Note: Descriptions are shown in the official language in which they were submitted.
4 ~ ~ ~ 6197-149E
The present invention relates to a method of preparing novel
intermediates used in the formation of anti-depressants for humans,
the anti-depressants being 5-(aminoalkyl)-ll-phellyl-5H-dibenzo[b,e][1,4]
diazepines.
This application is divided from copending application Serial No.
394, 124 filed January 14, 1982,~he latter application being directed
to novel compounds used as anti-depressants and having the formula:
~-o~
~ ~ `-N ~ ~
(C~12~ NRlR
wherein X is selected from the group consisting of hydrogen, chlorine,
bromine or ~luorine, and Rl and R2 are both hydrogen or Rl is hydrogen
whcn R is methyl.
Waslder, A. in Brîtish Patent 907,646 discloses preparation of
eertain o ~he dib~nzodiazepines utilized in the method of this invention;
e.g., the active ingredient of the compound of example 1 below in the form
of the maleate salt.
Wander, A. in Bri~ish 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 parasympathologics, antihistamines, spasmolytics, tranquilizers
and psychic energizers.
Greig, M.E., et al, in J. Med. Chem. 14~ No. 2 page 153 (1971)
discloses anaphylaxis activity of certain dibenzodiazepine homologs in mice
5i6~
particularly 2-chloro-S-(dimethylaminoethyl)-ll-phenyl-511-dibenzo[b,e][1,4]
diazepine.
According to the present invention, ~here is provided a method of
preparing a compound selected from those having the formula:
/ C~
HN~
\ N /
(ICH2)3
\~0
~>
wherQin X is selected from the group consisti.ng of hydrogen, chlorine, bromine
and fluorine, which comprises reacting a compound of the formula
\~ N ~' /
o f 2 3 0
~/ ~C ~
~\
with a benzoyl halide or a halogen substituted benzoyl halide.
~4~
The present invention, ~ogether withthat of applicant's aforementioned
Canadian application Serial No. 394,124, will now be further described.
Pharmaceutically accep~able 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. Represen~ative of wea~ acids are fumaric, maleic, succinic,
oxalic, cyclohexamic, and the like.
For the purpose of demonstrating antidepressant utility for the
compounds of ~ormula I, the procedure given by Englehardt, E.L., et al., J.
Med. Chem. 11~2): 325 (196~ which has been indicative in the past of usefulness
of compounds for treating human depression wasused as follows: 20 mg/kg of
the compound to be tested was administered to five adult female mice ~ICR-DUB
straill), 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 absence of complete eyalid closure ~ptosis) was
assessed in each animal~ An ED50 (Median Effective Dose~ may be established
or cach tosted compoundin blocking tetrabena~ine induced depression in mice,
~eollowing the procedure given by Litchfield et al., J. Pharmacol. Exp. Therap.
95: 9~113 (19~9)~ 'I'he preferred dibenzodiazcpine useEul in the method of
__,
this invention is the active agent of Example l; namely, 5~3-dimethylamino
propyl)-ll-phenyl-5H-diben~o[b,e][1,4]diazepine.
In the method disclosed in aforementioned Serial No. 394,124, the
usual dosage forms of active substance comprised of ~he ac~ive 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-dimethylam.inopropyl radical are prepared by c.yclodehydration of the N-
(3-dimethylaminopropyl~-o-benzami~o-diphenylamines as in British Patent
907,646 using a dehydrating-condensation catalyst; for example, phosphorus
pentoxide or oxyhalogenides of phosphorus, preferably the latter, in a suitable
solvent; e,g,, 1,1,2,2-tetrachloroethane. The equation is:
X POCl ~ ~'X
NH - - 3 --~ ",~ N
C~` ~1 ~
(CIH2)3 ~CIH2)3
IIa N(CH3)2 N(CH3)2 a
where:in X has the values assigned under Formula I above.
