IE43841B1 - Triazolylbenzophenone derivatives and preparation thereof - Google Patents

Triazolylbenzophenone derivatives and preparation thereof

Info

Publication number
IE43841B1
IE43841B1 IE2215/76A IE221576A IE43841B1 IE 43841 B1 IE43841 B1 IE 43841B1 IE 2215/76 A IE2215/76 A IE 2215/76A IE 221576 A IE221576 A IE 221576A IE 43841 B1 IE43841 B1 IE 43841B1
Authority
IE
Ireland
Prior art keywords
formula
compound
alkyl
benzophenone
triazol
Prior art date
Application number
IE2215/76A
Other versions
IE43841L (en
Original Assignee
Shionogi & Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co filed Critical Shionogi & Co
Publication of IE43841L publication Critical patent/IE43841L/en
Publication of IE43841B1 publication Critical patent/IE43841B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/92—Oxygen atoms with hetero atoms directly attached to nitrogen atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Anesthesiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The compounds of the formula Ia in which the substituents have the meaning stated in Claim 1 are obtained by hydrazinolysis of phthalyl derivatives of the formula IV. The resulting products can be used as anxiolytics, sedatives, hypnotics, spasmolytics, muscle relaxants, antidepressants and can furthermore be employed as starting materials for the preparation of pharmacologically active compounds.

