CA1184493A - Anti-depressant compositions - Google Patents
Anti-depressant compositionsInfo
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- CA1184493A CA1184493A CA000447322A CA447322A CA1184493A CA 1184493 A CA1184493 A CA 1184493A CA 000447322 A CA000447322 A CA 000447322A CA 447322 A CA447322 A CA 447322A CA 1184493 A CA1184493 A CA 1184493A
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- dibenzo
- diazepine
- dimethylaminopropyl
- phthalimido
- propyl
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Abstract
ABSTRACT OF THE DISCLOSURE
A method of treating depression with compositions containing 5-(aminoalkyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazeepines having the formula:
A method of treating depression with compositions containing 5-(aminoalkyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazeepines having the formula:
Description
~8~
6197-1~9D
The present invention relates to a method of treating depression in humans with certain composi~ions containing 5-(aminoalkyl)~ phenyl-5H-dibenzo [b,e][1,4]diazepines.
This application is divided from copending application Serial No.
394,12~ filed January 14, 1982, the la~ter application being directed to novel compounds and their method of preparation, the novel compounds having the formula:
X
N
(CH2)3NR R
wherein X is selected from the group consis~ing of hydrogen, chlorine, bromine or fluorine, and Rl and R2 are both hydrogen or R1is hydrogen when R2 is methyl.
The novel compounds are also useful in treating depression.
Wander, A. in British Patent 907,646 discloses prepara~ionof cer~ain of the dibenzodiazepines utilized in the method ofthis invention; e.g., the active ingredient of the compound of example 1 belowin the form of the maleate salt.
Wander, A. in British Patent 959,994 discloses utility of reduced forms; e.g., 5-~aminoalkyl)-11-phenyl-10,11-dihydro-5H-dibenzo[b,e~[1,4]
diazepines as parasympa~hologics, antihistamines, spasmolytics, tranquilizers and psychic energizers.
Greig, M.E., e~ al, in J. Med. Chem. 1~, No. 2 page 153 ~1~71) discloses anaphylaxis activity of certain dibenzodiazepine homologs in mice - 1 - ~
~8~
particularly 2-chloro-5-(dimethylaminoethyl)-11-phenyl-5H-dibenzo[b~e][1,4]
diazepine.
According to the present invention, there is provided a pharmaceutical composition for treating depression in unit dosage form comprising (a) a pharmaceutically effective amount of a compound having the formula:
~ ~ X
N
N ~
(C~12)3N(CH3)2 X isselected from the group consisting of hydrogen, chlorine~
bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof, and (b) a pharmaceutical carrier therefor.
The present :invention, together with that of applicants aforementioned application Serial No. 394,124, will now be further described.
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, cyclohexamic9 and the like.
For the purpose of demonstrating antidepressant utility for the compounds of Formula I, the proceclure given by Englehardt, E.L.9 et al., J. Med. Chem. ll~2): 325 ~1968) which has been indicative in the past of usefulness of oompounds for treating human depression was used as follows:
6197-1~9D
The present invention relates to a method of treating depression in humans with certain composi~ions containing 5-(aminoalkyl)~ phenyl-5H-dibenzo [b,e][1,4]diazepines.
This application is divided from copending application Serial No.
394,12~ filed January 14, 1982, the la~ter application being directed to novel compounds and their method of preparation, the novel compounds having the formula:
X
N
(CH2)3NR R
wherein X is selected from the group consis~ing of hydrogen, chlorine, bromine or fluorine, and Rl and R2 are both hydrogen or R1is hydrogen when R2 is methyl.
The novel compounds are also useful in treating depression.
Wander, A. in British Patent 907,646 discloses prepara~ionof cer~ain of the dibenzodiazepines utilized in the method ofthis invention; e.g., the active ingredient of the compound of example 1 belowin the form of the maleate salt.
Wander, A. in British Patent 959,994 discloses utility of reduced forms; e.g., 5-~aminoalkyl)-11-phenyl-10,11-dihydro-5H-dibenzo[b,e~[1,4]
diazepines as parasympa~hologics, antihistamines, spasmolytics, tranquilizers and psychic energizers.
Greig, M.E., e~ al, in J. Med. Chem. 1~, No. 2 page 153 ~1~71) discloses anaphylaxis activity of certain dibenzodiazepine homologs in mice - 1 - ~
~8~
particularly 2-chloro-5-(dimethylaminoethyl)-11-phenyl-5H-dibenzo[b~e][1,4]
diazepine.
According to the present invention, there is provided a pharmaceutical composition for treating depression in unit dosage form comprising (a) a pharmaceutically effective amount of a compound having the formula:
~ ~ X
N
N ~
(C~12)3N(CH3)2 X isselected from the group consisting of hydrogen, chlorine~
bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof, and (b) a pharmaceutical carrier therefor.
The present :invention, together with that of applicants aforementioned application Serial No. 394,124, will now be further described.
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, cyclohexamic9 and the like.