'I'lle novel compounds of ~'ormula I wherein the 5-position is sub-
s~itutcd by the 3-aminopropyl radical are prepared by cyclodehydration of
novel N-[3-(1-phthalimido)propyl]-o-benzanrido-diphenylamines (IIb) and there-
a:~t~r converting the phthalim.ido moiety to amino (NH2) with hydrazlne and
ac.i~. 'I'hc~ equation is:
~~~ ~X ~ x
C~0 PQCl ~ l)NH2NH2
\ 3 ~ ~ 2)Acid ~ ~ - N \
C ~ l X (Cl ~ 2)3
0~c~N ~C~O IIb o~ ~ 0 III N1~2 Ib
wherein X has the values assigned under Formula I. Compounds of Formula III
are also nove.l.
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 wi~h triethylorthoformate followed by reaction with sodium
~orohydride ~procedure of Crocket ~ Blanton, 1974(1): 55-6 Synthesis). The
equation is as follows:
~--X ~X
I) ~F.tO)
_ 2) NaBH4 ~
~ 12)3 Ib IHCH3 IC
N~'2
The start.ing benzamido compounds II (IIa and IIb) are prepared by
l() a modlicat:ion o the procedure of British Patent 907,646. Ortho-nitro-
dipholly:lami.ne is f:irst rcductively alkylated with a solution of ~-chloropropyl
~llme~hylam:ine or 3-(1-ph~halimi.do)-1-chloropropane and following this the
nitro moiety is reduced with hydrogen over palladium on carbon to give
the corresponding ortho amino compound. The amino radicalin the ortho
position is then reacted with benzoyl halide or a substituted benzoyl
halide. The equation is as ~ollows:
C~ o~ VI
1) NaH
2~ Cl-(CH2)3Q
2 ~ ~
(Cj~12)3 V
H2/Pd-C
H2~ ~ IV
(ICH2)3
Pyridine ~ C-Cl
~3"o-x
N~
(1~2)3 II
Q = -N(CH3)2 or l-phthalimido.
~.~ 8~
~ a~tion 1
N-(3-Dimethylam opro~yl~-o-aminodiphenylamine.
A rnixture 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
ethyl alcohol and 1.5 g of 10~ palladium-on-carbon ca-talyst was shaken under
hydrogen atmosphere at room temperature for 1 hr. After approximately 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:
lOb,.p.,_c._ Amt.?g
Fraction 1 80-130/0.2 mm 4.0
2 13V-137/0.2 mm 7.0
3 137-142/0.2 mm 15.5
'I'hin layer chrol~atography using 20% methyl alcohol - 80% benzene on silica
gel, showed ~raction 3 to be quite pure.
~pa o 2
N-t3-Dimethylaminopropyl~-o-ben~ d~diLb~ D-~
To a ~oluti,on of 15.5 g ~0.0575 mole) of N-(3-dimethylaminopropyl)
~o-anlinodiphenylamine in 100 ml of pyridine cooled to about 5C. under nitrogen
atnlosphere was added 17.8 g (0.063 mole) of benzoyl chloride. A small amount
of benzene was used to wash the remaining benzoyl chloride into the reaction
vessel. The mixture was stirred for 1 hr and the vessel stoppered and placed
in 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. 'rhe methylene chloride layer was dried over
i6~
magnesium sulfate and evapora~ed under reduced pressure. Residual pyridine
was then removed under high vacuum (0.2 mm Hg) over nigllt. Weight of the
residual oil, the free base, was 24.9 g.
