Note: Descriptions are shown in the official language in which they were submitted.
~ SZ7~
Background of the Invention
The present invention relates to substituted 2-pyridones
and 4-pyridones useful as antiinflammatories.
The chemistry used to produce the compounds of this
invention is new. It involves what may be called the aeid catalyzed
dehydrative dimerization of acetoacetarnides. Acid catalyzed reac-
tions o acetoacetan~ides have been described previously in the
literature but under the conditions used have aIways led to products
derived from internal cyclization of the acetoacetamide molecule i.e.
carbostyrils, 4-pyranones or 4-hydroxyquinaldines (I,. Knorr,
Chem. Ber. 16, 2593 (1883); i}~id 17, ~40 ~1884~; ibid 17, 2870
(1884); L. Pinorr, Ann 236, 69 (1886); A.K. Mallams and S.S.
lsraelst~ J. Org. Chem 29, 3548 (i964); ~bid 29, 3555 (1964))).
The conditions u~ed in this invention lead not to the above products
but to 4 or 2-pyridones which are derived from two molecules of the
acetoacetamide. Thus, for example, acetoacetanilide in benzene with
a trace of PTSA (para-toluene sulfonic acid) and azeotropic removal
of water ~ives a 4-pyridone. ~ ~
5~ e ll~/~hn~ , ' .,
The present invention relates ~o a compound of the
formula I,
... :
O~' --N _ R1
R5X~`~C = O I,
R2 ~2
~1 . .
or a pharmaceutically acceptable acid addition salt thereof,
wherein both of substituents Rl are the same, and are
alkyl havi~g one to six carbon atoms,
. .
.
I . .
5Z7~3
phenyl; or phen~l substituted with halogen, alkoxy having one
to four carbon atoms, alkylthio having one to four carbon
atoms, or alkyl having 1 to 4 carbons; both of substituents
R2 are the same, and are alkyl having one to six carbon atoms,
phenyl, or phenyl substituted with halogen; and R5 is
hydrogen or halogen.
The present invention also relates to a process for
the preparation of a compound of the formula I or the acid
addition salt thereof, wherein Rl, R2 and R5 are as set forth
above, comprising dehydratively dimerizing a compound of the -:
formula
O O
.. ..
R2 _ C - C~R5 - C - NHRl
wherein Rl, R2, and R5 are as defined above, in the presence
of an acid catalyst, and, if desired, preparing the acid
addition salt.
The present invention also relates to a compound
of the formula
o R6 : ' '
~ " I ..
- C ~ ~ II,
R6 ~J ~0
~8 .
or the acid addition salt thereof, wherein R6 is alkyl having
one to four carbon atoms; R7 is hydrogen; and R8 is cycloalkyl
having from three to ten carbon atoms, alkyl having from one
to eighteen carbon atoms, or alkyl having from one to eighteen
: carbons substituted with phenyl or with substituted phenyl,
the suhstituents on the phenyl being alkoxy having one to our
caxbon atoms or halogen, with the proviso that if R6 is methyl
and R7 is hydrogen, R8 may not be methyl.
- 2 -
.. ~, . .. ~ .
~5i27~3
The present invention also relates to a process for
the preparation of a compound of the formula II, or the acid
addition salt thereof, wherein R6 is alkyl having one to four
carbon atoms; R7 is hydrogen; and R8 is cycloalkyl having from
three to ten carbon atoms, alkyl having from one to eighteen
carbon atoms, or alkyl having from one to eighteen carbon atoms
substituted with phenyl or with substituted phenyl, the
substituents on the phenyl being alkoxy ha~ing one to four
carbon atoms or halogen, comprising dehydratively dimerizing
a compound of the formula -
O O .-
R6 _ C - CHR7 - C - NHR8
wherein R6, R7 and R8 are as defined above.
The present invention also relates to a method of
reducing edema in animals co~prising administering to the
affected animal a pharmacologically ef~ective amount of a com-
pound o~ the ~ormula I or an acid addition salt thereof
wherein Rl, R2 and R5 are as set foxth above, or a pharmaco-
logically efective amount of a compound of the formula II
or an acid addition salt thereof, wherein R6 is alkyl having
one to four carbon atoms; R7 i9 hydrogen; and R8 is cycloalkyl
having from three to ten carbon atoms, alkyl having fxom one
to eighteen carbon atoms, or alkyl having from one to eiyhteen
carbon atoms substituted with phenyl or with substituted phenyl,
the substituents on the phenyl being alkoxy having one to
four carbon atoms or halogen.
The present invention also relates to a pharmaceutical
composition comprising a compound of the formula I or II,
wherein Rl, R2, R5, R6, R7 and R8 are as deined above,
together with a diluent or carrier.
- 3 -
'~
.. . ...
7~3
Description of the Preferred Embodiments
It has been found that in the processes of the present
invention alkyl or cycloalkyl substituted acetoacetamides always give
2-pyridones whereas very unexpectedly ~he aryl substituted aceto- 1 :
acetamides give 4-pyridones. Thus, for example,
E~ O 1,
CH
O O , ~ ~:
" " R ~~ -- alkyl or
C~I3~ CH2~C-NHR bellzene~PoTsA ~ 3 . R cycloalkyl
or-
. ,EI - N - R
H ~ =O
_ J~ ~_ R = aryl
CE13 `Nr H3
R j.
C:ompounds of the 4-pyridone structure can also be made by an !
adaptatiQn of the method of Ziegler et. al. fCA:70,965g2p (1969j]. .
. .
~O
-~ .
,'..
. '''`"'. ~'
- 4
~` 3
'$ .~
,~ :
-
5;~7i~
--5--
The structure of certain of the 4-pyridones of the present invention
has been proven by using this alternate synthesis. That is, . .
H Ph
o O O \N/ diketene
~ PhNH2 ~- I .
CH3-C-~ H2-C-NHPh > CH3-C=CH-C-~HPh
~ ~ ~N - Ph
11 ~ '.:''
i ---- > ~ C = O .:
N \ , ~:
-E~O ~H3 I h CH3
The alternate synthesis above can also be used to make 4-pyridones
not available via the dehydrative dimerization route namely those of
the general structure (A) where R1 and R3 are different. The
latter synthesis has been used to prepare some of these compounds.
O '
I; N - R
2s ~ ~r =o
CH3 ~ 3 CH3 A
. .
It has been found that the compounds disclosed herein
are pharmaceu~i~ally active entities in t he reduct~ion of edema in
.
3Q cases of inflamma~ion, particularly in the treatment oi arthritic :`
conditions in animals.
In general, the dehydrative dimerizations reactions used
to prepare the: compounds disclosed herein were carried out by
dissolving or suspending the approprlate acetoacetamide in benzene,
:~
-5-
.
. . . . . .. .
-6~ LS2~
or more preferably in toluene, containing from a trace (i.e., about
0.5% by weight based on the weight of reactant) to one equivalent
of paratoluene-sulfonic acid mono-hydrate (PTSA . H2O) and then
heating the mixture to the boiling (i . e ., about 80C for benzene
and about 110~C for toluene) at atmosphere pressure. The appara~
tus was fitted with a Dean-Stark trap so that water ~ormed in the
reaction could be continuously removed. With aromatic acetoaceta-
mides traces (i.e., about 0.5 to 2% by weight based on the weight
of reactant) of PTSA.H2O were used since the use of a full equiva-
lent often leads to production of the corresponding carbostyril
rather than the desired 4-pyridone. On the other hand, Eor alkyl
or cycloalkyl-substituted acetoacetamides where the carbostyril
cannot form, it is often advantageous (but not necessary) to use
one equivalent of PTSA . H2O . In such cases this often speeds the
reaction and/or gives a purer product. l~eaction times for the
dehydrative dimerization reactions range from 3 to 48 hours but are
preferably in the 12 to 16 hour range. As would ~e obvious to one
~killed in the art, other inert solvents and other catalysts (for
example, other sulfonic acids or sulfuric acid) would be suitahle for
use in the dehydrative dimerization reactions.
Preparations of 4-pyridones by the alterna te synthesis
described above were carried out by dissolvmg or suspending the
appropriate beta-(aminosubstituted)-crotonanilide (made from the
corresponding acetoacetam~de and the desired amine) in toluene and
adding one equivalent of diketene (50% in acetone~ dropwise. The
mixture was refluxed for about 4 hours and the HC1 salt of the
4~pyridone was then isolated by adding 10% HC1 to the reaction
mix~ure and removing the precipitated salt by filtration. The salt
could then be converted to the free base by trea~nent with 10%
;aqueous NaOH.
-6-
, . ............. . ,, , ~ . ................ . . .
. ................. . . .. . . .
-7~ LS2'7~
In addition to the method of the preceding para-
graph, the HCI salts of the 2- and 4-pyridones disclosed herein
were prepared by several methods. One method involved suspend-
ing the isolated pyridone in 10% aqueous HCl solution, stirring for
5 about 15 minutes, and then removing the water insolu~le salt ~y
filtration. Another method involved dissolving the pyridone in a
solvent such as toluene or chloroform and then treating the solution
~vith 10% aqueous HCl. The use of such a "co-solvent" often aids
greatly in obtaining a pure product. A third method involved
10 dissolving the free base in a solvent and bubbling a dry gaseous
HCI. All the salts are to some degree unstable when heated above
about 100C and revert to the corresponding free ~ase. Thus when
pyridinecar~oxamide, N, 1-dicyclohexyl-1, 6-dihydro-2,4-dimethyl-
6-oxo, hydrochloride salt was heated at 110C for 4 hours it was
15 about 90% converted to the free base. This property of the salts is
reflected in the melting points reported herein. The melting range
was often wide and was found to depend upon the rate of heating.