For the purpose of demonstrating antidepressant utility for the compounds of Formula I, the proceclure given by Englehardt, E.L.9 et al., J. Med. Chem. ll~2): 325 ~1968) which has been indicative in the past of usefulness of oompounds for treating human depression was used as follows:
- 2 20 mg/kg o-f 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, I.P.) of tetrabenazine (as the methane sulfonate salt). Thirty minutes later, the presence or absenceofcomplete eyelid closure ptosis) was assessed in each animal. An ED50 (Median Effec~ive 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: 99-113 (1949). The preferred dibenzodiazepine useful in the method of this invention is the active agent of Example l;
namely, 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[bJe~[],~]diazepine.
In the method of this invention the usual dosage forms of active substance comprised of the active ingredient of Formula I with a suitable pharmaceutical carrier to provide solutions, syrups, elixirs, tablets, capsules, suppositories, powders, and the like are employed.
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-benzamido-diphenylamines as in British Patent 907,6~6 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:
~X ~X
~ 0 POC13 C - NH ^ ~ N~
N, ~ NC
~Cl~l2)3 (lH2~3 IIa N(CH3~2 N(CH3~2 Ia wherein X has the values assigned under FormulaI above.
The novel compounds of Formula I wllerein the 5-position is substituted by the 3-aminoyropyl radi.cal are prepared by cyclodehydration of novel N-[3~ phthalimido)propyl]-o-benzamido-diphenylamines ~IIb) and thereafter converting the phthalimido moiety to amino (NH2) ~ith hydrazine and acid. The equation is:
C POC13 ~ l)NH2N112 C~
~ ~ 2)Acid LN
C/ IN ~
(ICH2) 3 (~ll2) 3 (fH2) 3 ~`C' \ ~' 0~ ~0 NH2 IIb III Ib wherein ~ 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 3-monomethylpropyl amine are prepared by further reaction of the 3-amino-propyl compound with triethylorthoformate followed by reaction with sodium ~orohydride (procedure of Crocket ~ Blanton, 1974(1): 55-6 Synthesis). The equation is as follows:
- X 1) (EtO)3CH
2) NaBH4 ,~
( IH2)3 Ib IHCH3 IC
The starting henzamido compounds II (IIa and IIb) are prepared by a modification of the procedure of British Patent 907,646. Ortho-nitro-diphenylamine is first reductively alkylated with a solution of ~-chloropropyl dimethylamine or 3- (l-phthalimido)-l-chloropropane and following this the nitro moiety is reduced with hydrogen over palladium on carbon to give the corresponding ortho amino compound. The amino radicalin the ortho position is then reacted with benzoyl halide or a substituted benzoyl halide. The equation is as follows:
Nl ~ VI
1 ~ NaH
~) Cl- (CH2) 3Q
C/~
( I H2) 3 ~1, H2/Pd-C
~/ Nl ~ IV
(CH2) 3 Pyridine J~ ~ C-Cl ~X
C
NH ~
(IH2)3 II
Q
Q = -N(CH3)2 or l-phthalimido.
-- 6 _ ~E_ration 1 N-(3-Dimethylaminopropyll-o-aminodiphenylamine~
A mixture of 32.0 g (0.107 mole) of N-(3-dimethylaminopropyl)-o~
nitrodiphenylamine (b.p. 155 /0.4 to 174C./ 0.33 mm), 100 ml of 200 proof e-thyl alcohol and 1.5 g of 10% palladium-on-carbon catalyst was shaken under hydrogen atmosphere at room temperature for 1 hr. After approximately the theoretical amount of hydrogen was absorbed the catalys~ was filtered off through a celite filter cake and solvent removed under reduced pressure. The residue was distilled under high vacuum as follows:
10b.p.,c.
Fraction 1 80-130/0.2 mm 4.0 2 130-137/0.2 mm 7.0
Pharmacol. Exp. Therap. 96: 99-113 (1949). The preferred dibenzodiazepine useful in the method of this invention is the active agent of Example l;
namely, 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[bJe~[],~]diazepine.
In the method of this invention the usual dosage forms of active substance comprised of the active ingredient of Formula I with a suitable pharmaceutical carrier to provide solutions, syrups, elixirs, tablets, capsules, suppositories, powders, and the like are employed.
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-benzamido-diphenylamines as in British Patent 907,6~6 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:
~X ~X
~ 0 POC13 C - NH ^ ~ N~
N, ~ NC
~Cl~l2)3 (lH2~3 IIa N(CH3~2 N(CH3~2 Ia wherein X has the values assigned under FormulaI above.
