Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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.
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
AHR-410
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
NH2 NHCH3
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:
02N
~ 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.
410
~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.
410
12
~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
13
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
16
~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.
1110
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~.
