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Claims for Patent: 7,314,938

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Claims for Patent: 7,314,938

Title:Modulators of cellular adhesion
Abstract: The present invention provides compounds having formula (I): ##STR00001## and pharmaceutically acceptable derivatives thereof, wherein R.sub.1-R.sub.4, n, p, A, B, D, E, L and AR.sup.1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).
Inventor(s): Shen; Wang (San Mateo, CA), Barr; Kenneth (San Francisco, CA), Oslob; Johan D. (Sunnyvale, CA), Zhong; Min (Foster City, CA)
Assignee: Sunesis Pharmaceuticals, Inc. (South San Francisco, CA)
Application Number:10/982,463
Patent Claims: 1. An isolated compound of the structure (I): ##STR00223## or a pharmaceutically acceptable salt, ester, salt, of such ester or prodrug thereof; wherein R.sup.1 and R.sup.2 are each independently hydrogen, --(CH.sub.2).sub.mOH, --(CH.sub.2).sub.maryl, --(CH.sub.2).sub.mheteroaryl, wherein m is 0-6, --CH(R.sup.1A)(OR.sup.1B), --CH(R.sup.1A)(NHR.sup.1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, wherein U is absent, --O--, --S(O).sub.0-2--, --SO.sub.2N(R.sup.1A), --N(R.sup.1A)--, --N(R.sup.1A)C(.dbd.O)--, --N(R.sup.1A)C(.dbd.O)--O--, --N(R.sup.1A)C(.dbd.O)--N(R.sup.1B)--, --N(R.sup.1A)--SO.sub.2--, --C(.dbd.O)--, --C(.dbd.O)--O--, --O--C(.dbd.O)--, aryl, heteroaryl, alkylaryl, alkylheteroaryl, --C(.dbd.O)--N(R.sup.1A)--, --O--C(.dbd.O)--N(R.sup.1A)--, --C(.dbd.N--R.sup.1E)--, --C(.dbd.N--R.sup.1E)--O--, --C(.dbd.N--R.sup.1E)--N(R.sup.1A)--, --O--C(.dbd.N--R.sup.1E)--N(R.sup.1A)--, --N(R.sup.1A)C(.dbd.N--R.sup.1E)--, N(R.sup.1A)C(.dbd.N--R.sup.1E)--O--, N(R.sup.1A)C(.dbd.N--R.sup.1E)--N(R.sup.1B)--, --P(.dbd.O)(OR.sup.1A)--O--, or --P(.dbd.O)(R.sup.1A)--O--; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano, isocyanate, --OR.sup.1B, --SR.sup.1B; --N(R.sup.1B).sub.2, --NHC(.dbd.O)OR.sup.1B, --NHC(.dbd.O)N(R.sup.1B).sub.2, --NHC(.dbd.O)R.sup.1B, --NHSO.sub.2R.sup.1B, --NHSO.sub.2N(R.sup.1B).sub.2, --NHSO.sub.2NHC(.dbd.O)OR.sup.1B, --NHC(.dbd.O)NHSO.sub.2R.sup.1B, --C(.dbd.O)NHC(.dbd.O)OR.sup.1B, --C(.dbd.O)NHC(.dbd.O)R.sup.1B, --C(.dbd.O)NHC(.dbd.O)N(R.sup.1B).sub.2, ----C(.dbd.O)NHSO.sub.2R.sup.1B, --C(.dbd.O)NHSO.sub.2N(R.sup.1B).sub.2, --C(.dbd.S)N(R.sup.1B).sub.2, --SO.sub.2R.sup.1B, --SO.sub.2--O--R.sup.1B, --SO.sub.2--N(R.sup.1B).sub.2, --SO.sub.2--NHC(.dbd.O)OR.sup.1B, --SO.sub.2--NHC(.dbd.O)--N(R.sup.1B).sub.2, --SO.sub.2--NHC(.dbd.O)R.sup.1B, --O--C(.dbd.O)N(R.sup.1B).sub.2, --O--C(.dbd.O)R.sup.1B, --O--C(.dbd.O)NHC(.dbd.O)R.sup.1B, --O--C(.dbd.O)NH--SO.sub.2R.sup.1B, --O--SO.sub.2R.sup.1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, wherein each occurrence R.sup.1A and R.sup.1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, --COR.sup.1C, or --CONR.sup.1CR.sup.1D; wherein each occurrence of R.sup.1C and R.sup.1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R.sup.1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, --CN, --OR.sup.1C, --NR.sup.1CR.sup.1D or --SO.sub.2R.sup.1C; R.sup.3 is --C(.dbd.O)OR.sup.3A, --C(.dbd.O)H, --C(.dbd.O)NH(R.sup.3A, wherein R.sup.3A is hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or R.sup.3A, taken together with R.sup.1 or R.sup.2, forms a heterocyclic moiety; R.sup.4, for each occurrence, is independently hydrogen, halogen, --CN, --NO.sub.2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR.sup.1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, and E are independently CHR.sup.i; D is N; wherein each occurence of R.sup.i is independently hydrogen, halogen, --CN, --NO.sub.2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; p is 1; and L is C.dbd.O.