The novel compounds of Formula I wllerein the 5-position is substituted by the 3-aminoyropyl radi.cal are prepared by cyclodehydration of novel N-[3~ phthalimido)propyl]-o-benzamido-diphenylamines ~IIb) and thereafter converting the phthalimido moiety to amino (NH2) ~ith hydrazine and acid. The equation is:
C POC13 ~ l)NH2N112 C~
~ ~ 2)Acid LN
C/ IN ~
(ICH2) 3 (~ll2) 3 (fH2) 3 ~`C' \ ~' 0~ ~0 NH2 IIb III Ib wherein ~ 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 3-monomethylpropyl amine are prepared by further reaction of the 3-amino-propyl compound with triethylorthoformate followed by reaction with sodium ~orohydride (procedure of Crocket ~ Blanton, 1974(1): 55-6 Synthesis). The equation is as follows:
- X 1) (EtO)3CH
2) NaBH4 ,~
( IH2)3 Ib IHCH3 IC
The starting henzamido compounds II (IIa and IIb) are prepared by a modification of the procedure of British Patent 907,646. Ortho-nitro-diphenylamine is first reductively alkylated with a solution of ~-chloropropyl dimethylamine or 3- (l-phthalimido)-l-chloropropane and following this the nitro moiety is reduced with hydrogen over palladium on carbon to give the corresponding ortho amino compound. The amino radicalin the ortho position is then reacted with benzoyl halide or a substituted benzoyl halide. The equation is as follows:
Nl ~ VI
1 ~ NaH
~) Cl- (CH2) 3Q
C/~
( I H2) 3 ~1, H2/Pd-C
~/ Nl ~ IV
(CH2) 3 Pyridine J~ ~ C-Cl ~X
C
NH ~
(IH2)3 II
Q
Q = -N(CH3)2 or l-phthalimido.
-- 6 _ ~E_ration 1 N-(3-Dimethylaminopropyll-o-aminodiphenylamine~
A mixture of 32.0 g (0.107 mole) of N-(3-dimethylaminopropyl)-o~
nitrodiphenylamine (b.p. 155 /0.4 to 174C./ 0.33 mm), 100 ml of 200 proof e-thyl alcohol and 1.5 g of 10% palladium-on-carbon catalyst was shaken under hydrogen atmosphere at room temperature for 1 hr. After approximately the theoretical amount of hydrogen was absorbed the catalys~ was filtered off through a celite filter cake and solvent removed under reduced pressure. The residue was distilled under high vacuum as follows:
10b.p.,c.
Fraction 1 80-130/0.2 mm 4.0 2 130-137/0.2 mm 7.0
3 137-142/0.2 mm 15.5 Thin layer chromatography using 20% methyl alcohol - 80% benzsne on silica gel, showed Fraction 3 to be quite pure.
Pr~ n 2 N-(3-Dimethylaminopropyl)-o-ben~amidodi~henylamine.
To a solution of 15.5 g (0.0575 mole) of N-~3-dimethylaminopropyl) -o-aminodiphenylamine in 100 ml of pyridine cooled to about 5C. under nitrogen atmosphere was added 17.8 g (0.063 mole) of ben~-oyl chloride. A small amount of benzene was used to wash the remaining ben7oyl chloride into the reac~ion vessel. The mixture was stirred for 1 hr and the vessel stoppered and placed in the refrigerator over the weekend. The solvent wasthen 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 sulfate and evapora~ed under reduced pressure. Residual pyridine was then removed under high vacuum (0.2 mm Hg) over night. Weight of ~he residual oil, the free base, was 24.9 g.
Oxalate Salt - To a hot solution of 4.0 g of the free base in isopropyl alcohol was added 1.~5 g (0.0107 mole) of oxalic acid dihydra~e. The precipitated oxalate salt of the ti~le compound weighed 3.5 g and melted a~
162-5C. The salt after drying 1 hr at 97-98C. (refluxing propyl alcohol) and overnight at room temperature all at 0.1 mm Hg., analyzed as follows:
Analysis: Calculated for C26H29N305: C,67;37; HJ6-31; N,9-06 Found : C,67.42; H,6.35; N,9.01 Preparation 3 Following the procedure of Preparation 2 andsubstituting 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
Pr~ n 2 N-(3-Dimethylaminopropyl)-o-ben~amidodi~henylamine.
To a solution of 15.5 g (0.0575 mole) of N-~3-dimethylaminopropyl) -o-aminodiphenylamine in 100 ml of pyridine cooled to about 5C. under nitrogen atmosphere was added 17.8 g (0.063 mole) of ben~-oyl chloride. A small amount of benzene was used to wash the remaining ben7oyl chloride into the reac~ion vessel. The mixture was stirred for 1 hr and the vessel stoppered and placed in the refrigerator over the weekend. The solvent wasthen 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 sulfate and evapora~ed under reduced pressure. Residual pyridine was then removed under high vacuum (0.2 mm Hg) over night. Weight of ~he residual oil, the free base, was 24.9 g.
Oxalate Salt - To a hot solution of 4.0 g of the free base in isopropyl alcohol was added 1.~5 g (0.0107 mole) of oxalic acid dihydra~e. The precipitated oxalate salt of the ti~le compound weighed 3.5 g and melted a~
162-5C. The salt after drying 1 hr at 97-98C. (refluxing propyl alcohol) and overnight at room temperature all at 0.1 mm Hg., analyzed as follows:
Analysis: Calculated for C26H29N305: C,67;37; HJ6-31; N,9-06 Found : C,67.42; H,6.35; N,9.01 Preparation 3 Following the procedure of Preparation 2 andsubstituting 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-ben20yl chloride, there are obtained:
N-(3-dimethylaminopropyl)-o-~2-chlorobenzamido) diphenylamine, N-~3-dimethylaminopropyl)-o-~3-chIorobenzamido) diphenylamine, N-~3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2-bromobenzamido) diphenylamine J
N-(3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine.
