US 5,472,964 AGranted

Diaryl 5,6-fused heterocyclic acids as leukotriene antagonists

AssigneeMerck Frosst Canada, Inc.

InventorsRobert N. Young, Marc Labelle, Yves Leblanc, Yi B. Xiang, Cheuk K. Lau, Claude Dufresne, Yves Gareau

Life of this patent

Estimating the term…

Abstract

Compounds having the formula I: ##STR1## are antagonists of the actions of leukotrienes. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.

Claims5

Dependent claims

A compound of the formula:

##STR14## wherein:
R.sup.1 is H or R.sup.2 ;
R.sup.2 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, --CH.sub.2 F, --CHF.sub.2, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.2 groups joined to the same atom may form a monocyclic or bicyclic ring of up to 8 members comprising carbon atoms and up to 2 heteroatoms chosen from O, S, and N;
R.sup.3 is H or R.sup.2 ;
R.sup.4 is R.sup.3, halogen, --NO.sub.2, --CN, --OR.sup.3, --SR.sup.3, N(R.sup.3).sub.2, NR.sup.3 COR.sup.7, S(O)R.sup.2, or S(O).sub.2 R.sup.2 ;
CR.sup.3 R.sup.22 may be the radical of a standard amino acid;
R.sup.5 is H, halogen, --NO.sub.2, --N.sub.3, --CN, --SR.sup.2, --S(O)R.sup.2, S(O).sub.2 R.sup.2, --N(R.sup.3).sub.2, --OR.sup.3, --COR.sup.3, or lower alkyl;
R.sup.6 is --(CH.sub.2).sub.s --C(R.sup.7).sub.2 --(CH.sub.2).sub.s --R.sup.8 or--CH.sub.2 CON(R.sup.20).sub.2 ;
R.sup.7 is H or lower alkyl;
R.sup.8 is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S, and O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or B) the radical W--R.sup.9 ;
R.sup.9 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteratom in the ring;
R.sup.10 is H, lower alkyl, or benzyl;
R.sup.11 is lower alkyl, --COR.sup.14, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.12 is H, R.sup.11, or two R.sup.12 groups joined to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to two heteroatoms chosen from O, S, and N;
R.sup.13 is lower alkyl, lower alkenyl, lower alkynyl,--CF.sub.3, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.14 is H or R.sup.13 ;
R.sup.15 is H, oxetanyl or R.sup.11 ;
R.sup.16 is H, lower alkyl, or OH;
R.sup.17 is lower alkyl, lower alkenyl, lower alkynyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.18 is R.sup.13 ;
R.sup.19 is H, lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, Ph, CH.sub.2 Ph, or CH.sub.2 CH.sub.2 Ph;
R.sup.20 is H, lower alkyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.20 groups joined to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to two heteroatoms chosen from O, S, and N;
R.sup.21 is H or R.sup.17 ;
R.sup.22 is R.sup.4, CHR.sup.7 OR.sup.3, or CHR.sup.7 SR.sup.2 ;