Usually E~Cl gas could be detected at temperatures above 100C.
Often the final solid melted at about the same temperature as the
20 free base indicating that conversion had largely occurred during
the heating period.
The structures of the various pyridones were deduced
from their infrared and nuclear magnetic resonance (n.m.r. )
spectra and an elemental analysis. The n.m.r. spectra are parti-
25 cularly useful in distinguishing the 4-pyridones from the 2-pyri-
dones in that the hydrogen on nitrogen in the former is hydrogen
bonded and hence absorbs at typically 12 to 13 ppm (parts per
million) whereas the equivalent non-hydrogen bonded N-H oE the
2-pyridones absorbs typically from 9.0 to 10.0 ppm. In order to
.
.
.
. . - :. , '.
'.: . , ~ , .
- '~
5Z7~3
confirm the above assignment the compound
f. H\
H ~ - C - O
3 CH
was prepared from
1 0 CE13X~COOEi
. . '
which was prepared by the method of J.N. Collie and T.P. Hilditch
~J. Chem. Soc. 91, 787 (1907)) and the compound
O CH3
CH3
was prepared by the method of Wiley et . al . ~J . A . C . S . 76, ~31
(1954) ~and J.A.C.S. 75, 244 (1953)?. Further indication of the ;~ .
assigned structures was ~he fact ~hat all the pyridones formed
hydrochloride salts when treated with dilute hydrochloric acid. The
salts could be converted back to the frae bases on trea~nent with
dilute sodium hydroxide solution.
'. ' ' ~' :
;~ ' ,: ',
, , :~''.
:' ~ . ' '
.
.'.
g ~ 527~3
Eacample 1
3-Pyridinecarboxamide, 1,4-dihydro-2,6-dimethyl-N,1-
diphenyl-4-oxo (Compound 1)
~A) By DehYdrative Dimerization (The method of
Equation (1)
A mixture consistin~ of 35.4 g (0.20 mole)of butanamide,
N-phenyl-3-oxo, O . 5 g PTSA . H20 and - 2û0 ml of benzene was
brought to reflux in a flask fitted with a Dean-Stark trap. After
24 hours the mixture was cooled and washed twice with 50 ml
portions of 10% aqueous NaOH to remove unreacted starting mater-
ial. The benzene layer was separated, dried wi~h anhydrous
Na2SO~l and the benzene was then removed under reduced pressure
to give a crystalline residue. This was recrystalli2ed from 95%
ethanol to give 9 . 5 g ~30% yield) of the title compound having a
melting point of 200-205C. .
Ana1ysis: Calcul~ated for C20H18N202: C, 75 45; H, 5.7Q;
Found: C, 75.55; H, 5,78; N, 8.83
N.m.r. (delta (CDCl3~): 1.81(s,3H); 2.45(s,3H);
6.4û (s,1H~; 6.90-7.80 (m,lOH); 1~:.77(s,1H)
ppm
I.r. (Nu (max)(KBr)): 1~75 (s), 1620~s), 1590(s),
1555(s), 1520(s), 1485(s), 1~55(s), 1435(s),
1335(m), 1310(m) cm~1.
Mass spectrum (m/e): 318, 300, 118, 93
. ~.
~B) Bv Reacti~on of beta-anilinocrotonanilide with diketene
(The method of Equation (2))
2.7 n~ (û.0159 mole) of diketene (50~ in acetone) was
added dropwise tD a mixture of 4 g (0 . 0159 mole) of Beta ~anilino-
3 0 crotonanilide in 100 ml of toluene . The mixture was heated atre~lux for 4 hours and was then cooled and treated with 10
_9_
. ,
7~
-10-
aqueous HCl to precipitate the HCl salt of the desired 4-pyridone.
This was filtered off and washed with acetone. It was then placed
in a beaker and heated in a mixture of 50 ml of 10% aqueous NaOH
and 50 ml of toluene until two clear phases were obtained. The
5 phases were separated and the toluene phase was cooled in order to
precipitate the product which melted at 205- 207C. An inErared
spectrum of this product was identical with the infrared spectrum
of the product described above in paragraph (A).
In a repeat experiment it was found advantayeous t~ add
10 a trace of trimethylamine to the original reaction mixture in orcler to
improve the yield.
Example 2
3-Pyridinecarboxamide, 1,4-dihydro-2,6-dimethyl-N,1-
diphenyl-4-oxo, hydrochloride salt (Compound 2)
A rnixture consisting of 3.0 g (0.0094 mole) of 3-pyridine-
carboxamide, 1,6-dihydro-2,4-dimethyl-N,1-diphenyl-6-oxo- (Com-
potmd 1) in 50 ml of 5% aqueous hydrochloric acid was stirred
in a small beaker. The solid gradually dissolved and after three or
four minutes the solution became turbid and a precipi~ate formed.
20 The mixture was warmed briefly on the steam bath to ensure
complete reaction and then cooled and filtered. The precipitate was
washed with acetone and air dried. 3.2 g of the title product (96%
yield), having a melting point of 260-265C, was obtained.
N.m.r. (delta (dmsod6)): 2.12 (s,3H); 2.18)s,3H);
6.gO-7.90 (m, 11H~; 11.3(2,1H)
I.r. (Nu max (KBr)): 2000-3500 (broad), 1675 (s),
1620(s), 1590(s), 1540(s), 1530~B~, 1475(s),
1440(s), 1350(s), 1320(s), 1275(m), 1245~m),
1200(m), 1165(w), 1155(w), 1080(w), 1070(w),
1020(w), lOOO~w), 89d(m~, 865(m), 755(s),
700~s), 690(m) cm 1
- ' .
Example 3
3 -P~7rid;necarboxamid e, 1, 4- dihydro- 2, 6- dimethyl-N ,1-
di-(4-ch]orophenyl~-4-oxo (Compound 3)
A mixture consisting of 40 g (0.189 mole) of butanamide,
N-~4-chlorophenyl)-3-oxo-, 2 g of PTSA.H2O and 500 ml of toluene
was brought to reflux in a flask fi~ted with a Dean-Stark trap.
After 6 hours, the reaction mixture was cooled and was then
extracted with 100 ml of 10% aqueous NaOH solution. Crystalline
material began to separate immediately from the above mixture and
it was necessary to filter this solid material off before separating
the organic and aqueous phases. The solid was washed with water
and set aside. The toluene phase of the filtrate was separated and
dried with anhydrous sodium sulfate. About 300 ml of the toluene
was then removed under reduced pressure. A Eurther crop of
solid material deposited from the remaining solution. The two crops
were combined and were recrystallized ~rom ethanol to give 16.1 g
(44% yield) of the title compound having a melting point of
262-268C.
Analysis:Calculated for C20H16Cl2N2O2: ,
N, 7.23
Found: C, 61.83; H, 4.26;
N, 7.31
~` M.m.r. (delta (CDCl3)): 1.88(s,3H); 2.49 (s,3H),
6.42(s,1H), 7.10-7.80(m,8H), 12.85 (s,lH) ppm
I.r. v (max) (CHCl3) 1675(s~, 1630(s), 1590(m),
1525(s), 1490(s), 1455~m)/ 1420(m), 1400(m),
1340(m~, 1280(m~, il90(w), llOO(m), 1075(w),
1020(w), 1015(w), 860(m), 850(m), 830(m)
cm~l
5Z~3
E~sample 4
3-Pyridinecarboxamide, 1,4-dihYdro-2,6-dimethyl-N,1~
(4-chlorophenyl~-4-oxo, hydrochloride salt (Compound 4)
A mixture consisting of 40 g (0.189 mole) of butanarnide,
N-(4-chlorophenyl)-3-oxo, 2 g of PTSA.H2O and 500 ml of toluene
was brought to reflux in a flask fitted with a Dean- Stark trap .
After 6 hours the reaction mixture was cooled and then extracted
with 10Q ml of 10% aqueous NaOH solution. The crystalline material
(Compound 3) that separated was filtered off, washed with wa~er
and set aside. The toluene layer was separated from the aqueous
basic layer and washed with water. The solid material ~Compound
3~ was then added to the separated toluene layer and the mixture
was stirred Eor ï5 minutes with 100 ml of 10% aqueous HCl solution.
The resulting precipitate of the title compound was filtered, washed
with water and air dried. It was purified by adding 100 ml of
acetone to the dry solid and filtering. 16.3 g (41% yield~, having a
melting point of 290-300C, was obtained.
Analysis: Calculated for 520H17Cl3N2O2: N 6 61
20Found: C, 57.33; H, 4.18
N, 6.76
Example 5
' 3-Pyridinecarboxamide, 1,4-dihydro-2,6-dimethyl-N,1-di-
(2-methoxyphenyl)-4-oxo ~Compound S)
A mixture consisting of 30 g (0.0145 mole) of butanamide,
N-(2-methoxyphenyl)-3-oxo-, 0.~ g of PTSA.H2O and 200 ml of dry
benzene was brought to boiling in a flask fitted with a Dean-Stark
trap. After 48 hours the reaction mixture was cooled and the
precipitate which formed was separated by iltration to give 13 g
3~ ~479i yield~ of the title compound having a melting point of 228-
234~C. When this material was purified ~y recrystallization from
-
-12~
.
. . . , , , . ~, , ~ .. . ..
-13-
5~7i~
95% ethanol, it had a melting point of 237-240C. The melting point
of the corresponding hydrochloride salt, prepared by the method of
Example 2, was 241-245C.