Description

The present invention relates to certain triazolyl benzophenone derivatives and to the preparation thereof.
According to the present invention there is provided a compound of the formula: wherein R represents hydrogen, C-^-Cg alkyl, C^-Cg haloalkyl, the group -(CH2)n~X-R5 or the group - 3 Wn10 κ being hydrogen, C^-Cg alkyl, C2-Cg alkenyl, C2~Cg alkynyl, Cg-C1Q aryl or C2-Cg acyl, X being sulfur or oxygen, n being 0, 1, 2 or 3, and R6 and R7 each independently being hydrogen u? 0^-Cg alkyl, or the group R®~λR7 being pyrrolidino, piperidino, morpholino or γ-methylpiperazino; ^represents hydrogen or halogen; R2 represents halogen,nitro or trifluoromethyl; R3 represents C^-Cg alkyl, Cj_-Cg halo-alkyl, C^-Cg azido-alkyl, Cg-C1Q aryl, C2-Cg acyl or the group -CH—N ,10 9 R being hydrogen, Cj-Cg alkyl or C?-·^ aralkyl, R being hydrogen or C^-Cg alkyl, R10 being hydrogen, C^-C6 alkyl, C?-Clo aralkyl, or C2-C·^ «“^ino-acyl, or the Q I In group R—N—R being phthalimido, pyrrolidino, piperi4 dino, morpholino or γ-methylpiperazino; and R represents hydrogen, C1-Cg alkyl or C^-C^Q aralkyl.
The pharmaceutically acceptable acid addition salts of the above compounds are included in the present invent20 ion and such compounds and salts are useful as anxiolytics, sedatives, hypnotics, anti-convulsants,muscle relaxants, anti-depressants, or as synthetic intermediates therefor. - 4 In the above definition: alkyl may be e.g. methyl, ethyl, isopropyl, butyl, pentyl or hexyl; alkenyl may be e.g. vinyl, allyl, butenyl, pentenyl or hexenyl; alkynyl may be e.g. ethynyl, propynyl, butynyl or pentynyi; aryl may be e.g. phenyl, tolyl, xylyl or pyridyl? aralkyl may be e.g. benzyl, phenethyl or phenylpropyl; acyl may be e.g. formyl, acetyl, propionyl, benzoyl or carbobenzoxy; α-amino-acyl may be e.g. glycyl, alanyl, leucyl or phenylalanyl; and halogen may be e.g. chlorine, bromine, fluorine or iodine.
Example^, of ths present triazclylbenzophencne deri vatives (I) are:2',5 - dichloro -’2 - (3 - acetamidomethyl - 5 - methyl 4H - 1,2,4 -triazol - 4 - yl)-benzophenone; 2',5 - dichloro - 2 - (3 - propionamidomethyl - 5 methyl - 4H - 1,2,4 - triazol - 4 - yl)-benzophenone; 2',5 - dichloro -2-(3- isobutyramidomethyl - 5 methyl - 4H - 1,2,4 - triazol - 4 - yl) - benzophenone; 2',5 - dichloro - 2 - (3 - butyramidomethyl - 5 methyl - 4H - 1,2,4 - triazol - 4 - yl)' benzophenone; 2',5 - dichloro - 2 - (3 - pyruvamidomethyl - 5 - methyl - 4H 1,2,4 - triazol - 4 - yl) - benzophenone; 2',5 - dichloro - 2 - (3 - L - phenylalanylaminomethyl 5 - methyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone ; - chloro -2-(3- glycylaminomethyl - 5 - dimethylaminomethyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; - chloro -2-(.3- glycylaminomethyl - 5 - morpholino438-11 - 5 methyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; - chloro - 2 - (3 - glycylaminomethyl - 5 - piperidinomethyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; - chloro -2-/3- (4 - methoxybenzamidomethyl) - 5 5 CAiaet.iy laminomethyl - 4H - 1,2,4 - triazol - 4 yl/ - benzophenone; - chloro - 2 - (3 - butyramidomethyl - 5 - dimethylaminomethyl - 4H - 1,2,4 - triazol-4-)-benzophenone; - chloro -2-(3- acetamidomethyl -5- dimethylaminomethyl - 4H - 1,2,4 - triazoi-4-yl)-benzophenone; 2',5 - dichloro - 2 - (3 - glycylaminomethyl - 5 dimethylaminomethyl - 4H - 1,2,4 - triazol-4-yl)15 benzophenone; 2',5 - dichloro - 2 - (3 - glycylaminomethyl - 5 diethylaminomethyl - 4H - 1,2,4 - triazol-4-yl)benzophenone; 2',5 - dichloro -2-(3- glycylaminomethyl - 5 20 pyrrolidinomethyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; 2',5 - dichloro - 2 - (3 - glycylaminomethyl - 5 phenylthiomethyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone ; 2',5 - dichloro -2-(3- glycylaminomethyl - 5 - propylthiomethyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; 2',5 - dichloro -2-/3- (2 * diethylaminoacetamidomethyl) - 5 - diethylaminomethyl - 4H - 1,2,4 30 triazol - 4 - yl7 - benzophenone; 2',5 - dichloro -2-/5 - (2 - y- methylpiperazino acetamidomethyl) - 5 - γ - methylpiperazinomethyl 4H - 1,2,4 - triazol - 4 - yl7 - benzophenone; - 6 2',5 - dichloro -2-/3- (Ntt -glycyl - glycylaminomethyl) - 5 - methyl - 4H - 1,2,4 - triazol-4-yl7“ benzophenone; 2',5 - dichloro -2-/3- (Na - L - phenylalanyl glycylaminomethyl) - 5 - methyl - 4H-l,2,4-triazol4-yl7-benzophenone; - chloro - 2 - (3 - glycylaminomethyl - 5 - acetoxymethyl - 4H - 1,2,4 - triazol-4-yl)benzophenone; - chloro - 2 - (3 - glycylaminomethyl - 5 - pyrrolidinomethyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; 2',5 - dichloro - 2 - (3 - glycylaminomethyl - 5 - methyl4H - 1,2,4 - triazol - 4 - yl)-benzophenone; - chloro - 2 - (3 - glycylaminomethyl - 4H - 1,2,4 triazol - 4 - yl) - benzophenone; - chloro - 2 - (3 - glycylaminomethyl - 5 - methyl 4H - 1,2,4 - triazol - 4 - yl)-benzophenone; - chloro -2-/3- (2 - chloroacetamidomethyl) - 5 methyl - 4H - 1,2,4 - triazol-4-y17benzophenone; - chloro -2-/3- (2 - dimethylaminoacetamidomethyl) 5 - methyl - 4H - 1,2,4 - triazol-4-yl7“benzophenone; - chloro -2-/3- (2 - methylaminoacetamidomethyl) 5 methyl --4H - 1,2,4 - triazol-4-yX7-benzophenone ; - chloro - 2 - /J - (2 - diethylaminoacetamidomethyl) 5 - methyl - 4H -1,2,4 - triazol-4-yl7“benzophenone; 21,5 - dichloro -2-/3- (2- chloroacetamidomethyl) 5 - methyl - 4H - 1,2,4 - triazol-4-y17“benzophenone ; 21,5 - dichloro -2-/3- C2 - dimethylaminoacetamidomethyl) - 5 - methyl - 4H - l,2,4-triazol-4~yl7benzophenone; 3 8 4.1 - 7 2',5 - dichloro -2-/3-(2- diethylaminoacetamidomethyl) - 5 - methyl - 4H - 1,2,4 - triazol-4-yl7benzophenone ; - chloro - 2 - (3 - glycylaminomethyl - 5 - propar5 ;’yT~“-'-hyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone; - chloro - 2' - fluoro - 2 - (3 - glycylaminomethyl 5 - morpholinomethyl - 4H - 1,2,4-ίΓΐαζο1~4·νγ1)benzophenone; and - chloro - 2 - (3 - L - phenylalanylaminomethyl - 5 methyl - 4H - 1,2,4 - triazol-4-yl)-benzophenone.
The triazolylbenzophenone derivatives (I) can, for example, be prepared by three routes (Routes A, B and C) as shown in the following scheme:4 3 8 4 .ί Route Route B (continued) 3 8 41 - 10 In the above scheme A represents a reactive group (e.g. halogen or a residue of an ester); Ar represents phenyl or 2-halogenophenyl; hal represents halogen; HMT represents hexamethylenetetramine; R'L1' represents hydrogen, cl~Cg alkyl or aralkyl; met represents alkali metal; Q represents phthalimide; and R,. R2, R^, R®, R^, R®, · and' R^-θ are each as ' defined above..
Preferred embodiments of the above routes are explained in the following description by way of illustration .
Route A This route is effected by treating quinazoline derivatives (II) or (III) with a weak acid Ce.g. acetic acid, monochloroacetic acid, propionic acid, benzoic acid or p-toluenesulfonic acid) to give as a product the phthalimide derivative (IV) and hydrazinolyzing the product (IV) to give the triazolylbenzophenone derivative (la). The first reaction can be carried out, in general, by using an excess of weak acid preferably without a solvent at room temperature or with warming. The hydrazinolysis of the phthalimide derivative (IV)· can be carried out in a conventional manner' such as by treating with hydrazine . hydrate in a suitable solvent (e.g. ethanol, methanol, dimethylformamide, benzene, dimethylsulfoxide or chloroform) with heating. The hydrazinolysis can result in a high yield of high purity product (Ia).
The product (Ia) can be condensed with a phthalyl derivative of an α-amino acid (e.g. glycine, phenylalanine, alanine or leucine) of a reactive derivative thereof (e.g. chloride or ester) in a manner conventional for amino acid condensation such as in the presence of a condensing agent (e.g. dicyclohexylcarbodiimide) in a suitable inert solvent (e.g. dimethylformamide, dioxane or dimethylsulfoxide), and then the resultant phthalyl 3 8 41 - ll product hydrazinolyzed as described above to give the second product (lb).
The starting quinazoiine derivatives (11) and (III) can be derived, for example, from the aminobenzophenone ς 3ήΓ.ι-Γ-·<«β ίνττ) an,5 the quinazoiine derivative (.XV), respectively, as below:- HV wherein Cbz represents a carbobenzoxy group; and A, Ar,*Q, 2 4 8 R, R , R and R are each as defined above. 3 8 41 - 12 Route Β, The starting triazole (V), used in the form of a salt of the acid (e.g. the hydrochloride or hydrobromide) , is reacted with a reactive derivative of an α-halogenoacetic acid (VII). Reactive derivative in this context means an active derivative of carboxy including acid halogenide, acid anhydride, acid azide and active ester. This reaction is effected in the conventional manner for amido-bonding formation such as in an inert solvent (.e.g. dimethylformamide, hexamethylphosphoric triamide or pyridine) at room temperature or with cooling or heating. The resultant intermediate halide (VIII) can be converted into the product (la) of Route A by treating with ammonia or hexamethylenetetramine in a solvent (e.g. methanol, ethanol, diglyme Or dimethylformamide) at room temperature or with warming. Alternatively, product (Ia) may be obtained by treating halide (VIII) with an alkali metal azide (e.g. sodium azide or potassium azide) in-an inert solvent (e.g. dimethylformamide, dimethylsulfoxide, pyridine or chloroform) at room temperature or with warming and then reducing the resultant azido compound (Ic) with a reducing agent (e.g. stannous chloride in sodium hydroxide or zinc dust) or hydrogenating it over a catalyst (e.g.
Raney nickel, palladium carbon or platinum oxide) in a conventional manner such as in an inert solvent (e.g. methanol, ethanol, dimethylformamide, benzene or tetrahydrofuran) at room temperature or with cooling or heating.
The intermediate halide (VIII) may also be reacted with an amine (IX) (e.g. methylamine, dimethylamine, diethylamine, pyrrolidine, morpholine, piperidine or γmethylpiperazine) in an inert solvent (.e.g. dimethylformamide, methanol, ethanol, acetone or hexamethylphosphoric triamide) at room temperature or with heating to give the product (Id). 3 8 41 - 13 The starting triazole (V) may alternatively, be reacted with a reactive derivative of a phthaiyl-aamino sicid (VI) to give the phthalimide derivative (IV) described in Route A; and the triazole (V) can also be converted into the product (lb) by condensing it with a protected peptide (e.g. phthalylglycyl-glycine) and subjecting the resulting product to deprotection (e.g. hydrazinoiysis) in a conventional manner.
The starting triazole (V) can be prepared, for example, from the aminobenzophenone (XVIII) as shown in the following scheme:43841 NH7CH-CN.H?SO4 Cbz-Cl ^Cbz-NHCIICN EtOH-HCl NaOH „4 R NH R Cbz-NHCH-C-OEt.HCl EtOH Cbz-NHCH-C(OEt), --—> -> CO-Ar R2 J/ \ / (XVIII) 3 8 41 - 15 wherein Ac represents acetyl; Et represents ethyl; and A, Ar, Cbz, R, R2 and are each as defined above.
Route C.
The triazole (V) is reacted with the acylating agent (X) (R3CO=acyl) in a conventional manner to give the product (Ie). Examples of the acylating agent are acetyl chloride, acetic anhydride, propionyl chloride, butyryl bromide, isobutyryl chloride, benzoyl chloride and pyruvoyl chloride. If R of the product (Ie) is halo-alkyl, product (Ie) can further be converted into the product (If) by treating with the amine (XI). This reaction is effected as in the step (VUI+Id) of Route B.
The starting compound (V) /R=halo-alkyl, R5 N(CH5)/ n R7 lb or r5-x_(ch2) ~7, used in Route B and Route C, can be prepared as shown in the following scheme:43841 (XXIc) / 3 8 41 - 17 wherein A° represents hydrogen, alkali metal, or active o metal (e.g. silver or thallium): and A, Ac, Ar, Cbz, R , R , R , X and n are each as defined above.
