Diphenylmethyl picolinic acid derivatives and their use as anti-acne agents

Disclosed herein are substituted diphenylmethyl picolinic acids, pharmaceutically acceptable salts, amides and esters thereof. The compounds disclosed are useful as topical anti-acne agents.

This invention relates to picolinic acids bearing diphenylmethyl or 
substituted diphenylmethyl substituents. More particularly, this invention 
relates to novel diphenylmethyl substituted picolinic acids, esters, 
amides and pharmaceutically acceptable salts thereof and to their use in 
the treatment and alleviation of acne. 
The tangible embodiments of this invention are represented by the following 
structural formula: 
##STR1## 
and the pharmaceutically acceptable salts thereof wherein X is a 
diphenylmethyl group having the structural formula: 
##STR2## 
wherein R.sub.4 is a member of the group consisting of hydrogen and lower 
alkyl; each R.sub.1 is a member of the group consisting of hydrogen, 
halogen, hydroxy, alkyl, alkoxy, trifluoromethyl, and phenyl; Q is a 
member of the group consisting of hydroxy, alkoxy, cyanoalkoxy, glyceryl, 
--NR.sub.2 R.sub.3, --O-alkylene-NR.sub.2 R.sub.3, --NR.sub.2 
-alkylene--OH; R is a member of the group consisting of hydrogen, lower 
alkyl and X.sub.1, X.sub.1 being defined the same as X; R.sub.2 and 
R.sub.3 which may be the same or different are members selected from the 
group consisting of hydrogen and alkyl or R.sub.2 and R.sub.3 together 
with the amido nitrogen atom may form a 5 to 7 membered ring which may 
contain a second heteroatom selected from the group consisting of oxygen 
and nitrogen; with the proviso that when R is other than hydrogen, X must 
be located at the 5-position of the pyridine ring. 
As used herein the term "alkyl" means a straight, branched chain or 
cyclized hydrocarbyl having up to 12 carbon atoms. The term "alkoxy" means 
a straight, branched chain or cyclized hydrocarbyl which is bonded to an 
oxygen atom by a single bond. When such terms are modified by the term 
"lower" then such radicals contain up to six carbon atoms. Representative 
of the alkyl and alkoxy groups are methyl, ethyl, n-butyl, t-butyl, octyl, 
dodecyl, isopropyl, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, 
methoxy, ethoxy, n-butyloxy, t-butyloxy, octyloxy, dodecyloxy, 
isopropyloxy, cyclopropyloxy, cyclopentyloxy, cycloheptyloxy, 
cyclooctyloxy, and the like, with the lower alkyl and lower alkoxy groups 
being preferred. 
The term "--O-alkylene-NR.sub.2 R.sub.3 ", which is sometimes also 
described herein as "aminoalkyloxy", represents an alkylene group 
consisting of a divalent straight, branched or cyclized hydrocarbyl having 
up to 12 carbon atoms, which is between an oxygen atom and the NR.sub.2 
R.sub.3 group. Preferably, the alkylene moiety has up to six carbon atoms. 
Among the preferred "--O-alkylene-NR.sub.2 R.sub.3 " groups are: 
aminoethoxy, aminopropyloxy, mono and dialkylaminoethoxy, mono and 
dialkylaminovaleryloxy, piperidinoethoxy, morpholinoethoxy, 
piperazinoethoxy, pyrrolidinoethoxy, morpholinopropyloxy, 
morpholinovaleryloxy and piperazinoisopropyloxy. 
Examples of groups represented by "NR.sub.2 R.sub.3 " are amino, mono and 
dialkylamino, morpholino, pyrrolidino, piperidino and piperazino. 
In view of the foregoing definition of the terms "NR.sub.2 R.sub.3 " and 
"O-alkylene-NR.sub.2 R.sub.3 ", the definition of the terms "NR.sub.2 
-alkylene-OH" and "O-alkylene-CN" (cyanoalkoxy) are obvious. 
The term "glyceryl" is the radical generally shown as --OCH.sub.2 
CHOHCH.sub.2 OH. 
Exemplary of the salts of the picolinic acid of Formula I, i.e. wherein "Q" 
represents hydroxy, are those formed with alkali metals, alkaline earth 
metals and non-toxic organic bases such as N-methyl glucamine and 
alcoholamines, preferably diethanolamine. 
The compounds of this invention may be prepared by a series of reactions 
which individually are known to those skilled in the chemical art. The 
preferred reaction sequence by which the compounds of this invention 
having a diphenylmethyl substituent at the 5-position may be prepared is 
initiated by the reaction wherein a benzhydrol (II) is condensed with a 
2-hydroxypyridine (III) to produce a substituted diphenylmethyl pyridone 
(IV). This condensation is effected by heating a mixture containing 
equimolar quantities of the reactants within the temperature range of 
about 225.degree. C. to about 275.degree. C. (preferably about 245.degree. 
C.) in the presence of a strong acid, such as, for example, sulfuric acid. 
The pyridones (IV) are treated with a phosphorous oxyhalide reagent, e.g. 
phenylphosphonic dichloride, at an elevated temperature thereby forming 
the corresponding 2-halogeno pyridine (V). The 2-halogeno compound is 
converted to its 2-cyano analog (VI) by conventional means. The 2-cyano 
analog is then hydrolyzed to the corresponding substituted diphenylmethyl 
picolinic acid (Ia). The foregoing reactions are depicted by the following 
flow diagram: 
##STR3## 
In the process described by the sequence set forth above, R.sub.1, R, 
R.sub.4 and X are as defined for formula I. 