Prepara~ion 4 N-~3-(1-Phthalimido)propyl]-o-am~nodiphenylamine.
o-Nitrodiphenylamine is reacted with sodium hydride and 3-~1-phthalimido) -l-chloropropane to give N-3-~1-phthalimido)propyl-o-nitrodiphenylamine which is then reduced with hydrogen over palladium-on-carbon in ethanol to give the title compound.
Preparation S
When in the procedure of Preparation 2, N-3-(1-phthalimido)propyl-o-aminodiphenylamine is reacted with each of the followingacyl chlorides-in ex-cess in the manner of Preparation 2:
2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-ben~oyl chloride, and 4-chloro-benzoyl chloride, there are obtained:
N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, ~89~
N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine~
N-3-(l-phthalimido)propyl-o-(3-fluorobenzamido) diphenylamine I
N-3-(l-phthalimido)propyl-o-~2-bromobenzamido~
diphenylamine;
N-3-~1-phthalimido)propyl-o-~3-bromobenzamido) diphenylamine, and N-3-(1-phthalimido)propyl-o~ chloroben~amido) diphenylamine.
The following non-limiting examples will further illustrate the compounds which are useful in the practice of the method of this invention.
Example l
N-(3-dimethylaminopropyl)-o-~2-chlorobenzamido) diphenylamine, N-~3-dimethylaminopropyl)-o-~3-chIorobenzamido) diphenylamine, N-~3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2-bromobenzamido) diphenylamine J
N-(3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine.
Prepara~ion 4 N-~3-(1-Phthalimido)propyl]-o-am~nodiphenylamine.
o-Nitrodiphenylamine is reacted with sodium hydride and 3-~1-phthalimido) -l-chloropropane to give N-3-~1-phthalimido)propyl-o-nitrodiphenylamine which is then reduced with hydrogen over palladium-on-carbon in ethanol to give the title compound.
Preparation S
When in the procedure of Preparation 2, N-3-(1-phthalimido)propyl-o-aminodiphenylamine is reacted with each of the followingacyl chlorides-in ex-cess in the manner of Preparation 2:
2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-ben~oyl chloride, and 4-chloro-benzoyl chloride, there are obtained:
N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, ~89~
N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine~
N-3-(l-phthalimido)propyl-o-(3-fluorobenzamido) diphenylamine I
N-3-(l-phthalimido)propyl-o-~2-bromobenzamido~
diphenylamine;
N-3-~1-phthalimido)propyl-o-~3-bromobenzamido) diphenylamine, and N-3-(1-phthalimido)propyl-o~ chloroben~amido) diphenylamine.
The following non-limiting examples will further illustrate the compounds which are useful in the practice of the method of this invention.
Example l
5-(3 Dimethylaminopropyl)~ phenyl-5H-dibenzo [b,e][l,~]diazepine, fumarate [1:1].
A stirred mixture of 18.9 g (0.05 mole) of N-(3-dime~hylaminopropyl) -o-benzamidodiphenylamine and 32.19 g ~0.2 mole) of phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane was heated at 150C. under nitrogen atmos-phere 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 lO00 ml. The aqueous suspension was extracted twice with methylelle chloride and the methylene chloride layer discarded. The aqueous layer was basified with 3 ~ sodium hydroxide and extracted with three - 250 ml portions of methylene chloride. Thess three methylene chloride washes were combin~d, dried over mag-nesium sulfate 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 (0.039 mole) of fumaric acid. The fumarate salt was collected by filtration, yielding 13 g when dried, m.p.
168-170C.
Analysis: Calculated for C28H29N304: C,71.32; ~1~ 6 20;
Found : C,71.19; H, 6.19;
N, 8.89 Following the procedure of Example 1 and substituting equal molar amoun~s 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-bromobenzamido) diphenylamine, N-~3-dimethylaminopropyl)-o-~3-bromobenzamido) diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine, there are obtained:
11-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~[1,4]
diazepine, fumarate, 11-~3-chlorophenyl)-5-~3-dimethylaminopropyl)-5~1-dibenzo[b,e][1,4]
diazepine~ fumarate~
1l-(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b~e][l,~ldiazepine, fumarate, 11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5~1-dibenzo[b,e][1,4]diazepine, fumarate, 11-(2-bromophenyl)-5-~3-dimethylaminopropyl)-5H-dibenzo[b,e][l,4]diazepine, fumarate, 11-(3-bromophenyl)-5-(3-dimethylaminopropyl)-511-dibenzo[b,e][1,4~diazepine, fumarate, and ~ 4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e][1~4]diazepine, fumarate.