The product compounds (I) can be converted into pharmaceutically or veterlnarily acceptable acid addition salts thereof such as those of inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or thiocyanic acid) or of organic acids (e.g. acetic acid, succinic acid, oxalic acid, maleic acid, malic acid, phthalic acid, methanesulfonic acid, citric acid, toluenesulfonic acid or tartaric acid) for, for example, the purposes of preparation or crystallization, or as a result of solubility properties, or to achieve an improvement in stability.
The triazolylbenzophenone derivatives (I) and their pharmaceutically or veterlnarily acceptable acid addition salts are useful as anxiolytics, sedatives, anticonvulsives, hypnotics, muscle relaxants, antidepressants, or as synthetic intermediates therefor. Thus, for example, 2', 5dichloro-2-(3-glycylaminomethyl-5-methyl-4H~l,2,4-triazol4-yl)-benzophenone showed an Ε°50 of 0.23 mg/kg (mouse, per os) in anticonvulsive activity against pentylenetetrazole, and an ED5o of 0-25 mg/kg (mouse, per os) in potentiating narcosis against thiopental sodium; and 2', 5dichloro-2-(3-glycylaminomethyl-5-dimethylaminomethyl-4H1,2,4-triazol-4-yl)-benzophenone showed an of 0.75 mg/kg (mouse, per os) in anticonvulsive activity as above. The other triazolylbenzophenone derivatives (I) show similar pharmacological activities.
The triazolylbenzophenone derivatives and their pharmaceutically or veterlnarily acceptable acid addition salts may be used singly or in combination with pharmaceutically or veterlnarily suitable diluents, carriers, or excipients such as wheat starch, corn starch, potato starch or gelatin. The choice of carrier(s) is determined 3841 - 18 by the preferred route of administration, the solubility of the substance and standard pharmaceutical practice. Examples of types of pharmaceutical preparations are tablets, capsules, pills, suspensions, syrups, powders and solutions. These preparations can be prepared by conventional methods.
Thus, the invention provides a pharmaceutical or veterinary formulation which comprises a compound of the invention or a salt thereof formulated for pharmaceutical or veterinary use, respectively .
The invention also includes a pharmaceutical or veterinary composition Which comprises a compound of the invention or a salt thereof and a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier of excipient.
Such formulations and compositions may be in unit dosage form.
The invention also provides a method of inducing an anxiolytic, sedative, hypnotic, anticonvulsant, muscle relaxant or antidepressant effect in an animal, which method comprises administering to the animal an effective amount of a compound of the invention, a salt thereof, a formulation of the invention, or a composition of the invention.
A suitable dosage of the triazolylbenzophenone derivatives (I) or of their pharmaceutically acceptable acid addition salts for adults is from 0.2 mg to 30 mg per day.
The triazolylbenzophenone derivatives (I) and their acid addition salts are also useful as growth promotors for domestic livestock and poultry. Thus, the invention further provides a method of promoting growth in an animal, which method comprises administering to the animal an effective amount of a compound of the invention, a salt thereof, a formulation of the invention, or a composition of the invention.
The invention will now be further illustrated and described by means of the following Examples.
Example 1. (1) To a solution of 2-phthalimidoacetyl chloride (1.5 g) in benzene (20 ml) and dimethylformamide (10 ml), -chloro-2-(3-aminomethyl-5-methyl-4H-l,2,4-triazol-4yl)-benzophenone dihydrobromide (2.3 g) is added with ice cooling and stirring, and the temperature within the flask is gradually returned to room temperature. The reaction mixture is allowed to stand at room temperature, neutralized with saturated aqueous sodium bicarbonate, and shaken with ethyl acetate. The precipitated crystals are filtered, washed with methanol and dried to give 5-chloro-2-/7-(2-phthalimidoacetamidomethyl)-5-methyl4H-1,2,4-triazol-4-y17-benzophenone (1.68 g) as crystals melting at 251-253°C.
Anal. Calcd. for C^H^N^Cl! C' 63·-1·0'' H' 3·92; N, 13.62; Cl, 6.90. Found; C, 63.08; H, 4.03; N, 13.80; Cl, 7.07. (2) To a solution of 5-chloro-2-/3-(2-phthalimidoacetamidomethyl)-5-methyl-4H-l,2,4-triazol-4-yl7-benzophenone (2.3 g) in ethanol (20 ml), hydrazine hydrate (0.92 g) is added, and the resultant mixture is refluxed for 1 hour. The precipitated phthalylhydrazide is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate and water in order, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on a column of silica gel, and the product obtained from the eluate by evaporation is recrystallized from ethyl acetate to give 5 * chloro -2-(3 glycylaminomethyl - 5 methyl - 4H - 1,2,4 - triazol - 4 - yl)-benzophenone hydrate as crystals melting at 110 to 113°C. The yield is 94%. 8 41 Anal. Calcd. for ci9H18N5O?.C1 ·Η20: C' 56·79? .01; N, 17.82; Cl, 8.80. Found: C, 57.12; H, 5.07; N, 17.52; Cl, 9.00.
Oxalate dihydrate, m.p. 112-114°C. (recrystallized from water-acetonitrile).
Example 2. (1) Using 2',5 - dichloro - 2 - (3 - aminomethyl 5 - methyl - 4H - 1,2,4-triazol-4-yl)-benzophenone dihydrobromide, the reaction is effected as in Example 1 (1), whereby 2',5-dichloro-2-/3-i(2-phthalimidoacetamidomethyl)-5-methyl-4H-l,2,4-triazol-4-yl7-benzophenone is obtained as crystals melting at 219-231°C. (2) Using 2',5-dichloro-2-/3-(2-phthalimidoacetamidomethyl)-5-methyl--4H-l,2,4-triazol-4-yl7-benzophenone, the reaction is effected as in Example 1 (2), whereby 2',5 - dichloro -2-(3- glycylaminomethyl - 5 - methyl 1,2,4 - triazol - 4 - yl)-benzophenone is obtained as crystals melting at 163 to 165°C.
Anal. Calcd. for C^gH^yNj^Cl.,: C, 54.56; H, 4.10; N, 16.74; Cl, 16.95. Found: C, 54.37; H, 4.13; N, 16.45; Cl, 17.00.
Dihydrochloride monohydrate, m.p. 178.5-181,5° C. (recrystallized from ethanol/ethyl acetate).
Example 3. (1) To a solution of 5-chloro-2-(3-aminomethyl5-methyl-4H-l,2,4-triazol-4-yl)-benzophenone dihydrobromide (0.5 g) in dimethylformamide (3 ml), chloroacetyl chloride (0.2 g) is added dropwise with ice cooling, and the resultant mixture is stirred. The reaction mixture is allowed to stand at room temperature overnight, mixed with water (3 ml), neutralized with aqueous sodium bicarbonate and shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous 4 38 41 saline solution in that order, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from ethyl acetate/nhexane to give 5 - chloro -2-/3- (2 - chloroaceta5 midomethyl) - 5 - methyl - 4H - 1,2,4 - triazol - 4 - yl7 benzophenone (0.35 g) as crystals melting at 140 to 141°C (2) A suspension of 5-chloro-2-/3-(2-chloroacetamidomethyl)-5-methyl-4H-l,2,4-triazol-4-yl7~benzophenone (1.35 g) and potassium phthalimide (0.7 g) in dimethylformamide (10 ml) is warmed at 50 to 60°C. for 3 hours. The reaction mixture is shaken with methylene chloride. The methylene chloride layer is washed with water and saturated aqueous saline solution in that order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is crystallized from ethyl acetate/ether to give 5-chloro-2-/3-(2phthalimido-acetamidomethyl)-5-methyl-4H-l,2,4-triazol4-yl7~benzophenone as crystals melting at 251 to 253°C.
Example 4. (1) Using 2',5-dichloro-2-(3-aminomethyl-5methyl-4H-l,2,4-triazol-4-yl)-benzophenone dihydrobromide, the reaction is carried out as in Example 3 (1), whereby 2',5 - dichloro - 2 - /3 - (2 - chloroacetamidomethyl) - 5 - methyl - 4H - l,2,4-triazol-425 yl7-benzophenone is obtained as crystals melting at 151 to 153°C. (2) Using the above product, the reaction is carried out as in Example 3 ¢2), whereby 2',5 - dichloro /3-(2- phthalimidoacetamidomethyl) - 5 - methyl 30 4H - 1,2,4 - triazol - 4 - yl7 - benzophenone is obtained as crystals melting at 219° to 231°C. 3841 Example 5.
To a solution of 5-chloro-2-/3-(2-chloroacetamidomethyl)-5-methyl-4H-l,2,4-triazol-4-yl7-benzophenone (0.4 g) in methanol (4 ml) and chloroform (8 ml), is added 40% aqueous dimethylamine (0.5 g) and the resultant mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated under reduced pressure, and the residue is shaken with methylene chloride (20 ml). The methylene chloride layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, whereby 5-chloro-2-/3-(2-dimethylaminoacetamidomethyl)-5-methyl-4H,l,2,4-triazol-4-yl7benzophenone is obtained as a colorless oil.
NMR (CDC13), fi, 2.10 (s., CH3) , 2.23 (s., N(CH3)2), 2.86 (s., COCH2N=), 4.36 (ABX, CH2NHC0).
Oxalate hydrate, m.p. 176.5-177.5°C. (recrystallized from ethanol).
Anal. Calcd. for C2iH22N5O2C1·(COOH)2.H2O: C, 53.13; H, 5.04; N, 13.46; Cl, 6.81. Found: C, 53.54: H, 5.07; N, 13.02; Cl, 6.83.
Examples 6 to 10.
Using the following starting material (V), the reaction is carried out as in Example 5, whereby the corresponding product (Id) is obtained. *3841 (V) R°-NH-R10 (IX) Cl Ex. No. V VIII Id R R1 R9 R10 m.p. (°C) or IR (cm-1) 6 Me Cl Me Me 148-148.5 7 Me H Et Et 60 (bubbling, citrate) 8 Me Cl Et Et 136.5-137.5 9 Me H Me H 187-188 (oxalate) 10 Me Cl Me H oil, 3320 (NH), 1670(CO) in CHClg Note: The abbreviations have the following significance: Me (methyl), Et (ethyl) H (hydrogen), Cl (chlorine), m.p. (melting point), IR (infra-red absorption spectrum).
Example 11. (1) A solution of 3-(Na-carbobenzoxyglycyl-glycylamino)-4-hydroxy-4-phenyl-6~chloro-3,4-dihydroquinazoline (1.5 g) in acetic acid (20 ml) is refluxed with heating for 2 hours. The reaction mixture is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate (30 ml). The ethyl acetate layer is washed with aqueous sodium bicarbonate and water in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate/ methanol to give 5-chloro»2-/3-(N-carbobenzoxyglycyl)aminomethyl - 4H — 1,2,4 - triazol - 4 - yiy - benzophenone as a colorless oil (0.515 g).
IR (CHClg), 3400, 3280, 1720, 1680 cm1.
NMR (CDClg), 6, 3.8 (broad, d., CH^NHCOO), 4.2 (broad, d., GH2~NH), 5.1 (s., (COOCHjCgHj). *3841 - 25 (2) To a solution of 5-chloro-2-/3-(N-carbobenzoxyglycyl)aminomethyl-4H-l,2,4-triazol-4-yI7-benzophenone (2.1 g) in anisole (4 ml), 30% hydrogen bromideacetic acid is added. The resultant mixture is stirred for 1 hour and mixed with ether. The precipitate is filtered, washed with ether and dissolved in methylene chloride (20 ml). The methylene chloride layer is washed with saturated aqueous sodium bicarbonate, water and saturated aqueous saline solution in order, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 5 chloro - 2 - (3 - glycylaminomethyl - 4H - 1,2,4 - triazol - 4 yl) - benzophenone as a colorless oil (0.39 g).
IR (CHC13,, 3330, 1670, 1595 cm-1.
NMR (CDC13), 6, 1.70 (broad m., NH2), 3.27 (broad m., C0CH2NH2), 4.47 (ABX, CH-jNH) , 8.Q7 )s., (-N=CIJ-N=) .
Oxalate, m.p. 140°C. (bubbling).
Anal. Calcd. for C18H16N5O2C1.|(COOH)2.|h20: C, 47.42; H, 4.17; N, 13.16; Cl, 6.67. Found; C, 47.54; H, 4.12; N,13.4O; Cl, 6.69.
Example 12. (1) A solution of 3-/Nw-(2-phthalimidoacetyl)-glycylamino7-4-hydroxy-4-phenyl-6*-chloro-3,4-dihydroquinazoline (0.7 g) in acetic acid (5 ml) is refluxed with heating for 2.5 hours. The reaction mixture is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium bicarbonate and water in that order, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate-methanol (20:1) to give 5 - chloro -2-/3(2 - phthalimidoacetamidomethyl) - 4H - 1,2,4 - triazol 43841 - 26 4-yl/benzophenone as crystals melting at 214 to 215°C.
IR (CHC13), 1780, 1720, 1690 cm-1. (2) Using 5 - chloro -2-/3- (2 - phthalimidoacetamidomethyl) - 4H - 1,2,4 - triazol-4-yl7-benzo5 phenone, the reaction is effected as in Example 1 (2), whereby 5 - chloro - 2 -(3 - glycylaminomethyl - 4H 1,2,4 — triazol - 4 - yl) - benzophenone is obtained as a colorless oil.