Analysis: Calculated for C22H22N2O4: C, 69.82; H, 5.86; N, 7.40
Found: C, 69.73; H, 5.71; N, 6.67
N.m.r. ~delta (CDCl3)): 1.85(s,3H); 2.4B~s,3H,~
3.26(s,3H); 3.43(s,3H); 6 48(s,1H?; 6.20-8.70
(m,8H); 12.23(s,1H) ppm
I.r. (Nu (max)(CHCl3)): 3000, 1660, 1595, 1490,
1460, 1275, 1255, 1025 cm 1.
HCl Salt I.r. (Nu (max)(KBr): 3200, 3000, 2350, 1770, 1620,
1530, 1460, 1450, 1~30, 1350, 1280, 1250, 1220,
1200, 1130, 1040, 1020, 890, 800, 750 cm~1 `
Example 6
3-Pyrldinecarboxamide, 1,4-dihydro-2,6-dimethyl-N,1- - -
is~2,4,6-tri-methylphenyl)-4-oxo (Compound 6)
A mixture consi~ting of 45.0 g (0.205 mole) of butanamide,
3-oxo-N-~2,4,6-tr~methylphenyl), 0.2 g of PTSA.H20 and 400 ml of
toluene was brought to reflux in a flask fitted with a Dean-Stark
2 trap. AEter 21.5 hours the reaction mixture was cooled. The
toluene solution was washed with 200 ml oE 10% NaOH and was then
dried ~th anhydrous potassium carbonate. The toluene was distilled
off to give 12.5 g of crude product. The product was recrystallized
from toluene and 30-60 petroleum ether (50:50) to give 7.0 g or
17% of the title compound having a melting point of 195-196.5C.
Analysis: Calculated for C26H30N~O2: C, 77.58; H, 7.51; N, 6.96
F~und: C, 77.18; H, 7.53; N, ô.92
:-
~13-
,
. ~
, . ~ .. . ~ - , .; , . . ., : .
5;~78
Example 7
3-Pyridinecarboxamide, 1,4-dihydro-2,6-dimethYl-N,1-
bis(2,4,6-trimethylphenYl~-4-oxo,hydrochloride salt
(Compouna 7)
- 5 A solution of 7 .1 g (0 . 0176 mole) of 3~pyridinecarboxa-
mide, 1,4-dihydro-2,6-dimethyl-4-oxo-N,1-bis(2,4,6~trimethylphe-
nyl)- in 200 ml of warm toluene was shaken with 100 ml of 10%
aqueous HCl solution. The resulting precipitate was separated by
filtration and air dried. It was purified by adding 100 ml of
10 acetone to the dry solid and filtering. This yielded 6. 5 g (84%
yield) of the title compound having a melting point of 258-265C.
Analysis: Calculated for C26H31ClN2O2: C, 71.13; H, 7.12; N, 6.38
Found: C, 71.67; H, 7.13; N, 6. 43
Example 8
3-PYridinecarboxamide, N, l-dibutYl-l, 6-dihydro-2, 4-
~imethyl-6-oxo (Compound 8)
A mixture consisting of 34.0 g ~0.216 mole) of butanamide,
N-butyl-3-oxo-, 41.2 g (0.216 mole) of PTSA.H2O and 400 ml ~
toluene was brought to reflux in a flask fitted with a Dean-Stark
20 trap. After 16 hours, the reaction mixture was cooled. The
toluene solution was washed with 250 ml of 10% NaOH and was then
dried with anhydrous potassium carbonate. Addition of an equal
volume~of 30-60 petroleum ether and subsequent cooling led to the
formation of crystals. The crystals were filtered to give 25.0 g of
25 crude product. The product was recrystalliæed from toluene and
30~-60 petroleum ether ~50:50) to give 20.9 g or 69.4% o~ the title
compound having a melting point of 73.5-75C.
.~nalysis: Calculated for C16H26N202: N 10 06
~ Found: C, 69.01; H, 9.58; N, 9.63
. . .
--14~
: ; . .....
Example 9
3-~ridinecar~oxamide, N ,1-dibutyl-1, 6-dihydro-2 ,-1-
dimethyl-6-oxo, hydrochloride salt (C mpound 9~
A solution of 5 . 0 g (0 . 018 mole) of 3-pyridinecarboxa-
mide, N,l-dibutyl-1,6-dihydro-2,4 dimethyl-6-oxo- in 200 ml of
toluène was treated with anhydrous HCl, which was bubbled in
through a gas dispersion tube. A precipil:ate forrned, and the
treatment was continued until further precipitation ceased. The
product was filtered and air dried to give 5.3 g (94% yield) of the
title compound having a melting point of 145-151C.
Analysis: Calculated for C16H27CIN2O2: C, 61.03; H, 8.64; N, 8.90
Found: C, 60.78; H, 8.74; N, 8.64
Example 10
3-Pyridinecarboxamide, N,l-dicyclooctyl-1,6-dihydro-?,4-
dimethyl-6-oxo, hydrochloride salt ~Compound 10?
The starting material (butanamide, N-cyclooc$yl-3-oxo)
was synthesized by adding 91 ml (0 . 533 mole) of a 50% diketene
solution in acetone to 67.7 g of cyclooctylamine dissolved in 500 ml
OI toluene. After complete addition (1 hr) the mixture was stirred
1 additional hour and the toluene was removed. The residue was
crystalliz~d ~rom 500 ml of 60-:L10 petroleum ether plus 100 ml of
toluene by cooling to -10C to give 77.0 g (68% yield) of product
having a melting point of 38-40~C.
A mixture consisting of 10 g (0.0475 mole) of the above
~5 butanamide, 9 . 02 g (û . 0475 mole) of PTSA . H20 and 200 ml of
toluene was brought to reflux in a flask fitted with a Dean- Stark
trap. After 5 hours the mixture was cooled and extracted firs~
with lG% NaOH solution and then with water. 25 ml of 10% aqueous
HCI was added to the toluene solution and a white solid precipitated
.
'
-15-
16~ .5Z7~
immediately. The precipitate was removed by filtration, washed
with acetone, and then ether and air ~ried to give 3 . 2 g (~2%
yield) of the title compound, having a melting point of 200-205C.
Analysis: Calculated for C24H39ClN2O2: C, 68.14; H, 9.29; N, 6.62
Found: C, 70.39; H, 9.35; N, 6.79
N.m.r. (delta (CDCl3)): 1.10 to 2.20 (m,28H), 2.36
(s,3H); 2.62 (s,3H); 4.10 (broad, lH~; 4.18
~broad, lH); 7.2 (s,1H); 8.35 (~road, 1H);
8.80 (broad, lH)
Example 11
3-Pyridinecarboxarnide, N,1-d_yclooctyl-1,6-dihYdro-
2 ,4-dimethyl-6-oxo (Compound 11 )
A mixture consisting of 1. 0 g (0 . 00238 mole) of 3-pyri-
dinecarboxamide, N ,1- dicyclooctyl-1, 6- dihydro-2, 4- dime thyl-6-oxo,
hydrochlaride salt (Compound 10), 5 ml of 10% aqueous NaOH and
10 ml of toluene were mixed and heated for 1 hour on a steam bath.
The toluene layer was then separated from the aqueous layer, dried
with sodium sulfate and the toluene was then removed. The residue
was crystallized from a mixture of 1: 3 toluene/30-60 petroleum
ether to give 0.86 g (94% yield~ of the title compound hav;ng a
melting point of 176-179C.
Analysis: Calculated for C24H38N2O2: C, 74.57; H, 9.91; N, 7.25
Found: C, 74.50; H, 9.84; N, 7.02
- Example 12 -
3-Pyridinecarboxamide, 1,4-dihydro-2,6-dimethyl-N,1-
di-(n-butyl)-4-oxo (Cornpound 12a)
The starting material, bu~enamide, N-~n-butyl)-3-(n-
bu$ylamino) was prepared by mixing 15.7 g (0.10 mole) of butana-
mide, N-(n-~utyl)-3-o~o, 9.9 ml ~0.10 mole) of n-butylarnine and
200 ml of ~enzene in a flask fitted with a Vean-St3rk trap. The
. .
-16-
.
.
-17~ 2~3
mixture was refluxed for 4 hours while the water of reaction was
collected. The mixture was cooled and extracted with 2 x 50 ml of
water, then 1û0 ml of 10% aqueous NaOH, then 100 ml of water.
The benzene layer was dried with Na2SO4 and the benzene removed
to leave 22 g of a clear yellow oil whose infrarled and n.m.r. spectra
were in full accord with the structure being butenamide, N,
(n-butyl)-3-(n-butylamino) .
17 rnl (0.10 mole) of diketene (50% in acetone) was added
to a solution of the starting material in 200 ml of toluene. After
complete addition, the reaction mixture was refluxed for 4 hours
and then allowed to cool. A solution of 100 ml of 1û% aqueous HCI
was then added and the HCI salt (Compound lZb) of the title
compound precipitated. It had a melting point of 129-13~C. The
HCI salt was removed from the toluene/water mixture ~y filtration
and was washed with toluene and then with water. It was then
mixed with a warm mixture of 50 ml of 10% NaOH and lS0 ml of
toluene. When all the solid was dissolved, the phases were
separated, the toluene layer was dried with sodium sulfate, and the
tduene was removed under reduced pressure to leave a yellow oil
which did not crystallize. An infrared and n.m.r. spectrum of this
oil were in full accord with the title structure.
