Oxolabdanes useful as pharmaceuticals for reducing intraocular pressure

Novel oxolabdanes, intermediates and processes for the preparation thereof, and methods for reducing intraocular pressure utilizing compounds or compositions thereof are disclosed.

The present invention relates to oxolabdanes. More particularly, the 
present invention relates to oxolabdanes of formula 1 
##STR1## 
wherein: (a) Z a group of the formula CO or a group of the formula 
CHOR.sub.1 wherein R.sub.1 is hydrogen, a group of the formula R.sub.2 CO 
wherein R.sub.2 is hydrogen or loweralkyl, or group of the formula R.sub.3 
R.sub.4 R.sub.5 Si wherein R.sub.3, R.sub.4 and R.sub.5 are loweralkyl; 
(b) Y is a group of the formula CO or a group of the formula CHOR.sub.6 
wherein R.sub.6 is hydrogen or a group of the formula R.sub.8 CO wherein 
R.sub.8 is hydrogen, loweralkyl, CH.sub.3 CHOH, HOCH.sub.2 CHOH, 
##STR2## 
or a group of the formula R.sub.10 O(CH.sub.2).sub.n wherein R.sub.10 is 
hydrogen or loweralkyl and n is 2, 3 or 4; 
(c) R.sub.7 is hydrogen or a group of the formula R.sub.8 CO wherein 
R.sub.8 is hydrogen, loweralkyl, CH.sub.3 CHOH, HOCH.sub.2 CHOH, 
##STR3## 
or a group of the formula R.sub.10 O(CH.sub.2).sub.n wherein R.sub.10 is 
hydrogen or loweralkyl and n is 2, 3 or 4; 
(d) R.sub.9 is hyrogen or a group of the formula OR.sub.13 wherein R.sub.13 
is hydrogen; 
(e) R.sub.6 and R.sub.7 taken together form a group of the formula CO or a 
group of the formula SO; 
(f) R.sub.1 and R.sub.13 taken together form a group of the formula CO, a 
group of the formula SO, or a group of the formula CHNR.sub.14 R.sub.15 
wherein R.sub.14 and R.sub.15 are loweralkyl of 1 to 6 carbon atoms and W 
is a group of the formula CH.sub.2 or a group of the formula CO, with the 
proviso that the compound exists exclusively as the 11-keto tautomer when 
R.sub.9 is OR.sub.13 wherein R.sub.13 is hydrogen, the optical and 
geometric isomers thereof, or a pharmaceutically acceptable acid addition 
salt thereof, which are useful for reducing intraocular pressure, alone or 
in combination with inert adjuvaats. 
Subgeneric to the oxolabdanes of the present invention are compounds of 
formula 1 wherein: 
(a) W is a group of the formula CO; Z is a group of the formula CHOR.sub.1 
wherein R.sub.1 is hydrogen or a group of the formula R.sub.2 CO wherein 
R.sub.2 is loweralkyl of 1 to 6 carbon atoms; and R.sub.9 is a group of 
the formula OR.sub.13 wherein R.sub.13 is hydrogen; 
(b) W is a group of the formula CO; Z is a group of the formula CHOR.sub.1 
wherein R.sub.1 is hydrogen or a group of the formula R.sub.2 CO wherein 
R.sub.2 is loweralkyl of 1 to 6 carbon atoms; and R.sub.9 is hydrogen; 
(c) W is a group of the formula CH.sub.2 ; Z is a group of the formula CO 
or a group of the formula CHOR.sub.1 wherein R.sub.1 is a group of the 
formula R.sub.2 CO wherein R.sub.2 is loweralkyl of 1 to 6 carbon atoms; Y 
is a group of the formula CO; and R.sub.9 is hydrogen; 
(d) R.sub.6 and R.sub.7 taken together form a group of the formula CO or a 
group of the formula SO; 
(e) R.sub.1 and R.sub.7 taken together to form a group of the formula CO or 
a group of the formula SO; and 
(f) R.sub.1 and R.sub.13 taken together form a group of the formula 
CHNR.sub.14 R.sub.15. 