Example 3 When in ~he procedure of Example 1 prior ~o addition of fumaric acid, the following are substituted for N-~3-dimethylaminopropyl)-o-benzamidodiphenylamine:
N-3-(1-phthalimido)propyl-o-benzamidodiphenylamine, N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine, N-3-(l-phthalimido)propyl-o-(3-fluorob0nzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-bromobenzamido) diphenylamine, N-3~ phthalimido)propyl-o-(3-bromobenzamido) diphenylamine, and N-3-(1 phthalimido?propyl-o-(4-chlorobenzamido) diphenylamine, there are obtained:
5-[3-(1-phthalimido)propyl]-11-phenyl-5H-dibenzo [b,e][1,4]diazepine, 5-[3-(1-phthalimido)propyl]-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]diazcpine~
5-[3-(1-phthalimido)propyl]-11-(3-chlorophenyl)-5H-dibenzo[b,e][l,4]diazepineJ
5-[3-(1-phthalimido)propyl]-11-~2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine, 5-[3-(1-phthalimido3propyl]-11-(3-fluorophenyl)-5H-dibenzo[b,e][1~4]dia~epine, 5-[3-(1-phthalimido)propyl]-11-~2-bromophenyl)-5H-dibenzo[b,e][l,4]diazepine, 5-[3-(1-phthalimido)propyl]-11-(3-bromophenyl)-5H-dibenzo[b,e][l,4]dia~epine, 5-[3-(1-phthalimido)propyl]-11-(4-chlorophenyl)-5H-dibenzo[b,e][l,4]diazepine.
Example 4 5-(3-Aminopropyl)-ll-phenyl-5H-dibenzo[b,e][1,4]
diazepine hydrochloride.
A mixture of 0.035 mole of 5-[3-(1-phthalimido)propyl-11-phenyl-5H-dibenzoCb,e]c1~4]diazepine, 0.039 mole of hydrazine hydrate and 175 ml of 190 proof ethyl alcohol is re~luxed for 2.5 hr and allowed to stand for several hours. A solution of 10 ml concentrated hydrochloric acid in 50 ml ~ater is ~fl~
added to the mixture and the mixture is stirred for several hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The hydrochloride salt is isolated by recrystallization ~rom a suitable solvent and dried under reduced pressure.
Example 5 Following the procedure of Example 4 and substituting equal molar amounts of the following for 5-[3-~1-phthalimido)propyl]-11 phenyl-5H-dibenzo [b,e][1,4]diazeRine:
11-(2-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(3-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(2-fluorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(3-fluorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(2-bromophenyl)-5-[3-(1-phthalimido)propyl]-SH-dibenzo[b,e][l,4]diazepine, 11-(3-bromophenyl)-5-~3-~1 phthalimido)propylj-5H-dibenzo [b,e][1,4]diazepine, and 11-(4-chlorophenyl~-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,e]~l,4]diazepine, there are obtained.
5-(3-aminopropyl)-11-~2-chlorophenyl)-5H-dibenzo [b,e][1,4]diazepine hydrochloride, -i - 14 -5-(3-aminopropyl)~ (3-chlorophenyl)-5~1-dibenzo ~b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11--(2-~luorophenyl)-5H-dibenzo [b,e~[1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo [b,e][l,~]diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-bromophenyl)-SH-dibenzo [b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-bromophenyl)~5~1-dibenzo [b,e][l,~]diazepine hydrochloride, 5-(3-aminopropyl)-11-~-chlorophenyl)-5H-dibenzo [b,el~1,4]di~zepine hydrochloride.
Example 6 N-Me~hyl-ll-phenyl-5H-d _enzo~b,e3[1,4~diaze~in~5-propanamine,~hydrochloride.
The hydrochloride salt of 5-(3-aminopropyl)-11-phenyl-5H-dibenzo [b,e][1,4~diazepine is converted to the free base by partitioning between dilute sodium hydroxide and methylene chloridel dryingand concentrating the me*hylene chloride layer to dryness, adding dry benzene and again concentrating to drive off the benzene. The resulting free base is dissolved in a large excess of freshly distilled triethylorthoformate with refluxing for several hours. The mixture is concentrated in vacuo~ e*hanol is added and the mixture concentrated again. The resulting imidate is dissolvedin ethanol and sodium borohydride is added with stirring at 15-20 C. until thin-layer chromatography indicates the absence of substantial amount of starting ma~erial. The mixture is cooled and gradually flooded with water followed by extraction with ethylacetate. I`he ethylacetate layer is washed to neutrality and salted, filtered and evaporated. Crude -free base is isolated by column chromatography and reacted with ethereal hydrogen chloride and recrys~allized to give ~he ~itle compound.