Oxalate _alt - To a ho~ solution of 4.0 g of ~he free base in
isopropyl alcohol was added 1.35 g ~0.0107 mole~ of oxalic acid dihydrate. The
prccipitated oxalate salt of the title compound weighed 3.5 g and mclted at
l62-S C. The salt after drying 1 hr a~ 97-98C. (refluxing propyl alcohol)
and overnight at room temperature all at 0.1 mm Hgo ~ analyzed as follows:
Analysls: Calculated for C26H29N305: C,67;37; H,6.31; N,9.06
Found : C,67.42; H,6.35; N,9.01
Pre~aration 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-berlzoyl chlorlde, and
~-chloro-benzoyl chloride,
there are obtained:
N-(3-dimethylaminopropyl)-o-(2-chlorobenzamido)
diphenylamine,
N-(3-dimethylaminopropyl)-o-(3-chloroben~amido)
diphenylamine,
N-(3-dimethylaminopropyl)-o-(2-fluorobenzarnido)
diphenylamine,
N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido)
diphenylamine,
N-(3-dimethylaminopropyl)-o-(2-bromobenzamido)
diphenylamine,
N-(3-dimethylaminopropyl)-o-(3-bromobenzamido)
diph~nylamine, and
N-(3-dimetllylaminopropyl)-o-~4-chlorobenzamido)
diphenylamine.
Preparation 4
, . ~
1~ N~ 3-(l-Phthalimido)~ropyll-o-ami--n-odiphenylamine.
o-Nitrodiphenylamine is reacted with sodium hydride and 3-~1-phthalimido)
-l-chloropropane to give N-3-(1-phthalimido)propyl-o-nitrodiphenylamine which
:is t~lcn reduced with hydrogen over palladium-on-carbon in ethanol to give the
title compound.
Whcn in the proeedure of Preparation 2, N-3-(1-phthalimido)propyl-o-
aminod;ip}lenylarn:ine is reacted with each of the follow:ingacyl chlorides in ex-
ccss in the manner of Yreparation 2:
2-chloro-b~nzoyl 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,
, ,. _ g _
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)
cl i.phcnylamine,
N-3~(1-phthalimido)propyl-o-(2-bromobenzamido)
d:iphenylamine,
N-3-(1-phthalimido)propyl-o-(3-bromobenzamido)
diphcnylamine, and
N-3-(1-phthalimido)propyl-o-(4-chlorobenzamido)
~1 iphellylam;irle .
'l'he ~ollowi.ng non-limiting examples will further illustrate the
comp~unds which are useful in the practice of the method o~ this invention.
Exa~
5-~_-Dimethyl n~l~r~ e _ -5~1-dibenzo
Lb~e][l,_l _ zepine, fumarate ~
~ stirred m:ixture of 18.9 g (0.05 mole) of N-(3-dimethylaminopropyl)
-o-bonzamidod:ip}lenylamine 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
]000 ml of crushed ice and then diluted with enough water for a final volwne o~
1000 ml. The aqueous suspension was extracted twice with methylene chloride
and the methylene chloride layer discarded. The aqueous layer was basified with
3 N sodium hydroxide and extracted with three - 250 ml portions of methylene
chloride. rrhese three methylene chloride washes were combined, 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 compo~md. The oil was dissolved in
- 10 -
hot isopropyl alcohol and reacted wi.th 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: Calcula~ed for C28H~gN304 C,71-32; H~ 6 20;
Fourld. : C,71.19; H, 6.19;
N, 8.89
x~le 2
Following the procedure of Example 1 and substituting equal molar
amounts of the following for N-~3-dimethylaminopropyl~-o^benzamidodiphenylamine:
N-(3-dimethylaminopropyl)-o-(2-chlorobenzamido)
1~ diphenylamine,
N-(3-dimethylaminopropyl)-o-(3-chlorobenzamido)
~I:i.pl~cny.lamine,
N-(3~dimethylami.nopropyl)-o-(2-fluorobenzamido)
cl:iph~nylamine,
N-(3-dimethylaminopropyl)-o-(3-fluorobenzamido)
d:i.phenylam:ine~
N-(3-d:i.methylaminopropyl)-o-(2-bromobenzamido)
d:iphenylamine,
N-(3-dimethylaminopropyl)-o-(3-bromobenzamido)
diphenylamine, and
N-t3-dimethylaminopropyl)-o-~4-chlorobenzamido)
diphenylamine,
there are obtained:
l1-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[b,e~[l,4]
diazepine, fumarate,
11-~3-chlorophenyl)-5-(3-dimethylaminopropyl)~5~1-dibenzo[b,e][1,4]
diazep:ine, fumarate,
6~
11-(2-fluorophenyl)-5-~3-dime~hylaminopropyl)-5H-
dibenzo[b,e][l,4]diazepine, fumarate,
11-(3-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-
dibenzo[b,e][1,4]diazepine, fumarate,
11-(2-bromophenyl)-5-~3-dimethylaminopropyl)-5H-
d:ibenzo[b,e][l,4]diazepine, fumarate,
1].-(3-bromophenyl)-5-(3-dimethylaminopropyl)-5H-
dibenzo[b,e][l,4]diazepine, fumarate, and
11-(4-chlorophenyl)-5-~3~dimethylaminopropyl)-5H-
dibenzo[b,e~[l,4]diazepine, fumarate.