The present invention also relates to compounds of formula 
##STR4## 
wherein R.sub.1, R.sub.6 and R.sub.7 are each independently hydrogen or a 
group of the formula R.sub.16 CO wherein R.sub.16 is loweralkyl, or the 
optical and geometric isomers thereof, which are useful for reducing 
intraocular pressure and as intermediates for the preparation of the 
oxolabdanes of the present invention. 
As used through the specification and appended claims, the term "alkyl" 
refers to a straight or branched chain hydrocarbon radical containing no 
unsaturation and having 1 to 8 carbon atoms such as methyl, ethyl, 
1-propyl, 2-propyl, 1-butyl, 1-pentyl, 2-pentyl, 3-hexyl, 4-heptyl, 
2-octyl, and the like; the term "alkanol" refers to a compound formed by a 
combination of an alkyl group and a hydroxy radical. Examples of alkanols 
are methanol, ethanol, 1- and 2-propanol, 1,2-dimethylethanol, hexanol, 
octanol and the like. The term "alkanoic acid" refers to a compound formed 
by combination of a carboxyl group with a hydrogen atoms or alkyl group. 
Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 
2,2-dimethylacetic acid, hexanoic acid, octanoic acid, and the like; the 
term "halogen" refers to a member of the family consisting of fluorine, 
chlorine, bromine or iodine. The term "alkanoyl" refers to the radical 
formed by removal of the hydroxyl function from an alkanoic acid. Examples 
of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, 
hexanoyl, octanoyl, and the like. The term "acyl" encompasses the term 
"alkanoyl" and refers to the radical derived from an organic acid by 
removal of the hydroxyl function. Examples of acyl radicals are 
tetrahydrofuroyl, 2,2-dimethyl-1,3-dioxolanoyl, 1,4-dioxolanoyl, 
methoxyacetoxy, and the like. The term "lower" as applied to any of the 
aforementioned groups refers to a group having a carbon skeleton 
containing up to and including 6 carbon atoms. 
In the formulas presented herein the various substituents are illustrated 
as joined to the labdane nucleus by one of two notations: a solid line 
(--) indicating a substituent which is in the .beta.-orientation (i.e., 
above the plane of the molecule) and a broken line (---) indicating a 
substituent which is in the .alpha.-orientation (i.e., below the plane of 
the molecule). The formulas have all been drawn to show the compounds in 
their absolute stereochemical configuration. Inasmuch as the starting 
materials having a labdane nucleus are naturally occurring or are derived 
from naturally occurring materials, they, as well as the final products, 
have a labdane nucleus existing in the single absolute configuration 
depicted herein. The processes of the present invention, however, are 
intended to apply as well to the synthesis of labdanes of the racemic 
series. 
In addition to the optical centers of the labdane nucleus, the substituents 
thereon may also contain chiral centers contributing to the optical 
properties of the compounds of the present invention and providing a means 
for the resolution thereof by conventional methods, for example, by the 
use of optically active acids. A wavy line (.about.) connecting a group to 
a chiral center indicates that the stereochemistry of the center is 
unknown, i.e., the group may exist in any of the possible orientations. 
The present invention comprehends all optical isomers and racemic forms of 
the compounds of the present invention where such compounds have chiral 
centers in addition to those of the labdane nucleus. 
The novel oxolabdanes of the present invention are synthesized by the 
processes illustrated in Reaction Schemes A, B, and C. 
To prepare an 11,12-dioxolabdane 4, an 11-oxolabdane 2 wherein R.sub.1 is 
hydrogen is oxidized to an 11,12-dioxo-9.alpha.-hydroxylabdane 3 which is 
reduced to 4. The oxidation is performed by treating 2 with selenium 
dioxide in a heteroaromatic solvent. Among heteroaromatic solvents there 
may be mentioned pyridine, picoline, lutidine and collidine. Pyridine is 
the preferred solvent. While the reaction temperature is not critical, the 
oxidation is preferably conducted at the reflux temperature of medium to 
promote a reasonable rate of reaction. The reduction is performed by 
treating 3, characterized by the presence of a 9.alpha.-hydroxy group, 
with zinc in an alkanoic acid. Included among alkanoic acids are acetic 
acid, propionic acid, and the like. Acetic acid is preferred. While the 
reduction temperature is not narrowly critical, it is generally performed 
at a temperature within the range of about 0.degree. to about 50.degree. 
