IE51880B1 - 5-(aminoalkyl)-11-phenyl-5h-dibenzo(b,e)(1,4)diazepines in the treatment of depression - Google Patents
5-(aminoalkyl)-11-phenyl-5h-dibenzo(b,e)(1,4)diazepines in the treatment of depressionInfo
- Publication number
- IE51880B1 IE51880B1 IE2770/81A IE277081A IE51880B1 IE 51880 B1 IE51880 B1 IE 51880B1 IE 2770/81 A IE2770/81 A IE 2770/81A IE 277081 A IE277081 A IE 277081A IE 51880 B1 IE51880 B1 IE 51880B1
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- dibenzo
- hydrogen
- dimethylaminopropyl
- diazepine
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- C—CHEMISTRY; METALLURGY
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- 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
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- 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
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Abstract
5-(Aminoalkyl)-11-phenyl-5H-dibenzo [b,e][1,4]diazepines having the formula: (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
The present invention relates to certain
-(aminoalkyl)-11-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 Specification No. 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 Specification No. 959,994 discloses utility of reduced forms; e.g., 5-(aminoalkyl)-ll-phenyl10,ll-dihydro-5H-dibenzo[b,e][1,4]diazepines as parasympathologics, antihistamines, spasmolytics, tranquilizers and psychic energizers.
IS Greig, Μ. Ε., et al, in J. Med. chem. Ill, No. 2 page I55 (1971) discloses anaphylaxis activity of certain dibenzodiazepine homologs in mice particularly 2-chloro-5(dimethylaminoethy1)-ll-phenyl-5H-dibenzo[b,e][1,4 jdiazepine.
According to the present invention there are provided compounds having the formula;
Fonnula I
.
.
T 2 wherein R and R 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 fn treating depression.
The invention also extends to compounds having the formula
.
Formula I
2 wherein R and R 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: 20 mgAg 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 15 ptotic dose (32 mgAg, I.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 EDSQ (Median Effective Dose) may be established for each tested compound in blocking tetra20 benazine induced depression in mice, following the procedure given by Litchfield et al., J. Pharmacol. Exp. Therap. 9o:
9.9-113 (1949). The preferred dibenzodiazepine useful in the method of this invention is the active agent of Example 1; namely, 5-(3-dimethylaminopropyl)-11-phenyl5H-dibenzojb,e] ]l, 4jdiazepine.
It is therefore an object to provide compounds and pharmaceutical compositions useful in the treatment of depression.
Generally, the usual dosage forms are employed.
They comprise active substance (.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-C3-dimethylaminopropyl)-o-benzamido-diphenylaniines as in British Patent Specification No. 907,646 using a dehydrating-condensation catalyst; for example, phosphorus 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.
- 6 The novel compounds of Formula I wherein the 5“ position is eubetituted by the J-aminopropyl radical era prepared by cyclodehydration of novel N-[3-{1-phthalimido) propyll-o-benzamido-diphenylamines (lib) and thereafter converting the phthalimido moiety to amino (Hlfe) with, hydrazine and acid. The equation ie:
wherein X has the values assigned under Formula I. compounds of Formula III are also novel.
The novel compounds of Formula I wherein the 5-position is substituted by J-monomethylpropyl amine are prepared by further reaction of the 3-aminopropyl compound with triethylorthoformate followed by reaction with sodium borohydride (procedure of Crocket & Blanton, 197^(1): 55-6 Synthesis). The equation is as follows:
- 7 Ihe starting benzamido expounds of Formula XI (XXa and XXb) are prepared by a modification of the procedure of British Patent Specif ication No. 907,646. Qrtho-nitro-diphenylanine ie first reduetively alkylated with a aolution of p-ehloropropyl dimethylamine or 5-(1-phthalimido)-1-chloropropane and following this the nitro moiety ie 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:
Ha /Pd-C
Formula
II
Q = -N(CH3)a 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 12 are examples of compounds of Formula I, Examples 13 to 15 are examples of pharmaceutical compositions in accordance with the invention.
Example 1
. N-(3-Dimethylaminopropyl)-o-aminodiphenylamine.