R.sup.23, R.sup.24, and R.sup.25 is each independently H, lower alkyl, --CN, --CF.sub.3, C(R.sup.3).sub.2 OH, COR.sup.3, CO.sub.2 R.sup.7, CON(R.sup.20).sub.2, OR.sup.3, SR.sup.2, S(O)R.sup.2, S(O).sub.2 R.sup.2, N(R.sup.12).sub.2, halogen, or an electron pair;
R.sup.26 is H, lower alkyl, --SR.sup.27, --OR.sup.28, --N(R.sup.28).sub.2, --CO.sub.2 R.sup.7, CON(R.sup.28).sub.2, --COR.sup.7, --CN, CF.sub.3, NO.sub.2, SCF.sub.3, or halogen;
R.sup.27 is lower alkyl, phenyl, or benzyl;
R.sup.28 is R.sup.27, H, or COR.sup.7, or two R.sup.28 groups joined to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to 2 heteroatoms chosen from O, S, or N;
m and m' are independently 0-8;
p and p' are independently 0-8;
m+p is 1-10 when X.sup.2 is O, S, S(O), or S(O).sub.2 and Z.sup.1 is a bond;
m+p is 0-10 when Z.sup.1 is HET(R.sup.23 R.sup.24 R.sup.25);
m+p is 0-10 when X.sup.2 is CR.sup.3 R.sup.16 ;
m'+p' is 1-10 when X.sup.3 is O, S, S(O), or S(O).sub.2 and Z.sup.2 is a bond;
m' +p' is 0-10 when Z.sup.2 is HET(R.sup.23 R.sup.24 R.sup.25);
m' +p' is 0-10 when X.sup.3 is CR.sup.3 R.sup.16;
s is 0-3;
Q.sup.1 is tetrazol-5-yl, --CO.sub.2 R.sup.3, --CO.sub.2 R.sup.6, --CONHS(O).sub.2 R.sup.13, --CN, --CON(R.sup.20).sub.2, NR.sup.21 S(O).sub.2 R.sup.13, --NR.sup.21 CON(R.sup.20).sub.2, --NR.sup.21 COR.sup.14, OCON(R.sup.20).sub.2, --COR.sup.19, --S(O)R.sup.18, --S(O).sub.2 R.sup.18, --S(O).sub.2 N(R.sup.20).sub.2, --NO.sub.2, NR.sup.21 CO.sub.2 R.sup.17, --C(N(R.sup.12).sub.2).dbd.NR.sup.21, --C(R.sup.19).dbd.NOH, P(O)(OR.sup.10).sub.2 or C(R.sup.3).sub.2 OR.sup.3 ;
or if Q.sup.1 is CO.sub.2 H and R.sup.22 is --OH, --SH, CHR.sup.7 OH or --NHR.sup.3, then Q.sup.1 and R.sup.22 and the carbons through which they are attached may form a heterocyclic ring by loss of water;
Q.sup.2 is H, OR.sup.15, lower alkyl, halogen, or Q.sup.1 ;
W is O, S, or NR.sup.3 ;
X.sup.1 is O, S, --S(O)--,--S(O).sub.2 --, .dbd.NR.sup.3, --C(R.sup.3).sub.2 --, or a bond;
X.sup.2 and X.sup.3 are independently O, S, S(O), S(O).sub.2, CR.sup.3 R.sup.16, or a bond;
Y is --CR.sup.3 .dbd.CR.sup.3 --, --C(R.sup.3).sub.2 --X.sup.1 --, --X.sup.1 --C(R.sup.3).sub.2 --, --C(R.sup.3).sub.2 --X.sup.1 --C(R.sup.3).sub.2 --, --CH(CH.sub.2)CH--, --C.tbd.C--, --CO--, --NR.sup.3 CO--, --CONR.sup.3 --, O, S, or NR.sup.3 ;
Z.sup.1 and Z.sup.2 are independently HET(R.sup.23 R.sup.24 R.sup.25) or a bond;
HET is the diradical of benzene, pyridine, furan, thiophene, thiazole, or 1,2,5-thiadiazole;
HETA is HE.sup.1 or HE.sup.2
HE.sup.1 is ##STR15## HE.sup.2 is ##STR16## A and A.sup.1 is each independently N or CR.sup.5 ;
B is O, S, or S(O);
D is N or CR.sup.4 ;
E is CR.sup.4 when D is CR.sup.4 ;
E is CR.sup.3 when D is N;
or a pharmaceutically acceptable salt thereof.