In the preferred method for preparing the compounds of this invention 
wherein R represents a substituted diphenylmethyl moiety, (i.e. those 
compounds of Formula I wherein both R and X are the same diphenylmethyl 
substituent), 2-hydroxypyridine is reacted with a benzhydrol (II) under 
substantially the same reaction conditions described for the preparation 
of compounds IV in Reaction Scheme I, except the reaction is effected at 
from about 150.degree. to about 200.degree. to favor the condensation of 
the benzhydrol (II) at the 1-position (i.e. on the nitrogen atom of the 
pyridine moiety). When a second mole of substituted benzhydrol is 
subsequently condensed with the first condensation product (VIII), the 
reaction is effected at a temperature in the range of from about 
225.degree. to about 275.degree.. This reaction causes migration of the 
first benzhydryl moiety from the nitrogen atom, and the concomitant 
condensation of a second benzhydryl moiety to produce an appropriately 
substituted 3,5-[bis-(diphenylmethyl)]-2-hydroxypyridine (IX). The product 
is converted to the corresponding 3,5-[bis-(diphenylmethyl)]-picolinic 
acid (Ib) by substantially the same series of reactions described in 
Reaction Scheme I. These reactions are depicted in Reaction Scheme II. 
##STR4## 
wherein X and X.sub.1 are as previously defined. 
In a preferred method for preparing the compounds of this invention having 
a diphenylmethyl or a substituted diphenylmethyl group at the 4-position 
of the picolinic acid moiety, 4-benzhydrylpyridinium sulfate salt (whose 
preparation is known in the art) is reacted with formamide in the presence 
of ferrous sulfate and a peroxide, preferably t-butylhydroperoxide, to 
form the corresponding 4-benzhydryl picolinamide (XII). The latter 
compound is then subjected to hydrolysis under acidic conditions thereby 
forming the 4-benzhydryl picolinic acid directly. 
The foregoing reactions are depicted by the following flow diagram: 
##STR5## 
wherein R.sub.1 and R.sub.4 are as defined above. 
To prepare the compounds of this invention wherein R.sub.4 represents a 
lower alkyl radical, it is preferable first to alkylate a diphenylmethyl 
pyridine (XIII), and then follow the series of reactions set forth in 
Reaction Scheme III. The alkylation is effected in an inert solvent by 
reaction with a lower alkyl halide in the presence of sodium amide and 
excess ammonia, with ferric nitrate being present in catalytic quantities 
according to standard techniques known in the art. The foregoing reaction 
is depicted by the following reaction scheme: 
##STR6## 
wherein R.sub.1 is as previously defined and R'.sub.4 is lower alkyl. 
The amides and esters of this invention may conveniently be prepared from 
the acid (Ib) by first converting the acid to its cyanomethyl ester and 
then converting this ester to the desired end product by standard 
transesterification techniques. 
Conversion of an R-substituted (R.sub.1 -diphenylmethyl)picolinic acid to 
the corresponding cyanomethyl ester is usually effected by treating the 
acid at an elevated temperature with a halogenoacetonitrile in the 
presence of an acid acceptor, such as triethylamine. The reaction is, 
advantageously, effected in a non-reactive organic solvent such as 
acetone, methyl ethyl ketone, or the like. The reaction is allowed to 
proceed for from about 5 to about 20 hours, the reaction mixture is cooled 
and filtered. The filtrate is concentrated to a residue and triturated 
with water to yield the desired cyanomethyl ester. The cyanomethyl ester, 
is a key intermediate from which nearly all of the compounds having the 
various "Q" substitutents may be prepared. Indeed, from the cyanomethyl 
intermediate the compounds of this invention wherein "Q" represents 
glyceryl, alkoxy, --O-alkylene-NR.sub.2 R.sub.3, --NR.sub.2 R.sub.3 
(except when R.sub.2 and R.sub.3 both represent hydrogen), and --NR.sub.2 
-- alkylene-OH may be prepared by the use of the transesterification and 
amidation techniques. Of course, in those instances wherein the 
transesterification process is designed to produce an amine having a 
reactive hydrogen, in such reactions the amine groups are first protected 
(e.g. by standard benzylation procedures) and subsequent to the 
transesterification, the benzyl or ether protective groups are readily 
cleaved by standard techniques well known in the art. Similarly, when "Q" 
represents a hydroxyalkylamine, the terminal hydroxy moiety must first be 
protected e.g. with a hydroxy (ether) protecting group and then following 
transesterification the protecting group removed. These procedures are 
conducted according to techniques well known in the art. 
In those instances wherein it is desired to prepare amides wherein 
"NR.sub.2 R.sub.3 " is representative of NH.sub.2, such R-substituted 
5-(R.sub.1 -diphenylmethyl)picolinamides may be prepared by hydrolysis of 
the corresponding R-substituted 5-(R.sub.1 -diphenylmethyl)-.sub.2 
-cyanopyridine and may be isolated by conventional means. 
To prepare compounds of this invention wherein Q is a glyceryl ester, 
several different routes may be utilized, the choice being determined by 
the ready availability of the required starting compounds. Preferentially, 
the ester is prepared by the hydrolysis of an alkylidenedioxypropyl ester 
of an appropriately substituted diphenylmethyl picolinic acid. The 
alkylidenedioxypropyl ester is generally prepared by transesterification 
wherein a reactive alkyl ester such as a cyanomethyl ester is 
transesterified by a cyclic acetal of glycerol. The transesterification is 
generally effected by heating the reactive ester with the cyclic acetal of 
glycerol in the presence of catalytic amounts of tertiary amine catalyst, 
such as triethylamine at temperatures in the range of 
80.degree.-200.degree. C., about 100.degree. C. being preferred. Due to 
the nature of the transesterification it is advantageous to employ a large 
excess of cyclic acetal to drive the reaction to completion. Hydrolysis of 
the alkylidenedioxypropyl ester of the R-substituted (R.sub.1 
-diphenylmethyl)-picolinic acid to yield the desired glyceryl ester is 
usually effected by conventional techniques, such as by heating the 
intermediate in the presence of an acid. For example, by heating the 
intermediate in dilute acetic acid until the reaction is substantially 
complete and isolating the glyceryl ester by means known to the art. 
The following specific examples are set forth to teach those skilled in the 
art how to prepare the compounds of this invention. They should not be 
construed as limiting the scope of the invention but rather to exemplify 
the generic teaching hereinabove.

EXAMPLE I 
5-(Diphenylmethyl)-Picolinic Acid 
A. 5-(diphenylmethyl)-2-pyridone 
To a mixture of 92.1 g (0.5 mole) of benzhydrol and 142.7 g. (1.5 mole) of 
2-hydroxypyridine heated at 180.degree., add with stirring 1.5 ml. of 
concentrated sulfuric acid. Heat the mixture at 250.degree.-255.degree. 
for 2 hours with the removal of water. Pour the cooled reaction mixture 
into water, stir, and extract with chloroform. Concentrate the chloroform 
extracts to a residue containing 5-(diphenylmethyl)-2-pyridone. Triturate 
the residue with ethyl acetate and filter the solids to obtain 
5-(diphenylmethyl)-2-pyridone plus other isomers. Recrystallize from 
acetonitrile to obtain the product of this example, m.p. 
174.degree.-176.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
R.sub.1 -substituted benzhydrols to the process of the foregoing step to 
obtain thereby the corresponding R.sub.1 -substituted 
diphenylmethyl-2-pyridones: 
2-chlorobenzhydrol 
4,4'-difluorobenzhydrol 
4-phenylbenzhydrol 
4-trifluoromethylbenzhydrol 
3-methoxybenzhydrol, and 
4,4'-dimethylbenzhydrol 
B. 2-Chloro-5-(Diphenylmethyl)-Pyridine 
Heat 55 g. of the crude 5-(diphenylmethyl)-2-pyridone and 110 ml. of 
phenylphosphoric dichloride at 200.degree.-210.degree. with stirring for 6 
hours. Pour the cooled reaction mixture onto ice, basify with ammonium 
hydroxide, extract with ethyl ether, dry the ether extracts, and 
concentrate to a residue. Distill the residue at 
160.degree.-175.degree./0.15 mm. and crystallize the distillate from 
hexane to obtain 2-chloro-5-(diphenylmethyl)-pyridine, m.p. 
69.5.degree.-71.degree.. 
In a similar manner, subject an equivalent quantity of the following 
R.sub.1 -substituted diphenylmethyl-2-pyridones to the process of the 
foregoing step to obtain thereby the corresponding 2-chloro-(R.sub.1 
-substituted diphenylmethyl)-pyridines: 
5-(2-chlorophenyl-phenylmethyl)-2-pyridone, 
5-[bis-(4-fluorophenyl)-methyl]-2-pyridone, 
5-(4-biphenyl-phenylmethyl)-2-pyridone, 
5-(4-trifluoromethyl)phenyl-phenylmethyl)-2-pyridone, 
5-(3-methoxyphenyl-phenylmethyl)-2-pyridone, 
5-[bis-(4-methylphenyl)-methyl]-2-pyridone, and 
5-(diphenylmethyl)-3-methyl-2-pyridone. 
C. 5-(Diphenylmethyl)-Picolinic Acid 
Heat a mixture of 16.5 g. (0.059 mole) of 
2-chloro-5-(diphenylmethyl)-pyridine and 10.6 g. (0.059 mole) of cuprous 
cyanide in 120 ml. of hexamethylphosphoramide with stirring at 
210.degree.-220.degree. C. for 7 hours. Pour the cooled reaction mixture 
into a solution of 200 ml. of ethylenediamine in 500 ml. of water, and 
extract with benzene. Wash the benzene extracts with 10% aqueous sodium 
cyanide, then with water, dry, treat with activated charcoal, filter, and 
concentrate to obtain 2-cyano-5-(diphenylmethyl)-pyridine. This compound 
is converted directly to the title compound by heating at reflux with 13 
g. of potassium hydroxide pellets in 100 ml. water and 200 ml. ethylene 
glycol for 15 hours. Remove the ethylene glycol and water under reduced 
pressure, dissolve the residue in water, acidify with concentrated 
hydrochloric acid, and extract with chloroform. Dry the chloroform 
extracts. Concentrate the dried extracts to a residue and triturate the 
residue with isopropyl ether. Filter the solids, dry and recrystallize 
from ethanol to obtain 5-(diphenylmethyl)picolinic acid, m.p. 
189.degree.-191.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
2-chloro-(R.sub.1 -substituted diphenylmethyl)-pyridines to the process of 
the foregoing step to obtain thereby the corresponding (R.sub.1 
-substituted diphenylmethyl)-picolinic acids: 
2-chloro-5-(2-chlorophenyl-phenylmethyl)-pyridine, 
2-chloro-5-[bis-(4-fluorophenyl)-methyl]pyridine, 
2-chloro-5-(4-biphenyl-phenylmethyl)-pyridine, 
2-chloro-5-[4-(trifluoromethyl)-phenyl-phenylmethyl]-pyridine, 
2-chloro-5-(3-methoxyphenyl-phenylmethyl)-pyridine, 
2-chloro-5-[bis-(4-methylphenyl)-methyl]-pyridine, and 
2-chloro-5-(diphenylmethyl)-3-methylpyridine. 
EXAMPLE II 
Cyanomethyl 5-(Diphenylmethyl)-picolinate 
Suspend 4.3 g. (0.015 mole) of 5-(diphenylmethyl)-picolinic acid in 100 ml. 