2. The compound of claim 1, wherein R.sup.3 is carboxyl, protected carboxyl or a prodrug thereof, wherein R.sup.3 is C(.dbd.O)R.sup.3A, wherein R.sup.3A is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy, alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy, cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy, cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy, aryloxycarbonyloxyalkyloxy, arylcarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one of the structures: ##STR00224##

3. The compound of claim 1 wherein the compound of the structure: ##STR00225## wherein R.sup.4A and R.sup.4B are independently a halogen selected from F, Cl, Br or I; and R.sup.B1, R.sup.B2 and R.sup.E are independently hydrogen or substituted or unsubstituted lower alkyl.

4. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 is a moiety of the following: ##STR00226## wherein Ar.sub.2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R.sup.S is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G.sup.0R.sup.G1 wherein G.sup.0 is --O--, --S-- or --NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety.

5. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 is a moiety of the following structure: ##STR00227## wherein R.sup.1A is Ar.sub.2, --OR.sup.1B, --SR.sup.1B or --NR.sup.1BR.sup.1C; or an alkyl or heteroalkyl moiety; and Ar.sub.2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R.sup.1B and R.sup.1C are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or R.sup.1B and R.sup.1C, taken together with the nitrogen atom to which they are attached, form a heterocylic or heteroaryl moiety.

6. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 is a moiety of the following structure: ##STR00228## wherein Ar.sub.2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R.sup.2A is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R.sup.2A, taken together with a substituent on Ar.sub.2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety.

7. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sub.1)(R.sub.2)R.sup.3 is a moiety of the following structure: ##STR00229## wherein t is 1-3; and R.sup.P3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety.

8. The compound of claim 7, wherein t is 2 and R.sup.P3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety.

9. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 is a moiety of the following structure: ##STR00230## wherein R.sup.2A is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R.sup.2A, taken together with R.sup.2C or R.sup.2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R.sup.2C is hydrogen, CN, --C.dbd.NMe, .dbd.NO.sub.2, .dbd.NC(.dbd.O)NH.sub.2, .dbd.NS(O).sub.2R, .dbd.NS(O).sub.2NRR', --SO.sub.2R.sup.2G, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; wherein R and R' are each independently hydrogen or methyl, and R.sup.2G is lower alkyl; and R.sup.2D is Ar.sub.2, hydrogen, halogen, CN, NO.sub.2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety.

10. A compound of the structure (II) or (III): ##STR00231## or a pharmaceutically acceptable salt, ester, salt of such ester or prodrug thereof; wherein R.sup.4 for each occurrence, is independently hydrogen, halogen, --CN, --NO.sub.2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GR.sup.G1; n is an integer from 2-3; AR.sup.1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, D and E are connected by a single bond; wherein D is N and each occurrence of A, B, and E is --CHR.sup.i; wherein each occurrence of R.sup.i is independently hydrogen, halogen, --CN, --NO.sub.2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1, or any two adjacent occurrences of R.sup.i taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; p is 1; L is C.dbd.O; wherein R.sup.2A is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R.sup.2A, taken together with R.sup.2C or R.sup.2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R.sup.2C is hydrogen, CN, --C.dbd.NMe, .dbd.NO.sub.2, .dbd.NC(.dbd.O)NH.sub.2, .dbd.NS(O).sub.2R, .dbd.NS(O).sub.2NRR', --SO.sub.2R.sup.2G, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; wherein R and R' are each independently hydrogen or methyl, and R.sup.2G is lower alkyl; and R.sup.2D is Ar.sub.2, hydrogen, halogen, CN, NO.sub.2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1; wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --CO(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; or NR.sup.G1R.sup.G2 together form a cyclic moiety.

11. The compound of claim 10, wherein --C(.dbd.O)NHCH(CO.sub.2R.sup.3A)CH.sub.2N(R.sup.2A)C(.dbd.NR.sup.2C)R.su- p.2D is a moiety of the following structure: ##STR00232## wherein R.sup.2E and R.sup.2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R.sup.2E and R.sup.2F, taken together, form a substituted or unsusbtituted heterocyclic or heteroaryl moiety.

12. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 is a moiety with one of the following structures: ##STR00233## wherein R.sup.2A is hydrogen C.sub.1-6alkyl C.sub.2-6alkenyl aryl heteroaryl --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R.sup.2A, taken together with R.sup.2C or R.sup.2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R.sup.2C is hydrogen, CN, --C.dbd.NMe, .dbd.NO.sub.2, .dbd.NC(.dbd.O)NH.sub.2, .dbd.NS(O).sub.2R, or .dbd.NS(O).sub.2NRR'; wherein R and R' are each independently hydrogen or methyl; R.sup.2D is Ar.sub.2, hydrogen, halogen, CN, NO.sub.2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R.sup.2E and R.sup.2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R.sup.2E and R.sup.2F, taken together, form a substituted or unsubstituted heterocyclic or heteroaryl moiety.

13. The compound of claim 10, wherein --C(.dbd.O)NHCH(CO.sub.2R.sup.3A)CH.sub.2N(R.sup.2A)C(.dbd.NR.sup.2C)R.su- p.2D is a moiety with one of the following structures: ##STR00234## wherein R.sup.2E and R.sup.2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R.sup.2E and R.sup.2F, taken together, form a substituted or unsusbtituted heterocyclic or heteroaryl moiety.

14. The compound of claim 1 or 10, wherein the moiety --C(.dbd.O)NHCH(CO.sub.2R.sup.3A)CH.sub.2N(R.sup.2A)C(.dbd.NR.sup.2C)R.su- p.2D with one of the following structures: ##STR00235## ##STR00236## wherein R.sup.2C is lower alkyl; and R.sup.2E and R.sup.2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R.sup.2E and R.sup.2F, taken together, form a substituted or unsubstituted heterocyclic or heteroaryl moiety.

15. The compound of claim 11, wherein R.sup.2D is, or R.sup.2E and R.sup.2F together with the nitrogen atom to which they are attached form, a moiety with one of the following structures: ##STR00237## wherein s is an integer between 0 and 6; each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, isocyanate, NO.sub.2, --P(.dbd.O)(YR.sup.P5).sub.2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of R.sup.P5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R.sup.P5 may also be hydrogen; and each occurrence of R.sup.P2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of R.sup.P1 and R.sup.P2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety.

16. The compound of claim 12, wherein R.sup.2D is, or R.sup.2E and R.sup.2F together with the nitrogen atom to which they are attached form, a moiety with one of the following structures: ##STR00238## wherein each occurrence of R.sup.P1 is independently hydrogen, halogen, methyl, --OCH.sub.3, --OH, --NH.sub.2, --NHCH.sub.3, or --N(CH.sub.3).sub.2.

17. The compound of claim 13, wherein R.sup.2D is, or R.sup.2E and R.sup.2F together with the nitrogen atom to which they are attached form, a moiety with one of the following structures: ##STR00239##

18. The compound of claim 13, wherein --C(.dbd.O)NHCH(CO.sub.2R.sup.3A)CH.sub.2N(R.sup.2A)C(.dbd.NR.sup.2C)R.su- p.2D of the structure: ##STR00240## wherein each occurrence of R.sup.P1 is independently hydrogen, halogen, methyl, --OCH.sub.3, --OH, --NH.sub.2, --NHCH.sub.3 or --N(CH.sub.3).sub.2; R.sup.2A is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; and q is 1 or 2.

19. The compound of claim 14, wherein --C(.dbd.O)NHCH(CO.sub.2R.sup.3A)CH.sub.2N(R.sup.2A)C(.dbd.NR.sup.2C)R.su- p.2D with one of the following structures: ##STR00241## wherein each occurrence of R.sup.P1 is independently hydrogen, halogen, methyl, --OCH.sub.3, --OH, --NH.sub.2, --NHCH.sub.3 or --N(CH.sub.3).sub.2; R.sup.2A is hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, aryl, heteroaryl, --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; q is 1 or 2; and R.sup.2C is lower alkyl.

20. The compound of claim 4, wherein R.sup.3A is independently hydrogen, lower alkyl, phenyl or benzyl.

21. The compound of claim 4 wherein Ar.sub.2 is one of the following structures: ##STR00242## wherein s is an integer from 0-2; each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, isocyanate, NO.sub.2, --OR.sup.G1, --S R.sup.G1, NR.sup.G1R.sup.G2--, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of R.sup.P5 is independently lower alkyl, or when Y is O R.sup.P5 may also be hydrogen; each occurrence of R.sup.P2 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; R.sup.P3 is lower alkyl or --N(R.sup.P2).sub.2; and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety.