C., a reduction temperature of about 25.degree. C. being preferred. This 
process for the preparation of an 11,12-dioxolabdane 4 is preferred for 
the preparation of those compounds wherein R.sub.1 and R.sub.6 are 
hydrogen and R.sub.7 is a group of the formula R.sub.8 CO wherein R.sub.8 
is alkyl, and also provides access to 11,12-dioxo-9.alpha.-hydroxylabdanes 
3 wherein R.sub.1 and R.sub.9 are hydroxy and R.sub.7 is a group of the 
formula R.sub.8 CO wherein R.sub.8 is alkyl. 
To prepare an 11,12-dioxolabdane of formula 4 wherein R.sub.1 is R.sub.2 CO 
and R.sub.6 and R.sub.7 are R.sub.8 CO wherein R.sub.2 and R.sub.8 are 
alkyl, an 11-oxolabdane 2 wherein R.sub.1, R.sub.6, and R.sub.7 are as 
above is oxidized with selenium dioxide in a heteroaromatic solvent such 
as pyridine under substantially the same condition as those described for 
the synthesis of 3 wherein R.sub.1 and R.sub.6 are hydroxy and R.sub.7 is 
R.sub.8 CO wherein R.sub.8 is alkyl. 
11,12-Dioxolabdanes 3 bearing hydroxyl and/or alkanoyloxy groups at the 1-, 
6-, and 7-positions may be selectively alkanoylated or hydrolyzed by 
methods known in the art to provide hydroxy- and/or 
alkanoyloxy-11,12-dioxolabdanes 3, i.e., compounds of formula 3 wherein 
R.sub.1 is hydrogen or R.sub.2 CO wherein R.sub.2 is alkyl and R.sub.6 and 
R.sub.7 are hydrogen or R.sub.8 CO wherein R.sub.8 is alkyl. 
To prepare a 6.beta.-alkanoyloxy-11,12-dioxolabdane 3 wherein R.sub.6 is 
R.sub.8 CO wherein R.sub.8 is alkyl, a 
7.beta.-alkanoyloxy-11,12-dioxolabdane 4 wherein R.sub.7 is R.sub.8 CO 
wherein R.sub.8 is alkyl may be rearranged by, for example, treatment with 
either sodium hydroxide in methanol or lithium bis(trimethylsilyl)amide in 
tetrahydrofuran. 
To elaborate an 11,12-dioxolabdane 3 having a silyl group at the 
1-position, i.e., a compound of formula 3 wherein R.sub.1 is R.sub.3 
R.sub.4 R.sub.5 Si wherein R.sub.3, R.sub.4, and R.sub.5 are alkyl, one 
may treat an 11,12-dioxolabdone 3 wherein R.sub.1 is hydrogen with, for 
example, t-butyldimethylsilyl trifluoromethanesulfonate in triethylamine 
at a reaction temperature of about 25.degree. C. 
To introduce an acyl function at the 1-position of the labdane nucleus, 
i.e., to prepare an 11,12-dioxolabdane of formula 3 wherein R.sub.1 is 
acyl, a 1-hydroxylabdane 3 wherein R.sub.1 is hydrogen may be treated with 
an organic acid of formula 12 
EQU R.sub.2 CO.sub.2 H (12) 
wherein R.sub.2 is as hereinbeforedescribed in dichloromethane in the 
presence of 1,3-dicyclohexylcarbodiimide and a catalyst such as 
4-(N,N-dimethylamino)pyridine at a reaction temperature of about 
25.degree. C. To introduce an acyl function at the 6- or 7-positions of 
the labdane nucleus, i.e., to prepare an 11,12-dioxolabdane of formula 3 
wherein R.sub.6 and/or R.sub.7 is acyl, a 6.beta.,7.beta.-dihydroxylabdane 
3 wherein R.sub.6 or R.sub.7 is hydrogen may be treated with an organic 
acid of formula 13 
EQU R.sub.8 CO.sub.2 H (13 ) 
wherein R.sub.8 is as hereinbeforedescribed under conditions substantially 
similar to those employed for the introduction of an acyl function at the 
1-position. 
