new compound in which the 5-position in the general formula is substituted with 3-monomethylpropylamine is prepared by reacting a 3-aminopropyl compound with triethyl orthoformate and then with sodium borohydride [Crocket &
Blanton's method, 1974(1):55-6 synthesis]. The reaction formula is as follows. Starting compound benzamide (a,
b) is produced by a modification of the method described in GB 907646. Ortho-nitrodiphenylamine is first converted to β-chloropropyldimethylamine or
Reductive alkylation with a solution of -(1-phthalimido)-1-chloropropane followed by removal of the nitro moiety.
Hydrogen reduction using Pd/C gives the corresponding ortho-amino compound. The amino group at the ortho position is then reacted with a benzoyl halide or a substituted benzoyl halide. The reaction formula is as follows. Q=-N( _CH3 ) ₂ or 1-phthalimide production example 1 N-(3-dimethylaminopropyl)-o-aminodiphenylamine 32.0 g (0.107 mol) of N-(3-dimethylaminopropyl)-o - A mixture of nitrodiphenylamine (bp 155°/0.4-174°C/0.33 mm), 100 ml of 200 proof ethyl alcohol and 1.5 g of 10% Pd/C catalyst was shaken under hydrogen atmosphere at room temperature for 1 hour. After approximately the theoretical amount of hydrogen had been absorbed, the catalyst was removed through a Celite filter and the solvent was removed under reduced pressure. The residue was distilled under high vacuum as follows. bp, °C. Amount (g) Fraction 1 80-130°/0.2mm 4.0 2 130-137°/0.2mm 7.0 3 137-142°/0.2mm 15.5 20% methyl alcohol/80% benzene, thin layer chromatography using silica gel fraction 3 was shown to be extremely pure. Production Example 2 N-(3-dimethylaminopropyl)-o-benzamide diphenylamine N-
To a solution of (3-dimethylaminopropyl)-o-aminodiphenylamine [15.5 g (0.0575 mol)] in pyridine (100 ml) was added 17.8 g (0.063 mol) of benzoyl chloride. A small amount of benzene was used to flush residual benzoyl chloride into the reaction vessel. After stirring for 1 hour, the container was stopped and placed in the refrigerator until next week. The solvent was then evaporated under reduced pressure. residual oil
Dissolved in 100ml methylene chloride, 150ml 3N
Washed once with NaOH and three times with 250 ml of water. The methylene chloride layer was dried over magnesium sulfate and evaporated under reduced pressure. Then, the residual pyridine was removed under high vacuum (0.2
mmHg). The weight of the residual oil free base was 24.9 g. Oxalate Salt To a hot solution of 4.0 g of the free base in isopropyl alcohol was added 1.35 g (0.0107 mol) of oxalic acid dihydrate. The precipitated oxalate salt of the title compound was 3.5 g and melted at 162-5°C. 97% of this salt
It was dried at ~98°C (refluxing propyl alcohol) for 1 hour and at room temperature at 0.1 mmHg overnight and analyzed as follows. Analysis Calculated value (C ₂₆ H ₂₉ N ₃ O ₅ ): C, 67.37; H, 6.31; N, 9.06 Measured value: C, 67.42; H, 6.35; N, 9.01 Production example 3 Chlorination using the method of Production example 2 Using 2-chlorobenzoyl chloride, 3-chlorobenzoyl chloride, 2-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, 2-bromobenzoyl chloride, 3-bromobenzoyl chloride, 4-chlorobenzoyl chloride in place of benzoyl, N-(3-dimethylaminopropyl)-o-(2
-chlorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-chlorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(2
-fluorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-fluorobenzamide) diphenylamine, N-(3-dimethylaminopropyl)-o-(2
-bromobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-bromobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-chlorobenzamido)diphenylamine, was obtained. Production example 4 N-[3-(1-phthalimido)propyl]-o
-Aminodiphenylamine Reacting o-nitrodiphenylamine with sodium hydride and 3-(1-phthalimido)-1-chloropropane yields N-3-(1-phthalimido)propyl-o-nitrodiphenylamine. , which was then reduced with hydrogen in ethanol using Pd/C to give the title compound. Production Example 5 N-3-(1-phthalimide) by the method of Production Example 2
Propyl-o-aminodiphenylamine in excess of the following acyl chlorides: 2-chlorobenzoyl chloride, 3-chlorobenzoyl chloride, 2-fluorobenzoyl chloride, 3-fluorobenzoyl chloride, 2-bromobenzoyl chloride, 3-chlorobenzoyl chloride Bromobenzoyl and 4-chlorobenzoyl chloride are reacted to form N-3-(1-phthalimido)propyl-o-