22. The compound of claim 21 wherein Ar.sub.2 is one of the following structures: ##STR00243##

23. The compound of claim 4 wherein Ar.sub.2 is one of the following structures: ##STR00244## wherein R.sup.P3 is lower alkyl and R.sup.G1 is hydrogen or lower alkyl.

24. The compound of claim 5 wherein R.sup.1A is --NH.sub.2 or a moiety of the structure: ##STR00245## wherein R.sup.P1 is independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; and each occurrence of R.sup.P2 is independently hydrogen or lower alkyl.

25. The compound of claim 24 wherein R.sup.1A is --NH.sub.2 or a moiety of the structure: ##STR00246## wherein R.sup.P1 is hydrogen or lower alkyl.

26. The compound of claim 5 wherein R.sup.1A is a moiety with one of the following structures: ##STR00247## wherein s is an integer between 0 and 2; each occurrence of R.sup.P1 is independently lower alkyl or is -GR.sup.G1 wherein G is --O-- or --NR.sup.G2 and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R.sup.P2 is independently hydrogen, lower alkyl, aryl or heteroaryl.

27. The compound of claim 26 wherein R.sup.1A is a moiety with one of the following structures: ##STR00248## wherein G is --O-- or --NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen or lower alkyl.

28. The compound of claim 6, wherein --N(R.sup.2A)Ar.sub.2 is one of the following structures: ##STR00249## wherein X.sub.1 is N or CR.sup.P1; s is an integer from 0-5; and each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, NO.sub.2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R.sup.P3 is alkyl, heteroalkyl, aryl or heteroaryl.

29. The compound of claim 28, wherein --NH(R.sup.2A)Ar.sub.2 of the following structure: ##STR00250## wherein R.sup.P1 is hydrogen, halogen or lower alkyl.

30. The compound of claim 10 where R.sup.2D is Ar.sub.2, wherein Ar.sub.2 is one of the following structures: ##STR00251## wherein each occurrence of s is an integer from 0-6; X.sub.1 is CHR.sup.P1 or NR.sup.P2; X.sub.2 and X.sub.3 are independently CHR.sup.P1, NR.sup.P2, CHSO.sub.2R.sup.P3 or NSO.sub.2R.sup.P3; X.sub.5 is O, S or NR.sup.P2; each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, isocyanate, NO.sub.2, --P(.dbd.O)(YR.sup.P5).sub.2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of R.sup.P5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R.sup.P5 may also be hydrogen; each occurrence of R.sup.P2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of R.sup.P1 and R.sup.P2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and each occurrence of R.sup.P3 is independently alkyl, aryl, heteroaryl or --N(R.sup.P2).sub.2.

31. The compound of claim 30 wherein Ar.sub.2 is one of the following structures: ##STR00252## wherein X.sub.1 is N or CR.sup.P1; s is an integer from 0-6; each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, NO.sub.2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R.sup.3 is independently lower alkyl or aryl.

32. The compound of claim 1, wherein --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 has the structure --C(.dbd.O)NHC(.dbd.C(R.sup.S)Ar.sub.2)CO.sub.2R.sup.3A wherein R.sup.3A and R.sup.S, taken together, form a substituted or unsubstituted heterocyclic moiety.

33. The compound of claim 32, wherein --C(.dbd.O)NHC(.dbd.C(R.sup.S)Ar.sub.2)CO.sub.2R.sup.3A is one of the following structures: ##STR00253## wherein Ar.sub.2 is heterocycle, aryl or heteroaryl; and X.sub.1 is O, S or NH.

34. The compound of claim 32, wherein --C(.dbd.O)NHC(.dbd.C(R.sup.S)Ar.sub.2)CO.sub.2R.sup.3A is one of the following structures: ##STR00254## wherein X.sub.1 is O, S or NH; and X.sub.2 is N or CH.

35. The compound of claim 1, wherein AR.sup.1 is one of the following structures: ##STR00255## ##STR00256## wherein each occurrence of r is an integer from 0-6; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 is independently N or CR.sup.Q1; X.sub.5 is O, S or NR.sup.Q2; AR.sup.3 is a heterocyclic, aryl or heteroaryl moiety; each occurrence of R.sup.Q1 is independently hydrogen, OR.sup.Q3, OCF.sub.3, SR.sup.Q3, halogen, CN, isocyanate, NO.sub.2, CF.sub.3, NR.sup.Q3QR.sup.Q4, --SO.sub.2R.sup.Q3, alkyl-NR.sup.Q3R.sup.Q4, alkyl-C(.dbd.O)--NR.sup.Q3R.sup.Q4, alkyl-C(.dbd.O)R.sup.Q3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of R.sup.Q3 and R.sup.Q4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and R.sup.Q2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group.

