GB2106894A - 5-(Aminoalkyl)-11-phenyl-5H- dibenzo[b,e][1,4]diazepines - Google Patents
5-(Aminoalkyl)-11-phenyl-5H- dibenzo[b,e][1,4]diazepines Download PDFInfo
- Publication number
- GB2106894A GB2106894A GB08134501A GB8134501A GB2106894A GB 2106894 A GB2106894 A GB 2106894A GB 08134501 A GB08134501 A GB 08134501A GB 8134501 A GB8134501 A GB 8134501A GB 2106894 A GB2106894 A GB 2106894A
- Authority
- GB
- United Kingdom
- Prior art keywords
- dibenzo
- diazepine
- compound
- dimethylaminopropyl
- phenyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
5-(Aminoalkyl)-11-phenyl-5H-dibenzo [b,e][1,4]diazepines having the formula: <IMAGE> (wherein R<1> and R<2> each represent a hydrogen atom or a methyl group and X represents a hydrogen, chlorine, bromine or fluorine atom) and their salts are antidepressants.
Description
SPECIFICATION
Method of treating depression with 5-(aminoalkyl)-1 1 -phenyl-5H-dibenzo(b,e,1(1 4diazep- ines
The present invention relates to certain 5-(aminoalkyl)-1 1 -phenyl-5H-dibenzo[b,e,[1 ,4] diazepines for use in treating depression in humans, and to certain of the compounds which are novel.
Wander, A. in British Patent 907,646 discloses preparation of certain of the dibenzodiazepines utilized in the method of this invention; e.g., the active ingredient of the compound of example 1 below in the form of the maleate salt.
Wander, A. in British Patent 959,994 discloses utility of reduced forms; e.g., 5-(aminoalkyl) 11-phenyl-10,1 -dihydrn-5H-dibenzo[b,e,][1 ,4]diazepines as parasympathologics, antihistam- ines, spasmolytics, tranquilizers and psychic energizers.
Greig, M.E., et al, in J. Med Chem. 14m No. 2 page 153 (1971) discloses anaphylazis activity of certain dibenzodiazepine homologs in mice particularly 2-chloro-5-(dimethylaminoethyl)-1 1 -phenyl-SH-dibenzo[b,e,l[l ,4] diazepine.
According to the present invention there are provided compounds having the formula:
FormuLa I wherein R' and R2 each represent a hydrogen or a methyl group, and may be the same or different, and
X represents a hydrogen, chlorine, bromine or fluorine atom,
and the pharmaceutically acceptable acid addition salts thereof, for use in treating depression.
The invention also extends to compounds having the formula
Formula I wherein R' and R2 both represent a hydrogen atom or one represents a methyl group and the other represents a hydrogen atom.
Pharmaceutically acceptable acid addition salts are those salts which are physiologically compatible, such salts being formed either by strong or weak acids Representative of strong acids are hydrochloric, sulfuric and phosphoric acids. Representative of weak acids are fumaric, maleic, succinic, oxalic and cyclohexamic acids.
For the purpose of demonstrating antidepressant utility for the compounds of Formula I, the procedure given by Englehardt, E.L., et al., J. Med. Chem 11(2):325 (1968) which has been indicative in the past of usefulness of compounds for treating human depression was used as follows: 20mg/kg of the compound to be tested was administered to five adult female mice (ICR-DUB strain), intraperitoneally, 30 minutes prior to the administration of a ptotic dose (32 mg/kg l.P.) of tetrabenazine (as the methane sulphonate salt). Thirty minutes later, the presence or absence of complete eyelid closure (ptosis) was assessed in each animal. An ED50 (Median
Effective Dose) may be established for each tested compound in blocking tetrabenazine induced depression in mice, following the procedure given by Litchfield et al., J. Pharmacol. Exp.
Therap. 96:99-11 3 (1949). The preferred dibenzodiazepine useful in the method of this invention is the active agent of Example 1; namely, 5-(3-dimethylaminopropyl)-1 1-phenyl-5H- dibenzo[b,e,][1 ,4]diazepine.
It is therefore an object to provide a method of treating depression and pharmaceutical compositions therefor.
in the method of this invention the usual dosage forms are employed of active substance comprised of the active ingredient of Formula I with a suitable pharmaceutical carrier to provide pharmaceutical compositions such as solutions, syrups, elixirs, tablets, capsules, suppositories or powders.