(2-chlorobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(3-chlorobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(2-fluorobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(3-fluorobenzamide) diphenylamine, N-3-(1-phthalimido)propyl-o-
(2-bromobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(3-bromobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(4-chlorobenzamido)diphenylamine was obtained. The following examples further illustrate compounds useful in the present invention. Example 1 (Reference example) 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[b,e][1,b]diazepine, fumarate [1:1] 18.9g (0.05 mol) of N-(3-dimethylaminopropyl)-o-benzamido diphenylamine and 32.19 g (0.2 mol) of phosphorus oxychloride at 50%
The mixture was stirred into 1,1,2,2-tetrachloroethane (1,1,2,2-tetrachloroethane) and heated at 150° C. for 1.5 hours under a nitrogen atmosphere. Cooled somewhat, poured onto approximately 1000 ml of crushed ice, and diluted with enough water to bring the final volume to 1000 ml. The resulting aqueous suspension was extracted twice with methylene chloride and the methylene chloride layer was discarded. water layer to 3N
It was made basic with NaOH and extracted three times with 250 ml each of methylene chloride. The three methylene chloride extracts were combined, dried over magnesium sulfate, and dried in vacuo to give the free base of the title compound as a residual oil, 13.8 g. This oil was dissolved in hot isopropyl alcohol and reacted with 4.5 g (0.039 moles) of fumaric acid. Take the fumarate and dry it 13
I got g. mp168~170℃. Analysis: Calculated value (C ₂₈ H ₂₉ N ₃ O ₄ ): C, 71.32; H, 6.20; N, 8.91 Measured value: C, 71.19; H, 6.19; N, 8.89 Example 2 (Reference example) Example In method 1, an equimolar amount of N-(3-dimethylaminopropyl)-o-(2
-chlorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-chlorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(2
-fluorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-fluorobenzamide) diphenylamine, N-(3-dimethylaminopropyl)-o-(2
-bromobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(3
-bromobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(4
-chlorobenzamido) diphenylamine, using 11-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate, 11-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate, 11-(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate, 11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate, 11-(2-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate, 11-(3-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate, 11-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
[1,4]Diazepine, fumarate was obtained. Example 3 (Reference example) N-(3-
N-3-(1-phthalimido)propyl-o- instead of dimethylaminopropyl)-o-benzamide diphenylamine
Benzamido diphenylamine, N-3-(1-phthalimido)propyl-o-
(2-chlorobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(3-chlorobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(2-fluorobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(3-fluorobenzamide) diphenylamine, N-3-(1-phthalimido)propyl-o-
(2-bromobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(3-bromobenzamido)diphenylamine, N-3-(1-phthalimido)propyl-o-
(4-chlorobenzamide) using diphenylamine 5-[3-(1-phthalimido)propyl]-11
-Phenyl-5H-dibenzo[b,e][1,4]
Diazepine, 5-[3-(1-phthalimido)propyl]-11
-(2-chlorophenyl)-5H-dibenzo[b,
e] [1,4] diazepine, 5-[3-(1-phthalimido)propyl]-11
-(3-chlorophenyl)-5H-dibenzo[b,
e] [1,4] diazepine, 5-[3-(1-phthalimido)propyl]-11
-(2-fluorophenyl)-5H-dibenzo[b,
e] [1,4] diazepine, 5-[3-(1-phthalimido)propyl]-11
-(3-fluorophenyl)-5H-dibenzo[b,
e] [1,4] diazepine, 5-[3-(1-phthalimido)propyl]-11
-(2-bromophenyl)-5H-dibenzo[b,
e] [1,4] diazepine, 5-[3-(1-phthalimido)propyl]-11
-(3-bromophenyl)-5H-dibenzo[b,
e] [1,4] diazepine, 5-[3-(1-phthalimido)propyl]-11
-(4-chlorophenyl)-5H-dibenzo[b,
e][1,4]diazepine was obtained. Example 4 5-(3-aminopropyl)-11-phenyl-
5H-dibenzo[b,e][1,4]diazepine hydrochloride 0.035 mol of 5-[3-(1-phthalimido)propyl-11-phenyl-5H-dibenzo[b,e]
[1,4] A mixture of diazepine, 0.039 moles of hydrated hydrazine, and 190 proof ethyl alcohol.
