Journal of Medicinal Chemistry, 1978, Vol. 21, No. 7 623

Trisubstituted Pyrimidines and Triazines

(2) (3)

(4) (5)

(6)

Thromb. Diath. Haemorrh., 23, 486 (1970); (d) ibid., 25, 391 (1971); (e) Folia Haematol. (Leipzig), 98, 455 (1972); (f) Thromb. Diath. Haemorrh., 29, 154 (1973); (g) Arch. Znt. Pharmacodyn. Ther., 194,359 (1971); (h) J. D. Geratz, A. C. Whitmore, M. C.-F. Cheng, and C. Piantadosi, J. Med. Chem., 16,970 (1973); (i) J. D. Geratz, M. C.-F. Cheng, and R. R. Tidwell, J. Med. Chem., 18,477 (1975); 6) J. D. Geratz, M. C.-F. Cheng, and R. R. Tidwell, J. Med. Chem., 19,634 (1976); (k) R. R. Tidwell, L. L. Fox, and J. D. Geratz, Biochim. Biophys. Acta, 445, 729 (1976). 0. Dann, G. Bergen, E. Demant, and G. Volz, Justus Liebigs Ann. Chem., 749, 68 (1971). 0. Dann, H. Fick, B. Pietzner, E. Walkenhorst, R. Fernbach, and D. Zeh, Justus Liebigs Ann. Chem., 1975,160 (1975). 0. Dann, R. Ferbach, W. Pfeifer, E. Demant, G. Bergen, S. Lang, and G. Lurding, Justus Liebigs Ann. Chem., 760,37 (1972). 0. Dann, G. Volz, E. Demant, W. Pfeifer, G. Bergen, H. Fick, and E. Walkenhorst, Justus Liebigs Ann. Chem., 1973,1112 (1973). 0. Dann, E. Hieke, H. Hahm, H. Miserre, G. Lurding, and

R. Robler, Justus Liebigs Ann. Chem., 734, 23 (1970). (7) D. Zeh, Ph.D. Thesis, University of Erlangen-Nurnberg, 1975. (8) B. Pietzner, PbD. Thesis, University of Erlangen-Niirnberg, 1972. (9) K. G. Lisson, Ph.D. Thesis, University of ErlangenNurnberg, 1975. (10) F. E. King and R. M. Ackeson, J. Chem. SOC., 1396 (1949). (11) R. Roger and D. G. Neilson, Chem. Rev., 61, 179 (1961). (12) S. S. Berg and G. Newbery, J . Chem. SOC.,642 (1946). (13) J. N. Ashley, H. J. Barber, A. J. Ewins, G. Newbery, and A. D. H. Self, J . Chem. SOC.,103 (1942). (14) J. Stiirzebecher, F. Markwardt, and P. Walsmann, Thromb. Res., 9, 637 (1976). (15) B. F. Erlanger, N. Kokowsky, and W. Cohen, Arch. Biochem. Biophys., 95, 271 (1961). (16) L. Svendsen, B. Blomback, M. Blomback, and P. I. Olsson, Thromb. Res., 1, 267 (1972). (17) M. Dixon, Biochem. J., 55, 170 (1953). (18) S. W. Nye, J. B. Graham, and K. M. Brinkhous, Am. J. Med. Sci., 243, 279 (1962).

Synthesis and Antiinflammatory Activity of Trisubstituted Pyrimidines and Triazines Gregory B. Bennett,* Robert B. Mason, Lee J. Alden, a n d James B. Roach, J r . Department of Medicinal Chemistry, Pharmaceutical Division, Sandoz, Znc., East Hanover, New Jersey 07936. Received December 8, 1977 A series of mono-, bi-, and tricyclic pyrimidines and as-triazines was prepared and their antiinflammatory activity measured against carrageenan-induced edema in the rat. The more active analogues (ED,,), including 4-pyridylpyrimidines 4a (38),4b (47),and 4g (49) and 2-hydroxypyrimidine 8r (43),were then tested against adjuvant-induced edema in the rat. None was active in the adjuvant arthritis model. T h e search for new classes of nonsteroidal antiinflammatory agents which minimize gastrointestinal toxicity has led t o a number of clinical candidate^,'-^ including the nonacidic heterocycle, proquazone (21).3a*25 Despite these agents t h e need for more effective antirheumatic drugs continues t o grow. To this end, a series of mono-, bi-, and tricyclic pyrimidines a n d us-triazines has been prepared and tested for antiinflammatory activity. A description of the synthesis of these compounds as well as a description of the structure-activity relationships is presented in this

Scheme I NMe2

NH R3' methods NH2 C-F

methods A,

B

1

1:@xR3 3-10

X

lrnethods G, H

2

paper.

Chemistry. Chemically, our aim was t o construct both the pyrimidine a n d triazine ring systems from common ketone precursors. Of t h e methods a ~ a i l a b l e those ,~ outlined i n Scheme I were selected due t o their general applicability t o a variety of commercially available ketone systems as well as the simple nature of the reactions. Pyrimidine construction was accomplished by aminoformylation of an active methylene ketone 1 with Bredereck's reagent,5 followed by cyclization of the resulting protected 0-ketoaldehyde 2 [X = N(CH3),] with an amidine equivalent. In some cases t h e ketones were formylated under standard conditions6 with the resulting 0-ketoaldehyde 2 (X = OH) converted into t h e corresponding enol ether 2 (X = OCH2CH3)7prior to cyclization. The cyclization with an amidine equivalent was, in general, most successful when performed i n the presence of a n equivalent of sodium ethoxide rather t h a n under neutral or acidic conditions. Derivatization of t h e 2-amino- and

11

12 v

/

\

R'

1

o

N,~

R '1?!R3

14,16,18-20

21 2-chloropyrimidines provided additional analogues (Table

I). The regiospecific preparation of us-triazines from the same a-methylene ketones 1 was accomplished by anitrosation, reaction of the resulting a-keto oxime l l with hydrazine t o form an a-hydrazino oxime 12, a n d subseq u e n t exposure under nonequilibrating conditions t o a n

0022-2623/78/1821-0623$01.00/00 1978 American Chemical Society

624 Journal of Medicinal Chemistry, 1978, Vol. 21, N o . 7

Rennett, Mason, Alden. Roach

Table I. Protected 0-Ketoaldehydes 2 -

-

____ _ _ _ _

0

2a-1

2m-o

Yield Mp or b p (mm), ' C 2a 70-72 2b 115-117 2C 62 -7 0 2d 125-127 2e Oil 2f 150-160 (0.1) 2g 135-142 (0.1) 2h 110-120 (0.10) 2i 119-1 20 23 54.5-55.5 2k 68-73 (0 1) 21 98-105 (0.1) 2m 90-92' 2n 135-143 (0.75)' 20 120-125 (0.05)' __ ' See ref 24.

_- Compd

(%),

method 95, A 96, A 74, A 79, A 67, A 60, A 82, A 68, A 82, A 78, A 63, A 75, A 73, B 58, B 57, B

R'

n

R2

C,H, CH 3 4-C ,H,N H 3-C H,N H 2-C5H,N H 4-C,H4N CH 3 4-C,H4N C6H5 -(CH,),CH( t-Bu)CH,-(CHZ),N(CH3)CH,P-CH,OC,H, p-CH,OCbH, t-Bu C,H, t-Bu H -(CH2)10-

Analvses

CI 3 1 ,NO CI,Hl*N,O CI OH1 azo CI,Hl,NZO CI I H I J Z O

C, H, N C , H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C , H, N C, H, N C, H, N C. H, N

1'

bH1

bNZo

C13HZZN0

C9HlbN2B

NO, C &,,NO C,H, .NO C, ,II,.NO c,1Hl"O' CI " 1 2 0 CI 9 % '

1 2

3

-__

I_______

Emp formula

Table 11. Keto Oximes 11 and Hydrazino Oximes 1 2

c

,H,,O

__

__

c, €3

C, H C, H

- __.

__

_.

_ _ _ _ _ ~

._____

RtxWNOH ICH2)n

R2

lla-c, X 12a-c, X

-

Compd 1l a

llb 1IC'

lld lle 12a 12b 12c 12d 12e ' See ref' 1 7 .