A mixture of 22.0 g (0.107 mole) of N-(3-dimethylandnopropyl)-o-nitrodiphenylamine (b.p. 155° at 0.4 nm Hg pressure to 174°C at 0.33 nm Hg pressure), 100 ml of 200 proof ethyl alcohol and 1.5 g .of 10% palladium-an-carban catalyst was shaken under
. a hydrogen atmosphere at rocm tanperature for 1 hr. After approximately the theoretical amount of hydrogen was absorbed the catalyst was filtered off through a Ctelite (Trade i'ark) 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
130-137° at 0.2 mm Hg pressure 7.0
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.
- 9 Example 2A
S-( 3-Pimethylaminopropvl)-o-benzamidodlphenvlamine.
To a eolution of 15-5 g (0.0575 »ol·) of N-(3-dimethylaminopropyl )-o-aminodipheny lamine in 100 ml of pyridine
. cooled to about 5°C. under a nitrogen atmosphere was added
17.8 g (Ο.Ο63 Jftola) 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 chloride and the solution washed once with 150 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
24.9 g.
Example 2B. Preparation of the Oxalate Salt of 2A. - To a hot solution of 4.0 g of the free base of Exanple 2A In isopropyl’ alcohol was added 1.35 g (0.0107 mole) of oxalic acid dihydrate.
The precipitated oxalate salt of the title oonpovnd weighed 3.5 g and melted at 162-5°C. The salt after drying 1 hr at 97-98°C (refluxing propyl alcohol) and overnight at room tauterature all at 0.1 nm Hg pressure, analyzed as follows:
Analysis: Calculated for CBeHeeN305: C,67-37; H,6-31; Ν,9·θ6 Pound s C,67-42; H,6-35; H,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, therevrere obtained:
a) N-( 3-dime.thylaminopropyl) -o-( 2-chlorobenzamido) diphenylamine,
b) N-(3-dimethylaminopropyl)-0-( 3-chlorobenzamido) diphenylamine,
c) N-(3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine,
d) N-(3-dimethylaminopropyl)-0-( 3-fluorobenzamido) diphenylamine,
e) N-(3-dimethylaminopropyl)-o-( 2 -bromobenzamido) diphenylamine,
f) N- (3-dimethylaminopropyl) -o-( 3-bromobenzamido) diphenylamine, and
g) N-( 3-diinethylaminopropyl) -o-( 4,-chlorobenzamido) diphenylamine.
- 11 Examnle 4
N-r 3-(1-Phthal imido) propyn-o-tmlnodiphenylamine o-Nitrodiphenylamine was reacted with sodium hydride and 3-(l-Phthalimido)-l-chloropropane to give K-3-(lphtha1imido)propyl-o-nitrodiphenylamine whieh was then reduced with hydrogen over palladium-on-carbon in ethanol to give the title compound.
Examples 5a to Sg
When in the procedure of Example 2A, N-3-(lphthalimido)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 ^-chloro-benzoyl chloride, there were obtained:
a) N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine,
b) N-3-(l-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine,
e) Ν-J-(1-ph thalimido) propyl-o- (2 -fluorobenzamido) diphenylamine,
d) N-3-( l-phthaliitiido)propyl-o-(3-flu°robenzamido) diphenylamine,
e) N-3-(l-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) diphenylamine.
Example 6
-( 3-Dimethylaminopropyi)-ll-phenyl-5H-dibenzo rb.ey l,4ldiazepine, fumarate [lil] .
A stirred mixture of 18.9 9 (0.05 mole) of N-(3dimethylaminopropyl)-o-benzamidodipheny.lamine and 32.19 9 (0.2 mole) of phosphorus oxychloride in 50 ml of 1,1,2,2tetrachloroethane 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 agueous suspension was extracted twice with methylene chloride and the methylene chloride layer discarded. The aqueous layer was made basic with 3 N sodium hydroxide and extracted with three - 2p0 ml 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 13.8 g, the free base of the title compound. The oil was dissolved in hot isopropyl alcohol and reacted with 4.5 g (Ο.Ο39 mole) of fumaric acid. The fumarate salt was collected by filtration, yielding 13 g when dried, m.p. l68-170°c.
Analysis: Calculated for CasHasNgCU: C,71.32; H.6.20;
N.8.9I
Found : C,71.19; H 6.19?