Example 7 Follo~ing the procedure of Example 6 and substitutin~ equal molar amounts of the following for 5-(3-aminopropyl)-11-phenyl-5H-dibenæo[b,e][1,4]
diazepine:
5-~3-aminopropyl-11-~2-chlorophenyl)-SH-dibenzo[b,e][1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo~b,e][1,4]
diaæepine hydrochloride, 5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-~2-bromophenyl)-5H-dibenzo~b~e]~1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-~3-bromophenyl)-5H-dibenzo~b,e][1,4]
diazepine hydrochloride, and 5~-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride, there are obtained:
ll-t2-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4]
diazepin-5-propanamine hydrochloride, 11-(3-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4]
diazepin-5-propanamine hydrochloride, 11-(2-fluorophenyl)-N-methyl-5rl-dibenzo[b,e3[1,4]
diazepin-5-propanamine hydrochloride, 11-~3-fluorophenyl)-N-me'Lllyl-5H-dibenzo[b~e][1,~]
diazepin-5-propanamine hydrochloride, 11-(2-bromophenyl)-N-methyl-5H-diben~o[b,e][1,~3 diazepin-5-propanamine hydrochloride, 11-(3-bromophenyl)-N-methyl-~H-dibenzo[b,e~[1,4]
diazepin-5-propanamine hydrochloride, and 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 adminis-tration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutica].ly acceptable carriers and parenterally in the form of sterile solutions.
Exemplary of solid carriers ~or oral administration are such as lactose, magnesium, stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar 9 pectin or acacia.
Exemplary of liquid carriers ~or oral administration are vegetable oils and water.
For intramuscular admi.nistration 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 ampules.
Although very small quantities o 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 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 500 milligrams per unit dose. Daily dosages usually requlred should range from about 0.5 to a~out 20 mg/kg/day, preferaby 0.5 to 10 mg/kg. The active ingredients of the invention may be combined with other pharmacalogically active agents as s~ated 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, o~ course, be demonstrated according to standard medical principles under the direction of a physician or veterinarian.
The following formulations are representative for the pharmacologically active compounds of this invention.
FORMULATIONS
1. Capsules Capsules of 10 mg ~nd 50 mg of actlve ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.
10 mg. 50 mg.
Typical blend -Eor encapsulationPer Capsule Per 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 ac~ive ingredient and are as follows:
mg. per mg. per mg. per Ingredients Capsule Capsule Capsule .
Active ingredient, 100 250 500 as sal~
Lactose 214 163 95 Starch 87 81 47 Magnesium stearate 4 6 8 Total 399 500 650 In each case, uniformly blend the selected active ingredient with lactose, starchS and magnesium stearate and encapsulate the blend.
2. Tablets A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet follows. The formulation maybeusedfor other strengths o active ingredient by adjustment of weight of dicalcium phosphate.
Per Tablet, m~.
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
A stirred mixture of 18.9 g (0.05 mole) of N-(3-dime~hylaminopropyl) -o-benzamidodiphenylamine and 32.19 g ~0.2 mole) of phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane was heated at 150C. under nitrogen atmos-phere 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 lO00 ml. The aqueous suspension was extracted twice with methylelle chloride and the methylene chloride layer discarded. The aqueous layer was basified with 3 ~ sodium hydroxide and extracted with three - 250 ml portions of methylene chloride. Thess three methylene chloride washes were combin~d, dried over mag-nesium sulfate 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 (0.039 mole) of fumaric acid. The fumarate salt was collected by filtration, yielding 13 g when dried, m.p.
168-170C.
Analysis: Calculated for C28H29N304: C,71.32; ~1~ 6 20;
Found : C,71.19; H, 6.19;
N, 8.89 Following the procedure of Example 1 and substituting equal molar amoun~s 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-bromobenzamido) diphenylamine, N-~3-dimethylaminopropyl)-o-~3-bromobenzamido) diphenylamine, and N-(3-dimethylaminopropyl)-o-(4-chlorobenzamido) diphenylamine, there are obtained:
11-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~[1,4]
diazepine, fumarate, 11-~3-chlorophenyl)-5-~3-dimethylaminopropyl)-5~1-dibenzo[b,e][1,4]
diazepine~ fumarate~
1l-(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b~e][l,~ldiazepine, fumarate, 11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5~1-dibenzo[b,e][1,4]diazepine, fumarate, 11-(2-bromophenyl)-5-~3-dimethylaminopropyl)-5H-dibenzo[b,e][l,4]diazepine, fumarate, 11-(3-bromophenyl)-5-(3-dimethylaminopropyl)-511-dibenzo[b,e][1,4~diazepine, fumarate, and ~ 4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e][1~4]diazepine, fumarate.
Example 3 When in ~he procedure of Example 1 prior ~o addition of fumaric acid, the following are substituted for N-~3-dimethylaminopropyl)-o-benzamidodiphenylamine:
N-3-(1-phthalimido)propyl-o-benzamidodiphenylamine, N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine, N-3-(l-phthalimido)propyl-o-(3-fluorob0nzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-bromobenzamido) diphenylamine, N-3~ phthalimido)propyl-o-(3-bromobenzamido) diphenylamine, and N-3-(1 phthalimido?propyl-o-(4-chlorobenzamido) diphenylamine, there are obtained:
5-[3-(1-phthalimido)propyl]-11-phenyl-5H-dibenzo [b,e][1,4]diazepine, 5-[3-(1-phthalimido)propyl]-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]diazcpine~
5-[3-(1-phthalimido)propyl]-11-(3-chlorophenyl)-5H-dibenzo[b,e][l,4]diazepineJ
5-[3-(1-phthalimido)propyl]-11-~2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine, 5-[3-(1-phthalimido3propyl]-11-(3-fluorophenyl)-5H-dibenzo[b,e][1~4]dia~epine, 5-[3-(1-phthalimido)propyl]-11-~2-bromophenyl)-5H-dibenzo[b,e][l,4]diazepine, 5-[3-(1-phthalimido)propyl]-11-(3-bromophenyl)-5H-dibenzo[b,e][l,4]dia~epine, 5-[3-(1-phthalimido)propyl]-11-(4-chlorophenyl)-5H-dibenzo[b,e][l,4]diazepine.