of acetone with stirring and add 2.3 g. (0.023 mole) of triethylamine. To 
the resulting solution add dropwise 1.7 g. (0.023 mole) of 
chloroacetonitrile. Stir the reaction mixture at room temperature 
(25.degree. C.) for 15 minutes, then reflux for 4 hours. Cool and filter 
the reaction mixture. Concentrate the filtrate to a residue in vacuo and 
triturate the residue with hot isopropyl ether to yield the product of 
this example, yield 3.5 g., m.p. 95.degree.-98.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
(R.sub.1 -substituted diphenylmethyl)-picolinic acids to the process set 
forth above to obtain thereby the corresponding cyanomethyl (R.sub.1 
-substituted diphenylmethyl) picolinates: 
5-(2-chlorophenyl-phenylmethyl)-picolinic acid, 
5-[bis-(4-fluorophenyl)-methyl]-picolinic acid, 
5-(4-biphenyl-phenylmethyl)-picolinic acid, 
5-[4-(trifluoromethyl)-phenyl-phenylmethyl)-picolinic acid, 
5-(3-methoxyphenyl-phenylmethyl)-picolinic acid, 
5-[bis-(4-methylphenyl)-methyl]-picolinic acid, and 
5-(diphenylmethyl)-3-methylpicolinic acid 
EXAMPLE III 
5-(4-Chlorophenyl-Phenylmethyl)-Picolinic Acid 
A. 5-(4-Chlorophenyl-Phenylmethyl)-2-Pyridone 
Combine 109.3 g. (0.5 mole) of 4-chlorobenzhydrol with 142.7 g. (1.5 mole) 
of 2-hydroxypyridine and heat at 150.degree. C. with stirring until 
molten. Add about 2 ml. of concentrated sulfuric acid and continue heating 
to 240.degree.-250.degree. C. while removing water from the reaction 
mixture. Permit the reaction to continue for about 2 hours, then cool the 
reaction mixture to about 25.degree. C. Treat the resulting solid with 
ethyl acetate and water and filter to remove the undesired 
3-(4-chlorophenyl-phenylmethyl)-2-pyridone. The organic layer is separated 
and washed with water several times and dried over potassium carbonate and 
filtered. Concentrate the filtrate to half volume and filter to remove the 
remaining 3-substituted-2-pyridone. Evaporate the filtrate and dissolve 
the residue in ethyl ether. Upon standing overnight the 
5-(4-chlorophenyl-phenylmethyl)-2-pyridone crystallizes, yield 60 g., m.p. 
164.degree.-169.degree. C. 
B. 2-Chloro-5-(4-Chlorophenyl-Phenylmethyl)-Pyridine 
Combine 50 g. (0.174 mole) of the 5-substituted 2-pyridone from step A with 
125 ml. of phenylphosphonic dichloride and heat at 210.degree.-220.degree. 
C. for about 7 hours with stirring. Allow to stand overnight and pour onto 
ice. Basify with ammonium hydroxide and extract with ethyl ether. Dry the 
ether solution and concentrate to a residue. Distill the residue and 
collect the fraction boiling at 205.degree.-215.degree. C. at 0.55 mm. (49 
g.). 
C. 5-(4-Chlorophenyl-Phenylmethyl)-Picolinic Acid 
Dissolve 55 g. of the product of step B in 200 ml. of dry 
hexamethylphosphoramide and add 32 g. (0.36 mole) of cuprous cyanide. Heat 
the reaction mixture at 210.degree.-220.degree. C. for 7 hours. Pour the 
reaction mixture into about 500 ml. of ice water containing 200 ml. of 
ethylenediamine and extract with benzene. Wash the benzene extract with 
10% sodium cyanide solution then with water. Treat the benzene solution 
with activated charcoal and filter through a suitable filter aid. 
Evaporate the filtrate to dryness, dissolve the residue in 300 ml. of 
ethylene glycol and add 20 g. of potassium hydroxide dissolved in 100 ml. 
of water. Reflux the reaction mixture overnight and remove the solvent in 
vacuo. Dissolve the residue in water, treat with activated charcoal and 
filter. Acidify the filtrate with concentrated hydrochloric acid, extract 
the precipitate thus formed with chloroform and evaporate the extract to a 
residue. Triturate the residue with acetonitrile and obtain thereby the 
product of this example, m.p. 200.degree.-203.degree. C. 
EXAMPLE IV 
3,5-Bis-(Diphenylmethyl)-Picolinic Acid 
A. N-Diphenylmethyl-2-pyridone 
Combine 92.1 g (0.5 mole) of benzhydrol with 142.7 g. (1.5 mole) of 
2-hydroxypyridine and heat to 190.degree. C. with stirring. Add 1.5 ml. of 
concentrated sulfuric acid and follow the procedure of Example III, step A 
to obtain thereby the product of this step yield 68 g., m.p. 
142.degree.-145.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
R.sub.1 -substituted benzhydrols to the process set forth above to obtain 
thereby the corresponding N-substituted-2-pyridone: 
4-chlorobenzhydrol, 
4,4'-dichlorobenzhydrol, 
2-chlorobenzhydrol, 
4,4'-difluorobenzhydrol, 
4-phenylbenzhydrol, 
4-trifluoromethylbenzhydrol, 
3-methoxybenzhydrol, and 
4,4'-dimethylbenzhydrol 
B. 3,5-Bis-(Diphenylmethyl)-2-pyridone 
Combine 46 g. (0.18 mole) of N-substituted-2-pyridone with 33.2 g. (0.18 
mole) of benzhydrol and heat to 230.degree. C. Add about 1 ml. of 
concentrated sulfuric acid and heat at 250.degree.-260.degree. C. for 
about 2 hours. Cool the reaction mixture to about 25.degree. C. and stir 
the solid reaction product with hot acetonitrile, filter, wash and dry to 
obtain thereby the product of this step, yield 49 g., m.p. about 
240.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
N-substituted-(R.sub.1 -substituted diphenylmethyl)-2-pyridones to the 
process set forth above with the appropriately substituted benzhydrol to 
obtain thereby the corresponding 3,5-bis-(R.sub.1 
-substituted-diphenylmethyl)-2-pyridones: 
N-(4-chlorophenyl-phenylmethyl)-2-pyridone, 
N-[bis-(4-chlorophenyl)-methyl]-2-pyridone, 
N-(2-chlorophenyl-phenylmethyl)-2-pyridone, 
N-[bis-(4-fluorophenyl)-methyl]-2-pyridone, 
N-(4-biphenyl-phenylmethyl)-2-pyridone, 
N-[4-(trifluoromethyl)-phenyl-phenylmethyl]-2-pyridone, 
N-(3-methoxyphenyl-phenylmethyl)-2-pyridone, and 
N-[bis-(4-methylphenyl)-methyl]-2-pyridone, 
C. 2-Chloro-3,5-bis-(diphenylmethyl)-pyridine 
Combine 49.5 g. (0.11 moles) of 3,5-bis-(diphenylmethyl)-2-pyridone 
(prepared as described in step B) with 105 ml. of phenylphosphonic 
dichloride and heat the reaction mixture with stirring at 
200.degree.-210.degree. C. for 6 hours. Pour the reaction mixture onto ice 
and basify with ammonium hydroxide. Extract with ethyl ether, dry the 
extract and evaporate to yield a residue which is crystallized from 
ethanol to yield the product of this step, yield about 40 g., m.p. 