Analysis: Calculated for C16H26N2O2: C, 69.03; H, 9.41;
N, 10 . 06
Found: C, 68 . 30; H, 9 . 53;
~5 N, 10 . 63
Example 13
3~Pyridinecarboxamide, 1-(4-chlorophenvl)-1,4-dihydro-
?, 6-dimethyl-4-oxo-N-phenyl ~Compound 13a)
The starting material, butenamide, 3-(4-chlorophenyl3-
N-phenyl was made as follows: A mixture of 200 ml oE toluene,
- 19.5 (0.11 mole) of acetoacetanilide, lZ.7 g (0.10 mole) of p-chloro-aniline and 0.25 g of PT8A.H20 were refluxed together in a flask
''
-17-
-18~ 1527B
fi~ted with a Dean-Stark trap. After 3 hours 1.8 ml of water were
collected and the reaction mixture was cooled to room temperature
and extracted with 3 x 60 ml of 10% aqueous NaOH, followed by
2 x 80 ml of wa-ter. The toluene phase was dried with Na2SO4 and
5 the toluene was then removed under reduced pressure to yield 25 g
of an oil whose infrared and n.m.r. spectra indicated it to be
mainly butenamide, 3-(4-chlorophenyl)-N-phenyl. TLC on silica gel
using toluene/ethanol (6:1) as eluant showed only a small amount
of one impurity. The unpurified material was used to make 3-
pyridinecarboxamide, 1-(4-chlorophenyl)-1,4-dihydro-2,6-dimethyl-
4-oxo-N-phenyl .
O . 5 ml of triethylamine and 4 . 45 ml (0 . 026 mole) of
diketene ~50% in acetone) were added to a solution of 7.56 g (0.026
mole) of the starting material in 100 ml of toluene. The reaction
15 mixture was heated to reflux for 2 hours and was then allowed to
cool. A solution of 50 ml of 10% HCl was then added and the HCl
salt (Compound 13b) of the title compound precipitated. It decom-
posed at 250-260C. The salt was filtered from the toluene/water
mixture and washed with toluene. It was then mixed with 50 ml of
2 o 10% NaOH and 150 ml of toluene . The mixture was heated on a
steam bath until the solid material dissolved. The toluene phase
was then separated and dried over anhydrous sodium sulfate.
After removal of the toluene from the toluene phase by distillation a
white solid, having a melting point of 165-169C, remained. The
25 infrared and n.m.r. spectra were in a~reement with the title
struc~ure.
Analysis: Calculated for C20H17C1N2C)2: C 68 08; H, 4.85;
Found: C, 67.68; H, 4.84;
3 0
,
!
,, . ,. ` :: . ,~.; ,
-19- ~
27
~e 1q
3- ridinecarboxamide, 1-ethYl-1,4-dihydro-2,6-dimethx~-
4-oxo-N-(4-chlorophenyl? (Compoun 14a)
The starting material, 2-bu~enamide, 3-(ethylamino)-N-
5 (4-chlorophenyl) was prepared as follows: 10.6 g of bu~anamide,
N-(4-chlorophenyl)-3-oxo dissolved in dioxane was added dropwise
to 4 . 5 ml of 70% aqueous ethylamine . The reaction mixture was
stirred overnight at room temperature then 50 ml of water were
added and the mixture was stirred for 3 more hours. Finally the
product was filtered, to give 9. 6 g of 2-butenamide, 3-(ethyl-
amino)-N-(4-chlorophenyl), having a melting point of 130-132C.
0.5 ml of triethylamine and 3.4 ml (0.02 mole) o:E diketene
(50~ in acetone) were added to a solution of 4.76 g (0.02 mole) of
the starting material in 100 ml of toluene. The reaction mixture
was heated to reflux for 4 hours and then allowed to cool. Upon
addition of a solution of 50 ml of 10% HCI to the reaction mixture,
an oil precipitated. Most of the toluene and aqueous phases were
decanted and the remainder evaporated under vacuum to leave an
oil which upon the addition of acetone yielded the crystalline
hydrochloride salt (Compound 14b) of the title compound. The salt
decomposed at 260-266C. The salt was ~iltered and washed with
acetone; It was then n~xed with 30 ml of NaOH ~10%) and 150 ml of
toluene. The mixture was heated on a steam bath until the salt
dissolved. The toluene phase was then separated and dried over
anhydrous Na;2SO4. After removal of the toluene, a white solid
having a melting point of 190-193C, remained. The infrared and
n.m.r. spsctra were in agreement with the structure of the title
compound .
~nalysisCalculated for C16H17C1N2O2 C 63i05; H~ 5-62;
Found: C, 62.81; H, 5.82;
N, 9.49
-19- . ,
.
, . ~ . . . . ... .
, - - .
-20~ .5,'~7~3
Example 15
3-Pyridinecarboxamide, N,1-diodecyl-1,6-dihydro-2,4-
dimethyl-6-oxo (Compound 15~
A mixture consisting of 30. 0 g (0.112 mole) of butana-
mide, N-dodecyl-3-oxo, 21. Z g ~0 .112 mol~) oE PTSA . H2O and 400
ml of toluene was brought to reflux in a flask fitted with a Dean-
Stark trap. After 16 haurs, the reaction mixture was cooled~ The
toluene solution was washed with 200 ml of 10% NaOH and was then
dried with anhydrous potassium carbonate. Evaporation of mos~ of
the toluene and subsequent cooling of the remaining solution led to
the formation of crystals. The crystals were filtered and the
product was recrystallized from 65~-110 petroleum ether to give
21.9 g (78% yield~ of the title compound having a melting point of
65-66C .
Analysis: Calculated for C32H58N2O2: C 76 44; H, 11-~3; ~ ;
Found: C, 76,26; H, 11.38;
N, 5 . 84
Example 16
3-P~7ridinecarboxamide, 1,4-dihydro-2,6-dimethvl N,1-
bis-(4-bromophenyl)-4-oxo__nd its hydrochloride salt
27 g (0.105 mole) of butanamide, N-(4-bromophenyl)-3~
oxo, 0.5 g of PTSA.H2O, and 400 ml of toluene were brought to
reflux ~n a flask fitted with a Dean-Stark trap. After 16lf2 hours
the reaction mixture was cooled to about -15C and the crystalline
material was filtered and set aside. The filtrate was extracted with
50 ml of 10~6 NaOH and the toluene phase was then dried with
anhydrous potassium carbonate. Upon removal of about half the
toluene and cooling, a second crop of pr oduct was obtained . A
total of 12 g (48% yield) of 3-pyridine carboxamide, 1,4-dihydro-2,6
dimethyl-N,1-bis-~4-bromophenyl)-4-oxo having a meltir~g point of
255-257C was thus obtained.
-20-
- . . . . . .
-21~ L 527~3
Analysis: Calcul~ted for C20Hl6Br2N2o2 C~ N 5 83
Found: C, 50 . 05; H, 3 . 48
N, 6.13
N.m.r. (delta ~CDCl3)): 1.90 (s,3H); 2.50 (s,3H);
6.45 (s,1H); 6.90-7.90 (~, 8H); 12,85 (s,1H)
ppm
I.r. (Nu ~max)(KBr)): 2900, 1660, 1625, 1525,
14B0, 1410, 1390, 1335, î275, 1180, 1060, 1015,
825 cm~1.
Anhydrous hydrochloric acid was bubbled into the toluene
mother liquor from the above crystallization to give 4. 7 g of the
hydrochloride salt of the title compound having a melting point of
250-29SaC with decomposition.
Analysis: Calculated for C20H17Br2C1N2O2: C, 46 86; H, 3-34;
~ound: C, 46 . 51; H, 3 . 45;
N, 5.63
N.m.r. (delta (DMSOd6)): 2.11 and 2.18 (two singlets,
6H); 7.08 (s, 1H); 7.20-8.00 (m, 9H); 11.51
(s, lH) ppm
I.r. ~Nu (max)(KlBr)): 2100-3500 (broad), 1680,
1620, 1523, 1480, 1~70, 13as0~ 1250, :lO70, 1000,
825 cm~1.
Example 17
3-PS~ecarboxamide, -3-bromo-1, 4 dihydro-2, 6-
dimethyl-N ! 1- diphenyl-4-oxo~ (Co~ound 17)
A m~xture consistin~ oE 10 g (00032 mole) of 3-pyridine-
carboxamide, 1,4-dihydro-2,6-dimethyl N,1-diphenyl-4-oxo (Com-
pound 1), 5.62 g (0.032 mole) of N-bromosuccinimide, 150 ml of
car})on tetrachloride and about 0.1 g of ben~oyl peroxide was
.
~ 21-
, . .. . ~ .. . - ,............... .. . ~
-22~ L527B
refluxed for 2 hours. The mixture was then cooled and filtered.
The solid was dissolved in 150 ml of hot 3:2 ethanol/water, and the
solution was then cooled to precipitate 10 g (83% yield) oE the title
product having a melting point of 2û0-250C. Recrystallization from
95% ethanol gave the analytical sample, having a melting point of
207-~10C .
Analysis: Calculated for C20H17BrN2O2: C, 60 45; H, 4.28;
Found: C, 60.37; H, 4.17;
N, 6.91
N.m.r. (delta (CDCl3)~: 2.18 (s, 3H); 2.33 (s, 3H);
6.70-8.00 (m, 10H); 11~98 (s, lH) ppm
I.r. (Nu (max)(KBr)): 3240, 3040, 1670, 1580,
~520, 1480, 1440, 1310, 1250, 1180, 79S, 775,
lS 745, 695, 680 cm~1.
Examples 19-46
~,
The compounds shown in TABLE I and TABLE II below
were prepared by the above described methods. The specific
method used for each compound or corresponding salt is identified
20 in the Tables. TABLE III below shows n.m.r. anà i.r. data.
