CA1115278A - Anti-inflammatory 4-pyridones and their preparation - Google Patents

Abstract

Abstract of the Disclosure Substituted pyridones of the formulae and , I II

useful as antiinflammatories, are disclosed. The compounds of Formula I and Formula II may be prepared by the acid catalyzed dehydrative dimerization of acetoacetamides. Alkyl or cycloalkyl substituted acetoacetamides give 2-pyridones and aryl substituted acetoacetamides give 4-pyridones.

Description

~ 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~

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, :~

.
. . . . . .. .

-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.

, . ............. . ,, , ~ . ................ . . .
. ................. . . .. . . .

-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

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 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~

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~
.

. . . , , , . ~, , ~ .. . ..

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 .
' 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 . .

.
.

-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 '' -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;

, !
,, . ,. ` :: . ,~.; , -19- ~

~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.

- . . . . . .

-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.

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 ~ .;

~ t~ W 0~ .1 W W cr~ w ~ -- W ~ t~
D ~ ~ ~r n . ~
~ ~ ,~ . .. ..

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 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, 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 .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, 11~5, 1130, 1025, B00, 730 cm . . .

. . .

, . , , . .. ~ , i ...

S~7~3 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~
:: , . .

-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, 1115 cm -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 :

. ,. . . , . , ., ,. , : : :

7E~

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 ~ ~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 ~, - ' -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 -;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 .

-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.

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

.

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 : ::
: ;"

. . .

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.

-~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 - ' ' .

.

-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-- :

:.

- ' ' , ' '' .: ~

Claims (21)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the formula I

or the acid addition salt thereof, wherein both of substituents R1 are the same, and are alkyl having 1 to 6 carbon atoms, phenyl, or phenyl substituted with halogen, alkoxy having one to four carbon atoms, alkylthio having one to four carbon atoms, or alkyl having one to four carbon atoms: 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, comprising dehydratively dimerizing a compound of the formula R2 - ? - CHR5 - ? - NHR1 wherein R1, R2 and R5 are as defined above, in the presence of an acid catalyst, and, if desired, preparing a pharmaceutically acceptable acid addition salt.

2. A process as in Claim 1 with the proviso that if R2 is methyl and R5 is hydrogen, R1 may not be phenyl or 4-iodophenyl.

3. A process as in Claim 1 wherein R5 is hydrogen and R2 is methyl.

4. A process as in Claim 2 wherein R1 and R2 are 2-methoxyphenyl and R5 is hydrogen.

5. A process as in Claim 1 wherein R1 is 2-methylphenyl, R2 is methyl and R5 is hydrogen.

6. A process as in Claim 1 wherein R1 is phenyl, R2 is methyl and R5 is hydrogen.

7. A process as in Claim 1 wherein R1 is chlorophenyl, R2 is methyl and R5 is hydrogen.

8. A process as in Claim 1 wherein R1 is 4-chlorophenyl, R2 is methyl and R5 is hydrogen.

9. A process as in Claim 1 wherein R1 is 2,6-dimethyl-phenyl, R2 is methyl and R5 is hydrogen.

10. A process as in Claim 1 wherein R1 is 2,4,6,-trimethyl-phenyl, R2 is methyl and R5 is hydrogen.

11. A compound of the formula I

I

or a pharmaceutically acceptable acid addition salt thereof, wherein both of substituents R1 are the same, and are alkyl having one to six carbon atoms, phenyl, or phenyl substituted with halogen, alkoxy having one to four carbon atoms, alkylthio having one to four carbon atoms, or alkyl having one to four carbon atoms; both of substituents R2 are the same, and are alkyl having one to six carbon atoms, phenyl, phenyl substituted with halogen; and R5 is hydrogen or halogen, whenever prepared or produced by the process of Claim 1 or by an obvious chemical equivalent thereof.

12. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, with the proviso that if R2 is methyl and R5 is hydrogen, R1 may not be phenyl or 4-iodophenyl, whenever prepared or produced by the process of Claim 2 or by an obvious chemical equivalent thereof.

13. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R5 is hydrogen and R2 is methyl, whenever prepared or produced by the process of Claim 3 or by an obvious chemical equivalent thereof.

14. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R2 are 2-methoxy-phenyl and R5 is hydrogen, whenever prepared or produced by the process of Claim 4 or by an obvious chemical equivalent thereof.

15. A compound of claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is 2-methylphenyl, R2 is methyl and R5 is hydrogen, whenever prepared or produced by the process of Claim 5 or by an obvious chemical equivalent thereof.

16. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is phenyl, R2 is methyl and R5 is hydrogen, whenever prepared or produced by the process of Claim 6 or by an obvious chemical equivalent thereof.

17. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is chloro-phenyl, R2 is methyl and R5 is hydrogen, whenever prepared or produced by the process of Claim 7 or by an obvious chemical equivalent thereof.

18. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is 4-chlorophenyl, R2 is methyl and R5 is hydrogen, whenever prepared or produced by the process of Claim 8 or by an obvious chemical equivalent thereof.

19. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is 2,6-dimethylphenyl, R2 is methyl, and R5 is hydrogen, whenever prepared or produced by the process of Claim 9 or by an obvious chemical equivalent thereof.

20. A compound of Claim 11 or a pharmaceutically acceptable acid addition salt thereof, wherein R1 is 2,4,6-trimethylphenyl, R2 is methyl, and R5 is hydrogen, whenever prepared or produced by the process of Claim 10 or by an obvious chemical equivalent thereof.

21. A process as in Claim 2 wherein R1 is 2-methoxyphenyl, R2 is methyl and R5 is hydrogen.