Example 13. (1) To a solution of 2',5 - dichloro -2-/3(2 - chloroacetamidomethyl) - 5 - methyl - 4H - 1,2,4 triazol - 4 - yl7 - benzophenone (1.533 g) in dimethylformamide (15 ml), sodium azide (0.228 g) is added portion wise, and the resultant mixture is stirred at room tem15 perature for 2.25 hours and allowed to stand overnight.
The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is shaken with chloroform. The organic layer is washed with water, dried and evaporated to remove the chloroform. The residue is washed with ether to give 2',5 - dichloro *2-/3 (2 - azidoacetamidomethyl) - 5 - methyl - 4H - 1,2,4 triazol - 4 -’yl7-benzophenone (1.45 g). The yield is 93.2%.
IR (Nujol, registered Trade Mark), 2100 cm~^ (Nj).
NMR (CDCL3), 6 2.23 (s., CHj) , 3.9 (S., CH^) , 4.20 (ABX, CIlgNIi) , 8.37 (2) To a suspension of the above product (0.382 g) in 95% ethanol (10 ml), a solution of stannous chloride dihydrate (0.29 g) in 2N sodium chloride (4.1 ml) is added dropwise at from 0° to 4 °C, The reaction mixture is shaken with chloroform. The organic layer is evaporated under reduced pressure to remove the chloroform. The residue is washed with ether to give 2',5-dichloro-2-(3glycylaminomethyl-5-methyl-4H-l,2,4-triazol-4-yl)-benzo43841 phenone (0.33 g). The yield is 91¾.
Example 14. (1) A mixture of 5-chloro-2-/3-(N-carbobenzoxyaminomethyl)-5-chloromethyl-4H-l,2,4-triazol-4-yl7-benzophenone (0.995 g) and 30% hydrogen bromide-acetic acid (2 ml) is stirred at room temperature for 1.25 hours, and the mixture is washed with ether (50 ml) twice. The thusobtained free base is mixed with benzene (10 ml), acetyl chloride (0.5 g) and dimethylformamide (6 ml), and the resultant mixture is stirred at room temperature for 2 hours, and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate, and the precipitated crystals are filtered and washed with ether and chloroform in order to give 5-chloro-2-(3-acetamidomethyl — 5 - chloromethyl - 4H - 1,2,4 - triazol - 4 yl) - benzophenone (O.fi g) as crystals melting at 193 to 199°C. (decomp.).
Anal. Calcd. for C1gH.LgN4Cl2O2.H2O: C, 54.16; H, 4.31; N, 13.30; Cl, 16.83. Found: C, 54.57; H, 4.05; N, 13.01; Cl, 17.00.
U.V. λ ε) 259 (4.110). in ax (2) To a suspension of the above product (0.54 g) in ethanol (10 ml), aqueous 40% dimethylamine (1.2 ml) is added,and the resultant mixture is stirred at room temperature for 1 hour. Then, dimethylformamide (6 ml) is added to the mixture, which is stirred for 3 hours and allowed to stand overnight. The reaction mixture is evaporated under reduced pressure, and the residue is crystallized from water. The precipitate is filtered and recrystallized from ethyl acetate to give 5 - chloro -2-(3- acetamidomethyl - 5 - dimethylaminoraethyl - 4H - 1,2,4 - triazol - 4 - yl) - benzophenone (0.35 g).
Anal. Calcd. for C21H22N5O2C1: C' 61-24; 5·38’ N' - 28 17.00; Cl, 8.61. Found: C, 60.80; H, 5.61; N, 16.55; Cl, 8.70. 0V λ JtoH (log e)f 257 (4-141).
Examples 15 to 16.
Using the following reagent (X), the reaction is effected as in Example 14, whereby the following product (le, If) are obtained: Ex, Ho. X Ie XI If R3 m.p. (°C, Rfi R7 m.p. (°C) 15 Pr 147 Me Me 144-146 16 p-Met-Ph 137-138 Me Me 164-165 Note: The abbreviations have the following significance: Met (methoxy), Ph (phenyl).
Example 17.
A solution of pyruvic acid (0.33 g) and thionyl chloride (0.27 g) in chloroform (2 ml) is refluxed for 1 hour. After cooling, the solution is mixed with 2’,5dichloro - 3 - (3 - aminomethyl - 5 - methyl - 4H 1,2,4 - triazol - 4 - yl) - benzophenone dihydrobromide (1.31 g), benzene (6 ml) and dimethylformamide (11 ml) at 0°C. The resultant mixture is stirred at room temperature for 3 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer .is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate to give 2',5 - dichloro - 3 - (3 pyruvamidomethyl - 5 - methyl - 4H - 1,2,4 - triazol 4 - yl) - benzophenone (0.7 g) as crystals melting at 178 to 180°C.
Anal. Calcd. for ^qH-^N^C^Oj: C, 55.70; H, 3.74; N, 12.99; Cl, 16.44. Found; C, 55.63; H, 3.79; N, 12.95; Cl, 16.30.
UV λ Et0H (log ε) 215, 253, 290 mp (4.533, 4.022, max 3.398). 438 41 Example 18. (1) 'To a solution of 2 - carbobenzoxyaminomethyl 3 - amino - 4 - hydroxy - 4 - (2 - chlorophenyl) - 6 chloro - 3,4 - dihydroquinazoline (2.36 g) in dimethylformamide (15 ml), acetyl chloride (0.79 g) is added, and the resultant mixture is stirred at room temperature for 5 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water and evaporated to give 2-carbobenzoxyaminomethyl - 3 - acetamido - 4 - hydroxy -4-(2chlorophenyl) - 6 - chloro - 3,4 - dihydroquinazoline (2.1 g). (2) A mixture of the above product (2.7 g) and 30% hydrogen bromide-acetic acid (6 ml) is stirred at room temperature for lj hours. The reaction mixture is washed with ether to give 2-aminomethyl-3-acetamido-4-bromo-4(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline dihydrobromide dihydrate (2.85 g) as crystals melting at 169 to 175°C. (decomp); Anal. Calcd. for C17H15N4Cl2BrO.2HBr.2H2O: C, 32.00; H, 3.32; N,8.78; Cl, 11.11; Br, 37.26. Found: C,32.28; H, 3.11; N, 8.99; Cl, 11.40; Br, 37.54. (3) _ To a solution of 2-phthalimidoacetyl chloride (1.65 g) in hexamethylphosphoric -triamide (20 ml), the above product (2.3 g) is added, and the resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with ether and neutralized with aqueous sodium bicarbonate. The precipitate is filtered and shaken with chloroform. The chloroform layer is evaporated to remove the chloroform, and the residue is treated with ether to give 2-(2-phthalimidoacetamidomethyl)-3-acetamido-4-hydroxy-4-(2-chlorophenyl)-6-chloroquinazoline (1.15 g). This substance is recrystallized from ethyl acetate to give crystals melting at 165 to 168°C. 3 8 41 - 31 Anal. Calcd. for C27H21N5°5C12: C, 57.26? H, 3.74; N, 12.36; Cl, 12.52. Found; C, 57.33; H, 4.01; N, 11.73; Cl, 12.15.
UV λ ^χΗ (1°9 e) 219' 286 mu (4.852, 4.141). (4) A solution of the above product (1.15 g) in acetic acid (11 ml) is refluxed for 2.5 hours, and the reaction mixture is evaporated to remove the acetic acid. The residue is shaken with chloroform. The chloroform layer is washed with aqueous sodium bicarbonate and water in that order, dried and evaporated to remove the chloroform. The residue is treated with ethyl acetate to give 21,5-dichloro-2-/3-(2-phthalimidoacetamidomethyl) - 5 methyl - 4H - 1,2,4 - triazol - 4 - yl7 “ benzophenone (0.4 g). (5) The above product is treated with hydrazine hydrate as in Example 1 (2), whereby 2',5 - dichloro 2-(3- glycylaminomethyl - 5 - methyl - 4H - 1,2,4triazol-4-yl)-benzophenone is obtained.
Example 19. (1) To a mixture of hexamethylphosphoric triamide (12 ml) and chloroacetyl chloride (0.452 g), 2-aminomethyl-3-acetamido-4-bromo-4~(2-chlorophenyl)-6-chloro3,4-dihydroquinazoline dihydrobromide dihydrate (1.276 g) is added,and the resultant mixture is stirred at room temperature for 5 hours. The reaction mixture is mixed with ether and washed with aqueous sodium bicarbonate and water in that order. The precipitate is dried to give 2(2-chloroacetamidomethyl)-3-acetamido-4-hydroxy-4-(2chlorophenyl)-6-chloro-3,4-dihydroquinazoline (0,63 g). This product (0.6 g) is dissolved in acetic acid (6 ml) to give a solution, which Is refluxed for 2 hours. The reaction mixture is evaporated under reduced pressure.
The residue is extracted with ethyl acetate. The organic layer is washed with aqueous sodium bicarbonate and water - 32 in that order, dried and evaporated to remove the ethyl acetate. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 2',5 dichloro -2-/3-(2- chloroacetamidomethyl) - 5 methyl - 4H - 1,2,4 - triazol-4-yl7-benzophenone (0.15 g). (2) A mixture of the above product (0.86 g) and 15% ammonia-methanol (15 ml) is allowed to stand at room temperature-for 3 days, and the reaction mixture is evaporated to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 21,5-dichloro-2-(3-glycylaminomethyl5-methyl - 4H - 1,2,4 - triazol - 4 - yl) - benzophenone (0.42 g).
Example 20. (1) To a solution of 2-carbobenzoxyaminomethyl-3amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.84 g) in dimethylformamide (100 ml), chloroacetyl chloride (8.48 g) is added, and the resultant mixture is stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The ethyl acetate layer is evaporated under reduced pressure to remove the solvent, and the residue is washed with ether to give 2-carbobenzoxyaminomethyl-3-(2-chloroacetamido) - 4 - hydroxy - 4-(2chlorophenyl) - 6 - chloro - 3,4 - dihydroquinazoline (18.9 g). This product is reerystallized from ethyl acetate to give crystals melting at 130 to 134°C.
Anal. Calcd. for C^j-Etj-jN^ClgO^: C, 54.81; H 3.86; N, 10.23; Cl, 19.41. Found: C, 54.78; H, 3.66; N, 10.09; Cl, 19.38.
UV λ Et°H (log ε) 247, 285 mp (3.919, 4.098). max - 33 (2) A solution of the above product (0.75 g) in acetic acid (7 ml) is refluxed for 1.5 hours and evaporated under reduced pressure to remove the acetic acid. The residue is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure. The residue is treated with ether to give 2',5dichloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl -4H1,2,4-triazol-4-yl)-benzophenone (0.65 g). This product is recrystallized from ethyl acetate to give crystals melting at 170 to 171°C.
Anal. Calcd. for C25H19N4C13O3: C, 56.68; H, 3.61; N, 10.57; Cl, 20.07. Found; C, 56.69; H, 3.76; N, 10.34; Cl, 20.14.
UV λ ®t0H (log ε) 255, 293 mp (3.984, 3.831). max (3) A solution of the above product (1.32 g) in 30% hydrogen bromide-acetic acid (2.5 ml) is stirred- at room temperature for 1 hour. The reaction mixture is washed with ether (50 ml) twice, and the residue is mixed with chloroacetyl chloride (0.8 g), benzene (15 ml) and dimethylformamide (8 ml). The resultant mixture is stirred at room temperature for 4 hours. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is dissolved in methanol (20 ml) to give a solution which solution is mixed with 1-methylpiperazino (1.76 g) and potassium iodide (0.145 g). The resultant mixture is stirred at room temperature for 1.5 hours, allowed to stand overnight and refluxed for 4 hours. The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is shaken with chloroform. The chloroform layer is washed with water, dried and evaporated under reduced pressure to 3 8 41 remove the chloroform, whereby 2',5-dichloro-2-/3-(2—γ— methylpiperazlnoacetamidomethyl) - 5 - γ - methylpiperazinomethyl - 4H - 1,2,4 - triazol - 4 - yl7 - benzophenone (1.5 g) is obtained as an oil.
NMR (CDClg), δ, 3.0 (s., COCHgN), 3.5 (s., CH2N=), 4.33 (ABX, CH2NH), 7.80 (m., NH). Ν' Example 21.
Using diethylamine in lieu of 1-methylpiperazine, the reaction is effected as in Example 20 (3), 2',5-dichloro-2/3-(2-diethylaminoacetamidomethyl)-5-diethylaminomethyl-4H-l,2,4-triazol-4-yl7-benzophenone is obtained as an oil. The yield is 88%.
N 1.0 (t., J=14, C0CH2N(CH2CH3)2, 2.97 (s., C0CH2NEt2), 3.5 3;2' Example 22. (1) To a solution of 2',5-dichloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl-4H-l,2,4-triazol-4-yl)benzophenone (1.32 g) in methanol (20 ml) and chloroform (20 ml), potassium iodide (0.4 g) and diethylamine (3 ml) are added, and the resultant mixture is refluxed for 5 hours. The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the ethyl acetate. The residue is treated with ether to give 2’,5-dichloro - 2 - (3 - carboben43841 - 35 zoxyaminomethyl - 5 - diethylaminomethyl - 4H - 1,2,4 triazol-4-yl)-benzophenone (1.1 g). The product is reerystallized from ether-ethyl acetate to give crystals melting at 89 to 94°C. (2) A mixture of the above product (1.41 g) and 30% hydrogen bromide-acetic acid (2.5 ml) is stirred at room temperature for 2 hours and washed with ether (50 ml) twice. The free base is mixed with benzene (15 ml), 2-phthalimidoacetyl chloride (1.12 g) and dimethylformamide (8 ml) in order, and the resultant mixture is stirred at room temperature for 2 hours and allowed to stand overnight. The reaction mixture is mixed with ethyl acetate, neutralized with aqueous sodium bicarbonate. The ethyl acetate layer is washed with water, dried and evaporated under reduced pressure to remove the solvent. The residue is treated with ether to give 21,5-dichloro-2-/312-phthalimidoacetamidomethyl) - 5 - diethylaminomethyl 411 - 1,2,4 - triazol - 4 - yi7-benzophenone (1.4 g). The product is reerystallized from ethanol to give crystals melting at 212 to 214°C.