- 22 -
r r~
o ~n O .'
I.n
1- 0 ~ CO ~ ~ O ~D CO ~&
n ~ ~-~ o n ~ r e r~
~ o ~ ~ ~ ~ r o~
~ _ n
n o ~ r n ~ ~o
w~
S = n
W ~ ~ ~ ~ ~ W ~ W W ~ I
" ~ n n n
O ~ ~ ~ O ~ ~ ~ ;S ~
tr ~ 5 ~ ~ ;a~
o n ~ ~ ~ o~
Y ~
s~ ~ n a a ~ s s ~ xn ~n 1~
~ ~> w w w ~ ~ w ~ ~ ~ w ~ .;
5
~ t~ W 0~ .1 W W cr~ w ~ -- W ~ t~
D ~ ~ ~r n . ~
~ ~ ,~ . .. ..
0 3
i~1 ~III~IIIII e~ O
~ O ~ ~ ~ co 1 1 D
~ W ~ 5
o o o ~ oa r- I ~ ~ ~ cr~ Ul 1~ ~ Cl O
~ O O ~ ~ C
rr~ ~ ~ w U~ ~ r~
;o ~o o ~ o I
O ~ ~ ~I ~ O ~ C ~I
co ~o ~ ~ ~ ~ ~I 7 1~ u~ ~ w ~ ~o ~" o~
o o ~ o t~ J:` ~ t t o~ ~ 1 ~ ~ I n
o ~~Ct Co 9 ~ ~ ~ ~ t-
o~ ~ o~ ~ J` ~) Ul ~ cr~ ~ ~ ~ Cl~ ~ I 1~ te
g ~ ~It- ~ O~ ~I O t W t r~
~I X COJ~ t O t ~ G~ ~ ht: ~ O
K~ :' '
~ ~ ~ ~ ~ ~I ~ ~1~ ~ ~ J~ Ul ~ t~ :
r,~t oo ~ ~ 4~ ~ cuco ~ ~ W ~D O O ~
iJl Vl i1~ 2. . ~:
~ ~ ~tO P'~ ~ ~ I'~ I`.;t ~ ~: O
o O 0~ ~ ~ ~r~ o OVl O ~ O lu o a~ t~ t--
rr ~' o e~
N 1~ O :1 ;l ::
æ - ~" W ~t ` ," W ~t,0.. 00" ,'.,
~~ ~ a. ~
:~ g :: .
O ~ 'C rt : .
~ eo ~ :
O~ , ~r o :1
0~ 10 ~0 ' , ,
, ,., ',: , ~:
~7 . r
~ .
.. . . . . . . . . .... . ..
- .... - ~ ~ - , . .. . . ..
~L5~7~
o Ul
W W ~ W ~ ~ ~
~ ., .
P~ , . . . .
n: o
P
, ) ~ V ,
W~ ~ ~ ~ ~ ~ I ~ ,:
,~ , n
~ W ~ .
p. :o
,'~
W
,_ ~ g ~ a~
P'
CO o O P
Ul
h~
X ~ `~ I P ~,
IJI ~ ~ ~I ~ Cl.
n o o P
`I ~ o w ~ 1~ ~ . .
~ ~n ~ ~ _ vl'
~ ~ .
C
W O O 2~
`~ w ~ n
w ~ ~ X
C~ O ~ O n
p rr p- ~ ,;
~o o~ ~ WCo ~ ~ o oo
o. 2. C~. P
~ ~ . . .
O ~
t ~ t~ n ~
O~ ; .3 3 'o :9
rl, r~
c. ~ , ,.
. .
. ~. , , : : , ' .~
v, o ul
W ~ ~' ~ (~ ~ ~
fD
n ~~ P ~ n
~ q n~ ~ I Is P'
, a ~0 ~ ~ ~
0~ .
o ~ n
~ ~ . ~ '. .
o ~ ~ o ~ ~C~ ~ X O
P' ~
I r~ ~ o
U~ ~ ~I P
o~ ~,n ~ ~ ~ O n
o ~ cr~ ~ o ~~
o ~ o~ I o ~ ..
P :r
co ~ o o~ ~ 1~ ~ h~
W O ~ ~' ~ ~ !
`I X ~ O O~
I W
~ O ~t Co ~ D ~~ ca H D
~ ~n CO ~ ~ ~~ `I IJ. ~ ~
C~ ~
O ~ ~ ~ O ~ C~ t~ n~ H
OO~ P~ fD
o ~w n p.
o~ ~ ~ '' ~ ~ `~ ~ Sd~
or.~ ~t
o~ ~
,~ ~3
~I ~n ~ oo ~I ~ ~
oo ~o w~ ~ p :j :
~ ~ .
.
W
., .
o ~n ~n ~ ~ 4~ ~ ~D O ~D : .
~ ~ o ~
oo ~ ~ ~ ~ ~ o ~ ., . s
o ~ o~ ~. ~.
,_ ,~ ,~ ~ ~
P- C~ ~ ~ oo
~ .
o" , ~.
o ~ .
~ o ~ ~o o ~
rD' ~ ~ P'
~ ~ ~ :
:
~ ~5;27~3
-26-
ABLE III
Compound o:E Example Data
13 N.m.r. (delta (CDCl33): 1.85 (s,3}1);
2,59 (s,3H); 6.50 (s,lH); 6.80 to
8.60 (m,8H); 13.12 ~s, lH~ ppm
I.r. ~Nu (max)(CHC13)): 3000, 1665,
1625, 15~0, 1525~ 1475, 1435,
1335 J 1285, 1030, 860 cm 1
19 ~.m.r. (delta (CDC13)): 1.80 (s,3H);
1.98 ~s,3H); 2.45 ancl 2.49 ~two
singlets, 6H); 6.51 (s,lH); 6.80
to 8.40 (m,8~E); 12.73 (s,lH) ppm
I.r. (Nu (max)(CHC13)): 3000, 1665,
1625, 1580, 1523, 14~0, 1~i55, 1335
1275, 860 cm 1
N.m.rO (delta (CDCl )): 6.50 to 7.80 ~m,
21H); 12.00 ~s,lH) ppm
I.r. (Nu (max)~CHC13)~: 3000, 1675,
1625, 15~0, 1530, 1485, 1445,
1425, 1275, 870 cm 1
21 N.m.r. (delta (CDC13)): 1.90 (s,3H);
2.5D (s,3H); 3.75 and 3.78 (two
singlets, 9H); 3.91 (s,3H~; 6.48
(s,lH); 6.55 to 7.10 (m, 5H);
8.25 and 8.30 (two bands, 1~);
12.70 (s,lH) ppm
I.r. (Nu (max)(CHC13)): 2995, 2950,
2B40, 1660, 1600, 1525, 1460,
13~5, 1275, 1175, 10~0, 1020,
860 cm 1
21 (HCl Salt) I.r. (Nu (max)(KBr)): 3400 (broad),
2900, 2350 (broad), 1675, 1625,
160~, 1530~ 1510, 1475, 1345,
1275, 1220, 1035 cm
22 ~.m.r. (delta (CDCl )): 1.86 (s,3H);
2.0B ~s,6H);32.34 (s,6H); 2.97 (s,
3H); 6.60 (s,lH); 7.06 ~s,3H);
7.25 (s,3H); 11.92 ~s,lH)
I.r. ~Nu (max)(KBr)): 2900, 1630, 1515,
1460, 1545, 1240, 860, 780 cm 1
4~
~ -26-
5;27~3
-~7-
Compound_of Example Data
22 (HCl Salt)
I.r. (Nu (max)(KBr)): 2200 to 3600
(very broad band), 1650, 1620,
. 1515, 1450, 1340, 1225, 775,
750 cm 1
23 N.m.r. ~delta (CDCl3)~: 2.03 (s,3H);
2.61 ~s,3H); 3.81, 3.88 and 3.93
(3 singlets, 18H); 6.41 (s,2H);
6.49 (s,lH); 7.02 (s,2H); 12.71
(s,lH)
I.r. (Nu (max)(KBr): 3450 9 2940, 1660,
1590, 1523, 1~95, 1~50, 1410,
1325, 1225, 1120, 1000 cm 1
23 tHCl Salt) N.m.r. (delta ~DMSOd6)): 2.30 (s,6H);
3.62 (s,3H); 3.77 and 3.81 (two
singlets, 15H); 6.26 (broad
singlet, lH); 6.91 (s,2H); 7.11 (s,
2H); 7.32 (s,lH~; 11.12 (s,1H)
I.r. (Nu (max)(KBr)): 3400, 2900,
2350, 167S, 1600, 1500, 1460, 1410,
1335, 1230, 1125, 1000 cm 1
24 N.m.r. (delta (CDCl3)): 1.90 (s,3H);
2.49 (s,3H); 6.50 (s,lH~; 7.00 to
` 8.60 (m,6H); 13.15 ~s,lH) ppm
I.r. (Nu (max)(KBr)): 1670, 1630, 1580,
1515, 1475, 1380, 1335, 1290,
llB5, 1100, 855, B15 cm ~:
24 (HCl Salt) N.m.r. (delta (DMDOd6)): 2.02 (s,3H);
2.40 (s,3H); 6.50 (s,lH); 6.98 (s,
lH); 7.30 to 8.50 (m, 6H); :~:
12.60 (s,lH) ppm
I.r. (~u (max)(KBr)): 2100 to 2500 (broad
sbsorption), 1680, 1625, 1575, 1510,
--1
1470, 1340, 1100, 859, 819 cm
N.m.r. (delta (CDC13~): 1.90 (s33H); ~:
.