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-d imethylaminopropyl)-o-(3-chlorobenzamido) diphenylamine,
N-( 3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine,
N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido) diphenylamine,
- 13 Ν- (J-dimethylaminopropyl)-ο-(2-bromobenzamido) diphenylamine,
N-( 3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, end
N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine, there were obtained:
a) 11-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5Hdibenzorb,e][l,4]diazepine, fumarate,
b) 11-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-5Hdibenzo[b,e]Γ1, 4jdiazepine, fumarate,
c) 11-(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5Hdibenzorb,elf1,4]diazepine, fumarate,
d) 11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5Hdibenzo^b,e](l,4idiazepine, fumarate,
e) 11-(2-bromophenyl)-5-( 3-dimethylaminopropyl)-5Hd ibe nzo]b,e]]1,4]dia z epine, fumarate,
f) 11-(3-brosnophenyl )-5-( 3-dimethvlaminopropyl )-5Hdibenzo[b,e][l,4]diazepine, fumarate, and
g) 11-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-5Hdibenzo[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-(3dimethylaminopropyl)-o-benzamidodiphenylamine:
N-3-(1-phthalimido)propyl-o-benzamidodiphenylamine,
N-3-(1-phthalimido) propyl-o-( 2-chlorobenzamido) diphenylamine,
N-5-(l-phthalimido)propyl-o-( 3-chlorobenzamido) diphenylamine,
N-3-(1-phthalimido)propyl-o-( 2-fluorobenzamido) diphenylamine,
N-3-(l-phthalimido)propyl-o-(3-fluorobenzamido) diphenylamine,
N-3-(1-ph thalimido)propyl-o- (2-bromobenzamido) diphenylamine,
- 14 N-3-(1-phthalimido)propyl-o-(3-bromobenzamido) diphenylamine, and
N-3-( l-phthalimido)propyl-o-(^-chlorobenzamido) diphenylamine, there were obtained:
a) 5-[3-(1-phtha1imido)propyl]-ll-phenyl-5H~dibenzo fbje·'· l,4]diazepine,
b) 5-[5-(l-phthalimido)propyl]-ll-(2-chlorophenyl)-5Hd ibenzof b,e][1,4]diazepine,
c) 5-[3-(1-ph tha1imido)propyl]-11-(3-chlo rophenyl)-5Hdibenzo[b,e]r 1,4] diazepine,
d) 5-Γ 3-(1-phthalimido)propyl]-11-( 2 -f luorophenyl)-5Hdibenzo^ b,e]Γ1,diazepine,
e) 5-[3-(1-phthal im·ido)propyl]-ll-(3-fluorophenyl)-5Hdibenzofb,e][1,4]diazepi'ne,
f) 5-2 3-(1-ph thalim ido)propyl]-11-(2-bromophenyl)-5Hdibenzof b,e]Γ1,1diazepine,
g) 5-f 3-1 (1 -phthal imido) propyl ]-ll- (3-bromo phenyl) -5Hdibenzo[b,e][1, 4]diazepine,
h) 5-(5-(l-phthalimido)propyl]-ll-(4-chlorophenyl)-5Hdibenzo[b,e][l,4]diazepine.
Example 9
-f 3-Aminopropyl)-ll-Phenyl-5H-dibenzopb, eVl.^-!
diazepine hydrochloride·
A mixture of 0.035 mole of 5-[3-(1-phthalimidoJpropylll-phenyl-5H-dibenzorb,e][l,l|]diazepine, 0-039 mole of hydrazine hydrate and 175 ml of 190 proof ethyl alcohol was refluxed for 2-5 hr and allowed to stand for several hours.
A solution of 10 ml concentrated hydrochloric acid in 50 ml 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 hydrochloride salt was isolated by reerystallization from a suitable solvent and dried under reduced pressure.
Examples 10a to 10c
Following the procedure of Example 9 and subitituting equal molar amounts of the following for 5~[3-(l~pbthalimido) propyl]-ll-phenyl-5H-dibenzo[b,eirl,4ldiezepine!
