US 2001/0020030 A1 · Cell adhesion-inhibiting antiinflammatory compounds

Abstract

Compounds having Formula I 1 are useful for treating inflammation. Also disclosed are pharmaceutical compositions comprising compounds of Formula I, and methods of inhibiting/treating inflammatory diseases in a mammal.

A compound having Formula I 86

or a pharmaceutically acceptable salt or prodrug thereof, where the symbol ---- represents a single bond or a double bond, provided that when one bond is a double bond, the adjacent bond is a single bond;
E, F, and G are independently selected from
(1) carbon,
(2) nitrogen, and
(3) N+—0—,
provided that at least one of E, F or G is nitrogen or N+—0—, and further provided that at least one of E, F or G is carbon;
Y and Z are independently selected from
(1) carbon,
(2) nitrogen,
(3) oxygen, and
(4) S(O), where t is an integer O-2,
provided that at least one of Y or Z is other than carbon;
LA is selected from
(1) a covalent bond,
(2) —0—,
(3) —S(O)t—,
(4) —NR6— where R6 is selected from
(a) hydrogen,
(b) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from,
(i) aryl and
(ii) cycloalkyl of three to ten carbons,
(c) alkanoyl where the alkyl part is of one to ten carbons, and
(d) cycloalkyl of three to ten carbons,
(5) —C(W)— where W is selected from
(a) O and
(b) S, and
(6) alkenylene;
XA is selected from
(1) halo,
(2) alkyl of one to ten carbons optionally substituted with 1,2, or 3 substituents independently selected from
(a) oxo,
(b) cycloalkyl of three to ten carbons,
(c) —CO2R7 where R7 is selected from
(i) hydrogen and
(ii) alkyl of one to ten carbons optionally substituted with 1, or 2 substituents independently selected from
aryl and
cycloalkyl of three to ten carbons,
(d) —NR8R9 where R8 and R9 are independently selected from
(i) hydrogen,
(ii) alkyl of one to six carbons optionally substituted with 1 or 2 substituents independently selected from
—OH,
aryl,
heterocycle,
cycloalkyl of three to ten carbons, and
—NRARB where RA and RB are independently selected from
hydrogen and
alkyl of one to six carbons optionally substituted with 1 or 2 substituents selected from —OH,
(iii) alkanoyl where the alkyl part is of one to to ten carbons,
(iv) cycloalkyl of three to ten carbons,
(v) alkoxy,
(vi) heterocycle, and
(vii) aryl,
where (vi) and (vii) are substituted with 1 or 2 substituents independently selected from
alkyl of one to six carbons and
halo,
(e) —C(W)Rlo where W is previously defined and RIO is selected from
(i) hydrogen,
(ii) alkyl of one to ten carbons optionally substituted with 1, or 2 substituents independently selected from
aryl and
cycloalkyl of three to ten carbons,
(iii) —NR8R9, and
(iv) —OR7,
(f) —OH,
(g) aryl, and
(h) heterocycle,
where (g) and (h) can be optionally substituted with 1,2,3,4, or 5 substituents independently selected from
(i) alkyl of one to twenty carbons,
(ii) —NR8R9,
(iii) alkoxy of one to ten carbons,
(iv) thioalkoxy of one to ten carbons,
(v) halo,
(vi) perfluoroalkyl of one to three carbons,
(vii) alkenyl of two to ten carbons,
(viii) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
alkoxy of one to ten carbons and
—OH,
(ix) —CO2R7,
(x) aryl, and
(xi) —CHO,
(3) cycloalkyl of three to ten carbons,
(4) aryl,
(5) heterocycle
where (4) and (5) can be optionally substituted with 1,2,3,4, or 5 substituents independently selected from
(a) alkyl of one to twenty carbons,
(b) alkyl of one to ten carbons substituted with 1,2, or 3 substituents independently selected from
(i) —OR11 where R11 is selected from
hydrogen,
—C(W)Rl2 where R12 is selected from
alkyl of one to ten carbons,
cycloalkyl of three to ten carbons,
aryl, and
heterocycle, and
heterocycle optionally substituted with 1,2,3, or 4 substituents independently selected from
—OH and
alkyl of one to six carbons optionally substituted with 1 or 2 substituents selected from —OH,
(ii) alkoxy of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
alkoxy and
alkoxyalkoxy,
(iii) spiroalkyl of three to ten carbons, and
(iv) halo,
(c) alkoxy of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
(i) alkoxy and
(ii) alkoxyalkoxy,
(d) thioalkoxy of one to ten carbons,
(e) halo,
(f) perfluoroalkyl of one to three carbons,
(g) alkenyl of two to ten carbons optionally substituted with 1 or 2 substituents independently selected from
(i) —C(W)RIo and
(ii) —C(W)RI2,
(h) —CO2R7,
(i) —NR8R9,
(j) aryl,
(k) —C(W)R12,
(l) —CHO,
(m) —C(O)NR8R9,
(n) —CN,
(o) heterocycle optionally substituted with 1 or 2 substituents independently selected from
(i) alkyl of one to ten carbons and
(ii) perfluoroalkyl of one to three carbons,
(p) —C(W)R10,
(q) ethylenedioxy, and
(r) —OCF3,
(6) —OR7,
(7) hydrogen, and
(8) —NR8R9;
LB is selected from
(1) a covalent bond,
(2) —O—,
(3) —S(O)t—,
(4) —NR6—,
(5) —C(W)—, and
(6) —C(═NR13)— where R13 is selected from
(a) hydrogen,
(b) —NO2,
(c) —CN, and
(d) —OR14 where R14 is selected from
(i) hydrogen,
(ii) aryl, and
(iii) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
aryl and
—C(O)R15 where R15 is selected from
hydrogen,
—OH,
alkoxy, and
NRARB;
XB is selected from
(1) hydrogen,
(2) alkyl of one to ten carbons optionally substituted with 1,2, or 3 substituents independently selected from
(a) —CO2R7,
(b) —NR8R9,
(c) —C(W)NR8R9,
(d) heterocycle,
(e) aryl optionally substituted with 1 or 2 substituents independently selected from
(i) alkyl of one to ten carbons,
(ii) —NO2, and
(iii) —NRARB,
(f) —OR16 where R16 is selected from
(i) hydrogen and
(ii) —C(W)NRARB, and
(g) —NRAC(W)NR8Rg,
(3) alkenyl of two to six carbons optionally substituted with 1 or 2 substituents independently selected from
(a) —C(W)NRARB,
(b) —CO2R7, and
(c) heterocycle,
(4) —NR17R18 where R17 and R18 are independently selected from
(a) hydrogen,
(b) alkyl of one to ten carbons optionally substituted with 1,2, or 3 substituents independently selected from
(i) —OH,
(ii) —C(W)R10,
(iii) —NRAC(═N13)NRBR19 where RA, RB, and R13 are previously defined and R19 is selected from
hydrogen,
alkyl of one to ten carbons, and
—NO2,
(iv) heterocycle,
(v) aryl,
(vi) halo, and
(vii) —NRARB,
(c) alkoxy,
(d) aryl optionally substituted with 1,2, or 3 substituents independently selected from
(i) halo,
(ii) alkyl of one to ten carbons,
(iii) alkoxy of one to ten carbons, and
(iv) perfluoroalkyl of one to three carbons,
(e) heterocycle,
(f) —NRARB,
(g) —C(O)R20 where R20 is selected from
(i) hydrogen,
(ii) alkyl of one to ten carbons,
(iii) —OR12, and
(iv) —NRARB,
(h) cycloalkyl of three to ten carbons, and
(i) —OH,
(5) alkoxy,
(6) —OH,
(7) —NRAC(═NR13)NRBR19,
(8) —C(W)NR8R9,
(9) aryl,
(10) heterocycle,
where (9) and (10) can be optionally substituted with 1,2,3,4, or 5 substituents independently selected from
(a) halo,
(b) alkyl of one to ten carbons optionally substituted with 1,2, or 3 substituents independently selected from
(i) halo,
(ii) alkoxy of one to ten carbons,
(iii) —NRARB,
(iv) —OH,
(v) —CO2R7,
(vi) —C(W)NRARB, and
(vii) aryl,
(c) —NRARB,
(d) alkoxy of one to ten carbons,
(e) thioalkoxy of one to ten carbons,
(f) perfluoroalkyl of one to three carbons,
(g) —OH,
(h) —C(W)NR8Rg,
(i) —CO2R7,
(j) —NRAC(W)OR2, where RA is previously defined and R21 is selected from
(i) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents selected from
aryl and
cycloalkyl of three to ten carbons,
(ii) aryl, and
(iii) cycloalkyl of three to ten carbons,
(k) alkenyl of two to ten carbons,
(l) heterocycle,
(m) aryl, and
(n) —NO2,
(11) —CN,
(12) —CHO,
(13) halo, and
(14) —B(ORA)(ORB);
provided that when R1, R2, R3, R4, and R5 are hydrogen or absent, -LA- is a covalent bond, and —LB— is a covalent bond, then one of XA or XB is other than hydrogen;
and
R1, R2, R3, R4, and R5 are absent or independently selected from
(1) hydrogen,
(2) alkyl of one to six carbons optionally substituted with 1 or 2 substituents independently selected from
(a) —OC(O)R22, where R22 is selected from
(i) alkyl,
(ii) alkoxy, and
(iii) NRARB,
(b) alkoxy,
(c) —OH,
(d) —NRARB,
(e) heterocycle, and
(f) aryl,
(3) —CO2R7,
(4) —C(O)NRARB,
(5) —SR23 where R23 is selected from
(a) hydrogen,
(b) alkyl of one to six carbons,
(c) aryl optionally substituted with 1 or 2 substituents selected from
(i) alkyl of one to six carbons and
(ii) halo,
(6) —NRARB,
(7) halo,
(8) alkoxy,
(9) perfluoroalkyl of one to three carbons,
(10) —OH, and
(11) heterocycle,
provided that when E, F, and Y are carbon, G is nitrogen, Z is sulfur, —LA— is a covalent bond, and XA is halo, R1 is other than —CO2R7.

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Cell adhesion-inhibiting antiinflammatory compounds

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Cell adhesion-inhibiting antiinflammatory compounds

Life of this patent

Abstract

Claims23