To introduce a 6.beta.,7.beta.-sulfite or 6.beta.,7.beta.-carbonate 
function into an 11,12-oxolabdane 3, i.e., to prepare a compound of 
formula 3 wherein R.sub.6 and R.sub.7 taken together form a group of the 
formula SO or a group of the formula CO, respectively, a 
6.beta.,7.beta.-dihydroxylabdane of formula 3 may be contacted with a 
compound of formula 14 
EQU HalXHal (14) 
wherein X is SO or CO and Hal is bromo or chloro, preferably chloro, in 
pyridine at a reaction temperature of about 0.degree. C. 
In addition, by condensing a 1.alpha.,9.alpha.-dihydroxy-11,12-dioxolabdane 
3, i.e., a compound of formula 3 wherein R.sub.1 and R.sub.13 are 
hydrogen, with a halide 14 wherein X is SO or CO under the 
hereinbeforedescribed process conditions, one may obtain, respectively, a 
1.alpha.,9.alpha.-sulfite or a 1.alpha.,9.alpha.-carbonate, i.e., 
compounds of formula 3 wherein R.sub.1 and R.sub.13 taken together form a 
group of the formula SO or a group of the formula CO, respectively. 
To construct an 11,12-dioxolabdane 3 wherein R.sub.1 and R.sub.13 form a 
group of the formula CHNR.sub.14 R.sub.15 wherein R.sub.14 and R.sub.15 
are loweralkyl, i.e., an 
11,12-dioxolabdane-1.alpha.,9.alpha.-dihydroxylabdane is condensed with a 
formamide dialkylacetal of formula 15 
EQU (R.sub.17 O).sub.2 CHNR.sub.14 R.sub.15 ( 15) 
wherein R.sub.17 is alkyl and R.sub.14 and R.sub.15 are as above neat or in 
the presence of dimethylformamide at a condensation temperature of above 
45.degree. to about 65.degree. C. 
By applying the aforedescribed alkanoylation, hydrolysis, rearrangement, 
silylation, acylation, sulfite and carbonate formation, and condensation 
reactions to an 11,12-dioxo-9.alpha.-hydroxylabdane, i.e., a compound of 
formula 3 wherein R.sub.13 is hydrogen, and subsequently performing the 
aforementioned reduction, alkanoyloxy, hydroxy, silyl, acyl, sulfite, and 
carbonate derivatives of 4 may be prepared. 
To furnish a 1,6,11-trioxolabd-14-ene 6 wherein R.sub.7 is R.sub.8 CO 
wherein R.sub.8 is alkyl, a 1.alpha.,6.beta.-dihydroxyabd-14-en-11-one 5 
wherein R.sub.7 is as above is oxidized with a benzeneseleninic anhydride 
of formula 16 
##STR5## 
wherein R.sub.18 is hydrogen, alkyl, alkoxy, halogen, nitro or 
trifluoromethyl in the presence of an alkali metal hydride and an aromatic 
solvent. Among alkali metal hydrides are lithium hydride, potassium 
hydride and sodium hydride. Among aromatic solvents are benzene, toluene, 
and xylene. Benzeneseleninic anhydride is the preferred oxidizing agent. 
Sodium hydride and toluene are the preferred alkali metal hydride and 
reaction solvent. While the reaction temperature is not narrowly critical, 
it is preferred to conduct the oxidation at the reflux temperature of the 
reaction medium to assure a reasonable rate of reaction. 
To modify the substituent at the 7-position of a compound of formula 6, a 
7.beta.-alkanoyloxylabd-14-en-1,6,11-trione 6 wherein R.sub.7 is R.sub.8 
CO wherein R.sub.8 is alkyl, may be hydrolyzed under conventional 
conditions employing, for example, sodium carbonate in methanol to provide 
a 7.beta.-hydroxylabdane 6 wherein R.sub.7 is hydrogen and then condensed 
with an organic acid 13, i.e., an organic acid of the formula R.sub.8 
CO.sub.2 H, under conditions substantially similar to those 
hereinbeforedescribed to provide compounds of formula 6 wherein R.sub.7 is 
as described above. 