11-(2-ehlorophenyl)-5-(3-(1-phthalimido)propyl]-5Hdibenzo r b,a][1,41diezepine, ll-(3-chlorophenyl)-5-[3-(l-phthalimido)propyl2-5Hdibenzo[b,e]ri,43diazepine,
11-(2-fluorophenyl)-5-(3-(1-phthalimido)propyl]-5Hdibenzorb,e](l,4]diazepine,
11-(3-fluorophenyl)-5-(3-(1-phthalimido)propyl]-5Hdi-benzor b, e ] (1, 4 ] diazepine,
11-(2-bromophenyl)-5-(3-(1-phthalimido)propyl3-5Hdibenzo(b,e3(1,43diazepine,
11-(3-bromophenyl)15-(3-(1-phthalimido)propyl!-5Hdibenzorb,el(l,4]diazepine, and
11-(4-chlorophenyl)-5-(3-(1-phthalimido)propyl]-5Hdibenzo(b,e3(l,4ldiazepine, there were obtained:
a) 5-(3-aminopropyl)-ll-(2-chlorophenyl)-5H-dibenzo (b,eι(1,4 3diazepine hydrochloride,
b) 5-(3-aminopropyl)-11-(3-ehlorophenyl)-5H-dibenzo (b,e3ri,4ldiazepine hydrochloride,
c) 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo rb,ei(l,43diazepine hydrochloride ,
d) 5-( 3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo (b,e·^ 1,4ηdiazepine hydrochloride,
e) 5“(3-aminopropyl)-11-(2-bromophenyl)-5H-d ibenzo (b,elΓ1,4 3diazepine hydrochloride,
f) 5-( 3~aniinopropyl)-11-(3-bromophenyl)-5H-dibenzo rb,e3(l,43diazepine hydrochloride,
g) 5-( 3-sminopropyl)-11-(4-chlorophenyl)-5H-dibenzo ’ (b,e](1,4 3diazepine hydrochloride.
880
- 16 Example 11
N-Methyl-ll-phenvl-5H-dibenzorb,eir1,4idiazepin-5propanamlne, hydrochloride.
The hydrochloride salt of 5-(3-eminopropyl)-ll-phenyl5E-dibenzo[b,e][l,4]diazepine was converted to the free base by partitioning between dilute sodium hydroxide and methyleni 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)ll-phenyl-5H-dibenzo[b,e][l,4ldiazepine:
-(3-aminopropyl-ll-(2-chlorophenyl)-5H-dibenzo Γ b,e1[1,4idiazepine hydrochloride,
-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo [b,e Tr1,4 jdiazepine hydrochloride,
-( 3-aminopr-opyl) -ll-(2-fluorophenyl) -5H-dibenzo [b,ej[l,4]diazepine hydrochloride,
-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride,
-(3-aminopropyl)-11-(2-bromophenyl)-5H-dibenzo Γ b,ey1,4'diazepine hydrochloride,
- 17 5-(J-Bminopropyl)-11-(3-bromophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride, and
-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo [b,e][l,4]diazepine hydrochloride , there were obtained:
a) 11-(2-chlorophenyl)-N-methyl-5H-dibenzo[b, e ] [ 1,4 ] diazepin-5-propanamine hydrochloride,
b) 11-(3-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4] dinzepin-5-propanamine hydrochloride,
c) ll-(2-fluorophenyl)-N-methyl-5H-dibenzo[b,el[l,4] diazepin-5-propananiine hydrochloride ,
d) 11-(3-fluorophenyl)-N-methyl-5H-dibenzo[b,e][1,4] diazepin-5-propanamine hydrochloride,
e) 11-(2-bromophenyl)-N-methyl-5H-dibenzo[b,e][1,4] 15 diazepin-5-propanamine hydrochloride ,
f) 11-(3-bromophenyl)-N-methyl-5H-dibenzo[b,e][1,4] diazepin-5-propanamine hydrochloride , and
g) 11-( 4-chlorophenyl) -N-methyl-5H-.dibenzo[ b, e ] [ 1,4 ] dia2epin-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 inodes 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, 5θ> or 100 milligrams or 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 5θ0 milligrams per unit dose. Daily dosages usually required should range from about 0-5 to about 20 mgAq/day, preferably 0-5 to 10 mgAg· 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
- 19 5.
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 13a tol3e Capsules of 10 mg and 50 mg 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 10 mg 13b 50 mg Typical blend for Per Per encapsulation Capsule Caosule 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:
.