Example 4 5-(3-Aminopropyl)-ll-phenyl-5H-dibenzo[b,e][1,4]
diazepine hydrochloride.
A mixture of 0.035 mole of 5-[3-(1-phthalimido)propyl-11-phenyl-5H-dibenzoCb,e]c1~4]diazepine, 0.039 mole of hydrazine hydrate and 175 ml of 190 proof ethyl alcohol is re~luxed for 2.5 hr and allowed to stand for several hours. A solution of 10 ml concentrated hydrochloric acid in 50 ml ~ater is ~fl~
added to the mixture and the mixture is stirred for several hours. The mixture is filtered and the filtrate evaporated under reduced pressure. The hydrochloride salt is isolated by recrystallization ~rom a suitable solvent and dried under reduced pressure.
Example 5 Following the procedure of Example 4 and substituting equal molar amounts of the following for 5-[3-~1-phthalimido)propyl]-11 phenyl-5H-dibenzo [b,e][1,4]diazeRine:
11-(2-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(3-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(2-fluorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(3-fluorophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo [b,e][1,4]diazepine, 11-(2-bromophenyl)-5-[3-(1-phthalimido)propyl]-SH-dibenzo[b,e][l,4]diazepine, 11-(3-bromophenyl)-5-~3-~1 phthalimido)propylj-5H-dibenzo [b,e][1,4]diazepine, and 11-(4-chlorophenyl~-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,e]~l,4]diazepine, there are obtained.
5-(3-aminopropyl)-11-~2-chlorophenyl)-5H-dibenzo [b,e][1,4]diazepine hydrochloride, -i - 14 -5-(3-aminopropyl)~ (3-chlorophenyl)-5~1-dibenzo ~b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11--(2-~luorophenyl)-5H-dibenzo [b,e~[1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo [b,e][l,~]diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-bromophenyl)-SH-dibenzo [b,e][1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-bromophenyl)~5~1-dibenzo [b,e][l,~]diazepine hydrochloride, 5-(3-aminopropyl)-11-~-chlorophenyl)-5H-dibenzo [b,el~1,4]di~zepine hydrochloride.
Example 6 N-Me~hyl-ll-phenyl-5H-d _enzo~b,e3[1,4~diaze~in~5-propanamine,~hydrochloride.
The hydrochloride salt of 5-(3-aminopropyl)-11-phenyl-5H-dibenzo [b,e][1,4~diazepine is converted to the free base by partitioning between dilute sodium hydroxide and methylene chloridel dryingand concentrating the me*hylene chloride layer to dryness, adding dry benzene and again concentrating to drive off the benzene. The resulting free base is dissolved in a large excess of freshly distilled triethylorthoformate with refluxing for several hours. The mixture is concentrated in vacuo~ e*hanol is added and the mixture concentrated again. The resulting imidate is dissolvedin ethanol and sodium borohydride is added with stirring at 15-20 C. until thin-layer chromatography indicates the absence of substantial amount of starting ma~erial. The mixture is cooled and gradually flooded with water followed by extraction with ethylacetate. I`he ethylacetate layer is washed to neutrality and salted, filtered and evaporated. Crude -free base is isolated by column chromatography and reacted with ethereal hydrogen chloride and recrys~allized to give ~he ~itle compound.
Example 7 Follo~ing the procedure of Example 6 and substitutin~ equal molar amounts of the following for 5-(3-aminopropyl)-11-phenyl-5H-dibenæo[b,e][1,4]
diazepine:
5-~3-aminopropyl-11-~2-chlorophenyl)-SH-dibenzo[b,e][1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo~b,e][1,4]
diaæepine hydrochloride, 5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-~2-bromophenyl)-5H-dibenzo~b~e]~1,4]
diazepine hydrochloride, 5-(3-aminopropyl)-11-~3-bromophenyl)-5H-dibenzo~b,e][1,4]
diazepine hydrochloride, and 5~-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride, there are obtained:
ll-t2-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4]
diazepin-5-propanamine hydrochloride, 11-(3-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4]
diazepin-5-propanamine hydrochloride, 11-(2-fluorophenyl)-N-methyl-5rl-dibenzo[b,e3[1,4]
diazepin-5-propanamine hydrochloride, 11-~3-fluorophenyl)-N-me'Lllyl-5H-dibenzo[b~e][1,~]
diazepin-5-propanamine hydrochloride, 11-(2-bromophenyl)-N-methyl-5H-diben~o[b,e][1,~3 diazepin-5-propanamine hydrochloride, 11-(3-bromophenyl)-N-methyl-~H-dibenzo[b,e~[1,4]
diazepin-5-propanamine hydrochloride, and 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 adminis-tration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutica].ly acceptable carriers and parenterally in the form of sterile solutions.
Exemplary of solid carriers ~or oral administration are such as lactose, magnesium, stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar 9 pectin or acacia.
Exemplary of liquid carriers ~or oral administration are vegetable oils and water.
For intramuscular admi.nistration 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 ampules.
Although very small quantities o 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 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 500 milligrams per unit dose. Daily dosages usually requlred should range from about 0.5 to a~out 20 mg/kg/day, preferaby 0.5 to 10 mg/kg. The active ingredients of the invention may be combined with other pharmacalogically active agents as s~ated 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, o~ course, be demonstrated according to standard medical principles under the direction of a physician or veterinarian.
The following formulations are representative for the pharmacologically active compounds of this invention.
FORMULATIONS
1. Capsules Capsules of 10 mg ~nd 50 mg of actlve ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.
10 mg. 50 mg.
Typical blend -Eor encapsulationPer Capsule Per 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 ac~ive ingredient and are as follows:
mg. per mg. per mg. per Ingredients Capsule Capsule Capsule .
Active ingredient, 100 250 500 as sal~
Lactose 214 163 95 Starch 87 81 47 Magnesium stearate 4 6 8 Total 399 500 650 In each case, uniformly blend the selected active ingredient with lactose, starchS and magnesium stearate and encapsulate the blend.
2. Tablets A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet follows. The formulation maybeusedfor other strengths o active ingredient by adjustment of weight of dicalcium phosphate.
Per Tablet, m~.
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 Uniformly blend 1, 2, ~ and 5. Prepare 3 as a 10 per cent paste in water. Granulate the blend with starch paste and passthe wet mass through an 8 mesh screen. The wet granulation is dried and sized through a 12 mesh screen. The dried granules are blended with the calcium stearate and compressed.
3. Injectable - 2% sterile solution Per cc Active ingredient mg. 20 Preservative, e.g., chlorobutanol, w/vol. percent 0.5 Water for injection q.s.
Prepare solution, clarify by filtration, fill into vials, seal and autoclave.
Various modifications and equivalen~s will be apparent to one skilled in the art and may be made in the compounds, compositions and methods of the present invention without departing from the spirit and scope thereof, and it is therefore understood that the invention is to ~e limited only by the scope of the appended claims.
3. Injectable - 2% sterile solution Per cc Active ingredient mg. 20 Preservative, e.g., chlorobutanol, w/vol. percent 0.5 Water for injection q.s.
Prepare solution, clarify by filtration, fill into vials, seal and autoclave.
Various modifications and equivalen~s will be apparent to one skilled in the art and may be made in the compounds, compositions and methods of the present invention without departing from the spirit and scope thereof, and it is therefore understood that the invention is to ~e limited only by the scope of the appended claims.
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition for treating depression in unit dosage form comprising (a) a pharmaceutically effective amount of a compound having the formula:
X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof, and (b) a pharmaceutical carrier therefor.
X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof, and (b) a pharmaceutical carrier therefor.
2. A pharmaceutical composition of claim 1 wherein the compound is 5-(3-dimethylaminopropyl)-11 phenyl-5H-dibenzo[b,e][1,4]diazepine.
3. A pharmaceutical composition of claim 1 wherein the compound is 5-(3-dimethylaminopropyl)-11-phenyl-5H-dibenzo[b,ee][1,4]diazepine fumarate.
4 The pharmaceutical composition of claim l wherein the compound is 11-(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e]
or its fumarate hydrate salt.
or its fumarate hydrate salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30507681A | 1981-09-24 | 1981-09-24 | |
| US305,076 | 1981-09-24 | ||
| CA000394124A CA1199325A (en) | 1981-09-24 | 1982-01-14 | Method of treating depression with 5-(aminoalkyl)-11- phenyl-5h-dibenzo¬b,e|¬1,4| diazepines |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000394124A Division CA1199325A (en) | 1981-09-24 | 1982-01-14 | Method of treating depression with 5-(aminoalkyl)-11- phenyl-5h-dibenzo¬b,e|¬1,4| diazepines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1184493A true CA1184493A (en) | 1985-03-26 |
Family
ID=25669533
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000447322A Expired CA1184493A (en) | 1981-09-24 | 1984-02-13 | Anti-depressant compositions |
| CA000447323A Expired CA1184561A (en) | 1981-09-24 | 1984-02-13 | Intermediates for preparation of anti-depressants |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000447323A Expired CA1184561A (en) | 1981-09-24 | 1984-02-13 | Intermediates for preparation of anti-depressants |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1184493A (en) |
-
1984
- 1984-02-13 CA CA000447322A patent/CA1184493A/en not_active Expired
- 1984-02-13 CA CA000447323A patent/CA1184561A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1184561A (en) | 1985-03-26 |
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