J. Med. Chem. 1988,31,466-472
466
Pyrido[2,1-b]quinazolinecarboxamide Derivatives as Platelet Activating Factor Antagonists Jefferson W. Tilley,*t Barbara Burghardt,! Charles Burghardt,! Thomas F. Mowles,* Franz-Josef Leinweber,t Larry Klevans,*$ Richard Young,$ Gerry Hirkaler,! Kenneth Fahrenholtz,t Sonja Zawoiski,? and Louis J. Todarot Chemistry Research Department, Department of Pharmacology and Chemotherapy, and Department of Drug Metabolism, H o f f m a n n - L a Roche Inc., N u t l e y , New Jersey 07110. Received August 3, 1987 A series of N - [(heteroaryl)alkyl]pyrido[2,1-b]quinazolineswere evaluated for their ability to inhibit the binding of radiolabeled platelet activating factor (PAF) to its receptor on dog platelets. The most potent compounds in this series were found to be pyrido[2,1-b]quinazoline-8-carboxamides possessing a four- or six-carbon chain between the carboxamide nitrogen atom and a 3-pyridinyl or 5-pyrimidinyl moiety. Since earlier metabolism studies with pyridoquinazolinecarboxamides suggest that the carboxamide moiety is labile to hydrolysis in vivo, attempts were made to find isosteric replacements for this group. The substitutions examined led to a loss of activity; however, insertion of a methyl group on the carbon atom LY to the carboxamide nitrogen led to an enantioselective enhancement of potency. (~)-2-(1-Methylethyl)-N-[l-methyl-4-(3-pyridinyl)butyl]-ll-oxo-ll~-pyrido[2,l-b]quinazoline-8carboxamide (34) was more potent than the corresponding S enantiomer in the PAF binding assay and was also shown to be more resistant to degradation by amidases present in whole liver homogenates obtained from guinea l-methyl-4-(3-pyridinyl)butyl]-llpig, dog, and squirrel monkey. The corresponding rac-2-(l-methylethyl)-N-[ oxo-llH-pyrido[2,1-b]quinazoline-8-carboxamide (33) was found to inhibit transient PAF-induced thrombocytopenia and decreases in blood pressure in guinea pigs after intravenous or oral administration and to have a duration of action of >5 h after an oral dose of 200 mg/kg. Compound 33 thus represents the prototype of a new class of orally active PAF antagonists.
Platelet activating factor (PAF) l1 is a phospholipid ether with a 16-18 carbon alkyl chain,2which is released from a variety of cell types including stimulated platelets, neutrophils, basophils, macrophages, and vascular endothelial tissuea3 It has a myriad of biological effects. In 0 II
Scheme I
38
37
39
0-(CHz)i~ifW
1
addition to promoting platelet aggregation, PAF induces smooth muscle contraction, increased vascular permeability, hypotension, bronchoconstriction, and cardiac contractility A mediator role for PAF has been proposed in several human disease state^,"^ resulting in an intensive search for compounds capable of blocking the effects of PAF. Membrane binding assays have been widely used to assist this effort and have resulted in the identification of a number of PAF analogues as well as several seemingly unrelated compounds8 as PAF antagonists. In our efforts to identify novel PAF antagonists, we have relied on a binding assay using whole, wwhed dog platelets. Using this system, we have found that several members of a series of pyrido[2,1-b]quinazolinederivatives that had originally been prepared as spasmolytic agentsgJOwere potent inhibitors of PAF binding. Additionally, one compound, 33, effectively inhibits PAF-induced changes in blood pressure and platelet aggregation in the guinea pig after intravenous or oral administration. In this paper, we describe these studies and summarize the structure-activity relationships among compounds of this series. Chemistry Most of the compounds listed in Tables I and I1 have been previously d e ~ c r i b e d . ~The J ~ pyrimidinehexanamine 39 was prepared by a palladium-catalyzed coupling of 5-bromopyrimidine (37) with 5-hexyn-1-01 followed by reduction to the alcohol 38 and conversion to the corresponding amine as shown in Scheme I. Amide bond Chemistry Research Department. Department of Pharmacology and Chemotherapy. §Department of Drug Metabolism.
Scheme I1
41
42
15,X.N
23,X=N
16,X
2 4 , X = CH
E
CH
CH3
Scheme I11 0 W -/ ( C H Z ) , - B ~
43
-
&N.(CH2)6:3
c
"3
44
O
O H
3
~
i
HzNWMrN
45
.
L
i
.
~
c
8 HN ~
~
CH3
25
formation to give 11 was effected by reaction with the cyanomethyl ester 40.9 (1) Benveniste, J.; Henson, P. M.; Cochrane, C. G. J. E x p . Med. 1972, f36, 1356. Benveniste, J.; Tence, M.; Varenne, P.; Bi-
dault, J.; Boullet, C.; Polonsky,J. C. R. Seances Acad. Sci. Ser.
D.1979,289, 1037. Demopoulos,C. A.; Pinckard, R. N.; Hananhan, D. J. J. Biol. Chem. 1979, 254, 9355. (2) Ramesha, C. S.; Pickett, W. C. J. Irnrnunol. 1987, 138, 1559.
0022-2623/88/1831-0466$01.50/00 1988 American Chemical Society
~
3
-
Journal of Medicinal Chemistry, 1988, Vol. 31, No. 2 467
Pyridor2,l- b]quinazolinecarboxamide Derivatives
Table I. 2-Isopropyl-N-[(heteroaryl)alkyl]-ll-oxo-ll~-pyrido[2,l-~]quinazoline-8-carboxamides
?
h e D C + W C H d n - p e t
R
R1
compd
Rz n
Het
PAF binding: ICm FM"
R1
compd
Het
HO
PAF binding: 1C.m FM"
2
(CH&CH H
2
2.5
3
(CHJZCH H
3
>1(5)
1.0
4
(CH3)zCH H
5
>1 (9)
0.70
5
(CH3)zCH H
4
0.35
0.60
6
(CHJZCH H
6
0.40
1.0
7
(CH&CH H
7
>1 (19)
0.37
8
(CH3)zCH H
4
5.0
>1 (0)
9
(CHJZCH H
4
1.3
>1 (0)
10
(CHJ2CH H
4
0.45
11
(CH3)ZCH H
6
0.20
26
12
(CH3)tCH H
4
3.5
27 (CV-3988)
13
H
H
4
1.8
14
CH3
H
4
0.50
15
CH3
CH3 4
0.10
16
CH3
CH3 4
0.25
17
1.2
25
CH3
CH3
6
CH3
4
Fi
--+Q
(9)
> (4) 0.60
0.18
CHaO
OCHj
"For inactive compounds, the number in parentheses is the percent inhibition of specific binding observed at a concentration of 1.0 pM. Table 11. 2-Isopropyl-8-substituted-ll-oxo-llH-pyrido[ 2,1-b]quinazolines
PAF binding: X R1 Rz ICm, PM" > 1 (15) (CHd2 H H CHZNH H H >1 (15) H B >1 (16) COP SOzNH H H (7) CONH CH3 H 0.40 CONH CH3 H 0.25 35 CONH H CH3 0.60 36 CONH CH, CH3 1.2 " For inactive compounds, the number in parentheses is the percent inhibition of specific binding observed at a concentration of 1.0 pM. bRacemic. compd 29 30 31 32 33b 34
The 2,3-dimethylpyridoquinazolinecarboxylic acid 41 was converted to the relatively stable acid chloride 42 by (3) Vargaftig, B. B.; Benveniste, J. Trends Pharrnacol. Sci. 1983, 4 , 341.
treatment with thionyl chloride. Treatment with 5-pyrimidineb~tanamine~ afforded the corresponding amide 15. In order to test a hypothesis that a pyridinium moiety resulting from protonation of the pyridine ring of the active species might be mimicking the choline ammonium ion of PAF, the quaternary analogues 23 and 24 were prepared by treatment of 15 and 16, respectively, with iodomethane (Scheme 11). In addition, the (bromohexy1)phthalimide 43 was reacted with pyridine to give a high yield of the pyridinium salt 44. Hydrolysis with hydrobromic acid provided the amine 45, which was condensed with the acid chloride 42 to give the amide 25 (Scheme 111). (4) Braquet, P.; Vargaftig, B. B. Transplant. Proc. 1986,18 (Suppl 4), 10. (5) Morley, J. Agents Actions 1986, 15, 100. (6) Synder, F. Med. Res. Reu. 1985,5, 107. Venuti, M. C. Annu. Rep. Med. Chem. 1985,20, 193. (7) McManus, L. Pathol. Imrnunopathol. Res. 1986, 5, 104. (8) Braauet. P.: Godfroid. J. J. Trends Pharrnacol. Sci. 1986., 7.. 368 and'397. (9) Tillev. J. W.: Levitan. P.: Lind. J.: Welton. A. F.: Crowlev. H. J.; Tobias, L. D.; O'Donnell, M. Med. Chern. 1987, 30,"185. (10) Tilley, J. W.; Coffen, D. L.; Schear, B. H.; Lind, J. J . Org. Chern. 1987,52, 2469.
468 Journal of Medicinal Chemistry, 1988, Vol. 31, No. 2
Scheme IV
48
50
Tilley et al. Table 111. Relative Rate of Hydrolysis of PAF Antagonists in Whole Liver Homogenates" species com.pd guinea .pig sauirrel monkev dog 5 1.0 (n = 1) 33 0.35 0.18 0.49 f 0.18 ( n = 4) 1.9 f 0.7 ( n = 3) (n = 5) ,34 0.063 f 0.015