2.40 and 2.52 ~two singlets,
; 9H); 6.45 (s,1H); 6.90 to 7.80 (m,
8H); 12.80 (s,lN)
I.r. (Nu (max)~CH013)~: 2990, 2910,
1670, 1630~ 1590, 1525, 1490,
1~60, 1425, 1340, 1280, 11~0,
1~70, 1015, 970, ~60~ 840, :~
825 cm I
: -~7-
,.
;i27~ ~
-2~-
Compound_of Ex.lmple ~ Data
25 (HCl Salt) N.m.r. (delta (DMSO )): 2.22 (s,6H);
2.48 (s,3H)9 2.59 (s,3H); 7.10 to
8.00 ~m,9H); 8.45 (broad singlet,
1~); 11.25 (s,lH) ppm
I.r. (Nu lmax)(XBr)): 2100 to 3600
bro~d strong absorption~, 1675,
1625, 159d, 1525, 1490, 1460, 1425,
1340S 1320, 1275, 1245, 1195, 1080,
1015, 960, 880, 825 cm 1
26 N.m.r. (delta (DMSO )): 1.99 (s,3H);
2.20 (s,3H); 7.20 to 7~90 (m,
8H); 10.80 (s,lH)
I.r. ~Nu (max)(KBr)): 2900, 1670, 1595 -
1~25, 1~80, 1400, 1310, 1090, 900,
829, 770 cm 1
27 N.m.r. (delta (CDC13)): 1.90 (s,3H);
2.49 (s,3E); 3.80 (s,3H); 3.92 (s,
3H); 6.48 (s,lH); 6.60 to 7.70 t~,
5H); 8.30 td, J=2 cps, lH);
12.85 (s,lH) ppm
I.r. (~u (max)(RBr)): 3500, 2900,
1650, 158$, 1500, 1280, 1250,
1020, 880, 860, 810, 790 cm 1
-27 (~Cl Salt) N.m.r. (delta (DPiSO 6)): 2.08 (s,3H);
2.27 ~s,3H); 3.87 (s,6H); 7.00 to
8.50 (m,7H); 9,60 (broad singlet,
lH); 11.46 ~s,lH)
I.r. (Nu (~ax)tKBr)): 2100 to 3500 (broad)
1675, 1625, 1590, 1520, 1475, l~ilO,
1340, 1280, 1~50, 1015, 910, 875,
815 cm 1
28 N.m.r. (delta (CDC13)): 1.93 (s,3H);
2.52 (s,3H); 3.80, 3.88, 3.90,
a~d 3.93 (four singlets, 12H);
6.51 (s,lH); 6.70 to 7.30 (m,
3H); 8.45 (s,lH); 12.88 (s,1H)
ppm
I.r. (Nu ~max)(RBr)): 2900 (broad
band), 1660, 1500, 1450, 1390,
~ 133~, 1275, 1200, 10~5, ~0,
855, 780, 725 cm 1
-28-
.5;;:78
~29-
Compound of Example Data
.
28 (HCl Salt) N.m.r. (d~lta (CDCl3)): 2.05 (s,3H);
2,35 (s,3H); 3.80, 3.90 and 3.95
(three singlets, 12H); 6.80 to
7.30 (m,2H); 7.80 to 8.40 (m,3H);
9.80 (s,lH)
I.r. (~u (max)(KBr)): 2100 to 3500
(broad), 16759 1620, 1475, 1385,
1340~ 1210, 1025 cm 1
~9 N.m.r. (delta (CDC13)): 1.20 to 1.70 (m,
6,H); 1.93 (s,3H); 2.52 (s,3H);
3.80 to 4.30 (m,4H); 6.49 (s,1H);
6.70 to 7.80 (m,8H); 12.55 (s,lH)
ppm
I.r. (Nu (max)(KBr)): 2975, 2920, 1660,
1500, 1275, 1235, 1185, 1170,_
1120, 1040, 945, 850, 825 cm
29 (HCl Salt) N.m.r.- (delta (CDCl3)): 1.20 to 1.60
(m,6H); 1.90 (s,3H); 2.38 (s,3H);
3.70 to 4.30 (m,4H); 6.60 to
8.00 (m,9H); 10.88 (s,lH) ppm
I.r. (Nu (~ax)(KBr)): 2100 to 3500
(broad), 167S, 1620, 150S, 1470,
~230, 1170, 1040 c~ 1
N.m.r. (delta (CDC13)): 1.88 (s,3H);
2.49 (s,3H~; 6.50 (s,lH); 6.70 to
7~90 (m,7H); 8.30 to 8.60 ~pair
of doublets, lH); 12.95 (s,1H)
ppm
I.r. (Nu (max)(XBr)): 3Q00, 1660, 1625,
1575, 1500, ~460, 1425, 1330, 12~0,
1185, 1075, 1020, 845, 750 cm 1
30 (HCI Salt) N.m.r. (delta (DMSOd6)): 2.18 (s,3H;
2.37 (s,3H); 7.00 to 8.20 (m, 9H);
11.40 (s~lX); 11.63 (s,lH) ppm
I.r. (Nu (max)(KBr)): 2100 to 3500
(broad); 1675, 1615, 1575, 1515,
1460, 1425, 1325, 13~0, 1280,_
1235S 1195, 1025, 900, 750 ~m
31 N.m.r. ~delta ~CDC13)): 1.87 (s,3H);
1.29 and 1.32 (two singlets, 6H);
1.48 (s,3H); 3.75 (s,3H); 3.90 (s,
3H); 6.45 ~s,lH3; 6.60 to 7.40 (m,
5H); 8.30 (s,lH); 12.68 (s,1}l) ppm
45 ~ I.r. (Nu (max)(KBr)): 2900, 1660, 1525,
1510, 1330, 1~75, 1~50, 1225, 1170,
-1
11~5, 1130, 1025, B00, 730 cm
. . .
. . .
-29-
,
. , , . .. ~ , i ...
S~7~3
-30-
9~ L` ~ ~rl~ Da~a
31 (HCl Sal~) N.m.r. (delta (CDC133): 2.04 (s,3H);
2.28, 2.31 and 2.34 (3 singlets,
9H), 3.78 (s,3H); 3.85 ~s,3H~:
6.75 (s,lH); 6~80 to 8.40 ~m,7H);
9,60 (broad band, lH) ppm
I.r. (Nu (Nax)~KBr)): 1675, 1615, 1530,
1510, 1460, 1340, 1275, 1225, 1175,
~ .
1015, 800 rm
32 N.m.r. (delta (CDC13)): 1.85 (s,3H);
2.27 (s,3}1); 3.82 (s,3H); 3.96 ~s,
3~; 6.48 (s,lH); 7.10 to 8 . 80 ~m,
6H); 12.68 (s~lH) ppm
I.r. (Nu, ~max)(~Br)): 1700, 1660
1635, 1580, 1560, 1500, 1425~
1~00, 1280, 12509 1180, 1170,
1110, 9~5, 850 cm 1 ;
32 (HCl Salt) N.m.r. (delta ~CDC13)): 2.20 (s,3H);
2.29 (s,3H); 3.82 tS,3H); 3.90 (s,
3N); 7.00 to 8.70 (m,8H); 11.31 (s,
1~l) ppm
I.r. (Nu (max)): 2900, 1725, 1675, 1615
1500, 1470, 1425, 1275, i250
1110 cm 1
33 N.~.r. (delta ~CDCl )): 1.00 to 1.50 (m,
6H); 1.8B (s33H); 2.33 (q, j=
8cps, 2~); 2.54 (s,3}1); 2.85 (q, j=
8cps, 2H); 6.58 (s,lH); 6.90 to
7.80 (m,7H); 8.00 to 8.30 (m, lH);
12.70 (s,lH) ppm
I.r. (Nu (max)(KBr)): 2950, 1675, 1580,
1525, 1455, 1445, 1335, 1265, llB5,
860~ 770~ 760 cm I
33 (HCl Salt) N.m~r. (delta (CDC13)): 1.00 to 1.50 (m~
6H); 1.95 (s,3H); 2.05 to 2.55
(quartet with a singlet superim-
posed at 2.35, 5H); 2.86 (q, j=
8cps 7 2~); 7.00 to 7.90 (m, 9~);
10.30 (s,lH); 11.80 (broad band,
~ lH) ppm
: I.r. (Nu (max)~KBr)): 3400, 2950,
2400 (all braod), 1675, 1620, 1525,
- 1460, 1450, 1340, 750 cm 1
34 N.~.r. (delta (CDC13)): 1.95 ~s,3H);
2.52 (s,3H); 6.60 (s,lH)9 7.40 (s,
1~13; 7.62 ~s,lH); 12.70 (s,l1l) ppm
I.r. (Nu, (max)~KBr)): 3050, 2800, 1675,
1630, ~570, 15509 1500, 1440, 1375,
1325, 1275, 1180~ 1150, 850, 825,
S0 820 800 cm~
:: ,
-30-
. .
-31- ~ 2~
Compound of Ex~m~ Data
34 (HCl Salt) N.m.r. ~delta (DMSOdfi)): 2.03 (s,3H);
2.32 (s,3H); 6.95 (stlH)j i.62 (s,
lH); 7.76 (s,l}{); 8.15 (s,lH);
11.81 (s,lH) ppm
I.r. ~Nu (max)(KBr)): 3050, 2900, 2300
(all broad), 1680, 1620, 1550, 1510,
1475, 1440, 1375, 1340, 1295~ 1260,
1200t 1150, 1060, 855, 830 ~m 1
~.m.r. (delta ~CDC13)): 1.91 (s,3H);
2.53 (s,3H ; 6.48 (s,lH); 6.80 to
8.00 (m,8}1); 12.90 ~s,lH) ppm
I.r~ (Nu (max)(KBr)): 1670, 1630,
1585, 1520, 1465, 1420, 1335, -1
1185, 1100, 1070, 850, 780, 770 cm
35 ~HCl Salt) N.m.r. (delta (DMSO )): 2.09 and 2.16
(two singlets, 6H); 5.60 (broad
singlet, lH); 6.91 (s,lH); 7.10 to
8.00 (m,8H); 11,59 (s,lH) ppm
I.r. (Nu (max)(KBr)): 2100 to 3500
(broad band), 1675, 1610, 1575,
lS25, 1460, 1420, 1325, 1235,
ll9S, 1075, 860, 775 cm 1
36 N.m.r. (delta (CDCl3)): 1.91 (s,3H);
2.50 (s,3H); 6.46 (s,lH); 6.70 to
8.00 (m,8H); 12.80 ~s,lH) ppm
I.r. (Nu (max)(KBr)): 2800, 1670, 1625,
1520, 1475, 1410, ~390, 1335,
12~5, 1190, 1050, 1110, 1000,
825 cm 1
36 (HCl Salt) N.m.r. (delta (DMSO )): 2.20 (s,6H);
7.10 to 8.30 (m,lOE); 11.50 (s,l}l)
ppm -
I.r. (Nu (max)(KBr)): 2200 to 3500
(broad band), 16809 1625, 1525,
1~75, 1395, 1345, 132~, 1275,
1250, 1200, 1055, 1010, 820 cm
3~ N.m.r. (delta (CDC13)): 1.42 (t, j=
7.0 CpS 9 2H); 2.50 (s,3H); 4.13 (q 9
j=7.0 cps, 2H); 6.40 (s,1~); 6.60
to 7.80 (m,8H); 12.65 ts,lH) ppm
I.r. (Nu (max)~CHCl )): 2980, 1665,
1630,15~5, 153~, 1500, 1245, 1170,
-1
1115 cm
-31-
-32~ 5Z7~
Compound of Example Data
37 (HCl Salt)
I.r. (Nu max)(KBr)): 2100 to 3500
(broad band), 1675, 1615, 1540,
1500" 1465, 1435, 1325, 1245,
1190" 1170, 1115, 1080, 1030,
920, 850, 755, 690 cm 1
38 N.m.r. (delta (CDCl )): 2.05 ts,3H);
2.22 (s,3H);32.89 (d, J=4.5 cps,
3H~; 3.29 (s,3N); 5.92 ~s,lH);
7.95 (ql J=4.5 cps, lH) ppm
I.r. (Nu ~max)(CHC13)): 3450, 3260,
1650, 1560, 1530, 1415, 1375,
1350, 1315, 1160, 1140, 1080,
940, 960 c~ 1
39 N.m.r. (delta (CDC13)): 2.00 and 2.04
(two singlets, 6H); 2.60 to 3.10
(4 peak mult (multiplet), 4H~;
3.50 to 4.20 (7 peak multiplet,
4H); 4.02 ts,lH); 7.00 to 7.50
(mult., lOH) ppm
I.x. tNU tmax)tcHcl3)): 3430, 3250,
16~0, 1530, 1490, 1450, 1350,
1310, 1235, 1155, 1025, 855 cm
~.m.r. (delta (CDC13)): 0.89 tt, 6E);
1.05 to 1.85 (m, 16H); 2.10 (s,3H);
2.28 (s,3H); 3.00 to 4.00 (m,4H~;
5.95 (s,1}1); 7.92 tt, lH exchange-
able)
I.r. (Nu ~max)tCHC14)): 3250, 2950,
2925, 2850, 1650, 1575, 1530, 1465,
1375, 1300, 900 cm 1
41 ~.m.r. (delta ~CDC13)): 2.06 ts,3H);
2,15 (s,3H); 3.29 and 3.22 (two
singlets, 6H); 4.40 (d,2H);
4.92 (s,2H); 6.08 (s,lH); 6.50 to
7.40 (m, 8H); 7.75 tt, lH) ppm
I.~. (Nu (max)tCHC13)): 3440, 3250,
3000, 2840, 1660, 1515, 1250,
1175, 1030 cm 1
:
-32-
. ,. . . , . , ., ,. , : : :
7E~
-33-
Compound of Example Dat~
42 N.m.r. (delta (CDCl )): 1.00 to 3.00
tbroad mult.3~ith two singlets at
2.13 and 2.32, total of 26H);
3.10 to 4.30 (m, 2H); 5.98 (s,11l);
7.12 (d, lH, exchangeable) ppm
I.r. (~u max)(CHC13)): 3410, 3225,
2900, 2840, 1640, 1~50, 1325, 1140,
960, 890, 855 cm 1
42 t~lCl Salt) ~.m.r. ~delta (CDCl33): 1.00 to 2.10
(m, 20H); 2.38 (s, 3H); 2.63 (s,3H);
3.50 to 4.60 (m, 2H); 7.18 (s,3H);
8.00 ~o 8.80 (broad mult., 2H
exchangeable)
I.r. (N~ (max)(CHC13)): 3200, 2925,
1645, 1500, 1440, 1145 cm 1
43 (NCl Salt) N.m.r. (delta (CDCl3)): 0.40 to 1.00
(m, 6H); 1.00 to 2.00 (m, 20H);
2.38 (s, 3H); 2.65 ~s,3H);
3.40 ~broad, 2H); 4.15 (broad,
2E); 7.16 (s,lH); 8.40 (broad, lH);
- 11.35 (broad, lH)
.r. (N~ ~max)(KBr)): 3150, 2890, 2825,
2150, 1625, 1450, 1275, 720 cm 1
44 N.m.r. ~delta (CDCl )): 2.10 and 2.15
(two singlets3, 6H); 4.46 (d,2H~;
4.98 (s,2H); 6.10 (s,lH); 6.70 to
7.40 (m, 8H); 7.56 (t, lH, exchange-
able)
I.r. (Nu ~max)(KBr)): 3400, 3200, 3045,
1650, 1525, 1485, 1085, 1010,
. 845 cm~l
44 (HCl S~lt) N.m.r. (delta (DMSOd6)): 2.04 ~s,3H);
2.15 (2,3H); 4.34 (d,2E); 5.23
(s,2H); 6.25 (s,lH); 7.00 to 7.50
~m, 8H); 8.90 t~,lH) ppm
I~r. (Nu (max)(KBr)): 3150, 3000, 2150,
1630, 1485, 1285l 1080, 1015,
800 cm
~.m.r. (delta tCDC13)): 0.05 to 1.80
(m,18H~; 2.12 (2s,3H~; 2.29 (s,3H);
3.00 to 3.45 (m, 2H); 3.65 (d, 2H);
6.01 (~, lH); 7.55 (broad, lH) pp~
I.r. ~Nu ~max)(KBr): 3200~ 2850 9 1625,
1550, 1425, 1135, 870 cm 1
~':', .
' " .
.
34 ~5278
Compound of Example Data
45 ~HCl Salt) N.~.r. (delta (CDGl3): 0.60 to 2.10 ~m,
18H); 2.38 (~,3H); 2.64 ts,3H);
3.10 to 3.50 (broad, 2H); 4.18
(d,2H); 7.18 (s,lH); 8.10 to 8.60
~broad,lH); 9.00 to 9.50 (broad,~
lH)
I.r. (Nu (max)(KBr): 2700 to 3500 (broad
band), 1625, 1440, 1375, 1300 cm 1
46 N.m.r. (delta (CDCl )): 1~10 to 2.50
(broad mult.3with two singlets
at 1.09 and 1.30 superimposed,
22H); 4.00 to 4 70 (broad,lH);
5.90 (s,lN); 7.20 to 7.60 (broad,
lH) ppm
I.r. (Nu tmax)(KBr)): 3240, 2945, 2850
1650, 1575, 1525, 1435, 1145,
835 cm
46 (HCl Salt) N.m.r. (delta (CDCl3)): 1.30 to 2.30 (m,
16~1); 2.38 (s,3H): 2.65 (s,3H);
4.00 to 4.50 (broad,lH); 4.50 to
5.30 ~broad,lH); 7.20 (s,lH);
8.22 (d,lH); 9.30 to 9.80 (broad,
lH) ppm
I.r. (Nu (max)(KBr)): 28G0 to 3500
(~road band), 1625, 1545, 1480,
1425, 1275 cm 1
-34-
~ ~5~
~35-
TABLE IV lists the 4- and 2-pyr;idones which showed
inhibition of edema in the primary carrageenan assay.
The procedure used for measuring the inhibition of carra-
geenan induced edema was a modification of the method OI Winter,
et al ., Proc . Soc . Exptl. Biol . Med . 111 : 544 ~1962) . The device
used for measurement of the paw volume was an adaptation of the
water displacement procedure described by Adamkiewicz, et al.,
Can. J. Biochem. Physiol. 33: 332 (1955). The present compounds
were studied for their effectiveness in preventing the edema caused
by the intraplantar injection of 0.05 ml of a sterile 1.0% solution of
carrageenan. The present compounds were administered orally one
hour prior to the injection of the carrageenan into the left hind paw
of rats. At peak swelling time (3 hours) the volume of edema was
calculated by differential paw volume.
We have found that many of the compounds produced
significant inhibition of induced edema in rats at a dose rate of 200
mg/kg and ~hese are listed in TABLE IV, Column 2.