UV λ Et0H (log e) 218.5, 294 mu (4.85, 3.954). max (3) A suspension of the above product (1.12 g) and hydrazine hydrate (0.234 g) in ethanol (10 ml) is refluxed for 25 minutes. The precipitate is filtered off, and the filtrate is evaporated under reduced pressure to remove the ethanol. The residue is extracted with ethyl acetate. The ethyl acetate layer is washed with aqueous sodium bicarbonate and water in order, dried, and evaporated under reduced pressure to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 2',5-dichloro-2-(3-glycylarninomethyl-5-diethylaminomethyl-4H-l,2,4-trlazol“4-yl)benzophenone (0.8 g) as an oil. - 36 NMR (CDC13), δ, 0.73 (t., J=15, CH2Cg3), 3.53 (s., CH2NEt2), 4.37 (ABX, NHCHj), 8.13 (br., NH2).
Example 2 3.
Using dimethylamine in lieu of diethylamine, the reaction is effected as in Example 22, whereby the following products are obtained: (1) 2',5 - dichloro - 2 - (3 - carbobenzoxyaminomethyl - 5 - dimethylaminomethyl - 4H - 1,2,4 - triazol 4 - yl) - benzophenone, m.p. 123-125°C. (recrystallized EtOH from ethyl acetate); UV λ (log e) 253, 291 mp max (4.01, 3.837). (2) 2',5 - dichloro -2-/3- (2 - phthalimidoacetamidomethyl) - 5 - dimethylaminomethyl - 4H - 1,2,4 triazol - 4 - yl/ - benzophenone, m.p. 226-227°C. (recrystallized from ethanol); (3) 2',5 - dichloro - 2 - (3 - glycylaminomethyl 5 - dimethylaminomethyl - 4H - 1,2,4-triazol-4-yl)-benzophenone, m.p. 179-183°C. (recrystallized from ethyl EtOH acetate); UV λ (log ε) 214,250, 290 mp (4.056, 3.984, luaX 3.438) .
Example 24. (1) To a suspension of sodium hydroxide (0.08 g) in dimethylformamide (8 ml), thiophenol (0.33 g) is added with ice-cooling, and the resultant mixture is stirred with ice-cooling for 5 minutes. 2',5-Dichloro-2-(3-σarbobenzoxyaminQmethy l-5-chloromethyl-4H-l , 2,4-triazol-4yl)-benzophenone (1.06 g) is added to the mixture, which is stirred at room temperature for 2.5 hours. The reaction mixture is shaken with ethyl acetate, and the ethyl - 37.. acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is washed with n-hexane to give a gelatinous product, which is mixed with 30% hydrogen bromide-acetic acid (2.4 ml). The mixture is stirred at room temperature for 2 hours and washed with ether. The resultant crystals are filtered, washed with ether (50 ml), and mixed with benzene (10 ml), 2-phthalimidoacetyl chloride (0.672 g), and dimethylformamide (7 ml) in order. The mixture is stirred at room temperature for 3 hours and shaken with ethyl acetate. The ethyl acetate layer is washed with aqueous sodium bicarbonate and water in order, dried, and evaporated under reduced pressure to remove the solvent, whereby 2',5dichloro-2-/3-(2-phthalimidoacetamidomethyl)-5-phenylthiomethyl-4H-l,2,4-triazol~4-yl/-benzophenone (1.05g) is obtained The product is reerystallized from ethanol to give crystals melting at 220 to 221°C.
EtOH OV λ (log ε) 219,290 mu (4.902, 3.702). max (2) A suspension of the above product (0.84 g) and hydrazine hydrate (0.196 g) in ethanol (9 ml) is refluxed for 30 minutes, and the precipitate is filtered off. The filtrate is evaporated under reduced pressure to remove the solvent, and the residue is extracted with ethyl acetate. The ethyl acetate layer is washed with aqueous sodium bicarbonate and water in that order, dried, and evaporated under reduced pressure to remove the solvent.
The residue is chromatographed on a column of silica gel, which is eluted with methanol to give 2',5-dichloro-2-(3glycylaminomethyl-5-phenylthiomethyl~4H-l,2,4-triazol-4yl)-benzophenone (0.55 g) as powder.
Anal. Calcd. for C25H21N5Ci2SO2.l/4 H20: C, 56.55? H, 4.08: N, 13.19; Cl, 13.35; S, 6.04 Found: C, 56.58? H,4.18; N, 12.84; Cl, 12.87?S,6 .06 . 3 8 41 EtOH UV λ (log ε) 253 mp (4.137). max Example 25.
Using propyl mercaptan in lieu of thiophenol, the reaction is effected as in Example 24, whereby the follow5 ing products are obtained; (1) 21,5-dichloro-2-/3-(2-phthalimidoacetamidomethyl)-5-propylthiomethyl-4H-l,2,4-triazol-4-yi7-benzophenone, m.p. 172-l84°C. (recrystallized from ethanol); Anal. Calcd. for C3OH25N5SC12C>4.1/2 H20: C, 57.05; H, 4.15; N, 11.09; Cl, 11.23; S, 5.08. Found: C, 57.21; H, 4.39; N, 10.72; Cl, 11.54; S, 5.17. (2) 2',5-diohloro-2-(3-glycylaminomethyl-5-propylthiomethyl-4H-l,2,4-triazol-4-yl)-benzophenone oxalate dihydrate, m.p. 109-113°C. (recrystallized from dilute acetonitrile); Anal. Calcd. for C22H23NgSCl2O2.
(COOH)2.2H2O: C, 46.61; H, 4.73; N, 11.32; Cl, 11.46; S, 5.18. Found: C, 46.85; H, 4.39; N, 10.96; Cl, 11.33; S, 5.74.
Example 26.
Using pyrrolidine in lieu of diethylamine, the reaction is effected as in Example 22, whereby the following products are obtained: (1) 2',5':diohloro-2-(3-carbobenzoxyaminomefchyl“5pyrrolidinomethyl-4H-l,2,4-yl)-benzophenone, m.p. 14325 145°C. (recrystallized from ethyl acetate); yield, 97.4%. (2) 2',5-dichloro-2-/3-(2-phthalimidoacetamidomethyl)-5-pyrrolidinomethyl-4H-l,2,4-triazol-4-yl7-benzophenone, m.p. about 193°C.; yield, 90.8%. (3) 2',5-dichloro-2-(3-glycylaminomethyl-5-pyrro30 lidinomethyl-4H-l,2,4-triazol-4-yl)-benzophenone, m.p. 181-183°C. (recrystallized from ethanol); Anal. Calcd. for C23H24N6C12°2: C' 56<68; H' 4·96'- N' 17·24? Cl, 14.55. Found: C, 56.66; H, 5.06; N, 17.09; Cl, 14.62; yield, 75%. - 39 Example 27.
Using 5-chloro-2-(3-carbobenzoxyaminomethyl-5chloromethyl-4H-l,2,4-triazol-4-yl)-benzophenone and pyrrolidine, the reaction is effected as in Example 22, whereby the following products are obtained: (1) 5-chloro-2-(3-carbobenzoxyaminomethyl-5pyrrolidinomethyl-4H-l,2,4-triazol-4-yl)-benzophenone, m.p. 174.5-175.5°C. (recrystallized from methylene chloride/95% ethanol); yield, 92.1%. (2) 5-chloro-2-/3-(2-phthalimidoacetamidomethyl)5-pyrrolidinomethyl-4H-l,2,4-triazol-4-yl7-benzophenone, m.p. 245»247°C. (decomp.) (recrystallized from methylene chloride/95% ethanol); yield, 68.7%. (3) 5-chloro-2-(3-glycylaminomethyl-5-pyrrolidinomethyi-4H-l,2,4-triazol-4-yl)-benzophenone, m.p. 182-183°C. (recrystallized from isopropanol); Anal. Calcd. for C23H25°2N6C1: c' 6O·99? H' 5.56; N, 18.56; Cl, 7.83. Found: C, 61.08; H, 5.61; N, 18.56; Cl, 8.13; yield, 72.3%.
Example 28. (1, To a solution of sodium iodide (1.51 g) in acetonitrile (30ml), 5-chloro-2-(3-carbobenzoxyaminomethyl5-chloromethyl-4H-l,2,4-triazol-4-yl)-benzophenone (5.0 g) is added, and the resultant mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into water (100 ml) and shaken with benzene (50 ml) twice. The benzene layer is washed with water (100 ml) twice, dried over magnesium sulfate and evaporated under reduced pressure to remove the benzene. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give 5-chloro-2-(3-carbobenzoxyaminomethyl-5-iodomethyl-4H-l,2,4-triazol-4-yl)-benzophenone (3,61 g). The product is recrystallized from methylene chloride/ether to give crystals melting at 133 to 134°C. (decomp.). 438 640 (2) to a solution of thallous ethoxide (1.53 g) in dry benzene (60 ml), propargyl alcohol (0.354 ml) is added, and the resultant mixture is stirred at room temperature for 1 hour. The mixture is evaporated under reduced pressure to give thallium propargyloxide in a form of white crystals, which is dissolved in dry acetonitrile (60 ml). The above product (3.00 g) is added to the solution, which is stirred at room temperature for 42 hours. The precipitate is filtered off, and the filtrate is evaporated under reduced pressure to remove the solvent. The residue is dissolved in benzene (50 ml), washed with water thrice, dried over magnesium sulfate and evaporated under reduced pressure to remove the benzene. The residue is chromatographed on a column of silica gel, which is eluted with 10 to 50% ethyl acetate/methylene chloride to give 5-chloro-2-(3-carbobenzoxyaminomethyl-5-propargyloxymethyl-4H-l,2,4-triazol-4-yl)-benzophenone (817 mg) as an oil. (3) A mixture of the above product (817 mg) and 27.5% hydrogen bromide/acetic acid (3 ml) is stirred at room temperature for 1.5 hours. The resultant solution is mixed with dry ether (30 ml) to give a precipitate. The precipitate is washed with dry ether (20 ml) twice to give 5-chloro-2-(3-aminomethyl-5-propargyloxymethyl-4H1,2,4-triazol-4-yl)-benzophenone hydrobromide. To a suspension of this hydrobromide in dry benzene (20 ml), 2phthalimidoacetyl chloride (1.6 g) is added at room temperature . The resultant mixture is mixed with dry dimethy If ormamide (10 ml) and stirred at room temperature for 3 hours. The reaction mixture is poured into saturated aqueous sodium bicarbonate (50 ml)/water (50 ml) and stirred with ice-cooling for 30 minutes. The precipitate is filtered, washed with water and ether in order and dissolved in methylene chloride (about 50 ml). The organic layer is dried over magnesium sulfate and evaporated to - 41 remove the solvent. The residue is recrystallized from methylene chloride/ethanol to give 5-chloro-2-/J-(2~ phthallmidoacetamidomethyl)-5-propargyloxymethyl-4H1.2.4- triazol-4-y37'“benzophenone (682 mg) as crystals melting at 245 to 246°C. (decomp). (4) A solution of the above product (600 mg) and hydrazine hydrate (1.0 ml) in 95% ethanol (10 ml) is refluxed for 2 hours. The precipitate is filtered off, and the filtrate is evaporated under reduced pressure to io remove the solvent. The residue is extracted with methylene chloride, and the methylene chloride layer is shaken with 2N hydrochloric acid (50 ml) twice. The hydrochloric acid layer is made alkaline with aqueous ammonia and shaken with methylene chloride thrice. The methylene chlo15 ride layer is dried over potassium carbonate to give 5chloro-2-(3-glycylaminomethyl-5-propargyloxymethyl-4H1.2.4- triazol-4-yl)-benzophenone hydrate as a colorless oil. The product is crystallized from isopropanol/ether to give crystals melting at 93 to 95°C.
Anal. Calcd. for C22H2o03N5C1.H20: C, 57.96? H, 4.87; N, 15.36; Cl, 7.78. Found: C, 58.32; H, 4.88; N, 15.44; Cl, 8.15.
Example 29.
Using 5-chloro-21-fluoro-2-(3-carbobenzoxyamino25 methyl-5-chloromethyl-4H-l,2,4-triazol-4-yl)-benzophenone (m.p. 148-149°C.) and morpholine, the reaction is effected as in Example 22, whereby the following products are obtained: (1) 5 - chloro - 2' - fluoro -2-(3- carboben30 zoxyaminomethyl - 5 - morpholinomethyl-4H-i,2,4-triazol-4-yl)-benzophenone, m.p. 182-184.5°C. (recrystallized from ethyl acetate). (2) 5 - chloro - 2' - fluoro -2-/3- (2 phthalimidoacetamidomethyl) - 5 - morpholinomethyl-4H35 l,2,4-triazol-4-yl7-benzophenone, m.p. 269-27O°C. - 42 (recrystallized from methylene chloride/methanol). (3) 5 - chloro - 2' - fluoro -2-(3- glycylaminomethyl - 5 - morpholinomethyl-4H-l,2,4-triazol-4“ yl)-benzophenone, amorphous form.
Example 30. (1) A solution of 2',5 - dichloro -2-(3glycylaminomethyl - 5 - methyl - 4H - l,2,4-triazol-4yl)-benzophenone (1.18 g), phthalylglycine (1.00 g) and dicyclohexylcarbodiimide (1.05 g) in dimethylformamide (23 ml) is stirred at room temperature for 3 hours, and the reaction mixture is allowed to stand overnight. The precipitated urea is filtered off. The filtrate is mixed with excess of aqueous sodium carbonate, and the precipitate is separated by decantation. The residue is dissolved iri methylene chloride, washed with water, dried and concentrated. Crude product is columned on silica gel (ethyl acetate:methano1=1:4), and recrystallized from chloroform-methanol to give 2 *,5-dichloro-2-£3-(Na-2phthalimidoacetylglycylaminomethyl)-5-methyl-4H-l,2,4triazol-4-yl7_benzophenone (1.35 g) as crystals melting at 269 to 27O°C. (2) A suspension of the above product (1.10 g) and hydrazine hydrate (0.25 ml) in ethanol (10 ml) is stirred at reflux temperature for 2.5 hours. The reaction mixture is allowed to cool to room temperature, and the precipitated phthalylhydrazide is filtered off. The filtrate is concentrated under reduced pressure, and the residue is extracted with ethyl acetate. The ethyl acetate layer is washed with aqueous sodium bicarbonate, dried, and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from acetate/n-hexane to give 2,,5-dichloro-2-/3-(Na-glycyl-glycylaminomethyl)5-methyl-4H-l,2,4-triazol-4-yl/-benzophenone (210 mg) as hygroscopic crystals melting at 60 to 65°C. 3 8 41 - 43 Example 31. (1) A solution of 2',5-dichloro-2-(3-glycylaminomethyl-5-methyl-4H-l,2,4-triazol-4-yl)-benzophenone (1.08 g) and phthalyl-L-phenylalanine (800 mg) in dimethylformamide (13 ml) is mixed with a solution of dicyclohexylcarbodiimide (450 mg) in dimethylformamide (3 ml) at room temperature. The resultant mixture is stirred at room temperature for 4 hours and allowed to stand overnight. The reaction mixture is treated as in Example 30 (1), whereby, 2',5-dichloro-2-{3-/?Ta-(L-2-benzyl-2phthalimidoacetyl) -glycylaminomethyl7-5-methyl->-4H-l,2,4triazol-4-yl)-benzophenone (1.12 g) is obtained as crystals melting at 138 to 140°C (reerystallized from methylene chloride/n-hexane). (2) The above product is treated with hydrazine hydrate as in Example 30 (2), whereby 2',5-dichloro,r2-/3-(Na-Lphenylalanyl-glycylaminomethyl)-5-methyl-4H-l,2,4-triazol-4-yl/’-benzophenone is obtained as hygroscopic crystals melting at 65 to 70°C.
The dihydrochloride hydrate: m.p. 187-19O°C. (recrystallized from ethanol-ether).
Example 32. (1) A suspension of 5-chloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl-4H-l,2,4-triazol-4-yl)-benzophenone (1.0 g) and silver acetate (0.5 g) in acetonitrile (20 ml) is refluxed for 2 hours. The precipitated silver chloride is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, dried and evaporated under reduced pressure to give a pale yellow oil. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetate to give 5-chloro-2-(3-carbobenzoxyaminomethyl-5-acetoxymethyl-4H1,2,4-triazol-4-yl)-benzophenone (0.65 g) as a colorless oil.
, IR (film), 3280 (broad), 1745, 1715, 1660, 1595 cm J·' (2) A mixture of the above product (650 mg) and 30% hydrogen bromide/acetic acid (2 ml) is stirred at room temperature for 1 hour. The resultant mixture is mixed with excess of ether, and the precipitate is washed with ether thrice by decantation to give 5-chloro-2-(3aminomethyl-5'-acetoxymethyl-4H-l,2,4-triazol-4-yl)-benzophenone hydrobromide. To a suspension of the above product and 2-phthalimidoacetyl chloride (1.0 g) in benzene (10 ml), dimethylformamide (5 ml) is added at room temperature, and the resultant mixture is stirred for 3 hours. The reaction mixture is mixed with aqueous saturated sodium bicarbonate and extracted with methylene chloride. The ethyl acetate layer is washed thoroughly with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residual oil is triturated with ethyl acetate to give crystalline 5-chloro-2-/3-(2-phthalimidoacetamidomethyl)5-acetoxymethyl-4H - 1,2,4-triazol-4-yl7-benzophenone (700 mg). The product is recrystallized from ethanol to give crystals melting at 225 to 228°C. (3) A suspension of the above product (522 mg) and 100% hydrazine hydrate (45 mg) in ethanol (20 ml) is refluxed for 2 hours. The resultant mixture is evaporated under reduced pressure, and the residue is partitioned between methylene chloride and aqueous saturated sodium carbonate. The methylene chloride layer is separated, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with ethyl acetatemethanol (v/v=4/l) to give 5-chloro-2-(3-glycylaminomethyl-5-acetoxymethyl-4H-l,2,4-triazol-4-yl)-benzophenone. %H20 (120 mg). The product is recrystallized from ethyl acetate to give crystals melting at 123°C. (contracted). - 45 IR (Nujol), 3220, 1745, 1655 (broad), 1590 cm-1.
Anal.Calcd. for C^H^NgCl.^O: C, 55.94; II, 4.69; N, 15.53. Found: C, 55.76; H, 4.52; N, 15.71.
Example 33. (1) To a solution of L-2-phthalimido-3-phenylpropionyl chloride (2.7 g) in benzene (26 ml) and dimethylformamide (13ml), 2',5-dichloro-2-(3-aminomethyl-5methyl-4H-l,2,4-triazol-4-yl)-benzophenone dihydrobromide (3 g) is added at 0°C. in an ice bath with stirring. The reaction mixture is gradually warmed to room temperature and left on standing overnight. Aqueous saturated sodium bicarbonate is poured into the mixture, and the benzene layer is separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the solvent, whereby 2',5 - dichloro -2-/3- (L — 2 — benzyl - 2 phthalimidoacetamidomethyl) - 5 - methyl-4H~l,2,4-triazol4-yl/-benzophenone (2.5 g) is obtained as crystals melting at 238 to 24O°C.
IR (Nujol), 3190, 1780, 1715, 1680 (broad), 1590 cm 1. (2) A suspension of the above product (2.4 g) and 100% hydrazine hydrate (0.2 g) in ethanol (20 ml) is refluxed for 1 hour. The precipitate is filtered off, and filtrate is evaporated under reduced pressure. The residue is partitioned between methylene chloride and aqueous saturated sodium bicarbonate. The methylene chloride layer is dried over anhydrous sodium sulfate and evaporated. The viscous oil is treated with oxalic acid (400 mg) in ethyl acetate (15 ml) to give white precipitates. The precipitates are washed with ethyl acetate several times to give 2,5-dichloro-2-(3-L-phenylalanylamlnomethyl - 5 - methyl - 4H - 1,2,4 - triazol - 4 - yl) - benzophenone oxalate hydrate (1.9 g). Anal. Calcd. for C28H27N5O7C12: C, 54.55, II, 4.41; N, 11.36; Cl. 11.50 Found: C, 54.13? H, 4.34? N, 11.06; Cl, 11.31. £ 3 8 <2 i /q7D+29° (EtOH).
Examples 34-37 Using acyl chloride (X), the reaction is effected as in Example 33 (1), whereby the corresponding products (le) are obtained EX. No. X le R3 m.p. (°C) IR (cnT1) 34 Me 172-173 3220, 3180, 3020, 1670, 1650, 1590 (Nujol) 35 Et 165-167 3240, 1685, 1665, 1590 (Nujol) 35 Pr 125-127 3220, 1680, 1660, 1590 (Nujol) 37 i-Pr 176-178 3235, 3030, 1675, 1645, 1590 (Nujol) Example 38.
Using 5 - chloro - 2 - (3 - carbobenzoxyaminomethyl - 5 - chloromethyl - 4H - l,2,4-triazol-4-yl)benzophenone and dimethylamine, the reaction is effected as In Example 22, whereby the following products are obtained. (1) 5 - chloro -2-(3- carbobenzoxyaminomethyl - 5 - dimethylaminomethyl - 4H - 1,2,4 triazol - 4 - yl) - benzophenone, m.p. 123-125°C.; IR(CHC13), 3210, 1708, 1655 cm1. (2) 5 - chloro - 2 - /3” -(2- phthalimidoacetamidomethyl) - 5 - dimethylaminomethyl - 4H - 1,2,4 triazol - 4 - - benzophenone, m.p. 229-231°C. (recrystallized from ethanol); IR (Nujol), 3200, 1770, 1715, 1680, 1658 cm1. (3) 5 - chloro - 2 - (3 glycylaminomethyl - 5 - dimethylaminomethyl - 4H - 1,2,4 - triazol - 4 - yl) - benzophenone, m.p. 188-19O°C., IR (Nujol), 3340, 3200, 1680 cm1.
Anal. Calcd. for C2J.H23N6°2C1: C, 59.08; H, 5.48; N, 19.69; Cl, 8.30. Found: C, 59,21; H, 5.25; N, 19.56; Cl, 8.43.
Example 39.
Using 5 » chloro -2-(3- carbobenzoxyaminomethyl 5 - chloromethyl - 4H - l,2,4-triazol-4-yl)-benzophenone and piperidine, the reaction is effected as in Example 22, whereby the following products are obtained. (1) 5 - chloro - 2 - (3 - carbobenzoxyaminomethyl 5 - piperidinomethyl - 4H - 1,2,4 - triazol - 4 - yl) benzophenone, m.p. 169-171°C. (recrystallized from ethyl acetate); IR (Nujol), 3180, 1705 1670 cm 1. (2) 5 - chloro -2-/3- phthalimidoacetamidomethyl - 5 - piperidinomethyl-4H-l,2,4-triazol-4-yl743841 - 48 benzophenone, m.p. 246-248°c. (recrystallized from ethanol); IR (Nujol), 3220, 1765, 1715, 1695, 1660 cm1. (3) 5 - chloro - 2 - (3 - glycylaminomethyl - 5 piperidinomethyl - 4H - 1,2,4 - triazol-4-yl)-benzo5 phenone, %C2H5OCOCH3, m.p. 288°C.; IR (Nujol), 3220, 1730, 1680, 1660, 1590 cm-1.
Anal. Calcd. for C2gH31NgO3Cl: C, 61.11, H, 6.11; N, 16.44; Cl, 6.94. Found: C, 60.88; H, 6.23; N, 16.30; Cl, 7.14.
Example 40.
Using 5 - chloro -2-(3- carbobenzoxyaminomethyl - 5 - chloromethyl - 4H - 1,2,4-triazol-4-yl)-benzophenone and morpholine, the reaction is effected as in Example 22, whereby the following products are obtained. (1) 5 - chloro - 2 - (3 - carbobenzoxyaminomethyl - 5 - morpholinomethyl - 4H - 1,2,4-triazol-4-yl)-benzophenone, m.p. 175-176°C. (recrystallized from ethyl acetate) ; IR (Nujol), 3220, 1710, 1670 cm-1. (2) 5 - chloro -2-/3- (2 - phthalimidoacet20 amidomethyl) - 5 - morpholinomethyl - 4H - 1,2,4 - triazol - 4 - yl7 - benzophenone, m.p. 248-25O°C. (recrystallized from ethanol); IR (Nujol), 3200, 1765, 1710, 1695, 1660 cm 1. (3) 5 - chloro - 2 - (3 - glycylaminomethyl - 5 25 morpholinomethyl - 4H - 1,2,4-triazol-4-yl)-benzophenone, oil; IR (CHC13), 3200, 1660 (broad), 1590 cm-1, NMR (CDC13), δ, 2.0-2.9 (4H, m.), 3.1-3.9 (4H, m.), 3.4 (2H, s.), 4.37 (2H, ABX), 8.07 (IH, br. m.).
Example 41.
Using 5 - chloro - 2 - (3 - carbobertzoxy - aminomethyl — 5 — chloromethyl - 4H - 1,2,4 - triazol - 4 yl) - benzophenone and dimethylamine, the reaction is effected as in Example 22, whereby the following products - 49 are obtained. (1) 5 - chloro -2-(3- carbobenzoxyaminomethyl - 5 - dimethylaminomethyl-4H-l,2,4-triazol-4-yl)-benzophenone, m.p. 123-125°C. (2) 5 - chloro - 2- /3 - (L - 2 benzyl - 2 - phthalimidoacetamidomethyl)-5-dimethylaminomethyl - 4H > 1,2,4 - triazol - 4 - yl7 - benzophenone, oil; XR (CHC13), 3300, 3200, 1780, 1715, 1670 cm1. (3) 5 - chloro - 2 - (3 - L - phenylalanylaminomethyi - 5 - dimethylaminomethyl - 4H~l,2,4-triazol-4yl)-benzophenone, oil; /«7^ -4.0° (EtOH); IR (CHC13), 3340, 1665 (broad), 1595 cm1, NMR (CDCI3), S, 1.75 (6H, s.), 2.42 (2H, br. m.), 2.5-3.8 (3H, m.), 4.43 (2H, collapsed ABX), 8.25 (IH, br. m.).
Anal. Calcd. for CjgHggNgOjCl: C, 65.05; H, 5.65; N, 16.25; Cl, 6.86. Found: C, 64.81; H, 5.56; N, 16.00; Cl, 6.95.
Example 42. (1) To a solution of 2',5-dichloro-2-(3-aminomethyl-5-methyl-2H-l,2,4-triazol-4-yl)-benzophenone dihydrobromide (2.56 g) in dimethylformamide (20 ml), pyridine (0.8 ml) is added under cooling at -10°C., and the resultant mixture is stirred at -10 to -13°C. for 2 minutes. 2-(2-Phthalimidoacetamido)acetyl chloride (4.0 g) is added portionwise thereto, and the mixture is stirred at -10°C. for 3 hours. The reaction mixture is mixed with excess of aqueous sodium bicarbonate, and the precipitated product is separated by filtration and dissolved in methylene chloride (100 ml). The organic layer is washed with water, dried, and evaporated' to remove the methylene chloride. The residue is recrystallized from methanol/chloroform to give 2',5 - dichloro -2-/3(N01 - phthalyl - glycyl - glycylaminomethyl) - 5 - methyl - 4H - 1,2,4 - triazol - 4 - yl7 - benzophenone (2.0 g) 3 8 41 - 50 as crystals melting at 269 to 27O°C. (2) The above product is hydrazinolyzed as in Example 30 (2), whereby 2',5 - dichloro -2-/5- (Na glycyl - glycylaminomethyl) - 5 - methyl -4H- 1,2,45 triazol-4-y!7-benzophenone is obtained as crystals melting at 60 to 65°C.
Example 43. 21,5-Dichloro-2-(3-glycylaminomethyl-5-dimethylaminomethyl-4H-l,2,4-triazol-4-yl)-benzophenone ....... 2.. Og Wheat starch ..._____ _ - . — - ----2.7$. Og These are admixed and packed in hard gelatin capsules in a conventional manner, whereby 2,000 capsules are prepared. Each capsule contains 1 mg of 21,5-dichloro-2-(3 15 glycylaminomethyl - 5 - dimethylaminomethyl - 4H - 1,2,4 triazol - 4 - yl) - benzophenone as an active ingredient (weight of contents: 140 mg).
In so far as the present invention includes a method of inducing an anxiolytic, sedative, hypnotic, anticon20 vulsant, muscle relaxant or antidepressant effect in an animal, and a method of promoting growth in an animal, as defined in the appended claims, it will be clearly understood that no claim is made herein to any of these methods when used for the prevention or cure of disease in a human being.

Claims (55)

1. wherein R represents hydrogen, c i _c g alkyl, C^-Cg haloalkyl, the group -(CH 2 > -X-R 5 or the group —Wn-A c R being hydrogen, C^-Cg alkyl, C 2 ~Cg alkenyl, C 2 -C g alkynyl, Cg-C 10 aryl or C 2 ~ C 8 ac - 1 ' x being sulfur or oxygen, n being 0, 1, 2 or 3 and R® and R^ each indepen 6 I 10 dently being hydrogen or alkyl, or the group R -N*R? being pyrrolidino, piperidino, morpholino or γ-methyl1 2 piperazino? R represents hydrogen or halogen; R repre3 sents halogen, nitro or trifluoromethyl; R represents Cj-Cg alkyl, C^-Cg haloalkyl, Cj-Cg azido-alkyl, Cg-C 1Q 15 aryl, C 2 -Cg acyl or the group - 52 43341 R 8 —CH—Ν ,10 ρ R being hydrogen, C.-C, alkyl, or C_-C. n aralkyl, 9 χ ° τη* xu R being hydrogen or C^-Cg alkyl, R being hydrogen, Cj^-Cg alkyl, Cy-C 1Q aralkyl, or £ 2 ~ C 11 a ' am:i - n0 ” ac y 1 » or 9 ' 10 the group R -N-R being phthalimido, pyrrolidino, piperidino, morpholino or γ-methylpiperazino; and represents hydrogen, C^-Cg alkyl or C?-C lo aralkyl.
2. A compound of the formula: 12 3 wherein R , R and R are as defined in claim 1 and R g represents the group -(CH 2 ) n -X-R or the group - CCH 2>4 3 8 41 - 53 5 R being C^xCg alkyl, C 2 ~Cg alkenyl, a lkynyl Cg-C 30 aryl or C 2 -Cg acyl, and X, n, R® and R? are as defined in claim 1.
3. A compound of the formula: 1 2 wherein R and R are as defined in claim 1, R represents 3 hydrogen, C^Cg alkyl or C^-Cg halo-alkyl; R represents C^-Cg alkyl, C^-Cg halo-alkyl, C-pCg azido-alkyl, Οθ “Cj_ 0 aryl, C 2 ~Cg acyl or the group λ 9 R being hydrogen, C^-Οθ alkyl, or Cy-C^ 0 aralkyl, R being hydrogen or C^-Cg alkyl, and R^* 3 being C^-Cg alkyl, 9 I Cy-C^Q aralkyl or C 2 -C ll a ~ amino “ ac y 1 » or the group R -N15 R 9 10 being phthalimido, pyrrolidino, piperidino, morpholino or γ-methylpiperazino.
4. A compound as claimed in claim 1, wherein R is hydrogen, or σ χ _ 6 alkyl and R 3 represents the group 4 3 8 41 - 54 R 4 * * * 8 —CH—N \1O provided that R 10 * * * * 15 cannot be α-amino-acyl and the 9 I 10 group R -N-R cannot be γ-methylpiperazino.
5. A compound as claimed in claim 1, wherein R □ 5 represents hydrogen or alkyl, R represents 4 8 R and R each independently represents hydrogen, C. , 10 J-” 3 alkyl or C 7 _g phenylalkyl, R represents hydrogen, C l -C 3 al kyl, phenylalkyl, or C 2 ~C 7 a-aminpacyl, R 9 Q l IQ 10 represents hydrogen or C^-C 3 alkyl, or R -N-R represents pyrrolidino, piperidino, 4-hydroxypiperidino, or morpholino.
6. A compound as claimed in claim 5, wherein R is 4 8 hydrogen or methyl, R and R each independently repre15 sents hydrogen or C^-C 3 alkyl, R 10 represents hydrogen C l -C 3 or C 2 -C 7 α-3ΐη ί ηο3ι:: Υΐζ and represents halogen or nitro.
7. A compound as claimed in claim 1 and specifically referred to hereinbefore.
8. A pharmaceutically acceptable acid addition salt of a compound as claimed in any one of claims 1 to
7. 4384 - 55 9. A process for preparing a compound of the formula: N-N p 4 R R I I CH-NH-COCHNH(la) - ΟΟwherein R, R 1 , R 3 , R^ and R® are each as defined in claim 5 1, which process comprises (a) reducing an azido of formula (Ic) either with a reducing agent or by hydrogenation in the presence of a catalyst in an inert solvent; or (b) treating a halogeno derivative of formula (VIII) with ammonia or hexamethylenetetramine in an inert sol10 vent; or (c) hydrazinolyzing a phthalyl derivative of formula (IV) in an inert solvent: 43 8 4 1 - 56
10. A process as claimed in claim 9, which process comprises reacting a halogeno derivative of formula (VIII), wherein R is as defined in claim 4, with ammonia in an inert solvent. 5
11. A process as claimed in claim 9, which process comprises hydrazinolyzing a phthalyl derivative of formula (IV), wherein R is as defined in claim 4, in an inert solvent.
12. A process as claimed in claim 9, wherein the 10 reducing agent in process (a) is stannous chloride in sodium hydroxide or zinc dust.
13. A process as claimed in claim 9, wherein the hydrogenation catalyst in process (a) is Raney nickel, palladium carbon or platinum oxide.
14. A process as claimed in claim 9 or claim 10, wherein the halogeno derivative of formula (VIII) has been prepared by reacting a compound of the formula: with a reactive derivative of an α-halogeno-acetic acid. 20
15. A process as claimed in claim 9 or claim 11, wherein the phthalyl derivative of formula (IV) has been prepared either (a) by treating a quinazoline derivative of formula (II) or formula (III) as defined in the fore4 3 8 41 - 57 going reaction scheme for Route A with a weak acid, or (b) by reacting a compound of formula (V) as defined in claim 14 with a reactive derivative of a phthalyl-aamino acid. 5
16. A process as claimed in claim 15, wherein the weak acid is acetic acid, monochloroacetic acid, propionic acid, benzoic acid or p-toluenesulfonic acid.
17. A process as claimed in claim 15 or claim 16, wherein an excess of the weak acid is employed in the 10 absence of a solvent and at room temperature or with warming.
18. A process as claimed in any one of claims 15 to 17, wherein the derivative of formula (II) or formula (III) has been prepared substantially as described in the 15 foregoing reaction scheme from an aminobenzophenone derivative of formula (XII) or a quinazoline derivative of formula (XV), respectively, as defined in said scheme.
19. A process for preparing a compound of the formula: wherein R, R 1 , R 2 , R 4 and R 8 are each as defined in claim 1, which process comprises treating a halogeno derivative of formula (VIII) as defined in claim 9 with an alkali metal azide. 43 84
20. A process as claimed in claim 19, wherein the halogeno derivative of formula (VIII) has been prepared by a reaction as defined in claim 14.
21. A process as claimed in any one of claims 9, 5 12 or 13, wherein the compound of formula (Ic) has been prepared by a process as claimed in claim 19 or claim 20.
22. A process for preparing a compound of the formula: J[_L -CO r 8 rs: ΝΗ-ΟΟ 1 \ (Id) 10 wherein R, R^, R 3 , r\ R 8 , R 8 and R^ 0 are each as defined in claim 1, which process comprises reacting a compound of the formula: (VIII) - 59 4 2 3 41 wherein hal represents halogen, with a compound of the formula:
9. In R-NH-R (IX) in an inert solvent. 5 23. A process as claimed in claim 22, wherein R, R 10 and the group of R 9 -N-R 10 are as defined in claim 4.
24. A process as claimed in claim 22 or claim 23, wherein the compound of formula (VIII) has been prepared by a reaction as defined in claim 34,
10. 25. A process as claimed in any one of claims 22 to 24, wherein the compound of formula (IX) is reacted with the compound of formula (VIII) in an inert solvent at room temperature or with heating.
26. A process as claimed in claim 22, or in claim 11. 15 24 or claim 25 except when directly or indirectly dependent upon claim 23, wherein the compound of formula (IX) is methylamine, dimethylamine, diethylamine, pyrrolidone, morpholine, piperidine or γ-methylpiperazine.
27. A process for preparing a compound of the 20 formula: - 60 wherein R, R 1 , R 2 , R 4 and R 8 are each as defined in claim 1, and R 11 represents hydrogen, C^-Cg alkyl or C^-C^g aralkyl, which process comprises (a) condensing a compound of the formula: with a phthalyl derivative of an α-amino acid or a reactive derivative thereof and hydrazinolyzing the resultant phth-alyl product in an inert solvent; or (b) condensing a compound of the formula: with a protected peptide or a reactive derivative thereof and subjecting the resultant protected product to deprotection .
28. A process as claimed in claim 27, wherein the condensation of process (a) is effected in a solvent in the presence of a condensing agent.
29. A process as claimed in claim 27 or claim 28, 5 wherein the α-amino acid is glycine, phenylalanine, alanine or leucine.
30. A process as claimed in any one of claims 27 to 29, wherein the reactive derivative of the a-amino acid is a chloride or ester thereof. 10
31. A process as claimed in any one of claims 27 to 30, wherein the condensing agent is dicyclohexylcarbodiimide.
32. A process as claimed in claim 27, wherein the protected peptide of process (b) is phthalyl-glycyl15 glycine.
33. A process as claimed in claim 27 or claim 32, wherein deprotection in process (b) is achieved by hydrazinolysis in an inert solvent.
34. A process as claimed in any one of claims 27 to 12. 20 31, wherein the compound of formula (Ia) has been prepared by a process as claimed in any one of claims 9 to 18.
35. A process for preparing a compound of the formula: wherein R, R 3- , R 3 and R^ are each as defined in claim 1 3 and R represents C^-Cg alkyl, C^-Cg halo-alkyl, C 1 ~Cg azido-alkyl, Cg-C^ Q aryl or C 2 ~Cg acyl, which process comprises reacting a compound of the formula; with a compound of the formula; A— CO-R 3 (X) wherein A represents a reactive group, in an inert solvent.
36. A process as claimed in claim 35, wherein the 10 compound of formula (X) is selected from acetyl chloride, acetic anhydride, propionyl chloride, butyryl bromide, isobutyryl chloride, benzoyl chloride and pyruvoyl chloride .
37. A process for preparing a compound of the 15 formula: - 63 43841 wherein R , R 2 , R 4 , R®, R 7 and n are each as defined in 3 claim 1 and R represents C^-Cg alkyl, C^-Cg halo-alkyl, C^-Cg azido-alkyl, Cg-Ο^θ aryl, or c 2~ c g acyl, which 5 process comprises reacting a compound of the formula: wherein R is hal (C^n”' hal bein 5 halogen and n being as defined in claim 1, with a compound of the formula: R 6 -NH-R 7 (XX) 6 7 10 wherein R and R are each as defined in claim 1.
38. Λ process as claimed in claim 37, wherein 4 3 8 4 1 - 64 the compound of formula (Ie), wherein R is hal(CH 2 ) n -, and the compound of formula (XI) are reacted together in an inert solvent at room temperature or with heating.
39. A process as claimed in claim 37 or claim 38, wherein the compound of formula (Ie), wherein R is hal( CH 2^n - ' has been prepared by a process as claimed in claim 35 or claim 36.
40. A process as claimed in any one of claims 14, 20, 24, 25, 26, 27, 32, 33, 35 or 36, wherein the compound of formula (V) has been prepared from an aminobenzophenone of formula (XVIII) in a process substantially as described in the foregoing reaction scheme.
41. A process as claimed in claim 21, wherein the compound of formula (Ic) has been prepared by a process as claimed in claim 40 when dependent upon claim 20.
42. A process as claimed in claim 34, wherein the compound of formula (Ia) has been prepared by a process as claimed in claim 40 when dependent upon claim 14 or claim 15.
43. A process as claimed in claim 39, wherein the compound of formula (Ie), wherein R is hal(CH 2 ) n ~, has been prepared by a process as claimed in claim 40 when dependent upon claim 35 or claim 36.
44. A process for preparing a compound of formula (I) as defined in claim 1 substantially as hereinbefore described in any one of Examples 1 to 42.
45. A compound of formula (I) as defined in claim 1 which has been prepared by a process as claimed in any one of claims 9 to 44.
46. A pharmaceutically acceptable acid addition salt of a compound as claimed in claim 45.
47. A pharmaceutical or veterinary formulation which comprises a compound as claimed in any one of claims 1 to 7 or 45 or a salt as claimed in claim 8 or claim 46 4 a σ ί λ - 65 formulated for pharmaceutical or veterinary use, respectively.
48. A pharmaceutical or veterinary composition which comprises a compound as claimed in any one of claims 1 to 7 or 45 or a salt as claimed in claim 8 or claim 46 and a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient.
49. A formulation as claimed in claim 47 or a composition as claimed in claim 48 and in the form of a tablet, a capsule, a pill, a suspension, a syrup, a powder or a solution.
50. A formulation as claimed in claim 47 or a composition as claimed in claim 48 and in unit dosage form.
51. A composition as claimed in claim 48 and substantially as hereinbefore described in Example 43.
52. A method of inducing an anxiolytic, sedative, hypnotic, anticonvulsant, muscle relaxant or antidepressant effect in an animal, which method comprises administering to the animal an effective amount of a compound as claimed in any one of claims 1 to 7 or 45, a salt as claimed in claim 8 or claim 46, a formulation as claimed in any one of claims 47, 49 or 50, or a composition as claimed in any one of claims 48, 49, 50 or 51.
53. A method as claimed in claim 52 wherein from 0.2 mg to 30 mg of active compound or salt is administered per day.
54. A method of promoting growth in an animal, which method comprises administering to the animal an effective amount of a compound as claimed in any one of claims 1 to 7 or 45, a salt as claimed in claim 8 or claim 46, a formulation as claimed in any one of claims 47, 49 or 50, or a composition as claimed in any one of claims 48, 49, 50 or 51. 4 3 8 41 - 66
55. A method as claimed in claim 54 when applied to domestic livestock or poultry.
IE2215/76A 1975-12-30 1976-10-07 Triazolylbenzophenone derivatives and preparation thereof IE43841B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB53224/75A GB1531980A (en) 1975-12-30 1975-12-30 Triazolylbenzophenone derivatives and preparation thereof

