US 2003/0216389 A1 · Therapeutic morpholino-substituted compounds

Abstract

Morpholino-substituted pyridopyrimidine, quinolone, and benzopyranone derivatives inhibit phosphoinositide (PI) 3-kinase, an enzyme that regulates platelet-adhesion processes. As a consequence, the compounds in question have anti-thrombotic activity, as well as other pharmaceutical properties. The compounds claimed are represented by formula (I), (II) and (III). PI 3-kinase generates 3-phosphorylated PI second messengers which stimulate platelet adhesion under blood-flow conditions. Because platelet adhesion is a necessary step in the formation of a thrombus, inhibition by these compounds of PI 3-kinase under such conditions inhibits or prevents thrombus formation. The compounds are useful in treating PI 3-kinase-dependent conditions including cardiovascular diseases such as coronary artery occlusion, stroke, acute coronary syndrome, acute myocardial infarction, vascular restenosis, atherosclerosis, and unstable angina; respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD), and bronchitis; inflammatory disorders; neoplasms including cancers such as glioma, prostate cancer, small cell lung cancer, and breast cancer, and diseases linked to disordered white blood cell function, such as autoimmune and inflammatory diseases. 1

Claims78

Dependent claims

A compound having the following formula:

123
wherein
R is H, OH, F, Cl, Br, I, C1-C6 alkyl, aryl or (CH2)n-aryl;
R1 is OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-Cc alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
and
R3 is H, or substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted aryl.

3 more elements

A method for inhibiting phosphoinositide 3-kinase in a patient, comprising administering to a patient a compound having the following formula in an amount of effective for inhibiting the phosphoinositide 3-kinase in the patient:

134
wherein
R is H, OH, F, Cl, Br, I, C1-C6 alkyl, aryl or (CH2)n-aryl;
R1 is OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH≡CH-aryl, C≡C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
R2 is H, OH, F, Cl, Br, I, C1-C6 allyl, C3-C6 cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
and
R3 is H, or substituted or unsubstituted C1-C6alkyl, substiuted or unsubstituted aryl.

4 more elements

A method for preventing or treating respiratory disease comprising administering to a patient in need thereof an effective amount of a compound of the following formula:

140
wherein
R is H, OH, F, Cl, Br, I, C1-C6 alkyl, aryl or (CH2)n-aryl;
R1 is OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH═CH-aryl, C═C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
R2 is H, OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH═CH-aryl, C═C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3).-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO23, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
and
R3 is H, or substituted or unsubstituted C1-C6alkyl, substiuted or unsubstituted aryl.

4 more elements

A method for preventing or treating disease linked to disordered white blood cell function comprising administering to a patient in need thereof an effective amount of a compound having the following formula:

146
wherein
R is H, OH, F, Cl, Br, I, C1-C6 alkyl, aryl or (CH2)n-aryl;
R1 is OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH═CH-aryl, C2-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)7-aryl,(CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
R2 is H, OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
and
R3 is H, or substituted or unsubstituted C1-C6alkyl, substiuted or unsubstituted aryl.

4 more elements

A method for preventing or treating cancer comprising administering to a patient in need thereof an effective amount of a compound having the following formula:

152
wherein
R is H, OH, F, Cl, Br, I, C1-C6 alkyl, aryl or (CH2)n-aryl;
R1 is OH, F, Cl, Br, I, C1-C6 ally, C3-C6 cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR3)-aryl, NR3-C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n-NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n-O-alkyl, (CHR3)n—O-cycloalkyl, O—(CHR3)n-aryl, S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, 1, CN, CO2H, CO2R3, NO2, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO0-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
R2 is H, OH, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, CH═CH-aryl, C≡C-aryl, (CHR3)-aryl, NR3—C1-C6 alkyl, NR3-cycloalkyl, NR3—(CHR3)n-aryl, (CHR3)n—NR3-aryl, (CHR3)n—NR3-alkyl, (CHR3)n—NR3-cycloalkyl, (CHR3)n—O-aryl, (CHR3)n—O-alkyl, (CHR3)n—O-cycloalkyl, [O—(CHR3)naryl,]S—(CHR3)n-aryl, or CO-aryl, wherein n is 0, 1, or 2 and alkyl, cycloalkyl or aryl is optionally substituted with F, Cl, Br, I, CN, CO2H, CO2R3, NO, CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, OCF3, OR3, OSO2-aryl, substituted or unsubstituted amine, NHCOR3, NHSO2R3, CONHR3, or SO2NHR3;
and
R3 is H, or substituted or unsubstituted C1-C6alkyl, substiuted or unsubstituted aryl.

4 more elements

Dependencies are inferred from the claim text.

Therapeutic morpholino-substituted compounds

Life of this patent

Therapeutic morpholino-substituted compounds

Life of this patent

Abstract

Claims78