50 more elements

A compound of claim 1 of the formula:

##STR20## wherein the substituents are as follows:
TABLE 1 __________________________________________________________________________ EX A A' B D E Y Y.sup.1 W.sup.1 __________________________________________________________________________ 1 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 2 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 3 CH CH S CBr CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 4 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 5 CH CH S CCl CH CH.sub.2 CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 6 CH CH S CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 7 CH CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub. 2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 8 CH CH S CF CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 9 CH CH S CF CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 10 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 11 CH CH S CH CS(O).sub.2 PH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 12 CH CH O CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 13 CH CH O CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 14 CH CH S CCl CCl CH.dbd.CH OCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 15 CH CH S CCl CCl CH.dbd.CH OCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 16 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 17 CH CH S CCl CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 18 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 19 CH CH S CF CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 20 CH CH S CF CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 21 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 22 CH CH S CF CS(O).sub.2 CF.sub.3 CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 23 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c-Pr 24 CH CH S CBr CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 25 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 26 CH CH S CF CS(O).sub.2 CH.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 27 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 28 CH CH O CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 29 CH CH O CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 30 CH CH S N CCF.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 31 CH CH O CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 COOH (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 32 CH CH O CF CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 33 CH CH O CF CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 34 CH CH O CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 35 N CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 COOH (CH.sub.2).sub.2 Ph 36 CH CH O CF CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 37 CH CH O CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 38 CH CH O CF CS(O).sub.2 CF.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 39 CH CH O CCl CCN CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 40 CH CH O CBr CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 41 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br S 42 CH CH S CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 43 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 44 CH CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 45 CH CH S CF CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 46 CH CH S CF CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 47 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br Y 48 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 49 CH CH S CF CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br S 50 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 51 CH CH S CF CS(O).sub.2 CH.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 52 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 53 CH CH O CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 54 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 55 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br M 56 CH CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br a 57 CH CH S CF CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br y 58 CH CH S CF CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub. 2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 2 59 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 7 60 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br , 61 CH CH S CF CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br N 62 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br O 63 CH CH S CF CS(O).sub.2 CF.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 1 64 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 9 65 CH CH S CBr CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br 9 66 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 67 CH CH S CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub. 2).sub.2 (1,4-phe)( 1,1-c-Bu)OH 68 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 69 CH CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 70 CH CH S CF CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 71 CH CH S CF CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 72 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 73 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 74 CH CH S CF CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 75 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 76 CH CH S CF CS(O).sub.2 CH.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 77 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 78 CH CH O CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 79 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 80 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 81 CH CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 82 CH CH S CF CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 83 CH CH S CF CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 84 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 85 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 86 CH CH S CF CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub. 2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 87 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 88 CH CH S CF CS(O).sub.2 CF.sub.3 CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 89 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 90 CH CH S CBr CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)(1 ,1-c-Bu)OH 91 CH CH S CH CH CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 92 CH CH S CH CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 93 CH CH S CCl CH CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 94 CH CH S CH CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 95 CH CH S CF CH CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 96 CH CH S CF CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 97 CH CH S CCl CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 98 CH CH S CCl CCl CH.dbd.CH OCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)Br J 99 CH CH S CF CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 100 CH CH S CS(O).sub.2 CF.sub.3 CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 101 CH CH S CF CS(O).sub.2 CH.sub.3 CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 102 CH CH S CCl CCN CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 103 CH CH O CH CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 104 CH CH S CH CH CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 105 CH CH S CCl CH CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 106 CH CH S CH CF CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 107 CH CH S CF CH CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 108 CH CH S CF CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)c- Pr 124 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-phe)-O -c-Pr 125 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)-I g 126 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)C( (CH.sub.2).sub.3)OH 127 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)Br 8 128 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)Oc -pr 129 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 (CH.sub.2).sub.2 (1,4-phe)Br e 130 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (2,5-thi)Cl p 131 CH CH S CCl CCl CH.dbd.CH S(1,1-c-pr)CH.sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,4-phe)Br 0 132 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)C( CH.sub.2).sub.2 OCH.sub.3 133 