Similarly, to prepare a 6,11-dioxolabd-14-ene 8 wherein R.sub.1 and R.sub.7 
are, respectively, R.sub.2 CO and R.sub.8 CO wherein R.sub.2 and R.sub.8 
are alkyl, a 6.beta.-hydroxylabd-14-en-11-one 7 is oxidized with a 
benzeneseleninic anhydride 16 under essentially the same conditions 
utilized for the conversion of 5 to 6. The C.sub.1 - and C.sub.7 
-alkanoyoxy groups of the 6,11-dioxolabdane 8, i.e., a compound of formula 
8 wherein R.sub.2 and R.sub.8 are alkyl, may be hydrolyzed as discussed 
above to afford a 1.alpha.,7.beta.-dihydroxylabd-14-en-6,11-dione 8 
wherein R.sub.1 and R.sub.7 are hydrogen, which hydroxyl groups may be 
modified by condensation with a carboxylic acid of the formula R.sub.8 
CO.sub.2 H under reaction conditions also as discussed above. 
The labdane starting material for the processes of the present invention 
are fabricated from readily available precursors. For example, 
7.beta.-acetoxy-1.alpha.,6.beta.-dihydroxy-8,13-epoxylabd-14-en-11-one, 
i.e., the compound of formula 9 wherein R.sub.7 is R.sub.8 CO wherein 
R.sub.8 is methyl, is rearranged by means of lithium 
bis(trimethylsilyl)amide in tetrahydrofuran to 
6.beta.-acetoxy-1.alpha.,7.beta.-dihydroxy-8,13-epoxylabd-14-en-11-one, 
i.e., a compound of formula 10 wherein R.sub.6 is R.sub.8 CO wherein 
R.sub.8 is methyl, which is aceylated by acetic anhydride to 
8,13-epoxy-1.alpha.,6.beta.,7.beta.-triacetoxylabd-14-en-11-one 11, i.e., 
a compound of formula 11 wherein R.sub.1 is R.sub.2 CO and R.sub.6 and 
R.sub.7 are R.sub.8 CO wherein R.sub.2 and R.sub.8 are methyl. 
The labdanes of the present invention are useful in the treatment of 
elevated intraocular pressure by virtue of their ability to reduce 
intraocular pressure as determined by the method described by J. Caprioli, 
et al., Invest. Ophthalmol. Vis. Sci., 25, 268 (1984). The results of the 
determination expressed as percent decrease of outflow pressure is 
presented in the Table. 
TABLE 
______________________________________ 
Decrease in 
Concentration 
Outflow 
Compound (%) Pressure (%) 
______________________________________ 
7.beta.-acetoxy-8,13-epoxy- 
2 25.8 
1.alpha.,6.beta.,9.alpha.-trihydroxylabd- 
14-en-11,12-dione 
7.beta.-acetoxy-8,13-epoxy- 
1.0 51 
1.alpha.,6.beta.,9.alpha.-trihydroxy- 
0.1 23 
labd-14-en-11-one 
______________________________________ 
Intraocular pressure reduction is achieved when the present labdanes are 
administered to a subject requiring such treatment as an effective topical 
dose of a 0.01 to 3.0% solution or suspension. A particularly effective 
amount is about 3 drops of a 1% preparation per day. It is to be 
understood, however, that for any particular subject, specific dosage 
regimens should be adjusted according to the individual need and the 
professional judgment of the person administering or supervising the 
administration of the aforesaid compound. It is to be further understood 
that the dosages set forth herein are exemplary only and that they do not, 
to any extent, limit the scope or practice of the invention. 
Compounds of the invention include: 
(1) 
7.beta.-acetoxy-6.beta.,9.alpha.-dihydroxy-8,13-epoxy-1.alpha.-formyloxyla 
bd-14-en-11,12-dione; 
(2) 
7.beta.-acetoxy-1.alpha.-(t-butyldimethylsilyloxy)-6.beta.,9.alpha.-dihydr 
oxy-8,13-epoxylabd-14-en-11,12-dione; 
(3) 
1.alpha.,7.beta.-diacetoxy-6.beta.,9.alpha.-dihydroxy-8,13-epoxylabd-14-en 
-11,12-dione; 
(4) 
7.beta.-acetoxy-1.alpha.,9.alpha.-dihydroxy-8,13-epoxy-6.beta.-formyloxyla 
bd-14-en-11,12-dione; 
(5) 
6.beta.,7.beta.-diacetoxy-1.alpha.,9.alpha.-dihydroxy-8,13-epoxylabd-14-en 
-11,12-dione; 
(6) 
8,13-epoxy-6.beta.-[(2-hydroxypropionyl)oxy]-1.alpha.,7.beta.,9.alpha.-tri 
hydroxylabd-14-en-11,12-dione; 
(7) 
8,13-epoxy-6.beta.-[(2-tetrahydrofuroyl)oxy]-1.alpha.,7.beta.,9.alpha.-tri 
hydroxylabd-14-en-11,12-dione; 
(8) 
6.beta.-[(1,4-dioxan-2-yl)carbonyloxy]-8,13-epoxy-1.alpha.,7.beta.,9.alpha 
.-trihydroxylabd-14-en-11,12-dione; 
(9) 
6.beta.-[(2,2-dimethyl-1,3-dioxolano-4-yl)carbonyloxy]-8,13-epoxy-1.alpha. 
,7.beta.,9.alpha.-trihydroxylabd-14-en-11,12-dione; 
(10) 
8,13-epoxy-6.beta.-(methoxyacetoxy)-1.alpha.,7.beta.,9.alpha.-trihydroxyla 
bd-14-en-11,12-dione; 
(11) 
8,13-epoxy-6.beta.-[(2,3-dihydroxypropionyl)oxy]-1.alpha.,7.beta.,9.alpha. 
-trihydroxylabd-14-en-11,12-dione; 
(12) 
8,13-epoxy-1.alpha.,6.beta.,7.beta.,9.alpha.-tetrahydroxylabd-14-en-11,12- 
dione; 
(13) 
8,13-epoxy-7.beta.-formyloxy-1.alpha.,6.beta.,9.alpha.-trihydroxylabad-14- 
en-11,12-dione; 
(14) 
8,13-epoxy-7.beta.-[(2-hydroxypropionyl)oxy]-1.alpha.,6.beta.,9.alpha.-tri 
hydroxylabd-14-en-11,12-dione; 
(15) 
8,13-epoxy-7.beta.-[(2-tetrahydrofuroyl)oxy]-1.alpha.,6.beta.,9.alpha.-tri 
hydroxylabd-14-en-11,12-dione; 
(16) 
7.beta.-[(1,4-dioxan-2-yl)carbonyloxy]-8,13-epoxy-1.alpha.,6.beta.,9.alpha 
.-trihydroxylabd-14-en-11,12-dione; 
(17) 
7.beta.-[(2,2-dimethyl-1,3-dioxolano-4-yl)carbonyloxy)]-8,3-epoxy-1.alpha. 
,6.beta.,9.alpha.-trihydroxylabd-14-en-11,12-dione; 
(18) 
8,13-epoxy-7.beta.-(methoxyacetoxy)-1.alpha.,6.beta.,9.alpha.-trihydroxyla 
bd-14-en-11,12-dione; 
(19) 
8,13-epoxy-7.beta.-[(2,3-dihydroxypropionyl)oxy)-1.alpha.,6.beta.,9.alpha. 
-trihydroxylabd-4-en-11,12-dione; 
(20) 
7.beta.-acetoxy-8,13-epoxy-1.alpha.,6.beta.,9.alpha.-trihydroxylabd-14-en- 
11,12-dione-1,9-carbonate; 
(21) 
7.beta.-acetoxy-8,13-epoxy-1.alpha.,6.beta.,9.alpha.-trihydroxylabd-14-en- 
11,12-dione-1,9-sulfite; 
(22) 
1.alpha.-acetoxy-8,13-epoxy-6.alpha.,7.beta.,9.alpha.-trihydroxylabad-14-e 
n-11,12-dione-6,7-carbonate; 
(23) 
1.alpha.-acetoxy-8,13-epoxy-6.beta.,7.beta.,9.alpha.-trihydroxylabd-14-en- 
11,12-dione-6,7-sulfite; and 
(24) 
7.beta.-acetoxy-8,13-epoxy-1.alpha.,6.beta.,9.alpha.-trihydroxylabd-14-en- 
11,12-dione-1,9-dimethylformamide acetal. 