131.degree.-133.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
3,5-bis-(R.sub.1 -substituted diphenylmethyl)-2-pyridones to the process 
set forth above to obtain thereby the corresponding 
2-chloro-3,5-bis-(R.sub.1 -substituted diphenylmethyl)-pyridines: 
3,5-bis-(4-chlorophenyl-phenylmethyl)-2-pyridone, 
3,5-bis-[bis-(4-chlorophenyl)-methyl]-2-pyridone, 
3,5-bis-(2-chlorophenyl-phenylmethyl)-2-pyridone, 
3,5-bis-[bis-(4-fluorophenyl)-methyl]-2-pyridone, 
3,5-bis-(4-biphenyl-phenylmethyl)-2-pyridone, 
3,5-bis-[4-(trifluoromethyl)-phenyl-phenylmethyl]-2-pyridone, 
3,5-bis-(3-methoxyphenyl-phenylmethyl)-2-pyridone, and 
3,5-bis-[bis-(4-methylphenyl)-methyl]-2-pyridone. 
D. 3,5-Bis-(Diphenylmethyl)-Picolinic Acid 
Combine 38.4 g. (0.086 mole) of 2-chloro-3,5-bis-(diphenylmethyl)-pyridine 
(as prepared in step C) with 15.3 g. (0.17 mole) of cuprous cyanide in 180 
ml. of dry hexamethylphosphoramide. Heat the reaction mixture at 
210.degree.-220.degree. C. for 7 hours. Pour the reaction mixture into 
aqueous ethylenediamine, extract with benzene, wash the benzene extracts 
with 10% sodium cyanide then with water and dry over potassium carbonate. 
Filter and concentrate the filtrate to a residue. Dissolve the residue in 
300 ml. of ethylene glycol, add a solution of 15 g. potassium hydroxide in 
90 ml. of water and reflux for about 22 hours. Concentrate the reaction 
mixture to a residue in vacuo and acidify the residue with dilute 
hydrochloric acid. Extract with benzene, and concentrate the solution to a 
residue containing the title product which was purified by conversion to 
the diethanolamine salt followed by regeneration of the acid, m.p. 
172.degree.-175.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
2-chloro-3,5-bis-(R.sub.1 -substituted diphenylmethyl)-pyridines to the 
process set forth above to obtain thereby the corresponding 
3,5-bis-(R.sub.1 -substituted diphenylmethyl)-picolinic acids: 
2-chloro-3,5-bis-(4-chlorophenyl-phenylmethyl)-pyridine, 
2-chloro-3,5-bis-[bis-(4-chlorophenyl)-methyl]-pyridine, 
2-chloro-3,5-bis-(2-chlorophenyl-phenylmethyl)-pyridine, 
2-chloro-3,5-bis-[bis-(4-fluorophenyl)-methyl]-pyridine, 
2-chloro-3,5-bis-(4-biphenyl-phenylmethyl)-pyridine, 
2-chloro-3,5-bis-[4-(trifluoromethyl)-phenyl-phenylmethyl]-pyridine, 
2-chloro-3,5-bis-(3-methoxyphenyl-phenylmethyl)-pyridine, and 
2-chloro-3,5-bis-[bis-(4-methylphenyl)-methyl]-pyridine. 
EXAMPLE V 
4-(Diphenylmethyl)-Picolinic Acid 
A. 4-(Diphenylmethyl)-Picolinamide 
Dissolve 20 g. (0.082 mole) of 4-benzhydrylpyridine in 200 ml. of formamide 
and, with external cooling, add 4.35 ml. (0.082 mole) of sulfuric acid. 
Adjust the reaction temperature to 5.degree.-10.degree. C. while adding 
21.6 g. (0.24 mole) of t-butyl hydroperoxide and 67 g. (0.24 mole) of 
ferrous sulfate over a 30 minute interval. Remove the iron salts by 
filtration. Wash the precipitate with chloroform and water and separate 
the two liquid phases. Extract the aqueous phase with chloroform, wash the 
combined chloroform phases with water and dry. Concentrate the extract to 
a residue, dissolve the residue in ether, filter and obtain the product of 
this step from the ether solution, yield 3.5 g., m.p. 
165.degree.-170.degree. C. Additional product may be obtained by 
extracting the iron salts with refluxing chloroform. 
In a similar manner, subject an equivalent quantity of the following 
4-(R.sub.1 -substituted diphenylmethyl)-pyridines to the process set forth 
above to obtain thereby the corresponding 4-(R.sub.1 -substituted 
diphenylmethyl)-picolinamides: 
4-(4-chlorophenyl-phenylmethyl)-pyridine, 
4-[bis-(4-chlorophenyl)-methyl]-pyridine, 
4-(2-chlorophenyl-phenylmethyl)-pyridine, 
4-[bis-(4-chlorophenyl)-methyl]-pyridine, 
4-(4-biphenyl-phenylmethyl)-pyridine, 
4-[4-(trifluoromethyl)-phenyl-phenylmethyl]-pyridine, 
4-(3-methoxyphenyl-phenylmethyl)-pyridine, and 
4-[bis-(4-methylphenyl)-methyl]-pyridine. 
B. 4-(Diphenylmethyl)-Picolinic Acid 
Dissolve 5.3 g. of 4-(diphenylmethyl)-picolinamide (prepared in step A) in 
80 ml. of concentrated hydrochloric acid and heat to reflux. Continue to 
reflux the reaction mixture overnight. Remove 50 ml. of the solvent by 
distillation in vacuo, treat the residue with ice and basify with excess 
10% sodium hydroxide. Add 300 ml. of water and extract the solution with 
50 ml. of ethyl ether. Adjust the pH of the aqueous phase to about 5, 
recover the precipitate by filtration and dry to obtain thereby the 
product of this example, m.p. 172.degree.-177.degree. C. Crystallize the 
product from 75 ml. of acetonitrile, yield 3.8 g., m.p. 
176.degree.-178.degree. C. 