Compounds showing greater than 25% reduction of edema
in the initial assay were selected for further study to determine the
ED50 in edema reduction. In this test, a group of normal rats was
in~ected with carrageenan to induce edema. Then the rats were
treated with varying amounts of the above-described compounds,
and the ED50 was determined.
~5 The procedure used for measuring the inhibition of carra-
geenan-induced edema was the above-described modification of ~he
method of Winter, et al., and the device used fvr measurement of
the paw volume was the above-described adaptation of the water
displacement procedure described by Adamlciewicz, et al. The
above compounds were studied for their effec~iveness in preventing
-35-
~,
- '
-
78
-36-
the edema caused by the intraplantar injection of 0.05 ml of a
sterile 1.0% solution of carrageenan. Compouncls were administered
orally one hour prior to the injection of the carrageenan into the
left hind paw of rats. At peak swelling time ~3 hours) the volume
of edema was calculated by diEferential paw volumes. The ED50
value was obtained for each compound and is defined as that dose
which reduced edema formation by 25% or more compared with the
mean control response (parallel run) in 50% of the animals. The
results of this test are given in T~BLE IV, Column 3.
Compounds which gave satisfactory ED50 in the carra-
geenan assay were reevaluated in the adrenalectomized rat assay
(TABLE IV, C:olumn 4). The method used was identical to that
described above, except that the animals used were adrenalecto-
mized several days prior to assay. Since the results in the non-
adrenalectomized animals were similar to those obtained in the
adrenalectomized animals, it can be inferred that the antiinflam-
matory activity of the test compounds was not caused by the release
of endogenous adrenocortical steroids.
A study of TABLE IV shows that compounds listed therein
are not adrenal whips and that the antiinflan~natory activity exhi-
bited by them in the adrenalectomized rat is genuine and therefore
they are compounds with considerable activity.
TABLE IV also shows which compounds demonstrated
central nervous system activit~v in a Neuropharmacological Profile
~NPP), which is a well established pharmacological method.
The adjuvant-induced arthritis test was conducted in rats
using the most active compound. This test requires one month
(from 0 to day 31). In ~he first seventeen days (0 - 17), the
di3ease is in a developing stage, while for t]he rernainder of the
month (18 - 31) the disease is fully developed. The results of this
test, given in terms of percen-t reduction of swelling in t]he hind
-36-
-
;i27
paw of the rat are shown in TABLE V and compared to phenylbuta-
zone at 100 mg/kg.
The method used in the adjuvant-induced arthritis test
was essentially that of Newbould, Brit. J. Pharmacol. 21: 127,
5 1973. The test compound was studied in the developing arthritic
state and in the established arthritic state. Separate groups of
thirteen rats were administered the compound orally using methyl-
cellulose as the vehicle. In the study on the developing disease,
administration of the test compound began on day 1 and on day 2
10 each animal was injected with 0. 5 ml/kg of a 0 . 5% suspension of
heat-killed Mycobacterium tuherculosis into the plantar surface of
the leEt paw. Foot volumes were measured by a water displacement
device on the day of administration of the Mycobacterium and again
on days 3, 10 and 17. The test compound was administered once
15 daily. Body weights were recorded daily and the ~animals were
examined for the spread of the inflammation and the dëgree of
secondary lesions observed and scored as "m~ld, moderate, or
severe". For study in the established disease, another group of
rats was injected with the Mycobac~erium and foot volumes were
20 measured and after twenty days were again measured and aclmini-
stration of the test compounds began and continued for eleven
days. Foot volume measurements were repeated on day 27 and day
31. The extent of the spread of the inflammation and the degree of :
lesions were recorded daily as were the body weights. The e~fect
25 OI the test compound was measured by the percentage reduction in
lef~ hind paw volumes as compared to the hind paw volumes oI the
control groups.
Probably the most interesting data was ob-tained in the
adjuvant arthritis assay on compound 4. This compound was tested
at 2.5" 5 and 10 mg/kg. In the developing assay there was a
dose-related response in that 5 mg/kg was more effective than at
i
-37-
.
-38~ S~7~
2.5 or 10 mg/kg. On day 10 of the assay at 5 mg/kg there was a
23% inhibition in the primary lesion. This is about equivalent to
what one would see with aspirin at 300 mg/kg. In the developed
assay, the 2 . 5 mg/kg dose was almost inactive, whereas at the 5
mg/kg dose there was a significant reversal of the arthritic state.
There was also a diminution in the numbers and extent of secondary
lesions in the animals. It would appear that the 5 mg/kg dose is
the lowest effective dose.
-38 -
39 ~fL1527B
TABLE IV
Compound % Reduction *~ Salt or
of Exampleof Edema ED50 Adl-enal ~D50 ~ree Base
2 33 200 ~- 562 Salt
4** 62 0.538(0.36-0.807) 2.8 56 Salt
2628(10.5-77.0) 200 300 Salt
7** 53 * * * Salt
18 8 - - 562 Salt
19** 17 * * * Salt
22-~* 31 * * * Salt
1 25greater than 200 - 562 Free Base
3 584.55(2.65-7.83) 200 422 Free Base
6 - - 562 Free Base
7^'* 33 * * * Fr~e Baæe
18 2 - - 562 Free Base
19** 4980(48.5-132) 84.8 562 Free Base
0 - - 562 Free Base
21-~* 0 - - 562 Free Base
22 26 * * * Free Base
38 4 - - 562 Free Base
39 17 - - 316 Free Base
40 ~ 28 ~ * 472 Free Base
41 10 - - 562 Free Base
- test not do~e because co~pound failed previous test
25* test not done
** central nervous system activity observed in NPP
*** data obtained from NPP
-39
.
lS~
-~o-
TABLE V
~ESULTS OF ADJUVANT-INDUCED AFtTHRITIS TEST
IN RATS
% Reduction in Swelling - Hind Paw
Phenyl-
Compound 4 _ butazone
~.5 5 lO 100
DAY mg/kg ~L_~ mg/kg _~L~ :
3 12 1~ 5 1~ :
Developing Disease 10 8 23 21 34
17 12 4 25 65 : ::
: ;"
. . .
20 0 10 0 0
Develsped Disease 27 3 9 6 29 ~-
31 0 4 6 gl
L~thality for compound 4 for total of 31 days of st~ldy = /13.
,'
:
.
:
''.
~4~
. .
. ~
3L5~78
The compounds of the present invention, either alone, or
in the form of a pharmaceutical composition may be administered to
an animal subject in any of a number of forms and via any of
several routes. Thus, the compounds or ~ompositions thereo~: ~may
be orally administered in the form of tablets, pills, cap~ules, or in
the form of a suspension. The compounds may also be administered
parenterally in the form of an injectable solution or suspension.
The compounds or compositions thereof may also be administered
topically, in the form of an oin tment or rectally, in the form of a
suppository.
When orally administering the compounds or compositions j
use can be made of a tablet, pill or capsule consisting entirely of
the desired compound, although ordinarily, a composition comprising
an effective amount of the compound and varying amounts of one or
more physiologically inert materials such as carriers, vehicles,
binders and the like will be used. Additionally, the compounds may
be orally administered in the form of a suspension thereof in a
suitable vehicle such as a syrup.
When parenterally administering the compounds or compo-
sitions, use may be made of a parenteral solution or suspension of
the compound in a suitable sol~,-ent or suspension medium.
The compounds of the present invention may also be
administered rectally in the form of a suppository comprising an
effective amount of the desired compound and a suitable vehicle
such as petroleum jelly.
Finally, the compo~mds of the prssent invention may be
applieà topically in the form of an ointment, salve, cream or lotion
comprisin~ an effective amount of the desired compound and a
~uitable Yehicle such as petroleum jelly, etc.
The following examples illustrate how speciEic ormulations
of the compositions according to the invention may be prepareà.
-41-
-~2~ 5;278
xample 4~
Tablets may be prepared by the compression of a wet
granulation containing the following:
Ingredients In each
. . ~
Compound No. 4 lQO m~
Polyvinylpyrrolidone 6 mg
Lactose 25 mg
Alcohol, 3A, 200 proof 1 ml
Stearic Acid 3 mg
Talc 4 mg
Corn Starch 15 mg
Dosage: 1 Tablet 3 times a day.
Example 49
A liquid suspension for oral administration may be pre- -
pared in the follow'ng formulation:
Ingredients Irl each 5 cc
:
Compound No. 4 lO0 mg
Sodium carboxymethylcellulose5 mg . - .
Syrup USP q.s. to 5 cc -.
Dosage: 1 teaspoonful ~5 cc) every 3 to 4 hours
_
Example 50
- Dry filled capsules (DFC) consisting of . two seotions of
hard gelatin may be prepared from the following formulation:
: I~gredients In each
. ~
Compound No. 4 lO0 mg
Lactose USP ~OS.
Dosage: 1 capsule three times a day
- ' '
-42-
.
.
-43- ~ 5;~7~3
Example 51
An ointment for topical use may be prepared using the
following formulation
Ingredients I~ each
____
Compound No. 4 ~O gm
Hydrophilic petrolatum USP q.s. 100 gm
Do~age: To be applied to inflamed skin areas as needed.
_ . ., _ .
Example 52
A parenteral suspension for intra-muscular administration
may be prepared in the following formulation:
Ingredients
Compound No. 4 40 mg
Isotonic solution (0.85% saline) 5 cc
Surfactant (a 1% solution of
polysorbate 80 USP) 1 cc
- 20 Variations and modifications can, of course, be made
without departing from the spirit and scope of the invention.
,:
':
-~3-- :
:.
- ' ' , ' '' .: ~
