CA1199325A - Method of treating depression with 5-(aminoalkyl)-11- phenyl-5h-dibenzo¬b,e|¬1,4| diazepines - Google Patents
Method of treating depression with 5-(aminoalkyl)-11- phenyl-5h-dibenzo¬b,e|¬1,4| diazepinesInfo
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- CA1199325A CA1199325A CA000394124A CA394124A CA1199325A CA 1199325 A CA1199325 A CA 1199325A CA 000394124 A CA000394124 A CA 000394124A CA 394124 A CA394124 A CA 394124A CA 1199325 A CA1199325 A CA 1199325A
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- 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
METHOD OF TREATING DEPRESSION WITH
5-(AMINOALKYL)-11-PHENYL-5H-DIBENZO
[b,e][1,4]DIAZEPINES
ABSTRACT OF THE INVENTION
A method of treating depression with 5-(aminoalkyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazepines having the formula:
5-(AMINOALKYL)-11-PHENYL-5H-DIBENZO
[b,e][1,4]DIAZEPINES
ABSTRACT OF THE INVENTION
A method of treating depression with 5-(aminoalkyl)-11-phenyl-5H-dibenzo[b,e][1,4]diazepines having the formula:
Description
AMR~ll 1 0 METEIOD OF' TREATING DEPRF,SSION WITH
5-(~MINOALK~L)-11-P~ N~J-5H-DI13EN7.0 ~ b, e ~ [ 1, 4 ]DIAZEPINES
B~CKG ROUND OE' TE~ :[NVE~IT ION
1. Field of Invention~
Th~ present invention relates to a mekhod of treat1ng depre~sion in humans with certain 5-(aminoa1kyl)-11-pheny1~5H~dib~nzo~b~ e l ~1, 4 ~diazepines . Som2 o the 5 compounds are nove1.
5-(~MINOALK~L)-11-P~ N~J-5H-DI13EN7.0 ~ b, e ~ [ 1, 4 ]DIAZEPINES
B~CKG ROUND OE' TE~ :[NVE~IT ION
1. Field of Invention~
Th~ present invention relates to a mekhod of treat1ng depre~sion in humans with certain 5-(aminoa1kyl)-11-pheny1~5H~dib~nzo~b~ e l ~1, 4 ~diazepines . Som2 o the 5 compounds are nove1.
2. De~cription of the Prlor Art.
Wanderg A. in British Patent 907,646 di~clo~0s preparation of certain o the dibonzodiaz~pines ukilized in the method of thi~ invention; e.g., the active inyredient 10 of the compound o~ exampl~ 1 bf~low in the form of the maleate salt.
Wander, A. in British Patent 959g9911 di~c10ses utility of reduced .~orms, e.y., 5-(aminoalky1)~ pheny1-10 ,11 -dihydro-5H dibenæo~ b J e~l,4~diazepines as para 15 sympatho10gics, antihistaminesg spa3molytics, tranquilizexs and psychic energizers.
Greig, M. E.~ et al~ in J. Med~ Chem. 14, No. 2 page 1~3 (1971) discloses anaphylaxis activity of certain dibenæodiazepine homologs in mice particularly 2-chloro-5~
(dim~thylaminoethyl)-11-phenyl-5H dibenæocb~e~[~ ]dia2epine.
5UMM~RY OF THF, lNv~N~l~ION
The compounds use~ul in the method of treatin~
depression in this invention have the formula
Wanderg A. in British Patent 907,646 di~clo~0s preparation of certain o the dibonzodiaz~pines ukilized in the method of thi~ invention; e.g., the active inyredient 10 of the compound o~ exampl~ 1 bf~low in the form of the maleate salt.
Wander, A. in British Patent 959g9911 di~c10ses utility of reduced .~orms, e.y., 5-(aminoalky1)~ pheny1-10 ,11 -dihydro-5H dibenæo~ b J e~l,4~diazepines as para 15 sympatho10gics, antihistaminesg spa3molytics, tranquilizexs and psychic energizers.
Greig, M. E.~ et al~ in J. Med~ Chem. 14, No. 2 page 1~3 (1971) discloses anaphylaxis activity of certain dibenæodiazepine homologs in mice particularly 2-chloro-5~
(dim~thylaminoethyl)-11-phenyl-5H dibenæocb~e~[~ ]dia2epine.
5UMM~RY OF THF, lNv~N~l~ION
The compounds use~ul in the method of treatin~
depression in this invention have the formula
3~
~X
~ ~ Formula I
(cH~)3~RlRz wherein Rl and R~ are selected from the group consisting of hydrogen or methyl, X is selected from the group consisting of hydrogen~
chlorine, bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof.
Compounds wherein Rl and R~ are both hydrQgen or one is methyl and one is hydrogen are novel.
Pharmaceutically acceptable acid addition salts are those salts which are physiologically compatible, such salts being formed either by strong o~ weak. acids. Repre-sentative of strong acids are hydrochloric, sulfuric and phosphoric acids. Representative of wea~ acids are fumaric, maleic, succinic, oxalic, cyclohexamic, and the like.
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 use~ulness of compounds for treating human depression was used as follows: 20 mg ~g of the compound to be tested was adminis tered to five adult female mice (ICR-DU~ strain)~ intra-peritoneally,30 minutes prior to the administration of a ptotic dose (32 mg ~ g, I.P.) of tetrabenazine (as the methane sulfonate salt). l'hirty 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 compourld in blocking -tetra-benaz-ine induced depression in mice, ~ollowing the procedure given by Litchfield et al.~ J. Pharmacol. E~p. Therap. ~6:
~10 3~S
99-113 (1949). The preferred dibenzodiazepine useful in the method of ~his invention is the active agent oE
Example l; namely, 5-(3-dimethylaminopropyl)-11-phenyl~5H-dibenzo~b,e~l,4]diazepine.
It is therefore an object to provide a method of treating depr~ssion and pha~naceutical cornpositions therefor .
Additional objects and advantayes of the present invention will be apparent to one skilled in the art and others will become apparent from the following description of the best mode of carrying out th~ present invention and from the appended claims.