~xample 3
When in the procedure of Exarnple 1 prior to addition of fumaric
ac:i.d, thc following are substikuted for N-(3-dimekhylaminopropyl)-o-
betlzamidodiphenylamine:
N-3 ~l-phthalimido)propyl-o-benzamidodiphenylamine,
N 3-(1-phthalimido)propyl-o-(2-chlorobenzam:ido~
ù;iphcnylam.ine,
N-3-~1 phthalimido)propyl o-(3-chlorobenzamido)
diphenylam:ine,
N-3-tl-phthalimido)propyl o-(2-fluorobenzamidc)
diphenylamine,
N-3 (1-phthalimido)propyl-o-(3-fluorobenzamido)
diphenylamine,
N-3-(1 phthalimido~propyl-o-(2-bromobenzamido)
di.phenylamine,
N 3-(1-ph~halimido~propyl-o-(3-bromobenzamido)
diphenylamine, and
- 12 -
~4~
N-3-~1-phthalimido)propyl-o-~4-chloroben~amido)
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--
d:ibenzo[b,e][l,4~diazepine,
5-[3-(1-phthalimido)propyl]-11-~3-chlorophenyl)-5H-
di.benzo[b,e][l,4]diazepine,
5-[3-(1-phthalimido)propyl]-11-~2-fluorophenyl)-5H-
dibenzoLb,e][1,4]diazepine,
5-~3-(1-phthalimido)propyl]-11-~3-fluorophenyl)-5H-
d.i.l)enzoLb,e][1,4~diazepine,
5-[3-~1-phthalimido~propyl]~ 2-bromophenyl)-5H-
dlbonzo[b,e~[l,4]diazepine,
S-~3-~1-phthalimido~propyl]-11-~3-bromophenyl~-5H-
dibenzo[b,~l[l,4]diazepine,
5-[3-(1-phthali.mido~propyl]~ 4-chlorophenyl~-5H-
dibenzo[b,e][l,4~d:iazepine.
Example 4
5-(3-Amino~ y~? ll_phenyl_5H dibenzo~b,e][1,4
diaze~ine ~
A mixture of 0.035 mole of 5-[3-~1-phthalimido)propyl-11-phenyl-
51-1-dibenzo[b,e]~1,4]diazepine, 0.039 mole of hydrazine hydrate and 175 ml of
190 proof ethyl alcohol is refluxed for 2.5 hr and allowed to stand for several
hours. A solution of 10 ml concentrated hydrochloric acid in 50 ml water is
- 13 -
5~
added to the mixture and the mixture is stirred for several hours. The
mixture is filtered and the filtrate e~aporated under reduced pressure. The
hydrochloride salt is isolated by recrystalliz~tion from a suitable solven~
and dried under reduced pressure.