36. The compound of claim 35, wherein AR.sup.1 is one of the following structures: ##STR00257## wherein X.sup.0 is F or Cl; X.sub.2 is N or CR.sup.Q1; X.sub.5 is CH, O, S or NH; R.sup.Q1 is hydrogen, methyl, --CF.sub.3, --OCH.sub.3, --OCF.sub.3 or halogen.

37. The compound of claim 36, wherein AR.sup.1 is one of the following structures: ##STR00258##

38. The compound of claim 37, wherein AR.sup.1 is one of the following structures: ##STR00259##

39. The compound of claim 1, wherein AR.sup.1-L- is one of the following structures: ##STR00260##

40. The compound of claim 39, wherein AR.sup.1-L- is one of the following structures: ##STR00261##

41. The compound of claim 3 wherein AR.sup.1-L- is a moiety with one of the following structures: ##STR00262## and --C(.dbd.O)NHC(R.sup.1)(R.sup.2)R.sup.3 is a moiety having one of the following structures: ##STR00263## wherein R.sup.2A is hydrogen C.sub.1-6alkyl C.sub.2-6alkenyl aryl, heteroaryl, --C(.dbd.O)R.sup.2B or --SO.sub.2R.sup.2B, wherein R.sup.2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R.sup.2A, taken together with R.sup.2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R.sup.3A is hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety; and R.sup.2D is a moiety having one of the following structures: ##STR00264## wherein s is an integer between 0 and 6; each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, isocyanate, NO.sub.2, --P(.dbd.O)(YR.sup.P5).sub.2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --NR.sup.G2 --, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of R.sup.P5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R.sup.P5 may also be hydrogen; and each occurrence of R.sup.P2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of R.sup.P1 and R.sup.P2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety.

42. The compound of claim 41 wherein R.sup.2A and R.sup.3A are each hydrogen.

43. The compound of claim 41 wherein R.sup.2D is a moiety with one of the following structures: ##STR00265## wherein each occurrence of R.sup.P1 is independently hydrogen, halogen, methyl, --OCH.sub.3, --OH, --NH.sub.2, --NHCH.sub.3, or --N(CH.sub.3).sub.2.

44. The compound of claim 43 wherein R.sup.2D is a moiety with one of the following structures: ##STR00266##

45. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, ester, salt of such ester or prodrug thereof; and a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent.

46. The pharmaceutical composition of claim 45, wherein the compound is present in an amount effective to modulate adhesion between intracellular adhesion molecules (e.g., ICAM-1, -2 and -3) and the leukocyte integrin family of receptors.

47. The pharmaceutical composition of claim 45, wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes.

48. The pharmaceutical composition of claim 45, wherein the compound is present in an amount effective to antagonize Mac-1 and/or LFA-1.

49. The compound of claim 1 of the structure: ##STR00267##

50. The compound of claim 1 of the structure: ##STR00268##

51. The compound of claim 1 of the structure: ##STR00269##

52. The compound of claim 1 of the structure: ##STR00270##

53. The compound of claim 1 of the structure: ##STR00271##

54. The compound of claim 1 of the structure: ##STR00272##

55. The compound of claim 1 of the structure: ##STR00273##

56. The compound of claim 1 of the structure: ##STR00274##

57. The compound of claim 1 with one of the following structures: ##STR00275## ##STR00276##

58. The compound of claim 1 with one of the following structures: ##STR00277## ##STR00278##

59. The compound of claim 1 with one of the following structures: ##STR00279## ##STR00280##

60. The compound of claim 1 with one of the following structures: ##STR00281## ##STR00282##

61. The compound of claim 1 with one of the following structures: ##STR00283## ##STR00284##

62. The compound of claim 10, wherein R.sup.2D is a moiety with one of the following structures: ##STR00285## wherein s is an integer between 0 and 6; each occurrence of R.sup.P1 is independently hydrogen, halogen, CN, isocyanate, NO.sub.2, --P(.dbd.O)(YR.sup.P5).sub.2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR.sup.G1 wherein G is --O--, --S--, --NR.sup.G2--, --CO--, --SO--, --SO.sub.2--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--, --NR.sup.G2C(.dbd.O)-- or --SO.sub.2NR.sup.G2--, and R.sup.G1 and R.sup.G2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of R.sup.P5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R.sup.P5 may also be hydrogen; and each occurrence of R.sup.P2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of R.sup.P1 and R.sup.P2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety.
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