DETAILED DESCRIPTION OF THE INVENTIO~
In the method of this invention the usual dosage forms f 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 ~-dimethylaminopropyl radical are prepared by cyclodehydration of the M-(3-dimethylamino-propyl)-o-benzamido-diphenylamines as in ~ritish Patent 907,645 using a dehydrating-condensation catalyst, for example, phosphorus pentoxide or oxyhalogenides of phos-phorus, preferably the latter, in a suitable solvent e.g.,1,1,2,2-tetrachloro~thane. ~he equation iso H POCl3 ~ X
\ N, ~ ~ ~N ~
IIa (IC~l2)3 (CH2~3 la ~5 N(CH3~2 N(CH3~ 2 wherein X has the values assiyned under Formula I above~
l~lO
,1.,~6,:~"3~5 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~ phthalimido) propyl]-o-benzamido-diphenylamines (IIb) and thereafter converting the phthalimido moiety -to amino (NHz) with hydrazine and acid. The equation is:
10~ 1 X ~ l)NH~NHz ~ X
\ ~1 2)Acid ~N
C / (1 ~ (CH2~3 ~CHz~3 15 C~ ~C~O IIb ~C ~C~O III N~2 Ib wherein X has the values assigned under Formula I. Compounds of Formula III are al~o 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 tri-ethylorthoformate followed by reaction with sodium boro-hydride (procedure of Crocket & Blanton, 1974(1): 55-6 5ynthesis~. The equation is as follows:
30 ~ X ~ ~ X
1) (EtO)3CH y ~_N 2) NaBH4 ~ ~
35(CH2)3 Ib (CIHz)3 Ic l~lo 3~ ~ ~
The starting benzamido compounds II (IIa and IIb~
are prepared by a modi~ication of the procedure o British Patent 9079646. Ortho-nitro-diphenylamine is first reductively alkylated with a solution of 3-chloropropyl dimethylamine or 3~ phthalimido)-1-chloropropane and following this the nitro moiety is reduced with hydroyen 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 e~uation is as follows:
~ N ~ VI
1 NaH
1 2~ Cl-(CH2)3Q
~1~ V
(CH2~3 1 H2/Pd-C
~ N
(I~I2~s Pyridine ~ ~ COl-~50 ~//o C _ N ~ II
(III
~5 Q = -N(CH3)2 or l-phthalimido.
~o 3~5 Preparation 1 N-(3-Dimethylaminopropyl)-o-aminodiphenylamine.
A mixture of 32.0 g (0.107 mole) of N-(3-dimethyl-aminopropyl)-o-nitrodiphenylamine (b.p. 155/0.4 to 174 C./
o.33 mm), 100 ml of 200 proof ethyl alcohol and 1.5 g of 10~ palladium-on-carbon catalyst was shaken under hydrogen atmosphere at room temperature for 1 hr. After approxi-mately the theoretical amount of hydrogen was absorbed the catalyst was filtered off through a celite filter cake and solvent removed under reduced pressure. The residue was distilled under high vacuum as follows:
b.p. 7 C. Amt.,q Fraction 1 80-1~0/0.2 mm 4.0 2 130-137o/0.2 mm 7.0 3 137-142 /0.2 mm 15.5 Thin layer chromatography using 20~ methyl alcohol - 80~
benzene on silica gel, showed Fraction ~ to be quite pure.
Preparation 2 ~-(3-Dimethylaminopropyl)--o-benzamidodiphenylamine.
To a solution of 15.5 g (0.0575 mole) of N-(3-dimethyl-aminopropyl)-o-aminodiphenylamine in 100 ml of pyridine cooled to about 5 C. under nitrogen atmosphere was added 17.8 g (o.o6~ 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 the 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 sulfate and evaporated under reduced pressure. Residual pyridin~ was then removed under high vacuum (0.2 mm Hg) over night. Weight of the residual oil, the free base, was 24-9 g-~ 410 Oxalate Salt - To a hot ~olution of 4.0 g of the free base in isopropyl alcohol was added 1.35 y (0.0107 mole) of oxalic acid dihydrate. The precipitated oxalate salt of the title compound weighed 3.5 g and melted at 162-5 C. The salt after drying 1 hr at 97 98C. (refluxing propyl alcohol) and overnight at room ~emperature all at 0.1 mm Hg., analyzed as follows:
Analysis: Calculated for C25H29N3O5: C,67.37; H,6.31; ~,g.o6 Found : C,67.42; H,6~35; N,9.01 Preparation 3 Following the proceclure of Preparation 2 and substi-tuting 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
~X
~ ~ Formula I
(cH~)3~RlRz wherein Rl and R~ are selected from the group consisting of hydrogen or methyl, X is selected from the group consisting of hydrogen~
chlorine, bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof.
Compounds wherein Rl and R~ are both hydrQgen or one is methyl and one is hydrogen are novel.
Pharmaceutically acceptable acid addition salts are those salts which are physiologically compatible, such salts being formed either by strong o~ weak. acids. Repre-sentative of strong acids are hydrochloric, sulfuric and phosphoric acids. Representative of wea~ acids are fumaric, maleic, succinic, oxalic, cyclohexamic, and the like.
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 use~ulness of compounds for treating human depression was used as follows: 20 mg ~g of the compound to be tested was adminis tered to five adult female mice (ICR-DU~ strain)~ intra-peritoneally,30 minutes prior to the administration of a ptotic dose (32 mg ~ g, I.P.) of tetrabenazine (as the methane sulfonate salt). l'hirty 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 compourld in blocking -tetra-benaz-ine induced depression in mice, ~ollowing the procedure given by Litchfield et al.~ J. Pharmacol. E~p. Therap. ~6:
~10 3~S
99-113 (1949). The preferred dibenzodiazepine useful in the method of ~his invention is the active agent oE
Example l; namely, 5-(3-dimethylaminopropyl)-11-phenyl~5H-dibenzo~b,e~l,4]diazepine.
It is therefore an object to provide a method of treating depr~ssion and pha~naceutical cornpositions therefor .
Additional objects and advantayes of the present invention will be apparent to one skilled in the art and others will become apparent from the following description of the best mode of carrying out th~ present invention and from the appended claims.