Effective amounts of the compounds of the present invention may be 
administered to a subject by any one of various methods, for example, 
orally as in capsules or tablets, parenterally in the form of sterile 
solutions or suspensions, in some cases intravenously in the form of 
sterile solutions, or suspensions, and topically in the form of solutions, 
suspension or ointments, and by aerosol spray. The labdanes of the present 
invention, while effective themselves, may be formulated and administered 
in the form of their pharmaceutically acceptable addition salts for 
purposes of increased solubility and the like. 
Preferred pharmaceutically acceptable addition salts include salts of 
mineral acids for example, hydrochloric acid, sulfuric acid, nitric acid 
and the like, salts of monobasic carboxylic acids such as, for example, 
acetic acid, propionic acid and the like, salts of dibasic carboxylic 
acids such as, for example, maleic acid, fumaric acid and the like, and 
salts of tribasic carboxylic acids such as, for example, citric acid and 
the like. 
Effective quantities of the compounds of the invention may be administered 
orally, for example, with an inert diluent or with an edible carrier. They 
may be enclosed in gelatin capsules or compressed into tablets. For the 
purpose of oral therapeutic administration, the aforesaid compounds may be 
incorporated with excipients and used in the form of tablets, troches, 
capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. 
These preparations should contain at least 0.5% of active compound, but 
may be varied depending upon the particular form and may conveniently be 
between 4% to about 70% of the weight of the unit. The amount of active 
compound in such composition is such that a suitable dosage will be 
obtained. Preferred compositions and preparations according to the present 
invention are prepared so that an oral dosage unit form contains between 
0.1-30 milligrams of the active compound. 
The tablets, pills, capsules, troches and the like may also contain the 
following ingredients: a binder such as microcrystalline cellulose, gum 
tragancanth or gelatin; an excipient such as starch or lactose, a 
disintegrating agent such as alginic acid, corn starch and the like; a 
lubricant such as magnesium stearate; a glidant such as colloidal silicon 
dioxide; and a sweetening agent such as sucrose or saccharin or a 
flavoring agent such as peppermint, methyl salicylate, or orange flavoring 
may be added. When the dosage unit form is a capsule, it may contain, in 
addition to materials of the above type, a liquid carrier such as a fatty 
oil. Other dosage unit forms may contain other various materials which 
modify the physical form of the dosage unit, for example as coating. Thus, 
tablets or pills may be coated with sugar, shellac, or other enteric 
coating agents. A syrup may contain, in addition to the active compounds, 
sucrose as a sweetening agent and certain preservatives, dyes and 
colorings and flavors. Materials used in preparing these various 
compositions should be pharmaceutically pure and non-toxic in the amounts 
used. 
For the purpose of parenteral or topical therapeutic administration, the 
active compounds of the invention may be incorporated into a solution, 
suspension, ointment or cream. These preparations should contain at least 
0.01% of active compound, but may be varied between 0.5 and about 5% of 
the weight thereof. The amount of active compounds in such compositions is 
such that a suitable dosage will be obtained. Preferred compositions and 
preparations according to the present invention are prepared so that a 
parenteral dosage unit contains between 0.01 to 10 milligrams of active 
compound. 
The solutions or suspensions for topical or parenteral administration may 
also include the following components: a sterile diluent such as water for 
injection, saline solution, fixed oils, polyethylene glycols, glycerine, 
propylene glycol or other synthetic solvents; antibacterial agents such as 
benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or 
sodium bisulfite; chelating agents such as ethylendiaminetetraacetic acid; 
buffers such as acetates, citrates or phosphates and agents for the 
adjustment of tonicity such as sodium chloride or dextrose. The parenteral 
preparation can be enclosed in ampules or disposable syringes; the topical 
preparation may be enclosed in multiple dose vials or dropping bottles, 
made of glass or plastic. 
The following examples are for illustrative purposes only and are not to be 
construed as limiting the invention. All temperatures are given in degrees 
Centigrade.