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)F O 134 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)C( CH.sub.3).sub.2 OH 135 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)Cl t 136 CH CH O CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (2-th) 137 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)CF.sub.3 138 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-phe)(1 ,1-c-Bu)OH 139 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)SO .sub.2 -c-pr 140 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)(1 ,1-c-Bu)OH 141 CH CH S CCl CBr CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 142 CH CH S CCl CBr CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)C( CH.sub.3).sub.2 OH 143 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (4-F-1,2-ph e)C(CH.sub.3).sub.2 OH 144 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (4-Cl-1,2-p he)C(CH.sub.3).sub.2 OH 145 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (4-Cl-1,2-p he)(1,1-c-Bu)OH 146 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)CH .sub. 2 OH 147 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)CO .sub.2 CH.sub.3 148 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)(1 ,1-c-Hex)OH 149 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (4-Cl-1,2-p he)CH.sub.2 OH 150 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 Ph 151 CH CH S CCl CBr CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 152 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (6-Br-1,2-p he)CH.sub.2 OH 153 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)CO CH.sub.3 154 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 TdzH 155 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)CH (OH)CH.sub.3 156 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OCH.sub.3 157 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (6-Br-1,2-p he)C(CH.sub.3).sub.2 OH 158 CH CH S CCl CBr CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-Phe)Br 159 CH CH S CCl CBr CH.dbd.CH S(1,1-c-pr)CH.sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,2-Phe)Br 160 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-Phe)F 161 CH CH S CCl CBr CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-Phe)Cl 1 162 CH CH S CCl CF CH.dbd.CH S(1,1-c-pr)CH.sub.2 CO.sub.2 H (CH.sub.2).sub.2 (1,3-Phe)Cl ` 163 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-phe)C( CH.sub.3).sub.2 OH 164 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (5-((1,1-c- Bu)OH)-1,3-phe)- (1,1-c-Bu)OH 165 CH CH S CCl CCl CH.dbd. CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-phe)F ` 166 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 Thz 167 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)CF .sub.3 168 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)O- OX 169 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)(4 -OH-T4P) 170 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-phe)P( O)(OCH.sub.2 CH.sub.3).sub.2 4 171 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)S- c-Pr 172 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,4-phe)C( CH.sub.3).sub.2 OH 173 CH CH S CCl CF CH.dbd.CH SCH.sub.2 (1,1-c-pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,3-phe)C( CH.sub.3).sub.2 OH 174 CH CH S CCl CH O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 175 CH CH S CH CH O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 176 CH CH S CH CCl O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 177 CH CH S CH CF O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 178 CH CH S CCl CCl O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 179 CH CH S CH CBr O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 180 CH CH S CF CH O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 181 CH CH S CCl CH CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 182 CH CH S CH CH CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 183 CH CH S CH CCl CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 184 CH CH S CH CF CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 185 CH CH S CCl CCl CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 186 CH CH S CH CBr CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 187 CH CH S CF CH CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 188 CH CH S CCl CH CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 189 CH CH S CH CH CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 190 CH CH S CH CCl CH.dbd.CH S(CH.sub.2 ).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 191 CH CH S CH CF CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 192 CH CH S CCl CCl CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 193 CH CH S CH CPr CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 194 CH CH O CH CH CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 195 CH CH O CCl CH CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 196 CH CH O CBr CH CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 197 CH CH S CF CF O--CH.sub.2 SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 198 CH CH S CF CF CH.sub.2 --O SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub. 2 OH 199 CH CH S CF CF CH.dbd.CH S(CH.sub.2).sub.2 CO.sub.2 H S(CH.sub.2).sub.2 CON(CH.sub .3).sub.2 200 CH CH S CCl CH 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 201 CH CH S CH CH 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 202 CH CH S CH CCl 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 203 CH CH S CH CF 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 204 CH CH S CBr CH 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 205 CH CH O CH CH 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 206 CH CH O CCl CH 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 207 CH CH O CBr CH 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 208 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F i 209 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F f 210 CH CH S CH CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F f 211 CH CH S CH CF CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F e 212 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F r 213 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F e 214 CH CH S CBr CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F n 215 CH CH S CH CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)C l 216 CH CH S CCl CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)C l 217 CH CH S CBr CH CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub. 2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)C l 218 CH CH S CCl CCl 1,2-c-Pr SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 (1,2-phe)C( CH.sub.3).sub.2 OH 219 CH CH S CCl CCl CH.dbd.CH SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 (CH.sub.2).sub.2 S(1,4-phe)F . __________________________________________________________________________
6. A compound of,claim 1 of the formula:
##STR21## wherein A and A' are each --CH--;
B is S;
D is N;
E is CCH.sub.3 ;
Y is --CH.dbd.CH--;
Y.sup.1 is SCH.sub.2 (1,1-c-Pr)CH.sub.2 CO.sub.2 H;
and
W.sup.1 is (CH.sub.2).sub.2 (1,2-Phe)C(CH.sub.3).sub.2 OH. 7. A compound of claim 1 which is 1-(((1(R)-(3-(2(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl) -3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic
acid, or a pharmaceutically acceptable salt thereof. 8. A compound of claim 7 which is sodium 1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b ]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-1-hydroxy-1-methylethyl)phenyl)pro
pyl)thio)methyl)cyclopropaneacetate. 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and
a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs;
peripheral analgesic agents;
cycloxygenase inhibitors;
leukotriene antagonists;
leukotriene biosynthesis inhibitors;
H.sub.1 - or H.sub.2 -receptor antagonists;
antihistaminic agents;
prostaglandin antagonists;
and ACE antagonists. 11. A pharmaceutical composition of claim 10, wherein the second active ingredient is a
non-steroidal anti-inflammatory drug. 12. A pharmaceutical composition of claim 11, wherein the weight ratio of said compound of claim 1 to said
second active ingredient ranges from about 1000:1 to 1:1000. 13. A method of preventing the action of leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of claim 1.
4. The method of claim 13 wherein the mammal is man. 15. A method of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of
claim 1. 16. The method of claim 15 wherein the mammal is man. 17. A method of treating inflammatory diseases of the eye in mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