Mp or b p (mm), "C 1 53-15 6 113-115 Oil 1 6 4 dec 126-127 dec 165-168 dec 168-174 120-1 22 140-141 dec 174-175 dec

Yield (%), method 79, H 68, G 63 80, G 23, G 90, I 65, I 81, I 85, I 84, I

NOH

= =

0

X

NNH2

n

1 2

1 2

appropriately substituted orthoester8 (Table 11). Continuous fractional distillation of any alcohol evolved during t h e ring formation step ensured nonequilibrating conditions. T h e fully aromatized triazines 20a-d apparently result from intramolecular disproportionation (redox) of the expected dihydro N-oxides. Pharmacology. T h e us-triazines and pyrimidines were tested for antiinflammatory activity against carrageenan-induced edema in the rat,g a screen which produces a large number of false positive responses.10 T o each group of five animals with the exception of the control group, drug was administered orally a t a dose of 100 mg/kg of body weight, with one group receiving phenylbutazone a t a dose of 25 mg/kg as a standard. One hour after drug treatment carrageenan (0.1 mL) was administered to t h e right hind paw of all animals (including the control group). After an additional 3-3.5 h the left a n d right hind paw volumes of all animals were measured. T h e percent reduction in paw volume was calculated by subtracting the difference between right and left hind paw volumes in the drug-treated group from the difference in the control group

lld,e, X = 0 12d,e, X = NNH. R'

R2

-CH,CH,CH(t-Bu)CH,CbH5 CH, t-Bu H -CHzCH2CH(t-Bu)CHz'bH5 CH 3 t-Bu H

Emp formula

Analyses

C,,H, ,NOz C,H,NO, C6I-41NO2 CI,H,NO, CllH,lNO2 Cl ,HI ,N,O C,Hl I N3O C~HI~N~O cl

OH,

1 N3°

c,,HI 3N3O

-

C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N C, H, N

a n d dividing by the difference in the control group. T h e parenthesized values found in Tables 111-V are the average percent reduction from two groups of five animals. T h e dashes indicate a reduction of 2'-pyridyl (4a > 4e > 4d). Addition of a methyl moiety a t C-5 had an unpredictable effect on activity (4a vs. 4p and 4c vs. 40). A phenyl moiety a t C-5 enhanced potency when R3 = H (4c < 4n) b u t reduced activity when R3 = N H 2 (4a > 4m). T h e two cases in which a C-5 phenyl group was added in the C-4 t-Bu series and a comparison was possible (8a vs. 8p and 8j vs. 8x) showed slight increases in potency over the 5-H compounds. The 2-OH compound 8r was the most potent (EDso= 43 mg/kg) member of the C-4 t-Bu series. In the case of the 4-tert-butyl-5-phenylpyrimidines 8a-0, the 2-dimethylaminoacetyl analogue 8n was most potent. T h e potency trend 2-H > 2-NH2 > 2-Me was observed in the series 3c > 3a > 3b, 5b > 5a > 5c, 8c > 8a > 8b, a n d 1Oc = 10b > loa. None of the compounds tested against adjuvant-induced edema in the rat displayed a level of activity sufficient t o warrant further investigation. Based on additional testing

R3

Emp formula

"2

1'

CH3 H

CI $1 2NZ CI 1HlON2

2"

(%)c

IH11N3

C9H8N4

(3% H "2 2"

1'

C9H,N3 C9HJ4 C9H*N4

NHCN NHCH, NHCOCH, NHC02CH2CH3 NH, .CH31 NHCONH, C6HS

1'

"2

H H 2"

C10H7N5 1'

OH,

ON4

C11H10N40 ZH1

ZN402

CloHllN4~ 1'

0H9NS0

1'

SHl

1'

5H1 Z N 4

1N3

1'

SH1

1'

OHQN3

1 N3

C10H10N4

2"

H CH3 CH3 2"

Analyses

Carrageenan foot edema, EDSO

1'

2H1 9 N 3

CI 2H1 J

2

C13H20N2

C,H, ,N, C ~ H;N; ;

H CH3

'BH1

1N3

cl

3H1 3 N 2 C 1

"2

1'

ZHI

IN,

H Ci zHi 1 N2C1 CH, 1' qH1 5N2C1 CH, C,.,H,, _ ..N,Cl percent reduction. Dashes (-) indicate a reduction

Synthesis and antiinflammatory activity of trisubstituted pyrimidines and triazines.

Journal of Medicinal Chemistry, 1978, Vol. 21, No. 7 623 Trisubstituted Pyrimidines and Triazines (2) (3) (4) (5) (6) Thromb. Diath. Haemorrh., 2...
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