Publications (2)

Publication Number Publication Date
IE43841L IE43841L (en) 1977-06-30
IE43841B1 true IE43841B1 (en) 1981-06-03

Family

ID=10467048

Family Applications (1)

Application Number Title Priority Date Filing Date
IE2215/76A IE43841B1 (en) 1975-12-30 1976-10-07 Triazolylbenzophenone derivatives and preparation thereof

Country Status (19)

Country Link
JP (1) JPS5283469A (en)
AR (2) AR218613A1 (en)
AT (1) AT350052B (en)
AU (1) AU498113B2 (en)
BE (1) BE846410A (en)
CA (1) CA1126274A (en)
CH (1) CH623315A5 (en)
DE (1) DE2641164A1 (en)
DK (1) DK393576A (en)
ES (3) ES451896A1 (en)
FR (1) FR2336930A1 (en)
GB (1) GB1531980A (en)
HU (1) HU172539B (en)
IE (1) IE43841B1 (en)
IL (1) IL50664A (en)
NL (1) NL7610799A (en)
NZ (1) NZ181958A (en)
SE (1) SE7609813L (en)
ZA (1) ZA765851B (en)

Also Published As

Publication number Publication date
JPS5283469A (en) 1977-07-12
NZ181958A (en) 1979-03-28
ES451896A1 (en) 1978-01-16
AT350052B (en) 1979-05-10
HU172539B (en) 1978-09-28
IL50664A0 (en) 1976-12-31
NL7610799A (en) 1977-07-04
IL50664A (en) 1983-09-30
ES462244A1 (en) 1978-06-01
AU1749876A (en) 1978-03-16
AR220519A1 (en) 1980-11-14
AR218613A1 (en) 1980-06-30
ZA765851B (en) 1977-09-28
FR2336930B1 (en) 1978-12-22
SE7609813L (en) 1977-07-01
ATA684276A (en) 1978-10-15
GB1531980A (en) 1978-11-15
CA1126274A (en) 1982-06-22
IE43841L (en) 1977-06-30
AU498113B2 (en) 1979-02-08
DE2641164A1 (en) 1977-07-14
CH623315A5 (en) 1981-05-29
BE846410A (en) 1977-01-17
FR2336930A1 (en) 1977-07-29
ES462243A1 (en) 1978-06-01
DK393576A (en) 1977-07-01

Similar Documents

Publication Publication Date Title
DE69930947T2 (en) PIPERAZINE-4-PHENYL DERIVATIVES AS INHIBITORS OF INTERACTION BETWEEN MDM2 AND MDM2
US4591458A (en) 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives
JPH02117664A (en) 4-pyridone-3-carboxylic acid and its derivative
IE55798B1 (en) 2-substituted 4-amino-6,7-dimethoxyquinolines
US3349088A (en) Therapeutically valuable 1, 2-dihyro-1, 2, 4-benzotriazine derivatives and process for preparation thereof
DD216717A5 (en) PROCESS FOR THE PREPARATION OF BENZAZOCINON AND BENZAZONINONE DERIVATIVES
AU2008320718B2 (en) Indol-2-one derivatives disubstituted in the 3-position, preparation thereof and therapeutic use thereof
HU201550B (en) Process for producing 1,8-naphthyridine derivatives with twin ionic structure and pharmaceutical compositions comprising same
HUT59920A (en) Process for producing benzodiazepinones and pharmaceutical compositions containing them as active components
EP0217519B1 (en) 5-membered heterocyclic ring angiotensin converting enzyme inhibitors
JPS63295588A (en) Derivative of physiologically active substance k-252
JPH0826037B2 (en) Derivatives of physiologically active substance K-252
US3948928A (en) 3-Substituted-1,2-benzisoxazoles and pharmaceutically acceptable acid addition salts thereof
JPS62111962A (en) 3-phenylthiomethylstyrene derivative
US4052508A (en) Heterocyclic dihydroanthracen imines
US4564612A (en) Condensed, seven-membered ring compounds and their use
NZ209166A (en) 1-piperazinecarboxamides and pharmaceutical compositions
US4868175A (en) 4-Benzyl-1-(2H)-phthalazineone derivatives having an amino acid radical
US4160032A (en) Oxindoles as sleep-inducers
US4147700A (en) Triazolylbenzophenone derivatives and production thereof
IE43841B1 (en) Triazolylbenzophenone derivatives and preparation thereof
IE44184B1 (en) Imidazole derivatives,processes for their preparation and pharmaceutical compositions containing them
US3674787A (en) 2-(alpha-morpholinobenzyl)-anilides
US3998811A (en) Optically active 1,4-benzodiazepines and process for the preparation thereof
EP0748806A1 (en) POLYMORPHS B AND C OF 1- 2,4-DICHLORO-BETA-[(7-CHLOROBENZO[b]THIEN-3-YL)METHOXY]PHENETYL]IMIDAZOLE MONONITRATE