23 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/260,592Filed 16 Jun 1994 · continuation in part
Priority: 22 Dec 1992
Granted: 5 Dec 1995
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 491/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents

Family

Serial994,869Parent of this continuation-in-part · filed 22 Dec 1992
Serial174,937Parent of this continuation-in-part · filed 28 Dec 1993
US 5,472,964 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula:

##STR14## wherein:
R.sup.1 is H or R.sup.2 ;
R.sup.2 is lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, --CH.sub.2 F, --CHF.sub.2, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.2 groups joined to the same atom may form a monocyclic or bicyclic ring of up to 8 members comprising carbon atoms and up to 2 heteroatoms chosen from O, S, and N;
R.sup.3 is H or R.sup.2 ;
R.sup.4 is R.sup.3, halogen, --NO.sub.2, --CN, --OR.sup.3, --SR.sup.3, N(R.sup.3).sub.2, NR.sup.3 COR.sup.7, S(O)R.sup.2, or S(O).sub.2 R.sup.2 ;
CR.sup.3 R.sup.22 may be the radical of a standard amino acid;
R.sup.5 is H, halogen, --NO.sub.2, --N.sub.3, --CN, --SR.sup.2, --S(O)R.sup.2, S(O).sub.2 R.sup.2, --N(R.sup.3).sub.2, --OR.sup.3, --COR.sup.3, or lower alkyl;
R.sup.6 is --(CH.sub.2).sub.s --C(R.sup.7).sub.2 --(CH.sub.2).sub.s --R.sup.8 or--CH.sub.2 CON(R.sup.20).sub.2 ;
R.sup.7 is H or lower alkyl;
R.sup.8 is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S, and O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or B) the radical W--R.sup.9 ;
R.sup.9 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteratom in the ring;
R.sup.10 is H, lower alkyl, or benzyl;
R.sup.11 is lower alkyl, --COR.sup.14, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.12 is H, R.sup.11, or two R.sup.12 groups joined to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to two heteroatoms chosen from O, S, and N;
R.sup.13 is lower alkyl, lower alkenyl, lower alkynyl,--CF.sub.3, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.14 is H or R.sup.13 ;
R.sup.15 is H, oxetanyl or R.sup.11 ;
R.sup.16 is H, lower alkyl, or OH;
R.sup.17 is lower alkyl, lower alkenyl, lower alkynyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 ;
R.sup.18 is R.sup.13 ;
R.sup.19 is H, lower alkyl, lower alkenyl, lower alkynyl, --CF.sub.3, Ph, CH.sub.2 Ph, or CH.sub.2 CH.sub.2 Ph;
R.sup.20 is H, lower alkyl, Ph(R.sup.26).sub.2, CH.sub.2 Ph(R.sup.26).sub.2, or CH.sub.2 CH.sub.2 Ph(R.sup.26).sub.2 or two R.sup.20 groups joined to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to two heteroatoms chosen from O, S, and N;
R.sup.21 is H or R.sup.17 ;
R.sup.22 is R.sup.4, CHR.sup.7 OR.sup.3, or CHR.sup.7 SR.sup.2 ;
R.sup.23, R.sup.24, and R.sup.25 is each independently H, lower alkyl, --CN, --CF.sub.3, C(R.sup.3).sub.2 OH, COR.sup.3, CO.sub.2 R.sup.7, CON(R.sup.20).sub.2, OR.sup.3, SR.sup.2, S(O)R.sup.2, S(O).sub.2 R.sup.2, N(R.sup.12).sub.2, halogen, or an electron pair;