Example 5
Following the procedure of Example 4 and substitutin~ equal molar
amounts of the following for 5-[3-(1-phthalimido)propyl]-11-phenyl-5H-dibenzo
[b,e][1,4]diazepine:
11-(2-chlorophellyl~-5-[3-(l-phthalimido)propyl]-5H-dibenzo
[b,e][1,4]diazepine,
]1-(3-chlorophenyl)-5-[3-(1-phthalimido)p~opylJ-5H-dibenzo
[b,eJ[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,el~1,41diazepine,
1]-(2-bromophenyl)-5-[3-~1-phthalimido)propyl~-5H-
dibenzo~b,e][lg4Jdiazepine,
11-(3--bromophenyl)-S-[3-(1-phthalimido~propyl]-5H-dibenzo
2() [b,c~[1,4~diazepine, and
11-(4-chlorophenyl)-5-[3-(1-phthalimido)propyl]-5H-
dibenzo[b,e3[1,4]diazepine,
there are obtained.
5-(3-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo
Cb,e~[1,4]diazepine hydrochloride~
. - 14 -
5-(3-aminopropyl)-11-(3-chlorophellyl)-5H-dibenzo
[b,e][1,4]diazepine hydrochloride,
5-(3-aminopropyl)-11-~2-fluorophenyl)-5H-dibenzo
[b,e][1,4]diazepine hydrochloride,
5-(3-aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo
~b,el L 1,4~diazepine hydrochloride,
5-(3-aminopropyl)-11-(2-bromophenyl)-51-1-dibenzo
~b,e~[1,4~diazepine hydrochloride,
5-(3-aminopropyl)-11-(3-'bromophenyl)-511-dibenzo
[b,e~[1,4]diazepine hydrochloride,
S (3~aminopropyl)~ 4-chlorophenyl)-5H-dibenzo
Lb,e3~1,4~diazepine hydrochloride
Example 6
N-Methyl-ll-phenyl-5H-dibenzo[b e 1~1,4]diazep_n~5-
propanamine ydrochloride.
'I'he hydrochloride salt of 5-~3-aminopropyl)-11-phenyl-5H-dibenzo
~b,o]~ cliazcpine is converted to the free base by partitioning between
clilute sodium hydroxide and methylene chloride, dryingand concentrating the
m~thylene chloride laycr to dryness, adding dry benzene and again concentrating
~o drivc off the benzene. The resulting free base is dissolved in a large
excess of freshly distilled triethylor~hoformate with refluxing for se-reral
hours. The mixture is concentrated in vacuo, ethanol is added and the mixture
concentrated again. The resulting imidate is dissolvedin ethanol and sodium
borohydride is added with stirring at 15-20C. 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
- 15 -
ethylacetate. The ethylacetate layer is washed to neutrality and salted,
filtered and evaporated. Crude free base i.s isolated by column chromatogra.phy
and reacted with ethereal hydrogen chloride and recrys~allized to give the
~itle compound.
Example 7
Pollowing the procedure of Example 6 and substi~uting equal. molar
amounts of the following for 5-(3-aminopropyl)-11-phenyl-5H-dibenzo[b,e]~1,4]
diazepi.ne:
5-(3-aminopropyl-11-(2-chlorophenyl)-5H-dibenzo[b,e][1,4]
diazepine hydrochloride,
5-(3-aminopropyl)-11-~3-chlorophenyl)-5H-dibenzo[b,e][1,4]
dlazepi.ne hydrochloride,
5-(3-aminoprGpyl)-11-(2-fluorophenyl)-5H-dibenzo[b,e][1,4J
diazepi.ne hydrochloride,
5-(3-aminopropyl)-11-(3-fluorophenyl)-SH-dibenzo[b,e][1,4]
dlazcpine hydrochloride,
5-(3-aminopropyl) 11-(2-bromophenyl)-5H-dibenzo[b,e][1,4]
dia~epine hydrochloride,
$-(3-aminopropyl~ (3-bromophenyl)-SH-dibenzo[b,e][1,4]
di.azepine hydrochloride, and
5-(3-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[b,e][1~4]
diazepine hydrochloride,
there are obtained:
11-(2-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4]
dia.zepin-5 propanamine hydrochloride,
11-(3-chlorophenyl)-N-methyl-5H-dibenzo[b,e][1,4]
- 16 -
diazepin-~-propanamine hydrochloride,
~ 2-fluorophenyl)-N-methyl-5H-dibenzo[b,e][l,~]
diazepin-5-propanamine hydrochloride,
11-~3-fluorophenyl)-N-me~hyl-5H-dibenzo[b,e~[1,4]
diazepin-5-propanamine hydrochloride,
11-(2--bromophenyl)-N-methyl-5H-dibenzo~b,e~[1,4]
diazepin-5-propanamine hydrochloride,
11-(3-bromophenyl~-N-methyl-5~1-dibenzo[b,e][1,4
diazepin-5-propanamine hydrochloride, and
11-(~-chlorophenyl)-N-methyl-5~5-dibenzo[b,e][1,4]
diazepin-5-propanamine hydrochloride.
Yormulation and Administration
Eefective quantities of the foregoing pharmacologically active
colllpounds of Formula I may be administered to humans for therapeutic purposes
according to usual modes of administration and in usual forms, such as orally
in soluti.ons, emulsions, suspensions, pills, tablets and capsules, in
pharmaceutlcally acceptable carriers and parenterally in the form of sterile
solutions.
~ ,xcmplary of solid carriers for oral administration are such as
2() lactosc, magnesium, stearate, terra alba~ sucrose, talc, stearic acid, gelatin,
agar1 pectin or acacia.
Exemplary of liquid carriers for oral administr~tion are vegetable
oils and water.
For intramuscular administration the carrier or excipient may be a
sterile, parenterally acceptable liquid; e.g., water or a parenterally
acceptable oil; e.g., arachis oil contained in ampules.
i _ 17 -
s~
Although very small quantities of the a~tive materials of the
present invention are effective when minor therapy is involved or in cases of
administration to subjects having a relatively low body weigh~, 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, dcpending, of course, upon the emergency of the situa~ion, the compound
used, and the particular result desired. Twenty-five ~o 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 req~ired should range from
about 0.5 to about 20 mg/kg/day~ preferaby 0.5 to 10 mg/kg. The active
ingredients of the invention may be combined with other pharmacalogically
act;ive 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 ~e obtained consistent with the dosage form employed. Obviously, several
unit dosage forms may be administered at about the same time. The exact
in~ividual dosages as well as daily dosages will, of course, be de~.lpn~trated
.lccord:ing to standard medical principles under the direction of a physician
ox voterinarian.
rl'he following ormulations are representative for the pharmacologically
2~ active compounds of this invention.
FORM~LATIONS
1. Capsules
Capsules of 10 mg and 50 mg of active ingredient per capsule
are prepared. With the higher amounts of active ingredient, reduction may be
made in the amount of lactose.
- 18 -
10 mg. 50 mg.
Ty~ical blend for 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 active ingredient and are as follows:
100 250 500
mg. per mg. permg. per
Capsule a~Capsule
Active ingredient, 100 250 500
as salt
Lactose 214 163 95
S~arch 87 81 47
Magnesium stearate 4 6 8
Total399 500 650
In each case, uniformly blend the selected active ingredient with
lac~s~, starch, 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 maybeus~dfor other strengths
of active ingredient by adjustment of weight of dicalcium phosphate.
Per Tablet, mg.
1. Active ingredient 10.0
2. Corn starch 15.0
3. Corn starch (paste) 12.0
4. Lactose 35.0
5. Dicalcium phosphate 132.0
6. Calcium stearate 2.0
Total 202.0
- 19 -
Uniformly blend 1, 2, 4 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 equivalents will be apparent to one
skllled in the art and may be made in the compounds, compositions and methods
oP tlle present invention without departing from the syirit and scope thereof,
and it is therefore understood that the invention is to be limited only by
the scope of the appended claims.
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