The compounds of Formula I wherein the 5-position is substituted by the 3-dimethylaminopropyl radical are prepared by cyclodehydration of the N-(3-dimethylaminopropyl)-o-benzamidodiphenylamines as in British Patent 907,646 using a dehydrating-condensation catalyst; for example, phophorus pentoxide or oxyhalogenides of phosphorus, preferably the latter, in a suitable solvent; e.g., 1,1 2,2-tetrachloroethane. The equation is:
wherein X has the values assigned under Formula I above.
The novel compounds of Formula I wherein the 5-position is substituted by the 3-aminopropyl radical are prepared by cyclodehydration of novel N-[3-(1-phthalimido)propyl]-o-benzamido- diphenylarnines (llb) and therafter converting the phthalimido moiety to amino (N H2) with hydrazine and acid. The equation is:
wherein X has the values assigned under Formula I. Compounds of Formula Ill are also novel.
The novel compounds of Formula I wherein the 5-position is substituted by 3-monomethylpropyl amine are prepared by further reaction of the 3-aminopropyl compound with triethylorthoformate followed by reaction with sodium borohydride (procedure of Crocket a Blanton, 1974(1): 55-6 Synthesis). The equation is as follows:
The starting benzamido compounds of Formula II (lla and llb) are prepared by a modification of the procedure of British Patent 907,646. Ortho-nitro-diphenylamine is first reductively alkylated with a solution of ss-chioropropyl dimethylamine or 3-(1-phthalimido)-1-chloropropane and following this the nitro moiety is reduced with hydrogen over palladium on carbon to give the corresponding ortho amino compound.The amino radical in the ortho position is then reacted with benzoyl halide or a substituted benzoyl halide. The equation is as follows:
Q=-N(CH3)2 or 1-phthalimido.
The invention may be put into practice in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying Examples in which Examples 1 to 5 are examples of preparation of starting materials and Examples 6 to 1 2 are examples of compounds of Formula I, Examples 1 3 to 1 5 are examples of pharmaceutical compositions in accordance with the invention.
Example 1 N-(3-Dimethylaminopropyl)-o-,aminodiphenylamine A mixture of 32.0g (0.107 mole) of N-(3-dimethylaminopropyl)-o-nitrodiphenylamine (b.p.
155 at 0.4 mm Hg pressure to 174"C at 0.33 mm Hg pressure), 100ml of 200 proof ethyl alcohol and 1 .5g of 10% palladium-on-carbon catalyst was shaken under a hydrogen atmosphere at room temperature for 1 hr. After approximately the theoretical amount of hydrogen waC absorbed the catalyst was filtered off through a Celite (Registered Trade Mark) filter cake and solvent removed under reduced pressure.The residue was distilled under high vacuum as follows:
b.p., "C. Amt., g
Fraction 1 80-130" at 0.2 mm Hg pressure 4.0
Fraction 2 130-137" at 0.2 mm Hg pressure 7.0
Fraction 3 137-142" at 0.2 mm Hg pressure 15.5
Thin layer chromatography using 20% methyl alcohol - 80% benzene on silica gel, showed
Fraction 3 to be quite pure.
Example 2A N.(3-Dimethylaminopropyl)-o-benzamidodiphenylamine To a solution of 15.5g (0.0575 mole) of N-(3-dimethylaminopropyl)-o-aminodiphenylamine in 100ml of pyridine cooled to about 5"C. under a nitrogen atmosphere was added 1 7.8g (0.063 mole) of benzoyl chloride. A small amount of benzene was used to wash the remaining benzoyl chloride into the reaction vessel. The mixture was stirred for 1 hr and the vessel stoppered and placed in a refrigerator over the weekend. The solvent was then evaporated under reduced pressure. The residual oil was dissolved in 100 ml of methylene choride and the solution washed once with 1 50 ml of 3 N sodium hydroxide and three times with 250 ml of water.The methylene chloride layer was dried over magnesium sulphate and evaporated under reduced pressure. Residual pyridine was then removed under high vacuum (0.2 mm Hg) over night. The weight of the residual oil, the free base, was 24.99.
Example 2B.
Preparation of the Oxalate Salt of 2A. To a hot solution of 4.0g of the free base of Example 2A in isopropyl alcohol was added 1 .35g (0.0107 mole) of oxalic acid dihydrate. The precipitated oxalate salt of the title compound weighed 3.5g and melted at 162-5"C. The salt after drying 1 her at 97-98"C (refluxing propyl alcohol) an overnight at room temperature all at 0.1 mm Hg pressure, analyzed as follows:
Analysis:Calculated for C26H29N305: C,67.37; H,6.31; N,9.06
Found:C,67.42; H,6.35; N,9.01
Examples 3a to 3g
Following the procedure of Example 2A and substituting the following for benzoyl chloride: 2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride, and 4-chloro-benzoyl chloride, there were obtained: a) N-(3-dimethylaminopropyl)-o-(2-chlorobenzamido)diphenylamine, b) N-(3-dimethylaminopropyl)-o-(3-chlorobenzamido)diphenylamine, c) N(3-dimethylaminopropyl)-o-(2-fluorobenzamido)diphenylamine, d) N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido)diphenylamine, e) N-(3-dimethylaminopropyl)-o-(2-bromobenzamido)diphenylamine, f) N-(3-dimethylaminopropyl)-o-(3-bromobenzamido)diphenylamine, and g) n-(3-dimethylaminopropyl)-o-(4.chlorobenzamido)diphenylamine.
Example 4 N[3-(1-Phthalimido)propyl/-o-aminodiphenylamine. o-Nitrodiphenylamine was reacted with sodium hydride and 3-( 1 -phthalimido)-1 -chlompropane to give N-3-( 1 -phthalimido)-propyl-o-nitrodi.
phenylamine which was then reduced with hydrogen over palladium-on-carbon in ethanol to give the title compound.
Examples 5a to 5g
When in the procedure of Example 2A, N-3-(1-phthalimido)propyl-o-aminodiphenylamine is reacted with each of the following acyl chlorides in excess in the manner of Example 2A: 2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride, and 4-chloro-benzoyl chloride, there were obtained: a) N-3-( 1 phthalimido)propyl-o-(2-chlorobenzamido)diphenylamine, b) N-3-( 1 phthalimido)propyl-o-(3-chlorobenzamido)diphenylamine, c) N-3-( 1 -phthalimido)-propyl-o-(2-fluorobenzamido)diphenylamine, d) N-3-(1-phthalimido)propyl-o-(3-fluorobenzamido)diphenylamine, e) N-3-( 1 phthalimido)propyl-o-(2-bromobenzamido)diphenylamine, f) N-3-( 1 -phthalimido)propyl-o-(3-bromobenzamido)diphenylamine, and g) N-3-(1 -phthalimido)propyl-o-(4-chlorobenzamido)diphenylam i ne.
Example 6 5-(3-Dimethylaminopropyl)- 1 -phenyl-5H-dibenzo [b,el, 4]diazepine, fumarate [1:1].
A stirred mixture of 18.99 (0.05 mole) of N-(3-dimethylaminopropyl)-obenzamidodiphenylam.
ine and 32.1 9g (0.2 mole) of phosphorus oxychloride in 50 ml of 1,1 ,2,2-tetrachloroethane was heated at 150"C under nitrogen atmosphere for 1.5 hr. The mixture was cooled somewhat and poured over approximately 1000 ml of crushed ice and then diluted with enough water for a final volume of 1000 ml. The aqueous suspension was extracted twice with methylene chloride and the methylene chloride layer discarded. The aqueous layer was made basic with 3N sodium hydroxide and extracted with three-250ml portions of methylene chloride. These three methylene chloride washes were combined, dried over magnesium sulphate and evaporated under reduced pressure to give a residual oil weighing 13.89, the free base of the title compound.The oil was dissolved in hot isopropyl alcohol and reacted with 4.59 (0.039 mole) of fumaric acid. The fumarate salt was collected by filtration, yielding 139 when dried, m.p.
168-170"C.
Analysis: Calculated for C28H29N3O4: C,71.32; H,6,20;
N,8.91 Found:C,71.19; H6.19;
N,8.89
Examples 7a to 7g
Following the procedure of Example 6 and substituting equal molar amounts of the following for N-(3-dimethylaminopropyl)-o-benzamidodiphenylamine: 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-fluorobenzamido)diphenylamine, N-(3-dimethylaminopropyl)-o-(2-bromobenzamidio)diphenylamine, N-(3-dimethylaminopropyl)-o-(3-bromobenzamido)diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido)diphenylamine, there were obtained:: a) 11 (2-chlorophenyl)-5-(3-dimethylaminopropyl)-5 H-dibenzo[b,e][1 ,4]diazepine, fumarate, b) 11-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[bte][1,4]diazepine, fumarate, c) 11 -(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5 H-dibenzo[b,e,](1 ,4diazepine,fumarate, d) 11 -(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e][1 , 4]diazepine, fumarate, e) 11-(2-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[bte][1,4]diazepine, fumarate, f) 11 -(3-bromophenyl)-5-(3-dimethylaminopropyl-5H-dibenzo[b,e][1 ,4]diazepine, fumarate, and g) 11 -(4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e](1 ,4]diazepine, fumarate.
Examples 8a to 8h
When in the procedure of Example 6 prior to addition of fumaric acid, the following were substituted for N-(3-dimethylaminopropyl)-o-benzamidodiphenylamine: N-3-(1 -phthalimido)propyl-o-benzamidodiphenylamine,
N-3-(1 -phthalimido)propyl-o-(2-chlorobenzamido)d iphenylamine,
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-fluorobenzamido)diphenylamine,
N-3-(1 -phthalimido)propyl-o-(2-bromobenzamido)diphenylamine,
N-3-(1 phthalimido)propyl-o-(3-bromobenzamido)diphenylamine, and-N-3-( 1 -phthalimido)propyl-o-[4-chlorobenzamido)diphenylamine, there were obtained:: a) 5-(3-(1 -phthalimido)propyl]- 1 -phenyl-5H-dibenzo[b,e][ 1 ,4]diazepine, b) 5-[3-( 1 -phthalimido)propyl]-1 1 -(2-chlorophenyl)-5 H-dibenzo[b,e](1 ,4]diazepine, c) 5-[3-(1 -phthalimido)propyl]- 1 -(3-chlorophenyl)-5H-dibenzo[b,e][1 ,4jdiazepine, d) 5-[3-( 1 -phthalimido)propyl]-1 1 -(24luornphenyl)-5Hdibenwb,e][1 ,4]diazepine, e) 5-[3-(1 -phthalimido)propyl]-1 1 -(3-fluorophenyl)-5 Hdibenzo[b,e][1,4]diazepine, Hdibenzo(b,e][1,4]diazepine, f) 5-(3-(1-phthalimido)propyl]-11-(2-bromophenyl)-5H-dibenzo[b,e][1,4]diazepine, g) 5E3-(1 -phthalimido)propylj-1 1 -(3-bromophenyl)-SH-dibenzo[b,el[l ,$]diazepine, h) 5-[3-( 1 -phthalimido)propylj-1 1 -(4-chlorophenyl)-5H-dibenzo[b,e][1 ,4]diazepine.
Example 9
5-(3-Aminopropyl)-1 1-phenyl-5H-dibenzo[b,e][1,4] diazepine hydrochloride
A mixture of 0.035 mole of 5-[3-(1-phthalimido)propyl-11-phenyl-5H-dibenzo[b,e][1,4]diazep- ine, 0.039 mole of hydrazine hydrate and 175ml of 190 proof ethyl alcohol was refluxed for 2.5hr and allowed to stand for several house. A solution of 10 ml concentrated hyrochloric acid in 50ml water was added to the mixture and the mixture was stirred for several hours. The mixture was filtered and the filtrate evaporated under reduced pressure. The hydrochloric salt was isolated by recrystallization from a suitable solvent and dried under reduced pressure.
Examples 1 ova to 10g
Following the procedure of Example 9 and substituting equal molar amounts of the following for 5-[3-(1 -phthalimido)propyl]- 1 -phenyl-5 H-d ibenzoCb,ell:l ,4]diazepine: 11 -(2-chlorphenyl)-5-(3-( 1 -phthalimido)prnpylj-5 H-dibenzo[b,e][1 ,4]diazepine, 11 -(3-chlorophenyl)-5-[3-(1 -phthalimido)propyll-SH-dibenzoCb,elIl ,4]diazepine,
11 -(2-fluorophenyl)-5-[3-(1 -phthalimido)propyl]-SH-dibenzoCb,e]C1 ,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, 1 1 -(3-bromophenyl)-5-[3-( 1 -phthalimido)propyl]-5 H-dibenzo[b,el[l ,4]diazepine, and 11 -(4-chlornphenyl)-5-3-( 1 -phthalimido)propyl]-5 H-dibenw[b,e][1 ,4]diazepine, there were obtained: a) 5-(3-aminopropyl)- 1-(2-chlorophenyl)-5H-dibenzo-[b,e][1,4]diazepine hydrochloride, b)5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo[b,e](1,4]diazepine hydrochloride, c) 5-(3-aminopropyl)-l 1 -(2-fluorophenyl)-5 H-dibenzo[b,el[l ,4]diazepine hydrochloride, d) 5-(3-aminopropyl)- 1 -(3-fluorophenyl)-SH-dibenzoCb,el[l ,gdiazepine hydrochloride, e) 5-(3-aminoporpyl)- 1 -(2-bromophenyl)-5H-dibenzo[b,e][1 ,4]diazepine hydrochloride, f) 5-(3-aminopropyl)- 11 -(3-bromophenyl)-5H-dibenzo[b,e][1,4]diazepine hydrochloride, g) 5-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]diazepine hydrochloride.
Example 11
N-Methyl-11 -phenyl-5H-dibenzo, e][1, 4]diazepin-5-propanamine, hydrochloride.
The hydrochloride salt of 5-(3-aminopropyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazepine was converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride layer to dryness, adding dry benzene and again concentrating to drive off the benzene. The resulting free base was dissolved in a large excess of freshly distilled triethylorthoformate with refluxing for several hours. The mixture was concentrated in vacuo, ethanol was added and the mixture concentrated again. The resulting imidate was dissolved in ethanol and sodium borohydride was added with stirring at 15-20 C until thin-layer chromatography indicated the substantial absence of starting material.
The mixture was cooled and gradually flooded with water followed by extraction with ethylacetate. The ethylacetate layer washed to neutrality and salted, filtered and evaporated.
Crude free base was isolated by column chromatography and reacted with ethereal hydrogen chloride and recrystallized to give the title compound.
Examples 12a to 12g
Following the procedure of Example 11 and substituting equal molar amounts of the following for 5-(3-aminopropyl)-1 1 -phenyl-5 H-dibenzo[b,e][1 ,4]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[bte][1,4]diazepine hydrochloride, 5-(3-aminopropyl)- 11 (3-fluorophenyl)-5H-dibenzo[b,e][1 ,4]diazepine hydrochloride, 5-(3-aminopropyl)- 11 -(2-bromophenyl)-5 H-dibenzo[b,e][ 1 ,4]diazepine hydrochloride, 5(3-aminopropyl)-1 1 -(3-bromophenyl)-5 H-dibenzo(b,e]L1 ,4]diazepine hydrochloride, and 5-(3-aminopropyl)- 1 .(4-chlornphenyl)-5H-dibenzo[b,e]1 ,4]diazepine hydrochloride, there were obtained: a) 11 -(2-chlorophenyl)-N-methyl-5H-dibenzo[b, ,4]diazepin-5-propanamine hydrochloride, b) 11 (3-chlornphenyl)-N-methyl-5H-dibenzo[b,e]Ll ,4]diazepin-5-propanamine hydrochloride, c) 11 -(2-fluorophenyl)-N-methyl-5H-dibenzo[b, ,4]diazepin-5-propanamine hydrochloride, d) 11 -(44luorophenyl)-N-methyl-5 H-dibenzo(b,e][1 ,4]diazepin-5-propanamine hydrochloride,.
e) 11 -(2-bromophenyl)-N-methyl-5H-dibenzoCb,e ,4jdiazepin-5-propanamine hydrochloride f) 11 -(3-bromophenyl)-N-methyl-5H-dibenzo[b,e ,4]diazepin-5-propanamine hydrochloride, and g) 11 (4-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1 ,4]diazepin-5-propanamine hydrochloride.
Formulation and Administration
Effective quantities of the foregoing pharmacologically active compounds of Formula I may be administered to humans for therapeutic purposes according to usual modes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.
Exemplary of solid carriers for oral administration are such as lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
Exemplary of liquid carriers for oral administration are vegetable oils and water.
For intramuscular administration the carrier or excipient may be a sterile, parenterally acceptable liquid; e.g., water or a parenterally acceptable oil; e.g., arachis oil contained in ampoules.
Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually from five milligrams or above and preferably 10, 25, 50 or 100 milligrams of even higher, preferably administered three or four times per day, depending, of course, upon the emergency of the situation, the compound used, and the particular result desired. Twenty-five to 200 milligrams appears optimum per unit dose or usual broader ranges appear to be about 10 to 500 milligrams per unit dose, Daily dosages usually required should range from about 0.5 to about 20mg/kg/day, preferably 0.5 to 10 mg/kg.
The active ingredients of the invention may be combined with other pharmacologically active agents as stated above. It is only necessary that the active ingredient constitute an effective amount; i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, of course, be demonstrated according to be determined according to standard medical principles under the direction of a physician.
The following formulations are representative for the pharmacologically active compounds of this invention.
FORMULATIONS
Examples 1 3a to 1 3e Capsules of 1 Omg and 50mg of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.
Example 13a 1 3b 1 Omg 50mg
Typical blend for Per Per encapsulation Capsule Capsule
Active ingredient, as salt 10 50
Lactose 259 219
Starch 126 126
Magnesium stearate 4 4
Total 399 399
Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:
13c 13d 13e
100 250 500
mg. per mg. per mg. per
Ingredients Capsule Capsule Capsule
Active ingredient, 100 250 500 as salt
Lactose 214 163 95
Starch 87 81 47
Magnesium stearate 4 6 8
Total 299 500 650
In each case, the selected active ingredient was uniformly blended with the lactose, starch, and magnesium stearate and the blend then encapsulated.
EXAMPLE 14
A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet follows.
The formulation may be used for other strengths of active ingredient by adjustment of the weight of dicalcium phophate
Per Table, mg.
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 first uniformly blended. Ingredient 3 was prepared as a 10% paste in water. The blend was granulated with the starch paste and the wet mass passed through an 8 mesh (U.S sieve series) screen. The wet granulation was dried and sized through 1 2 mesh (U.S. sieve series) screen. The dried granules were blended with the calcium stearate and compressed. 8 mesh has openings of 2.38mm; 12 mesh of 1.68mm.
EXAMPLE 15
An injectable sterile 2% solution was made up as follows:
Per cc
Active ingredient mg. 20
Preservative, e.g.
chlorobutanol, w/vol. percent 0.5
Water for injection q.s.
The solution was prepared, clarified by filtration, filled into vials, sealed and autoclaved.
Claims (14)
1. A compound having the formula:
wherein R1 and R2 each represent a hydrogen atom or a methyl group,
X represents a hydrogen, chlorine, bromine or fluorine atom, and the pharmaceutically acceptable acid addition salts thereof, for use in treating depression.
2. A compound as claimed in Claim 1 which is 5-(3-dimethylaminopropyl)-1 1-phenyl-5H- dibenzo[b,e][1,4]diazepine.
3. A compound as claimed in Claim 1 which is 5-(3-dimethylaminopropyl)-1 1-phenyl-5H- dibenzo[b,e][1,4]diazepine, fumarate El :13.
4. A compound having the formula:
wheren X represents a hydrogen, chlorine, bromine or fluorine atom, and R1 and R2 both represent a hydrogen atom or R represents a hydrogen atom when R2 represents a methyl group, and the pharmaceutically acceptable acid addition salts thereof.
5. A compound having the formula:
wherein X represents a hydrogen, chlorine, bromine or fluorine atom.
6. A compound having the formula:
wherein X represents a hydrogen, chlorine, bromine or fluorine atom.
7. A compound as claimed in Claim 4 substantially as specifically described herein with reference to any one of Examples 6 to 1 2.
8. A compound as claimed in Claim 5 or Claim 6 substantially as specifically described herein with reference to any one of Examples 1 to 5.
9. A pharmaceutical composition for treating depression in unit dosage form comprising (a) an effective amount of a compound as claimed in any one of Claims 4 to 8, and (b) a pharmaceutical carrier therefor.
10. A pharmaceutical composition as claimed in Claim 9 in which the compound is 5-(3 dimethylaminopropyl)- 1 -phenyl-5 H-dibenzoEb,eJ(1 ,4]diazepine.
11. A pharmaceutical composition as claimed in Claim 10 in which the compound is 5-(3 dimethylaminopropyl).1 1 -phenyl-5H-dibenzob,e][1 ,4]diazepine fumarate.
1 2. A pharmaceutical composition as claimed in any one of Claims 9 to 11 substantially as specifically described herein with reference to any one of Examples 13, 14 or 1 5.
1 3. A pharmaceutical composition in unit dosage form comprising at least 5mg per unit dosage of a compound having the formula:
wherein R1 and R2 each represent a hydrogen atom or a methyl group,
X represent a hydrogen, chlorine, bromine or fluorine atom, or a pharmaceutically acceptable acid addition salt thereof.
14. A pharmaceutical composition as claimed in Claim 13, which composition comprises 5 (3-dimethylaminopropyl)- 11 -phenyl-5 H-dibenzoEbe]E1 ,4]diazepine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30507681A | 1981-09-24 | 1981-09-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2106894A true GB2106894A (en) | 1983-04-20 |
| GB2106894B GB2106894B (en) | 1985-05-30 |
Family
ID=23179221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08134501A Expired GB2106894B (en) | 1981-09-24 | 1981-11-16 | 5-(aminoalkyl)-11-phenyl-5h-dibenzo(b,e)(1,4)diazepines |
Country Status (31)
| Country | Link |
|---|---|
| JP (1) | JPS5865280A (en) |
| KR (1) | KR880001866B1 (en) |
| AT (1) | AT383121B (en) |
| AU (2) | AU549806B2 (en) |
| BE (1) | BE891535A (en) |
| CA (1) | CA1199325A (en) |
| CH (2) | CH657126A5 (en) |
| DE (1) | DE3149923A1 (en) |
| DK (1) | DK531281A (en) |
| ES (1) | ES507970A0 (en) |
| FI (1) | FI813975L (en) |
| FR (1) | FR2513249B1 (en) |
| GB (1) | GB2106894B (en) |
| GR (1) | GR75123B (en) |
| HK (1) | HK85785A (en) |
| HU (1) | HU187394B (en) |
| IE (1) | IE51880B1 (en) |
| IL (1) | IL64257A (en) |
| IN (1) | IN155657B (en) |
| IT (1) | IT1146729B (en) |
| LU (1) | LU83798A1 (en) |
| NL (1) | NL8105892A (en) |
| NO (1) | NO813838L (en) |
| NZ (1) | NZ198986A (en) |
| PH (1) | PH16696A (en) |
| PL (1) | PL234420A1 (en) |
| PT (1) | PT74285B (en) |
| SE (1) | SE448453B (en) |
| SG (1) | SG65485G (en) |
| YU (1) | YU43070B (en) |
| ZA (1) | ZA818481B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB907646A (en) * | 1959-01-23 | 1962-10-10 | Wander S A A | Method of production of new derivatives of diazepin |
| AT228215B (en) * | 1959-01-23 | 1963-07-10 | Wander Ag Dr A | Process for the production of new diazepine derivatives |
| AT226721B (en) * | 1959-09-22 | 1963-04-10 | Wander Ag Dr A | Process for the preparation of new, 5-substituted diazepines |
| NL256049A (en) * | 1959-09-22 |
-
1981
- 1981-11-06 SE SE8106594A patent/SE448453B/en not_active IP Right Cessation
- 1981-11-10 IL IL64257A patent/IL64257A/en unknown
- 1981-11-12 NO NO813838A patent/NO813838L/en unknown
- 1981-11-13 IN IN1260/CAL/81A patent/IN155657B/en unknown
- 1981-11-16 GB GB08134501A patent/GB2106894B/en not_active Expired
- 1981-11-17 GR GR66552A patent/GR75123B/el unknown
- 1981-11-17 NZ NZ198986A patent/NZ198986A/en unknown
- 1981-11-25 IE IE2770/81A patent/IE51880B1/en unknown
- 1981-11-25 PH PH26538A patent/PH16696A/en unknown
- 1981-11-27 LU LU83798A patent/LU83798A1/en unknown
- 1981-11-27 CH CH65/85A patent/CH657126A5/en not_active IP Right Cessation
- 1981-11-27 FR FR8122288A patent/FR2513249B1/en not_active Expired
- 1981-11-27 CH CH7633/81A patent/CH651028A5/en not_active IP Right Cessation
- 1981-11-30 DK DK531281A patent/DK531281A/en not_active Application Discontinuation
- 1981-12-07 ZA ZA818481A patent/ZA818481B/en unknown
- 1981-12-09 AT AT0526981A patent/AT383121B/en not_active IP Right Cessation
- 1981-12-10 FI FI813975A patent/FI813975L/en not_active Application Discontinuation
- 1981-12-10 IT IT68607/81A patent/IT1146729B/en active
- 1981-12-15 ES ES507970A patent/ES507970A0/en active Granted
- 1981-12-15 AU AU78513/81A patent/AU549806B2/en not_active Ceased
- 1981-12-15 HU HU813778A patent/HU187394B/en not_active IP Right Cessation
- 1981-12-16 DE DE19813149923 patent/DE3149923A1/en not_active Ceased
- 1981-12-18 BE BE0/206880A patent/BE891535A/en not_active IP Right Cessation
- 1981-12-23 PL PL23442081A patent/PL234420A1/en unknown
- 1981-12-29 NL NL8105892A patent/NL8105892A/en not_active Application Discontinuation
- 1981-12-29 JP JP56215952A patent/JPS5865280A/en active Granted
-
1982
- 1982-01-14 CA CA000394124A patent/CA1199325A/en not_active Expired
- 1982-01-15 PT PT74285A patent/PT74285B/en unknown
- 1982-02-02 KR KR8200419A patent/KR880001866B1/en active
- 1982-03-23 YU YU624/82A patent/YU43070B/en unknown
-
1985
- 1985-09-09 SG SG654/85A patent/SG65485G/en unknown
- 1985-10-18 AU AU48905/85A patent/AU576010B2/en not_active Ceased
- 1985-10-31 HK HK857/85A patent/HK85785A/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4229453A (en) | Substituted 5,6-dimethylpyrrolo[2,3-d]pyrimidine compounds, their production and their medicinal use | |
| IL32853A (en) | 5,11-dihydro-6h-pyrido(2,3-b)-(1,4)benzodiazepine-6-ones substituted in 11-position and processes for the production thereof | |
| US3862139A (en) | Heterocyclic benzamide compounds | |
| US4194045A (en) | 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds | |
| US4210648A (en) | II-Aminoacyl-5,11-dihydro-6H-pyrido(2,3-B) (1,4)benzodiazepin-6-ones and salts thereof | |
| WO1988007858A1 (en) | Sulfinyl and sulfonyl substituted 3-benzazepines | |
| US4316900A (en) | Piperazinopyrrolobenzodiazepines | |
| DE2424811B2 (en) | Pyrido-benzodiazepinones, process for their preparation and medicaments containing them | |
| US3732212A (en) | 1,2,3,10,11,11a-hexahydro-5h-pyrrolo(2,1-c)(1,4)benzodiazepine-5,11-diones | |
| US3860600A (en) | Octahydropyrrido{8 2,1-c{9 {8 1,4{9 benzodiazepines | |
| US3749785A (en) | Pharmaceutical compositions containing a tricyclic heterocyclic amide of a diallylamino-alkanoic acid | |
| GB2106894A (en) | 5-(Aminoalkyl)-11-phenyl-5H- dibenzo[b,e][1,4]diazepines | |
| US3373168A (en) | Certain benzazepinoxyridoindole compounds and their preparation | |
| US3458635A (en) | Compositions containing 3-di-substituted methylene pyrrolidines and methods of treating depression | |
| US4694003A (en) | Method of treating depression with 5-(aminoalkyl)-11-phenyl-5H-dibenzo(b,e)(1,4) diazepines | |
| IL26724A (en) | Benzodiazepine derivatives and process for the manufacture thereof | |
| CA1184493A (en) | Anti-depressant compositions | |
| KR850000452B1 (en) | Method for preparing carbamoyloxyamino-1, 4-benzodiazepine | |
| US3676432A (en) | 11,12-DIHYDRODIBENZ{8 b,f{9 AZOCIN-6(5H)-ONES | |
| US3825533A (en) | N-carboxymethyl-n-substituted glycinate esters of 3-hydroxy-1,4-benzo-diazepin-2-ones | |
| US4362666A (en) | Diazepinopyrrolobenzodiazepines | |
| NZ199610A (en) | Tricyclic pyrrole derivatives | |
| US3646010A (en) | Spiroazetidine-ethanoanthracenes | |
| DE2063178C3 (en) | 23-Dihydro-lH-thieno square brackets on 2'3 'to 23] or [3' ,? to 23] benzothiepine [4,5-c] pyrroles, processes for their preparation and therapeutic preparations containing them | |
| US3859285A (en) | 10, 11-dihydro-5h-benzo (4,5) cyclohepta (1,2-b) pyrazines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19951116 |