R.sup.26 is H, lower alkyl, --SR.sup.27, --OR.sup.28, --N(R.sup.28).sub.2, --CO.sub.2 R.sup.7, CON(R.sup.28).sub.2, --COR.sup.7, --CN, CF.sub.3, NO.sub.2, SCF.sub.3, or halogen;
R.sup.27 is lower alkyl, phenyl, or benzyl;
R.sup.28 is R.sup.27, H, or COR.sup.7, or two R.sup.28 groups joined to the same N may form a saturated ring of 5 or 6 members comprising carbon atoms and up to 2 heteroatoms chosen from O, S, or N;
m and m' are independently 0-8;
p and p' are independently 0-8;
m+p is 1-10 when X.sup.2 is O, S, S(O), or S(O).sub.2 and Z.sup.1 is a bond;
m+p is 0-10 when Z.sup.1 is HET(R.sup.23 R.sup.24 R.sup.25);
m+p is 0-10 when X.sup.2 is CR.sup.3 R.sup.16 ;
m'+p' is 1-10 when X.sup.3 is O, S, S(O), or S(O).sub.2 and Z.sup.2 is a bond;
m' +p' is 0-10 when Z.sup.2 is HET(R.sup.23 R.sup.24 R.sup.25);
m' +p' is 0-10 when X.sup.3 is CR.sup.3 R.sup.16;
s is 0-3;
Q.sup.1 is tetrazol-5-yl, --CO.sub.2 R.sup.3, --CO.sub.2 R.sup.6, --CONHS(O).sub.2 R.sup.13, --CN, --CON(R.sup.20).sub.2, NR.sup.21 S(O).sub.2 R.sup.13, --NR.sup.21 CON(R.sup.20).sub.2, --NR.sup.21 COR.sup.14, OCON(R.sup.20).sub.2, --COR.sup.19, --S(O)R.sup.18, --S(O).sub.2 R.sup.18, --S(O).sub.2 N(R.sup.20).sub.2, --NO.sub.2, NR.sup.21 CO.sub.2 R.sup.17, --C(N(R.sup.12).sub.2).dbd.NR.sup.21, --C(R.sup.19).dbd.NOH, P(O)(OR.sup.10).sub.2 or C(R.sup.3).sub.2 OR.sup.3 ;
or if Q.sup.1 is CO.sub.2 H and R.sup.22 is --OH, --SH, CHR.sup.7 OH or --NHR.sup.3, then Q.sup.1 and R.sup.22 and the carbons through which they are attached may form a heterocyclic ring by loss of water;
Q.sup.2 is H, OR.sup.15, lower alkyl, halogen, or Q.sup.1 ;
W is O, S, or NR.sup.3 ;
X.sup.1 is O, S, --S(O)--,--S(O).sub.2 --, .dbd.NR.sup.3, --C(R.sup.3).sub.2 --, or a bond;
X.sup.2 and X.sup.3 are independently O, S, S(O), S(O).sub.2, CR.sup.3 R.sup.16, or a bond;
Y is --CR.sup.3 .dbd.CR.sup.3 --, --C(R.sup.3).sub.2 --X.sup.1 --, --X.sup.1 --C(R.sup.3).sub.2 --, --C(R.sup.3).sub.2 --X.sup.1 --C(R.sup.3).sub.2 --, --CH(CH.sub.2)CH--, --C.tbd.C--, --CO--, --NR.sup.3 CO--, --CONR.sup.3 --, O, S, or NR.sup.3 ;
Z.sup.1 and Z.sup.2 are independently HET(R.sup.23 R.sup.24 R.sup.25) or a bond;
HET is the diradical of benzene, pyridine, furan, thiophene, thiazole, or 1,2,5-thiadiazole;
HETA is HE.sup.1 or HE.sup.2
HE.sup.1 is ##STR15## HE.sup.2 is ##STR16## A and A.sup.1 is each independently N or CR.sup.5 ;
B is O, S, or S(O);
D is N or CR.sup.4 ;
E is CR.sup.4 when D is CR.sup.4 ;
E is CR.sup.3 when D is N;
or a pharmaceutically acceptable salt thereof.

50 more elements

Facts

Application

08/260,592Filed 16 Jun 1994 · continuation in part

Priority

22 Dec 1992

Granted

5 Dec 1995

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 491/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents