Classes of Compounds that Interact with Integrins

A method of treatment of a disease or condition affected by integrin inhibition which comprises administering an effective amount of a compound of formula I,

• wherein the ring may be of any configuration;
• Z is sulphur, oxygen, CH2, NH, NRA or hydrogen, in the case where Z is hydrogen then R1 is not present, RA is selected from the set defined for R1 to R5,
• X is oxygen or NRA providing that at least one X of General Formula I is NRA, X may also combine independently with one of R1 to R5 to form an azide,
• R1 to R5 are independently selected from the group comprising H, —(CO)R6 or an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is optionally substituted, and can be branched or linear wherein substituents are selected from the group consisting of:
• OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, wherein R6 is selected from the group comprising an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is optionally substituted, and can be branched or linear wherein substituents include but are not limited to OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted,
• with the proviso that XR2, or XR3 or XR4 or XR5 is not NH2,
• with the further proviso that not more than one of R2 to R5 is hydrogen,
• where the group X is NRA and RA is not hydrogen, the groups RA and the corresponding group R2 to R5 may combine to form a cycle;
• or a pharmaceutically acceptable salt thereof, to a subject in need.

A compound of formula VI:

• or a pharmaceutically acceptable salt thereof;
• wherein R1 is selected from the group consisting of alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy or benzyloxy;
• R6 is alkyl, aryl, heteroaryl;
• R3 is alkyl, aryl or arylalkyl;
• R4 is aryl, arylalkyl;
• and wherein each of R1, R3, R4 and R6 may be further optionally substituted;
• and wherein the compound is effective to inhibit or effect the activity of an integrin receptor.

A method of inhibiting or effecting the activity of an integrin receptor which comprises contacting an integrin with a compound of the formula:

• wherein the compounds are selected from the compounds defined in the following Table:
• R1
• R2a
• R3
• R4
• OH
• -(3-aminophenyl)
• -(4-bromobenzyl)
• —CH2-CO2H
• OH
• -(3-aminophenyl)
• -(4-bromobenzyl)
• —CH2-CO2H
• OMe
• -(4-carboxyphenyl)
• -(4-bromobenzyl)
• -(3-aminobenzyl)
• OMe
• -(4-carboxyphenyl)
• -(4-bromobenzyl)
• -(3-aminobenzyl)
• OMe
• -(3-aminophenyl)
• —CH2-CO2H
• -Bn
• OMe
• -(3-aminophenyl)
• —CH2-CO2H
• -Bn
• OMe
• -(3-aminophenyl)
• —CH2-CO2H
• -(4-bromobenzyl)
• OMe
• -(3-aminophenyl)
• —CH2-CO2H
• -(4-bromobenzyl)
• OMe
• -(4-chlorophenyl)
• —CH2-CO2H
• -(3-aminobenzyl)
• OMe
• -(4-chlorophenyl)
• —CH2-CO2H
• -(3-aminobenzyl)
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• methyl ester
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• methyl ester
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• OMe
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• methyl ester
• OMe
• -phenyl
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OMe
• -phenyl
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OMe
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -Bn
• OMe
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -Bn
• OH
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -Bn
• OH
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -Bn
• OMe
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OMe
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OH
• —CH2-CH2-CO2H
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OMe
• -phenyl
• -(3-aminobenzyl)
• —CH2-CO2H
• OMe
• -phenyl
• -(3-aminobenzyl)
• —CH2-CO2H
• OH
• -phenyl
• -(3-aminobenzyl)
• —CH2-CO2H
• OMe
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OMe
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OEt
• -(3-aminophenyl)
• -Bn
• —CH2-CO2H
• OH
• -(3-aminophenyl)
• -Bn
• —CH2-CO2H
• OH
• -(3-aminophenyl)
• -Bn
• —CH2-CO2H
• OEt
• -(3-aminophenyl)
• -Bn
• -(4-carboxybenzyl)
• OEt
• -(4-carboxyphenyl)
• -Bn
• -(3-aminobenzyl)
• OEt
• -(4-carboxyphenyl)
• -Bn
• -(3-aminobenzyl)
• OEt
• -(3-aminophenyl)
• -(4-bromobenzyl)
• —CH2-CO2H
• OEt
• -(3-aminophenyl)
• -(4-bromobenzyl)
• —CH2-CO2H
• OEt
• -(3-aminophenyl)
• -(4-bromobenzyl)
• -(4-carboxybenzyl)
• OEt
• -(3-aminophenyl)
• -(4-bromobenzyl)
• -(4-carboxybenzyl)
• OH
• -(3-aminophenyl)
• -(4-bromobenzyl)
• -(4-carboxybenzyl)
• OH
• -(3-aminophenyl)
• -(4-bromobenzyl)
• -(4-carboxybenzyl)
• OEt
• —CH2-CH2-CO2H
• -(4-bromobenzyl)
• -(3-aminobenzyl)
• OEt
• —CH2-CH2-CO2H
• -(4-bromobenzyl)
• -(3-aminobenzyl)
• OH
• —CH2-CH2-CO2H
• -(4-bromobenzyl)
• -(3-aminobenzyl)
• OH
• —CH2-CH2-CO2H
• -(4-bromobenzyl)
• -(3-aminobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -Bn
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -Bn
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -(4-bromobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -(4-bromobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -(4-bromobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -(4-bromobenzyl)
• OEt
• -phenyl
• —CH2-CO2H
• -(3-aminobenzyl)
• OEt
• -phenyl
• —CH2-CO2H
• -(3-aminobenzyl)
• H
• -phenyl
• —CH2-CO2H
• -(3-aminobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• OH
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Bn
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• OH
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -(4-bromobenzyl)
• OEt
• -(4-chlorophenyl)
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OEt
• -(4-chlorophenyl)
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OH
• -(4-chlorophenyl)
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OH
• -(4-chlorophenyl)
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OEt
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Bn
• OEt
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Bn
• OH
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Bn
• OH
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Bn
• OEt
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OEt
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OH
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OH
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -(4-bromobenzyl)
• OEt
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• —CH2-CO2H
• OEt
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• —CH2-CO2H
• OEt
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OEt
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• H
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• —CH2-CO2H
• OH
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OH
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OH
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OBn
• -(3-aminophenyl)
• -Et
• —CH2-CO2H
• OBn
• -(3-aminophenyl)
• -Et
• —CH2-CO2H
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• -Et
• -(4-carboxybenzyl)
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• -Et
• -(4-carboxybenzyl)
• OBn
• —CH2-CH2-CO2H
• -Et
• -(3-aminobenzyl)
• OBn
• —CH2-CH2-CO2H
• -Et
• -(3-aminobenzyl)
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -Me
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -Me
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -Et
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• -Et
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• —CH2-CO2H
• H
• OBn
• -Me
• —CH2-CO2H
• -(3-aminobenzyl)
• OBn
• -Me
• —CH2-CO2H
• -(3-aminobenzyl)
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Me
• OBn
• —CH2-CH2-NH—C—(═NH)—NH2
• -(4-carboxybenzyl)
• -Me
• OBn
• -(3-aminophenyl)
• -(4-carboxybenzyl)
• -Et
• OBn
• -(3-aminophenyl)
• -(4-carboxybenzyl)
• -Et
• OBn
• -(3-aminophenyl)
• -(4-carboxybenzyl)
• H
• OBn
• -(3-aminophenyl)
• -(4-carboxybenzyl)
• H
• OBn
• -Et
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OBn
• -Et
• -(4-carboxybenzyl)
• -(3-aminobenzyl)
• OBn
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Me
• OBn
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Me
• OBn
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Et
• OBn
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Et
• OBn
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• H
• OBn
• -Et
• -(3-aminobenzyl)
• —CH2-CO2H
• OBn
• -Et
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• OBn
• -Et
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• O—CH2-CH2-NH—C(═NH)—NH2
• -Me
• -Bn
• —CH2-CO2H
• O—CH2-CH2-NH—C(═NH)—NH2
• -phenyl
• -(4-carboxybenzyl)
• -Me
• O—CH2-CH2-NH—C(═NH)—NH2
• -phenyl
• -(4-carboxybenzyl)
• -Me
• OEt
• —CH2-NH2
• -Bn
• —CH2-CO2H
• OEt
• —CH2-NH2
• -Bn
• —CH2-CO2H
• OEt
• —CH2-NH—C—(═NH)—NH2
• -Bn
• —CH2-CO2H
• OEt
• —CH2-NH—C—(═NH)—NH2
• -Bn
• —CH2-CO2H
• OEt
• —CH2-CH2-NH2
• -Bn
• —CH2-CO2H
• OEt
• —CH2-CH2-NH2
• -Bn
• —CH2-CO2H
• OEt
• —CH2-CH2-NH—C—(═NH)—NH2
• -Bn
• —CH2-CO2H
• OMe
• —CH2-CH2-CH2-NH2
• -Bn
• —CH2-CO2H
• OMe
• —CH2-CH2-CH2-NH2
• -Bn
• —CH2-CO2H
• OMe
• —CH2-CH2-CH2-NH—C—(═NH)—NH2
• -Bn
• —CH2-CO2H
• OMe
• —CH2-CH2-CH2-NH—C—(═NH)—NH2
• -Bn
• —CH2-CO2-CH3
• OMe
• -(4-aminomethyl)phenyl
• -Bn
• —CH2-CO2H
• OMe
• -(4-guanadinomethyl)phenyl
• -Bn
• —CH2-CO2H
• OMe
• -(4-guanadinomethyl)phenyl
• -Bn
• —CH2-CO2H
• OMe
• -(3,5-diaminophenyl)
• -Bn
• —CH2-CO2H
• OMe
• -(3,5-diaminophenyl)
• -Bn
• —CH2-CO2H
• OMe
• -3′-imidazole
• -Bn
• —CH2-CO2H
• OMe
• -3′-imidazole
• -Bn
• —CH2-CO2H
• OMe
• -4′-piperidine
• -Bn
• —CH2-CO2H
• OMe
• -4′-piperidine
• -Bn
• —CH2-CO2H
• OMe
• -4′-pipeiridine
• -Bn
• —CH2-CO2H
• OMe
• -4-aminomethylcyclohexane
• -Bn
• —CH2-CO2H
• OMe
• -4-aminomethylcyclohexane
• -Bn
• —CH2-CO2H
• H
• -(4-carboxyphenyl)
• -(4-bromobenzyl)
• —CH2-CO2H
• H
• -(4-carboxyphenyl)
• -(3-aminobenzyl)
• -Bn
• H
• -(4-chlorophenyl)
• -(3-aminobenzyl)
• -(4-carboxybenzyl)
• H
• -(3-aminophenyl)
• -Et
• —CH2-CO2H
• H
• —CH2-CH2-NH—C—(═NH)—NH2
• -Et
• -(4-carboxybenzyl)
• H
• -(4-guanadinomethyl)phenyl
• -Bn
• —CH2-CO2H
• H
• -(3,5-diaminophenyl) bis formamide
• -Bn
• —CH2-CO2H
• or a pharmaceutically acceptable salt thereof.