In a similar manner, subject an equivalent quantity of the following 
4-(R.sub.1 -substituted diphenylmethyl)-picolinamides to the process set 
forth above to obtain thereby the corresponding 4-(R.sub.1 -substituted 
diphenylmethyl)-picolinic acids: 
4-(4-chlorophenyl-phenylmethyl)-picolinamide, 
4-[bis-(4-chlorophenyl)-methyl]-picolinamide, 
4-(2-chlorophenyl-phenylmethyl)-picolinamide, 
4-[bis-(4-chlorophenyl)-methyl]-picolinamide, 
4-(4-biphenyl-phenylmethyl)-picolinamide, 
4-[4-(Trifluoromethyl)-phenyl-phenylmethyl]-picolinamide, 
4-(3-methoxyphenyl-phenylmethyl)-picolinamide, and 
4-[bis-(4-methylphenyl)-methyl]-picolinamide. 
EXAMPLE VI 
5-[Bis-(4-Chlorophenyl)-methyl]-Picolinic Acid 
A. 5-[Bis-(4-Chlorophenyl)-Methyl]-2-Pyridone 
Combine 50.6 g. (0.2 mole) of 4,4'-dichlorobenzhydrol with 57.1 g. (0.6 
mole) of 2-hydroxy pyridine, with stirring heat to 200.degree. C. and add 
dropwise 1.0 ml. of concentrated sulfuric acid. Increase the reaction 
temperature to 240.degree.-250.degree. C. and maintain at that temperature 
range while collecting water emanating from the reaction. Cool the 
reaction mixture, add a mixture of ethyl acetate and water with stirring 
and separate the liquid phases. Dry the organic phase, reduce the volume 
of ethyl acetate, cool to precipitate the crude product, yield 43 g. 
Crystallization from ethanol affords the product of this step, m.p. 
211.degree.-215.degree. C. 
B. 2-Chloro-5-[Bis-(4-Chlorophenyl)-Methyl]-Pyridine 
To a mixture of 35.2 g. (0.11 mole) of 
5-[bis-(4-chlorophenyl)-methyl]-2-pyridone and 11.8 g. (0.11 mole) of 
2,4-lutidine, add 50.6 g. (0.33 mole) of phosphorous oxychloride 
(dropwise) while heating the reaction mixture at 80.degree.. Then, heat 
the reaction mixture at 120.degree. C. for six hours. Pour the reaction 
mixture onto ice, basify with ammonium hydroxide, extract with benzene and 
remove both the benzene and residual 2,4-lutidine by distillation. Distill 
the residue at about 195.degree.-210.degree. C. (0.01 mm) to obtain 
thereby about 30 g. of the product of this step as a yellow viscous oil. 
C. 5-[Bis-(4-Chlorophenyl)-Methyl]-Picolinic Acid 
Dissolve the product of step B above in about 150 ml. of dry 
hexamethylphosphoramide, add 15.4 g. (0.172 mole) of cuprous cyanide and 
follow the procedure described in Example IV, step D to obtain the product 
of this example. 
EXAMPLE VII 
5-(4-Chlorophenyl-Phenylmethyl)-Picolinic Acid Diethanolamine Salt 
Combine 0.97 g. of 5-(4-chlorophenyl)-phenylmethyl)-picolinic acid (see 
Example IIIC) with 0.4 g. of diethanolamine in 100 ml. of ethyl acetate. 
Heat the reaction mixture and decant solvent from the brown insoluble 
residue. Upon standing, the product of this example precipitates from the 
ethyl acetate solution, m.p. 108.degree.-115.degree. C. 
EXAMPLE VIII 
5-[Bis-(4-Chlorophenyl)-Methyl]-Picolinic Acid Piperazine Salt 
Combine 19.8 g. (0.055 mole) of 5-[bis-(4-chlorophenyl) methyl]-picolinic 
acid with 4.7 g. of piperazine in hot methanol. Add 5 volumes of ether and 
collect the precipitate by filtration. Recrystallize the precipitate from 
ethanol to obtain thereby the product of this example, m.p. 
240.degree.-255.degree. C. 
The processes described in the last two examples, or either of them, may be 
used to prepare pharmaceutically acceptable salts of the compounds of this 
invention. Alternatively, other processes known in the art may be utilized 
in lieu thereof. 
EXAMPLE IX 
4-(1,1-Diphenylpropyl)-Picolinic Acid 
A. 4-(1,1-Diphenylpropyl)-Pyridine 
Dissolve 2.5 g. of sodium in 500 ml. of liquid ammonia in the presence of a 
catalytic amount of ferric nitrate. Add dropwise to the resulting 
suspension over a 20 minute interval a solution containing 24.5 g. of 
4-diphenylmethyl pyridine in 600 ml. of ether. Stir the resulting dark red 
mixture for an additional 20 minutes, then add 13 g. of ethyl bromide 
dropwise. Add an additional 500 ml. of ammonia, stir overnight, then add 
300 ml. of ether followed by 150 ml. of water. Separate the solvent 
layers. Wash the ether layer with water until neutral, dry and remove the 
solvent under reduced pressure to a residue. Distill the residue at 
192.degree.-200.degree. C./1.6 to 2 mm. and obtain thereby 14.7 g. of the 
title compound as an orange colored oil. 
B. 4-(1,1-Diphenylpropyl)-Picolinamide 
Subject the 4-(1,1-diphenylpropyl)-pyridine prepared in step A to the 
process of Example V, step A and obtain thereby 13.9 of a yellow oil which 
may be crystallized from acetonitrile to yield the title product, m.p. 
144.degree.-147.degree. C. 
C. 4-(1,1-Diphenylpropyl)-Picolinic Acid 
Dissolve 3.8 g. of 4-(1,1-diphenylpropyl)-picolinamide in 50 ml. of 
ethanol, add 100 ml. of 10% aqueous potassium hydroxide and heat the 
resulting mixture at reflux overnight. Remove the ethanol under reduced 
pressure, add water to the residue and adjust to about pH 5 with 10% 
aqueous hydrochloric acid. Filter the resulting solid and crystallize the 
precipitate from ethanol to obtain thereby the compound of this example, 
yield -- 1.6 g., m.p. 191.degree.-193.degree. C. 
EXAMPLE X 
5-(Diphenylmethyl)-Picolinic Acid 
A mixture of 8.2 g. 2-styryl-5-(diphenylmethyl)-pyridine and 120 ml. of 
acetone is cooled to -10.degree. C. and with vigorous stirring 6.66 g. of 
finely divided potassium permanganate is added slowly, in a portion-wise 
fashion, over a 1.5 hour period whilst maintaining the temperature below 
-5.degree. C. Allow the mixture to stand at -15.degree. C. for 15 hours, 
filter and wash the solids with chloroform and extract three times with 
150 ml. of boiling water. Acidify the aqueous extracts with hydrochloric 
acid and extract with ether. Discard the ether extracts and basify the 
aqueous phase to pH 2.5 and filter and dry the precipitated acid which is 
recrystallized from ethanol to yield the tiltle product (m.p. 
189.degree.-191.degree. C.). 
EXAMPLE XI 
5-(Diphenylmethyl)-Picolinic Acid 
18 g. 2-methyl-5-(diphenylmethyl) pyridine, 1 liter of water, 9 g. of 
potassiumpermanganate are heated on a steam bath for about 3 hours until 
the reaction mixture is colorless. 9 g. of potassiumpermanganate, 200 
milliliters of water are added and the reaction mixture is heated for 
about 5 hours until colorless. Filter and wash thoroughly with hot water 
(70.degree.-90.degree. C.), combine the filtrate and washes, cool to about 
25.degree. C., acidify with hydrochloric acid, and recover the 
5-(diphenylmethyl)-picolinic acid by filtration (m.p. 
189.degree.-191.degree. C.). 
Acne is a common inflammatory disease in areas where sebaceous glands are 
largest, most numerous, and most active. It is characterized by the 
appearance of comedones, pustles, papules, inflammed nodules, and in 
extreme cases infected sacs. In the more inflammatory types of acne, 
Corynebacterium acnes and Staphylococcus albus are usually among the 
infecting organisms. It is believed that these organisms aggravate the 
existing inflammatory condition by releasing enzymes (lipase) which break 
down the lipid in the sebum with the concomitant release of irritating 
fatty acids. Thus, an effective anti-acne agent ought be one which can 
prevent or substantially reduce the breakdown of lipid in the sebum 
thereby exerting an anti-inflammatory effect upon the skin. Ideally, the 
anti-acne agent should be effective topically in order to minimize the 
advent of untoward side effects which may occur during systemic treatment. 
For instance, the more frequently used anti-acne agents, the tetracyclines 
are believed to be causally related to side effects which appear with the 
long term systemic treatment usually required in treating acne. These 
adverse effects include gastrointestinal irritation, photosensitivity 
reactions, dizziness, nausea and vomiting. Thus, there is need for 
effective topically applied anti-acne agents. The compounds of this 
invention fill such a need. 
When tested in vitro by a slightly modified version of the test procedure 
described by A. Shalita and V. Wheatley, in J. Invest, Dermatol. 54, 413 
(1970), the compounds of this invention were shown to substantially 
inhibit the formation of free fatty acids from triglycerides by bacterial 
lipases, including those formed by Corynebacterium acnes. The free fatty 
acids produced were assayed by the automated colorimetric method of C. 
Dalton and C. Kowalski as described in Clinical Chem. 13, 744 (1967). 
Further, the test results clearly demonstrate that the anti-lipase 
activity of the compounds of this invention is substantially greater than 
that of hexachlorophene, or that of tetracycline. Additionally, neither 
hexachlorophene nor tetracycline exhibit substantial in vivo topical 
activity whereas the compounds of this invention do. Moreover, the instant 
compounds are substantially devoid of overt skin irritation upon repeated 
topical administration. They also exhibit little systemic toxicity 
following repeated topical application or upon systemic dosing via oral or 
intraperitoneal administration. 
As mentioned, the compounds of this invention are effective antibacterial 
agents, particularly against Corynebacterium acnes and S. albus. 
Additionally, the compounds of this invention are effective against other 
gram-positive organisms and they also are antitrichomonal; they being 
particularly effective against T. vaginalis. As such, the compounds may be 
used in the conventional manner for treating gram-positive infections and 
for treating trichomonal infections. Potency assays and formulations for 
such uses utilize standard techniques. 
The compounds of this invention are administered topically in 
pharmaceutical compositions having the conventional excipients. The 
compositions may be in the form of lotions, creams, aerosols and 
ointments. In these compositions, the active compound is present in the 
range of from about 0.5% to about 10% by weight, administration being from 
about 2 to about 5 times daily. 
As is generally the case wherein a family of compounds exhibit a particular 
utility, certain members are preferred over others. In the instant 
invention, a preferred group of compounds are those wherein R is hydrogen 
or X.sub.1, R.sub.1 is hydrogen or halogen and Q is hydroxy including the 
pharmaceutically acceptable salts thereof. Particularly preferred are the 
compounds wherein R.sub.1 is chloro and R is hydrogen. Another preferred 
group of compounds are those wherein R.sub.1 is hydrogen, R is X.sub.1, 
and Q is hydroxy, including the pharmaceutically acceptable salts thereof. 
Yet another preferred group of compounds within the family defined by 
formula I are those wherein R and R.sub.1 are as defined in said claim and 
Q is a member selected from the group consisting of polyhydroxyalkoxy, 
aminoalkyoxy. Particularly preferred are those compounds wherein the 
polyhydroxyalkoxy group in combination with the carbonyl to which it is 
attached forms a glyceryl ester. 
The compounds of this invention tested by the in vitro test procedures set 
forth herein below: 
A. In Vitro Test 
1. Isolation of Organisms: 
a. C. acnes organisms were obtained by gently squeezing the nasal surface 
of normal human volunteers. The expressed material was streaked across the 
surface of a Brain Heart Infusion Agar Plate and plates were incubated 
anaerobically at 37.degree. C. for 7 days. 
After 7 days the plates were examined and appropriate colonies were 
restreaked on blood agar to obtain isolated colonies. These plates were 
incubated aerobically for 28 hours. Suitable colonies were identified 
using gram staining. Those colonies positively identified as C. acnes were 
used to innoculate thioglycolate (10% glycerol) broth. After 7 days 
anaerobic incubation, the cultures were either frozen at -4.degree. C. for 
future use or used to innoculate a Brain Heart Infusion broth for 
immediate use as follows: After 7 days the cells were separated from the 
Brain Heart Infusion broth by centrifugation (10,000 rpm for 30 minutes at 
4.degree. C.). The cells were discarded and the broth used to prepare the 
enzyme. 
2. Enzyme Preparation 
A known volume of broth was added very slowly with mixing to chilled 
acetone (4.degree. C.) in a ratio of 1 volume broth to 1.5 volumes 
acetone. 
The mixture was kept at -4.degree. C. for 1/2 hour before filtering through 
a Buchner funnel using Whatman No. 1 paper. 
The precipitate was saved and redissolved in 1/5 its original volume of 
H.sub.2 O and lyophilized to yield the crude enzyme powder. This enzyme 
preparation is stable at -4.degree. C. for at least 6 months. 
3. Fatty Acid Free Olive Oil 
Ten ml. of olive oil was extracted with 10 ml. of anhydrous ether in a 250 
ml. separatory funnel together with 10 ml. of 10% Na.sub.2 CO.sub.3. The 
mixture was shaken well, pressure released and then allowed to stand until 
the layers separate. The bottom layer was discarded and the washing with 
Na.sub.2 CO.sub.3 repeated 4 more times. After discarding the bottom layer 
the remaining solution was placed in a beaker over a boiling water bath to 
remove all traces of ether (2-3 hours). One-tenth of gram of benzoic acid, 
2.5 g. gum acacia, and 90 ml. hot water were added to the washed olive oil 
and blended in an homogenizer for 1 minute at high speed. The mixture is 
stable at 4.degree. C. for 6 weeks. 
Test Procedure 
In Vitro 
Corynebacterium Acnes Lipase (Primary Screen) 
Semi-purified bacterial enzyme (prepared as described above) 0.15 ml. of a 
50 mg/ml. solution is allowed to react with 0.1 ml. of 10% fatty acid free 
olive oil solution in a 2 ml total volume at a pH of 7.0 (0.2 phosphate 
buffer) and at 37.degree. C. in an incubation vial. At the end of 3 hours, 
0.3 ml of the reaction mixture is removed for free fatty acid (FFA) 
analysis. The activity of the enzyme preparation is expressed in terms of 
microequivalents (.mu.eq) of FFA/liter of product. 
Staphylococcus aereus Lipase 
The assay conditions for this enzyme are the same as above except that the 
enzyme concentration is 5 mg/ml. 
System for Determination of In Vitro Bacterial Lipase Inhibition 
Test compounds (5.times.10.sup.-4 M .fwdarw. 5.times.10.sup.-8 M) are added 
to the incubation vial in buffered solution, maintaining a final volume of 
2 ml. Water insoluble compounds were first solubilized with an appropriate 
solvent (CHCl.sub.3, DMSO) and an aliquot added to the vial the solvent 
evaporated under N.sub.2 before addition of enzyme, substrate and buffer. 
Appropriate drug blanks without enzyme were included to assess any drug 
interference in the FFA assay. Incubation conditions and FFA analysis were 
the same as cited previously. 
##EQU1## 
The IC.sub.50 for the test compounds is calculated using least squares 
regression from results obtained by testing a number of different molar 
drug concentrations giving inhibition ranging from 20-80%. 
The following examples (i.e. Examples X through XIV inclusive) are directed 
to topical formulations in which the compounds of this invention may be 
utilized to elicit an antiacne response. The formulations are prepared by 
methods known in the art using the active compound in the form of an 
"micronized" solid. 
EXAMPLE X 
______________________________________ 
Ointment mg/gm 
______________________________________ 
5-(Diphenylmethyl)-Picolinic Acid 
20.0 
Propylene Glycol U.S.P. 40.0 
Mineral Oil, U.S.P. 50.0 
White Petrolatum, U.S.P. to make 
1.0 g. 
______________________________________ 
EXAMPLE XI 
______________________________________ 
Ointment mg/gm 
______________________________________ 
3,5-[Bis-(Diphenylmethyl)-Picolinic Acid 
20.0 
Propylene Glycol, U.S.P. 40.0 
Stearyl Alcohol, U.S.P. 50.0 
Polyethylene Glycol 400, U.S.P. 
600.0 
Polyethylene Glycol 4000, U.S.P. to make 
1.0 g. 
______________________________________ 
EXAMPLE XII 
______________________________________ 
Gel mg/gm 
______________________________________ 
4-(Diphenylmethyl)-Picolinic Acid 
20.0 
Propylene Glycol, U.S.P. 
300.0 
Polyethylene Glycol, 400 U.S.P. 
660.0 
Butylated Hydroxytoluene 
5.0 
Carbopol 940P 15.0 
Titanium Dioxide, U.S.P. 
10.0 
Sodium Hydroxide, U.S.P. 
0.7 
______________________________________ 
EXAMPLE XIII 
______________________________________ 
Cream mg/gm 
______________________________________ 
5-(4-Chlorophenyl-Phenylmethyl)-Picolinic Acid 
20.0 
Stearic Acid, U.S.P. 60.0 
Glyceryl Monostearate, Cosmetic 
100.0 
Propylene Glycol, U.S.P. 50.0 
Polyoxyethylene Sorbitan Monopalmitate, Cosmetic 
50.0 
Sorbitol Solution, U.S.P. 30.0 
Benzyl Alcohol, N.F. 10.0 
Purified Water, U.S.P., to make 
1.0 gm. 
______________________________________ 
EXAMPLE XIV 
______________________________________ 
Glycol Ointment mg/gm 
______________________________________ 
5-[Bis-(4-Chlorophenyl)-Methyl]-Picolinic Acid 
20.0 
Propyl Glycol Monostearate 20.0 
Propylene Glycol, U.S.P. 100.0 
White Wax U.S.P. 60.0 
White Petrolatum q.s. to make 
1.0 gm. 
______________________________________