The mixture was refluxed for 2.5 hours and left for 7 hours. 10 ml of concentrated hydrochloric acid was dissolved in 50 ml of water, added to the above mixture, and stirred for 7 hours. and the liquid was evaporated under reduced pressure. Isolating the resulting hydrochloride salt by recrystallization from a suitable solvent;
Dry under reduced pressure. Example 5 Using the method of Example 4, an equimolar amount of 11-( 2-chlorophenyl)-5-(3-(1-phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] diazepine, 11-(3-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] diazepine, 11-(2-fluorophenyl)-5-[3-(1-
phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] diazepine, 11-(3-fluorophenyl)-5-[3-(1-
phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] diazepine, 11-(2-bromophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] diazepine, 11-(3-bromophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] diazepine, 11-(4-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,
e] [1,4] using diazepine 5-(3-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-bromophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-bromophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride was obtained. Example 6 N-methyl-11-phenyl-5H-dibenzo[b,e][1,4]diazepine-5-propanamine hydrochloride 5-(3-aminopropyl)-11-phenyl-
The hydrochloride of 5H-dibenzo[b,e][1,4]diazepine was prepared by partitioning between dilute NaOH and methylene chloride, drying the methylene chloride layer, concentrating to dryness, adding dry benzene, and reconcentrating the benzene. was converted to the free base by removal of . The resulting free base was dissolved in a large excess of freshly distilled triethyl orthoformate and refluxed for several hours. The mixture was concentrated in vacuo, ethanol was added and reconcentrated. The resulting imidate was dissolved in ethanol and sodium borohydride was added with stirring at 15-20° C. until thin layer chromatography showed the absence of substantial amounts of starting material. cool,
Water was gradually poured into the mixture, followed by extraction with ethyl acetate.