DETAILED DESCRIPTION OF THE INVENTIO~
In the method of this invention the usual dosage forms f 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 ~-dimethylaminopropyl radical are prepared by cyclodehydration of the M-(3-dimethylamino-propyl)-o-benzamido-diphenylamines as in ~ritish Patent 907,645 using a dehydrating-condensation catalyst, for example, phosphorus pentoxide or oxyhalogenides of phos-phorus, preferably the latter, in a suitable solvent e.g.,1,1,2,2-tetrachloro~thane. ~he equation iso H POCl3 ~ X
\ N, ~ ~ ~N ~
IIa (IC~l2)3 (CH2~3 la ~5 N(CH3~2 N(CH3~ 2 wherein X has the values assiyned under Formula I above~
l~lO
,1.,~6,:~"3~5 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~ phthalimido) propyl]-o-benzamido-diphenylamines (IIb) and thereafter converting the phthalimido moiety -to amino (NHz) with hydrazine and acid. The equation is:
10~ 1 X ~ l)NH~NHz ~ X
\ ~1 2)Acid ~N
C / (1 ~ (CH2~3 ~CHz~3 15 C~ ~C~O IIb ~C ~C~O III N~2 Ib wherein X has the values assigned under Formula I. Compounds of Formula III are al~o 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 tri-ethylorthoformate followed by reaction with sodium boro-hydride (procedure of Crocket & Blanton, 1974(1): 55-6 5ynthesis~. The equation is as follows:
30 ~ X ~ ~ X
1) (EtO)3CH y ~_N 2) NaBH4 ~ ~
35(CH2)3 Ib (CIHz)3 Ic l~lo 3~ ~ ~
The starting benzamido compounds II (IIa and IIb~
are prepared by a modi~ication of the procedure o British Patent 9079646. Ortho-nitro-diphenylamine is first reductively alkylated with a solution of 3-chloropropyl dimethylamine or 3~ phthalimido)-1-chloropropane and following this the nitro moiety is reduced with hydroyen 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 e~uation is as follows:
~ N ~ VI
1 NaH
1 2~ Cl-(CH2)3Q
~1~ V
(CH2~3 1 H2/Pd-C
~ N
(I~I2~s Pyridine ~ ~ COl-~50 ~//o C _ N ~ II
(III
~5 Q = -N(CH3)2 or l-phthalimido.
~o 3~5 Preparation 1 N-(3-Dimethylaminopropyl)-o-aminodiphenylamine.
A mixture of 32.0 g (0.107 mole) of N-(3-dimethyl-aminopropyl)-o-nitrodiphenylamine (b.p. 155/0.4 to 174 C./
o.33 mm), 100 ml of 200 proof ethyl alcohol and 1.5 g of 10~ palladium-on-carbon catalyst was shaken under hydrogen atmosphere at room temperature for 1 hr. After approxi-mately the theoretical amount of hydrogen was absorbed the catalyst was filtered off through a celite filter cake and solvent removed under reduced pressure. The residue was distilled under high vacuum as follows:
b.p. 7 C. Amt.,q Fraction 1 80-1~0/0.2 mm 4.0 2 130-137o/0.2 mm 7.0 3 137-142 /0.2 mm 15.5 Thin layer chromatography using 20~ methyl alcohol - 80~
benzene on silica gel, showed Fraction ~ to be quite pure.
Preparation 2 ~-(3-Dimethylaminopropyl)--o-benzamidodiphenylamine.
To a solution of 15.5 g (0.0575 mole) of N-(3-dimethyl-aminopropyl)-o-aminodiphenylamine in 100 ml of pyridine cooled to about 5 C. under nitrogen atmosphere was added 17.8 g (o.o6~ 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 the 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 sulfate and evaporated under reduced pressure. Residual pyridin~ was then removed under high vacuum (0.2 mm Hg) over night. Weight of the residual oil, the free base, was 24-9 g-~ 410 Oxalate Salt - To a hot ~olution of 4.0 g of the free base in isopropyl alcohol was added 1.35 y (0.0107 mole) of oxalic acid dihydrate. The precipitated oxalate salt of the title compound weighed 3.5 g and melted at 162-5 C. The salt after drying 1 hr at 97 98C. (refluxing propyl alcohol) and overnight at room ~emperature all at 0.1 mm Hg., analyzed as follows:
Analysis: Calculated for C25H29N3O5: C,67.37; H,6.31; ~,g.o6 Found : C,67.42; H,6~35; N,9.01 Preparation 3 Following the proceclure of Preparation 2 and substi-tuting 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, 20 there are obtained-N-(3-dimethylaminopropyl)-o-(2-chlorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-chlorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2-fluorobenzamido) diphenylamine, ~-(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-(LI-chlorobenzamido) diphenylamine.
~9~
Preparation 4 N-C3-(l-Phthalimido)propyl~-o-aminodiphenylamine.
o-Mitrodiphenylamine 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 ~
When in the procedure of Preparation 2, N-3-(1-phthalimido)propyl-o-aminodiphenylamine is reacted with each of the following acyl chlorides in ex~ess 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-benzoyl chloride~ and 4-chloro-benzoyl chloride, there are obtained:
N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-bromobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-bromobenæamido) diphenylamine, and N-3-(1-phthalimido)propyl-o-(4-chlorobenzarnido) diphenylamine.
The following non-limiting examples will Eurther illustrate the compounds which are useful in the practice of the method of this invention.
o Example 1
~9~
Preparation 4 N-C3-(l-Phthalimido)propyl~-o-aminodiphenylamine.
o-Mitrodiphenylamine 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 ~
When in the procedure of Preparation 2, N-3-(1-phthalimido)propyl-o-aminodiphenylamine is reacted with each of the following acyl chlorides in ex~ess 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-benzoyl chloride~ and 4-chloro-benzoyl chloride, there are obtained:
N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(2-bromobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-bromobenæamido) diphenylamine, and N-3-(1-phthalimido)propyl-o-(4-chlorobenzarnido) diphenylamine.
The following non-limiting examples will Eurther illustrate the compounds which are useful in the practice of the method of this invention.
o Example 1
5-(3-Dimethylaminopropyi)~ phenyl-5H-dibenzo [b~e]~l~4~diazepine~ fumarate Cl~
A stirred mixture of 18.9 g (0.05 mole) of N-(3-dimethylaminopropyl)-o-benzamidodiphenylamine and 32.19 g (0.2 mole) oE phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane was heated at ]50C. under nitroyen 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 dis-carded. The aqueous layer was basified with 3 N sodium hydroxide and extracted with three - 250 ml portions of methylene chloride. These three methylene chloride washes were combined, dried over magnesium 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 C28H29N3O4: C,71.32; H,6.20;
N,8.91 Found : C,71.19, H 6.19, N,8.89 Example 2 Following the procedure of Example 1 and substituting equal molar amounts of the following for N-(3-dimethylamino-propyl)-o-benzamidodiphenylamine:
N-(3-dirnethylaminopropyl)-o-(2-chlorobenzamido) diphenylamine, N~(3-dimethylaminopropyl)-o~(3-chlorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2~fluorobenzamido) diphenylamine, N-(3 dimethylaminopropyl)-o-(3-fluorobenzamido) ~5 diphenylamine, ~10 N-(3-dimethylaminopropyl)-o-(2-bromobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, and N-(~-dimethylaminopropyl)-o-(4-chloroben~amido) diphenylamine~
there are obtained:
11-(2-chlorophenyl)-5-~-dimethylaminopropyl)-5H-dibenzo~b,e][l,4]diazepine, fumarateJ
11-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~1,4~diazepine, fumarate, 11-(2-fluorophenyl)-5-(3~dimethylaminopropyl)-5H-dibenzo~b,e~ 4]diazepine, fumarate, 11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5H
Aibenzo[b,e]rl,41diazepine, fumarate, 11-(2-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e][l,4~diazepine, fumarate, 11-(3-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~l,43diazepine, fumarate, and 11-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~[l,4]diazepine, fumarate.
Example 3 When in the procedure of Example 1 prior to addition of fumari.c acid, the following are substituted for N-(3-dimethylaminopropyl)-o~benzamidodiphenylamine:
~-3-(l-phthalimido)propyl-o-benzamidodiphenylamineg N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o--(2~fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-~3-fl~orobenæamido) diphenylamine, N-3-(l~phthalimido)propyl-o-(2-bromobenæamido) diphenylamine, 1~10 3~
N-3~ phthalimido)propyl-o-(3-bromobenzamido) diphenylamine 3 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~l,4~diazepine, 5-~3-(1-phthalimido)propyl~-11-(3-chlorophenyl)-5H-dibenzo~b,e~r 1,4]diazepine~
5 -r ~- (1-phthalimido)propyl]-11-(2-fluorophenyl)-5H-dibenzo~b~e~lJ4]dia2epine~
5-~3-(1-phthalim~ido)propyl~-11-(3-fluorophenyl)-5H-dibenzo~b~e~[l,4~diazepine, 5-~3-(1-phthalimido)propyl]-11-(2-bromophenyl)-5H-dibenzo[b,e]~l,41diazepine, 5 E 3~ ( 1 -phthalimido)prQpyl]-ll-(3-bromophenyl)-5H
dibenzoCbge][1,4]diazepine, 5-~3-(1-phthalimido)propyl]-11-(4-chlorophenyl)-5H-dibenzo~b,e][l,4]diazepine.
Example 1 5-~3-Aminopropyl)-ll-phenyl-5H-dibenæorb,e~rl~4 diazepine hydrochloride.
A mixture of 0.035 mole of 5-~3-(1-phthalimido~propyl-ll-phenyl-5H-dibenzo~b~e~1,4]diazepine, 0.039 mole of hydrazine hydrate and 175 ml of 190 proof ethyl alcohol i9 refluxed for ~.5 hr and allowed to stand for several hours.
A solution of 10 ml concentrated hydrochloric acid in 50 ml water is 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 from a suitable solvent and dried under reduced pressure.
~xample_~
Following the procedure of Example 4 and s~lbstituting equal molar amounts of the following for 5-[3-(1-phthalimido) propyl]-ll-phenyl-5H-dibenzo[b,elC1,4~diazepine:
11-(2-chlorophenyl)-5-[3~ phthalimido)propyl]-5~-dibenzorb,e~l,41diazepine, 11-(3-chlorophenyl)-5-[3-(1-phthalimido)propyll-5H-dibenzo[b,e]~l,4]diazepine, 11-(2-fluorophenyl)-5-~3-(1-phthalimido)propyl]-5H-dibenzo~b,e~1,4~diazepine, 1011-(3-fluorophenyl) 5-[3-(1-phthalimido)propyl]-5H-dibenzo~b,e][l,4]diazepine, 11-(2-bromophenyl)-5-~3-(1-phthalimido)propyl]-5H-dibenzo[b,el~l,4]diazepine, 11-(3-bromophenyl)-5-~3-(1-phthalimido)propyl~-5H-dibenzorb,e~l,4~diazepine, and 11-(4-chlorophenyl)-5-[3-(1-phthalimido)propyl~-5H-dibenzo~b,e~rl,4ldiazepine,there are obtained:
5-(3-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo ~b,el~1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo [b,e]~1,4~diazepine hydrochloride, 5-(3-aminopropyl)~ (2-~luorophenyl)-5H-dibenzo [b,el[1,4~diazepine hydrochloride, 255-(3-aminopropyl)-11-(3-fluorophenyl~-5H-dibenzo [b,el~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 rb,e~l,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo [b,e~[1,4]diazepine hydrochloride~
~1.0 ~t3 Example N~ le thyl~ phenyl -5H--clibenzor b ~ e l r :L ~ 4 ] diazepin-5 propanamine 9 hydrvchloride.
The hydrocllloride salt of 5~(3-aminopropyl)-1]-pherlyl-5H-dibenzoi;b,e][1,4~diazepine is converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride layer to drynessJadding dry benzene and again concentrating to drive off the benzene. The xesulting free base is dissolved in a large excess of freshly distilled triethyl-orthoformate with refluxing for several hours. The mixtureis concentrated in vacuo, ethanol is added and the mixture concentrated again. The resulting imidate is dissolved in ethanol and sod:ium borohydride is added with stirring at 15-20 C. until thin-layer chromatography indicates the absence of substantial amount of starting material. The mixture is cooled and gradually flooded with water followed by extraction with ethylacetate. The ethylacetate layer is washed to neutrality and salted, filtered and evaporated.
Crude free base is isolated by column chrom~tography ~nd reacted with etherea1 hydrogen chloride and recryst~llized to give the title compound.
Example 7 Following the procedure of Example 6 and substituting equal molar amounts of the following for 5-(3-aminopropyl)-ll-phenyl-5H-dibenzoib~e]~l~4~diazepine:
5-(3-aminopropyl-11-(2-chlorophenyl)-5H-dibenzo [b,e]rl,4~diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo ~b,e]~1,4]diazepine hydrochloride, 305-(3-aminopropyl)-11-(2-fluorophenyl)--5H-dibenzo ~b,e][1,4~diazepine hydrochloride, 5-(3~aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo ~b9e]~1,4]diaæepine hydrochloride, 5-(3-aminoprc~pyl)-11-(2-bromophenyl)-5H-dibenzo ~b,e]~1,41diazepine hydrochloride, I~lo 3 '~S
llJ
5~ anlirlopropyl)-11 ('3-hromophenyl)-5f~-diberlzo ,r~e~rl~43diazepine hyd~-ochloride, anr.l 5-(3-amirlopropyl)~ (4-chlorophenyl)-5H-dibenzo L~b,elr~ diaz~pine hydrvc~lloricle !
there are obtained, ll--(2-chlorophenyl) N-methyl-5~I~dibenzo~h,e~1,4]
diazepirl 5~prop~rlarnine hydrochloride, 11--(3-chlorophenyl)-N-methyl 5EI-dibenzo[~,e~1,4 dîazepin-5-propanamine hydrochloride, o 11- f 2-fll~orophenyl)-N-methyl-5H-dibenzo~b,el~1~4]
diazepirl-5~propanamine hydrochloride, 11-(3-fluorophenyl)-~-methyl-5H-dibenzo[b,e diazepin-5-propanamine hydrochloride, 11-(2-bromophenyl)-N-methyl-5H-dibenzo~b~e~1,4]
diazepin-5-propanamine hydrochloride, 11-(3-bromophenyl)~N-methyl-5H-dibenzo~b,e~C1,4 di.azepin-5-propanamine hydrochloride, and -chlorophenyl ~ -~l-methyl-5H-dibenzoL b, e ] [ 1, 4 ]
diazepin-5-prop~namine 'nydrochlorid~.
q~ 5 Formulation and ~dministrakion Effective quantities of the foregoing pharmacologically active compounds of Formula I may be a~ninistered to humans for therapeutic purposes according to usual modes of adminis-tration and in usual orms, such as orally in solu-tions, emulsions, suspensions, pills, tahlets and capsules9 in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.
Exemplary o~ solid carriers for oral administration are such as lactose~ magnesiumJ stearate, terra alba, sucrose, talc, stearic acid~ gelatin, agar, pectin or acacia.
Exemplary of liquid carriexs 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 parentexally acceptable oil; e.g., arachis oil contained in ampules.
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 ox 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. 'rwenty-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 20 mg ~g/day, preferably 0.5 to 10 mg ~g. The active ingredients of the invention may be combined wikh 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 dosaye form employed. ObviouslyJ
~5 several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, o~ cours4, be demonstrated according to ~10 ~tandard medlc~ rinciples un~P~r the direction o a physic: ian or vete:rinarian.
T~E3 :~ollc)wing formula'ciorl~ ara sepr~entatlve fo.r the pharTn~cologic~lly ac~:iv~ compound~ of t~ en~lon.
~ kllJI~T I01~7S
l . Cap~u le ~
Capsules o;~ lû mg ~rld 50 mg of ac:tive ingres~ier~t p~r cap~ule are ps~p~r~dO With the hi~he~ amount~; of active ingredient, reduction may be ~nade in thP am~unt of 10 lacto 10 mg. 5Q mg~
~ypical blend for encapsulationner Capsule Per Cap ule Active ingradient, as ~alt lO 50 Lactose 259 2l9 Starch 126 126 Magnesium ~tearate 11 4 Total 399 399 Additional capsule formul~ion3 preferably con~ain a higher do3age of active ingredient a:nd are a~ follo~:
lO0 2~0 500 mg . pe rmg . pe rmg . pe r IngredientsCapsule Capsule Capsule ~ Active ingredient, 100 25~ 50Q
as ~alt Lactoqe 214 163 95 Starch 87 ol 47 Magnesium stearate 4 6 Total 399 500 650 ~5 In each case, uniformly bLend the selec~ed active ingredient with lactose, starch, and magnesium stearate and encapsulate the blendO
2 . Tabl e ts A ~ypi~al formula~ion for a tablet containing ~,0 5.0 mg of active ingredient per tablet follows. The forTnulation ma~ b~ u~ed ~or o~her strengths o:~ ac~ive ingredient by adiu~tment o:f weight of d.is~alcium phosphclte.
3~
Per Tablet, mg.
1. Acti~e is3gredient 10.~ "
. C~ a 15 . C~
~0 ~or~ ~ g p~
5. Dicalciuq~ ph~ ?ha~ 132.0 xlo~al ~02 . O
Uniformly blend 1 j 2, ~ and 5 . P:rsspar~ 3 a~ a 10 p~r oenl: Ela~te in w~ter~ Ç~ranul~t;~ th~ ~lend wi~ a;~ch Raa~
10 and ~E3as~ the wet ~ hrough an 8 me~h ~c:r~e3n~ The w~t ~ramllation i~ dri.ec~ and sized ~hrough a ï2 me~h ~cx nO
The dried granule~3 ax0 bl~nd~d with th2 e~alcium ~t~axat~
and compre3se~.
3. Injectable - 2% terile solll~ion P2r cc Active ingx~di~nt mg. 2 Pxeserva t ive, e . g . J
chloxobut~nol, ~/~rol~ pexr~ent 0.5 water for i~jection q . s .
Pr2par~ solutioil, clarify by :Eiltration, fill into 20 ~ ls, seal and autoclav~.
Vaxious modi.fications and ~ ivalents will be ap~res~t to one skilled in th~ axt and may b~ made ir:l the l-ompounds, Gs:mpo-~itions and m2thods ~f the pre~ent inlJention ~itho~lt departing from the spixit and scope thereof, and it i~
25 ~herefoxe understood that t}le inv ntion is 1to be limlted only by the scope of th2 appended cl~im~.
A stirred mixture of 18.9 g (0.05 mole) of N-(3-dimethylaminopropyl)-o-benzamidodiphenylamine and 32.19 g (0.2 mole) oE phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane was heated at ]50C. under nitroyen 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 dis-carded. The aqueous layer was basified with 3 N sodium hydroxide and extracted with three - 250 ml portions of methylene chloride. These three methylene chloride washes were combined, dried over magnesium 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 C28H29N3O4: C,71.32; H,6.20;
N,8.91 Found : C,71.19, H 6.19, N,8.89 Example 2 Following the procedure of Example 1 and substituting equal molar amounts of the following for N-(3-dimethylamino-propyl)-o-benzamidodiphenylamine:
N-(3-dirnethylaminopropyl)-o-(2-chlorobenzamido) diphenylamine, N~(3-dimethylaminopropyl)-o~(3-chlorobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(2~fluorobenzamido) diphenylamine, N-(3 dimethylaminopropyl)-o-(3-fluorobenzamido) ~5 diphenylamine, ~10 N-(3-dimethylaminopropyl)-o-(2-bromobenzamido) diphenylamine, N-(3-dimethylaminopropyl)-o-(3-bromobenzamido) diphenylamine, and N-(~-dimethylaminopropyl)-o-(4-chloroben~amido) diphenylamine~
there are obtained:
11-(2-chlorophenyl)-5-~-dimethylaminopropyl)-5H-dibenzo~b,e][l,4]diazepine, fumarateJ
11-(3-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~1,4~diazepine, fumarate, 11-(2-fluorophenyl)-5-(3~dimethylaminopropyl)-5H-dibenzo~b,e~ 4]diazepine, fumarate, 11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5H
Aibenzo[b,e]rl,41diazepine, fumarate, 11-(2-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e][l,4~diazepine, fumarate, 11-(3-bromophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~l,43diazepine, fumarate, and 11-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~[l,4]diazepine, fumarate.
Example 3 When in the procedure of Example 1 prior to addition of fumari.c acid, the following are substituted for N-(3-dimethylaminopropyl)-o~benzamidodiphenylamine:
~-3-(l-phthalimido)propyl-o-benzamidodiphenylamineg N-3-(1-phthalimido)propyl-o-(2-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-(3-chlorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o--(2~fluorobenzamido) diphenylamine, N-3-(1-phthalimido)propyl-o-~3-fl~orobenæamido) diphenylamine, N-3-(l~phthalimido)propyl-o-(2-bromobenæamido) diphenylamine, 1~10 3~
N-3~ phthalimido)propyl-o-(3-bromobenzamido) diphenylamine 3 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~l,4~diazepine, 5-~3-(1-phthalimido)propyl~-11-(3-chlorophenyl)-5H-dibenzo~b,e~r 1,4]diazepine~
5 -r ~- (1-phthalimido)propyl]-11-(2-fluorophenyl)-5H-dibenzo~b~e~lJ4]dia2epine~
5-~3-(1-phthalim~ido)propyl~-11-(3-fluorophenyl)-5H-dibenzo~b~e~[l,4~diazepine, 5-~3-(1-phthalimido)propyl]-11-(2-bromophenyl)-5H-dibenzo[b,e]~l,41diazepine, 5 E 3~ ( 1 -phthalimido)prQpyl]-ll-(3-bromophenyl)-5H
dibenzoCbge][1,4]diazepine, 5-~3-(1-phthalimido)propyl]-11-(4-chlorophenyl)-5H-dibenzo~b,e][l,4]diazepine.
Example 1 5-~3-Aminopropyl)-ll-phenyl-5H-dibenæorb,e~rl~4 diazepine hydrochloride.
A mixture of 0.035 mole of 5-~3-(1-phthalimido~propyl-ll-phenyl-5H-dibenzo~b~e~1,4]diazepine, 0.039 mole of hydrazine hydrate and 175 ml of 190 proof ethyl alcohol i9 refluxed for ~.5 hr and allowed to stand for several hours.
A solution of 10 ml concentrated hydrochloric acid in 50 ml water is 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 from a suitable solvent and dried under reduced pressure.
~xample_~
Following the procedure of Example 4 and s~lbstituting equal molar amounts of the following for 5-[3-(1-phthalimido) propyl]-ll-phenyl-5H-dibenzo[b,elC1,4~diazepine:
11-(2-chlorophenyl)-5-[3~ phthalimido)propyl]-5~-dibenzorb,e~l,41diazepine, 11-(3-chlorophenyl)-5-[3-(1-phthalimido)propyll-5H-dibenzo[b,e]~l,4]diazepine, 11-(2-fluorophenyl)-5-~3-(1-phthalimido)propyl]-5H-dibenzo~b,e~1,4~diazepine, 1011-(3-fluorophenyl) 5-[3-(1-phthalimido)propyl]-5H-dibenzo~b,e][l,4]diazepine, 11-(2-bromophenyl)-5-~3-(1-phthalimido)propyl]-5H-dibenzo[b,el~l,4]diazepine, 11-(3-bromophenyl)-5-~3-(1-phthalimido)propyl~-5H-dibenzorb,e~l,4~diazepine, and 11-(4-chlorophenyl)-5-[3-(1-phthalimido)propyl~-5H-dibenzo~b,e~rl,4ldiazepine,there are obtained:
5-(3-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo ~b,el~1,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo [b,e]~1,4~diazepine hydrochloride, 5-(3-aminopropyl)~ (2-~luorophenyl)-5H-dibenzo [b,el[1,4~diazepine hydrochloride, 255-(3-aminopropyl)-11-(3-fluorophenyl~-5H-dibenzo [b,el~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 rb,e~l,4]diazepine hydrochloride, 5-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo [b,e~[1,4]diazepine hydrochloride~
~1.0 ~t3 Example N~ le thyl~ phenyl -5H--clibenzor b ~ e l r :L ~ 4 ] diazepin-5 propanamine 9 hydrvchloride.
The hydrocllloride salt of 5~(3-aminopropyl)-1]-pherlyl-5H-dibenzoi;b,e][1,4~diazepine is converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride layer to drynessJadding dry benzene and again concentrating to drive off the benzene. The xesulting free base is dissolved in a large excess of freshly distilled triethyl-orthoformate with refluxing for several hours. The mixtureis concentrated in vacuo, ethanol is added and the mixture concentrated again. The resulting imidate is dissolved in ethanol and sod:ium borohydride is added with stirring at 15-20 C. until thin-layer chromatography indicates the absence of substantial amount of starting material. The mixture is cooled and gradually flooded with water followed by extraction with ethylacetate. The ethylacetate layer is washed to neutrality and salted, filtered and evaporated.
Crude free base is isolated by column chrom~tography ~nd reacted with etherea1 hydrogen chloride and recryst~llized to give the title compound.
Example 7 Following the procedure of Example 6 and substituting equal molar amounts of the following for 5-(3-aminopropyl)-ll-phenyl-5H-dibenzoib~e]~l~4~diazepine:
5-(3-aminopropyl-11-(2-chlorophenyl)-5H-dibenzo [b,e]rl,4~diazepine hydrochloride, 5-(3-aminopropyl)-11-(3-chlorophenyl)-5H-dibenzo ~b,e]~1,4]diazepine hydrochloride, 305-(3-aminopropyl)-11-(2-fluorophenyl)--5H-dibenzo ~b,e][1,4~diazepine hydrochloride, 5-(3~aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo ~b9e]~1,4]diaæepine hydrochloride, 5-(3-aminoprc~pyl)-11-(2-bromophenyl)-5H-dibenzo ~b,e]~1,41diazepine hydrochloride, I~lo 3 '~S
llJ
5~ anlirlopropyl)-11 ('3-hromophenyl)-5f~-diberlzo ,r~e~rl~43diazepine hyd~-ochloride, anr.l 5-(3-amirlopropyl)~ (4-chlorophenyl)-5H-dibenzo L~b,elr~ diaz~pine hydrvc~lloricle !
there are obtained, ll--(2-chlorophenyl) N-methyl-5~I~dibenzo~h,e~1,4]
diazepirl 5~prop~rlarnine hydrochloride, 11--(3-chlorophenyl)-N-methyl 5EI-dibenzo[~,e~1,4 dîazepin-5-propanamine hydrochloride, o 11- f 2-fll~orophenyl)-N-methyl-5H-dibenzo~b,el~1~4]
diazepirl-5~propanamine hydrochloride, 11-(3-fluorophenyl)-~-methyl-5H-dibenzo[b,e diazepin-5-propanamine hydrochloride, 11-(2-bromophenyl)-N-methyl-5H-dibenzo~b~e~1,4]
diazepin-5-propanamine hydrochloride, 11-(3-bromophenyl)~N-methyl-5H-dibenzo~b,e~C1,4 di.azepin-5-propanamine hydrochloride, and -chlorophenyl ~ -~l-methyl-5H-dibenzoL b, e ] [ 1, 4 ]
diazepin-5-prop~namine 'nydrochlorid~.
q~ 5 Formulation and ~dministrakion Effective quantities of the foregoing pharmacologically active compounds of Formula I may be a~ninistered to humans for therapeutic purposes according to usual modes of adminis-tration and in usual orms, such as orally in solu-tions, emulsions, suspensions, pills, tahlets and capsules9 in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.
Exemplary o~ solid carriers for oral administration are such as lactose~ magnesiumJ stearate, terra alba, sucrose, talc, stearic acid~ gelatin, agar, pectin or acacia.
Exemplary of liquid carriexs 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 parentexally acceptable oil; e.g., arachis oil contained in ampules.
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 ox 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. 'rwenty-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 20 mg ~g/day, preferably 0.5 to 10 mg ~g. The active ingredients of the invention may be combined wikh 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 dosaye form employed. ObviouslyJ
~5 several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages will, o~ cours4, be demonstrated according to ~10 ~tandard medlc~ rinciples un~P~r the direction o a physic: ian or vete:rinarian.
T~E3 :~ollc)wing formula'ciorl~ ara sepr~entatlve fo.r the pharTn~cologic~lly ac~:iv~ compound~ of t~ en~lon.
~ kllJI~T I01~7S
l . Cap~u le ~
Capsules o;~ lû mg ~rld 50 mg of ac:tive ingres~ier~t p~r cap~ule are ps~p~r~dO With the hi~he~ amount~; of active ingredient, reduction may be ~nade in thP am~unt of 10 lacto 10 mg. 5Q mg~
~ypical blend for encapsulationner Capsule Per Cap ule Active ingradient, as ~alt lO 50 Lactose 259 2l9 Starch 126 126 Magnesium ~tearate 11 4 Total 399 399 Additional capsule formul~ion3 preferably con~ain a higher do3age of active ingredient a:nd are a~ follo~:
lO0 2~0 500 mg . pe rmg . pe rmg . pe r IngredientsCapsule Capsule Capsule ~ Active ingredient, 100 25~ 50Q
as ~alt Lactoqe 214 163 95 Starch 87 ol 47 Magnesium stearate 4 6 Total 399 500 650 ~5 In each case, uniformly bLend the selec~ed active ingredient with lactose, starch, and magnesium stearate and encapsulate the blendO
2 . Tabl e ts A ~ypi~al formula~ion for a tablet containing ~,0 5.0 mg of active ingredient per tablet follows. The forTnulation ma~ b~ u~ed ~or o~her strengths o:~ ac~ive ingredient by adiu~tment o:f weight of d.is~alcium phosphclte.
3~
Per Tablet, mg.
1. Acti~e is3gredient 10.~ "
. C~ a 15 . C~
~0 ~or~ ~ g p~
5. Dicalciuq~ ph~ ?ha~ 132.0 xlo~al ~02 . O
Uniformly blend 1 j 2, ~ and 5 . P:rsspar~ 3 a~ a 10 p~r oenl: Ela~te in w~ter~ Ç~ranul~t;~ th~ ~lend wi~ a;~ch Raa~
10 and ~E3as~ the wet ~ hrough an 8 me~h ~c:r~e3n~ The w~t ~ramllation i~ dri.ec~ and sized ~hrough a ï2 me~h ~cx nO
The dried granule~3 ax0 bl~nd~d with th2 e~alcium ~t~axat~
and compre3se~.
3. Injectable - 2% terile solll~ion P2r cc Active ingx~di~nt mg. 2 Pxeserva t ive, e . g . J
chloxobut~nol, ~/~rol~ pexr~ent 0.5 water for i~jection q . s .
Pr2par~ solutioil, clarify by :Eiltration, fill into 20 ~ ls, seal and autoclav~.
Vaxious modi.fications and ~ ivalents will be ap~res~t to one skilled in th~ axt and may b~ made ir:l the l-ompounds, Gs:mpo-~itions and m2thods ~f the pre~ent inlJention ~itho~lt departing from the spixit and scope thereof, and it i~
25 ~herefoxe understood that t}le inv ntion is 1to be limlted only by the scope of th2 appended cl~im~.
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The method of preparing a compound selected from those having the formula:
wherein X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and R1 and R2 are both hydrogen or R1 is hydrogen when R2 is methyl, and the pharmaceutically acceptable acid addition salts thereof, which comprises a) when R1 and R2 are both hydrogen, converting the phthalimido moiety in a compound of the formula by reaction with hydrazine and acid, or b) when R1 is hydrogen and R2 is methyl, further reacting the 3-aminopropyl product of a) with triethylorthoformate and subsequently with sodium borohydride.
wherein X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and R1 and R2 are both hydrogen or R1 is hydrogen when R2 is methyl, and the pharmaceutically acceptable acid addition salts thereof, which comprises a) when R1 and R2 are both hydrogen, converting the phthalimido moiety in a compound of the formula by reaction with hydrazine and acid, or b) when R1 is hydrogen and R2 is methyl, further reacting the 3-aminopropyl product of a) with triethylorthoformate and subsequently with sodium borohydride.
2. A method according to claim 1a) wherein the starting compound is prepared by cyclodehydration of a compound of the formula:
3. A method of preparing 5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine which comprises reacting 11-(2-fluoro-phenyl)-5-[3-(1-phthalimido)propyl]-5H-dibenzo[b,,e][1,4] diazepine with hydrazine hydrate and concentrated hydrochloric acid.
4. A method according to claim 1a) wherein X is 2-fluoro.
5. A method of preparing N-methyl-11-(2-f1uorophenyl)-5H-dibenzo [b,e][1,4]diazepin-5-propanamine which comprises reacting 5-(3-aminopropyl) -11(2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine prepared according to the method of claim 3 with triethylorthoformate and then reacting the resulting imidate product with sodium borohydride.
6. A method according to claim 1b) wherein X is 2-fluoro,
7. A method according to claim 5 which further comprises reacting with oxalic acid to give the oxalate salt.
8. A compound selected from those having the formula:
wherein X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and R1 and R2 are both hydrogen or R1 is hydrogen when R2 is methyl, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 1 or 2 or by an obvious chemical equivalent thereof.
wherein X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and R1 and R2 are both hydrogen or R1 is hydrogen when R2 is methyl, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process of claim 1 or 2 or by an obvious chemical equivalent thereof.
9. 5-(3-Aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo[b,c][1,4]
diazepine whenever prepared by the process of claim 3 or 4 or by an obvious chemical equivalent thereof.
diazepine whenever prepared by the process of claim 3 or 4 or by an obvious chemical equivalent thereof.
10. N-Methyl-]11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepin-5-propanamine whenever prepared by the process of claim 5 or 6 or by an obvious chemical equivalent thereof.
11. N-Methyl-11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4]diazepine-5-propanamine oxalate [1:1] whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
12. A process for the preparation of a compound selected from those having the formula wherein; X is selected from the group consisting of hydrogen, chlorine, bromine or flourine, R1 and R2 are both hydrogen, or R1 is hydrogen when R2 is methyl, and the pharmaceutically acceptable acid addition salts thereof, comprising the steps of Step 1) reductively alkylating o-nitrodiphenylamine with a solution of 3-(1-phthalimido)-1-chloropropane to give a N-3-(1-phthalimido)propyl-o-nitrodiphenylamine compound having the formula Step 2) reducing the compound prepared in step 1 to give an N-[3-(1-phthalimido)propyl]-o-amino diphenylamine having the formula Step 3) reacting the compound prepared in step 2 with a benzoyl chloride of the formula to give an N-[3-(phthalimido)propyl]-o-benzamidodiphenylamine of the formula Step 4) cyclodehydrating the compound prepared in step 3 to give a 5-(3-phthalimidopropyl)-11-phenyl-5H-dibenzo [b,e][1,4] diazepine of the formula Step 5) reacting the compound prepared in step 4 with hydrazine and an acid to give a 5-(3-aminopropyl)-1-phenyl-5H-dibenzo [b,c][1,4] diazepine of the formula wherein R1 and R2 are both hydrogen, and Step 6) optionally reacting the compound prepared in step 5 with (a) triethylorthoformate (b) NaBH4 to give an N-methyl-11-phenyl-5H dibenzo[b,e][1,4]diazepine-5-propanamine of the formula wherein R1 is hydrogen and R2 is methyl.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000447323A CA1184561A (en) | 1981-09-24 | 1984-02-13 | Intermediates for preparation of anti-depressants |
| CA000447322A CA1184493A (en) | 1981-09-24 | 1984-02-13 | Anti-depressant compositions |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30507681A | 1981-09-24 | 1981-09-24 | |
| US305,076 | 1981-09-24 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000447322A Division CA1184493A (en) | 1981-09-24 | 1984-02-13 | Anti-depressant compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1199325A true CA1199325A (en) | 1986-01-14 |
Family
ID=23179221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000394124A Expired CA1199325A (en) | 1981-09-24 | 1982-01-14 | Method of treating depression with 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 |
|---|---|---|---|---|
| AT228215B (en) * | 1959-01-23 | 1963-07-10 | Wander Ag Dr A | Process for the production of new diazepine derivatives |
| GB907646A (en) * | 1959-01-23 | 1962-10-10 | Wander S A A | Method of production of new derivatives of diazepin |
| NL256049A (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 GR GR66552A patent/GR75123B/el unknown
- 1981-11-17 NZ NZ198986A patent/NZ198986A/en unknown
- 1981-11-25 PH PH26538A patent/PH16696A/en unknown
- 1981-11-25 IE IE2770/81A patent/IE51880B1/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
- 1981-11-27 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 IT IT68607/81A patent/IT1146729B/en active
- 1981-12-10 FI FI813975A patent/FI813975L/en not_active Application Discontinuation
- 1981-12-15 HU HU813778A patent/HU187394B/en not_active IP Right Cessation
- 1981-12-15 ES ES507970A patent/ES507970A0/en active Granted
- 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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| MKEX | Expiry |