Example 13c 100 mg. per 13d 250 mg. per 13e 500 mg. per Ingredients Capsule Capsule Capsule Active ingredient, as salt 100 250 500 Lactose 214 163 95 Starch 87 81 47 Magnesium stearate _4 _6 _8 Total 299 500 650
.
- 20 5.
.
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 dicalciura phosphate.
Per Tablet, 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 a 12 mesh (U.S. sieve series) screen.
The dried granules were blended with the calcium stearate and compressed. 8 mesh has openings of 2.38 mm; 12 mesh of 1.68 mm.
EXAMPLE 15
An injectable sterile 2% solution was made up as follows:
.
- 21 Per cc
Active ingredient tag. 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 (17)
1. A compound having the formula: 1 2 wherein R and R 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)-ll-phenyl-5H-dibenzo[b,e] [1,4] diazepine.
3. A compound as claimed in Claim 1 which is 5-(3-dimethylaminopropyl)-ll-phenyl-5H-dibenzo[b,e] [1,4] diazepine, fumarate [1:1] .
4. A compound having the formula: wherein X represents a hydrogen, chlorine, bromine or ( 23 1 2 fluorine atom, end R and R both represent a hydrogen 1 2 atom or R represents a hydrogen atom when R 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. —24
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 12.
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 defined in any one of Claims 1 to 4, and (b) a pharmaceutical carrier therefor. ϊ - 25
10. A pharmaceutical composition as claimed in Claim 9 in which the compound is 5-{3-dimethylaminopropyl) -ll-phenyl-5H-dibenzoJb,e] [1,4] diazepine.
11. A pharmaceutical composition as claimed in Claim 9 in which the compound is 5-(3-dimethylaminopropyl)-ll-phenyl-5H-dibenzo [b,e] [1,4] diazepine fumarate.
12. 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 15.
13. A pharmaceutical composition in unit dosage form comprising at least 5mg per unit dosage of a compound having the formula: - 26 1 2 wherein R and R each represent a hydrogen atom or a methyl group, X represents 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-5H-dibenzo [b,e] [1,4] diazepine.
15. A process for producing a compound according to claim 1,substantially as hereindescribed with reference to the Examples.
16. A process for producing a compound according to claim 4, substantially as herein described with reference to the Examples.
17. A process for producing a compound according to claim 5, substantially as herein described in the Preparations. MACLACHLAN & DONALDSON Applicants' Agents
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30507681A | 1981-09-24 | 1981-09-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE812770L IE812770L (en) | 1983-03-24 |
| IE51880B1 true IE51880B1 (en) | 1987-04-15 |
Family
ID=23179221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2770/81A IE51880B1 (en) | 1981-09-24 | 1981-11-25 | 5-(aminoalkyl)-11-phenyl-5h-dibenzo(b,e)(1,4)diazepines in the treatment of depression |
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) | ES8207157A1 (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 |
| NL256053A (en) * | 1959-09-22 | |||
| AT226721B (en) * | 1959-09-22 | 1963-04-10 | Wander Ag Dr A | Process for the preparation of new, 5-substituted diazepines |
-
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 NZ NZ198986A patent/NZ198986A/en unknown
- 1981-11-17 GR GR66552A patent/GR75123B/el unknown
- 1981-11-25 IE IE2770/81A patent/IE51880B1/en unknown
- 1981-11-25 PH PH26538A patent/PH16696A/en unknown
- 1981-11-27 CH CH65/85A patent/CH657126A5/en not_active IP Right Cessation
- 1981-11-27 CH CH7633/81A patent/CH651028A5/en not_active IP Right Cessation
- 1981-11-27 FR FR8122288A patent/FR2513249B1/en not_active Expired
- 1981-11-27 LU LU83798A patent/LU83798A1/en unknown
- 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 HU HU813778A patent/HU187394B/en not_active IP Right Cessation
- 1981-12-15 ES ES507970A patent/ES8207157A1/en not_active Expired
- 1981-12-15 AU AU78513/81A patent/AU549806B2/en not_active Ceased
- 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 JP JP56215952A patent/JPS5865280A/en active Granted
- 1981-12-29 NL NL8105892A patent/NL8105892A/en not_active Application Discontinuation
-
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
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