The ethyl acetate layer was washed neutral, salted out, filtered and evaporated. The crude free base was isolated by column chromatography and reacted with ethereal HCl solution,
Recrystallization gave the title compound. Example 7 5-(3-aminopropyl)- by the method of Example 6
11-phenyl-5H-dibenzo[b,e][1,
4] Instead of diazepine, equimolar amount of 5-(3-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-bromophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-bromophenyl)-5H-dibenzo[b,e][1,4]
Diazepine hydrochloride, 5-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]
Using diazepine hydrochloride, 11-(2-chlorophenyl)-N-methyl-5H
-dibenzo[b,e][1,4]diazepine-5
-Propanamine hydrochloride, 11-(3-chlorophenyl)-N-methyl-5H
-dibenzo[b,e][1,4]diazepine-5
-Propanamine hydrochloride, 11-(2-fluorophenyl)-N-methyl-
5H-dibenzo[b,e][1,4]diazepine-
5-propanamine hydrochloride, 11-(3-fluorophenyl)-N-methyl-
5H-dibenzo[b,e][1,4]diazepine-
5-Propanamine hydrochloride, 11-(2-bromophenyl)-N-methyl-5H
-dibenzo[b,e][1,4]diazepine-5
-Propanamine hydrochloride, 11-(3-bromophenyl)-N-methyl-5H
-dibenzo[b,e][1,4]diazepine-5
-Propanamine hydrochloride, 11-(4-chlorophenyl)-N-methyl-5H
-dibenzo[b,e][1,4]diazepine-5
-Propanamine hydrochloride was obtained. FORMULATION AND ADMINISTRATION Effective amounts of the above pharmacologically active compounds of the general formula may be administered orally, for example, in the form of solutions, emulsions, suspensions, pills, tablets, capsules. It can be administered to humans for therapeutic purposes in a pharmaceutically acceptable carrier, or parenterally in the form of a sterile solution. Examples of solid carriers for oral administration are lactose,
These include magnesium, stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, and gum acacia. Examples of liquid carriers for oral administration are vegetable oils and water. For intramuscular administration, carriers or excipients include sterile parenterally acceptable liquids in ampoules;
For example, it may be water or a parenterally acceptable oil (eg, fallen oil). When administered to patients with mild symptoms or low body weight, the active ingredients of the present invention are effective in very small doses, but the unit dose will usually be 5 mg or more, preferably 10 mg or more.
25, 50 to 100 mg or more, preferably administered 3 to 4 times a day, this will of course depend on the condition, the compound used and the individual desired result. 25~200
mg and unit dose appears to be optimal, with the usual wider range being about 10-500 mg/unit dose. The daily dose usually required is about 0.5 to about 20
mg/Kg/day, preferably 0.5-10 mg/Kg.
The active ingredients of the invention can be used in combination with other pharmacologically active agents such as those mentioned above. It is only necessary that the active ingredient be present in an effective amount, ie, a suitable effective dose is selected to be consistent with the dosage form used.
Obviously, several unit dosage forms can be administered at about the same time. The exact individual dose and daily dose will, of course, be established according to standard pharmaceutical principles under the direction of a physician or veterinarian. The following formulation examples are representative for pharmacologically active compounds of the invention. Formulation Example 1 Capsules Capsules containing 10 mg and 50 mg of active ingredient per capsule were prepared. When increasing the amount of active ingredient, the amount of lactose can be reduced.

Table: Other capsules contained more active ingredients. The prescription was as follows.

Table: In each case, the selected active ingredients were homogeneously blended with lactose, starch, and magnesium stearate, and the resulting blend was filled into capsules. 2 Tablets A typical formulation for tablets containing 5.0 mg of active ingredient per tablet was as follows. This formulation could be used with other levels of active ingredient by adjusting the weight of dicalcium phosphate. mg/tablet 1 Active ingredient 10.0 2 Corn starch 15.0 3 Corn starch (paste) 12.0 4 Lactose 35.0 5 Dicalcium phosphate 132.0 6 Calcium stearate 2.0 Total 202.0 Ingredients 1, 2, 4, and 5 were uniformly blended. Component 3 was prepared as a 10% paste in water. The blend was granulated with starch paste and the resulting wet mass was passed through an 8 mesh screen. The wet granules were dried and sized using a 12 mesh screen. The dry granules were blended with calcium stearate and compressed. 3 2% sterile solution for injection per c.c. Active ingredient 20 mg Preservative (e.g. chlorobutanol)
A 0.5 w/v % water for injection solution was prepared, clarified by filtration, filled into vials, sealed, and autoclaved. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the scope or spirit of the invention.

Claims (1)

[Scope of Claims] 1. A compound represented by the following general formula and a pharmaceutically acceptable acid addition salt thereof. (X is selected from the group consisting of H, Cl, Br, F; R ¹ and R ² are both H, or when R ² is methyl, R ¹ is H)