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US 2010/0137285 A1Published application
Small molecule modulators of cytokine activity
AssigneeAngion Biomedica Corp.
InventorsDavid E. Zembower, Jasbir Singh, Rama K. Mishra
Life of this patent
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Abstract
The present invention provides compounds having formula (I) or (II): and pharmaceutically acceptable derivatives thereof, wherein m, p, R1, R2, R3 and R4 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 any of a number of diseases, disorders or conditions associated with HGF/SF or other cytokine activity.
Claims39
1-71. (canceled)
72-108. (canceled)
An isolated compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R4;
- p is an integer from 1 to 6;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety;
- m is an integer from 1 to 4;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Ra, for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently hydrogen, hydroxy, SO2Rd, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently hydrogen, —N(Re)2, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic;
- with the proviso that the compound does not have one of the following structures:
- wherein p and R4 are as defined above,
- wherein R4A is hydrogen, methyl, methoxy,
- chloro or —NO2,
14 more elements
A pharmaceutical composition comprising:
- a pharmaceutically acceptable carrier, adjuvant or vehicle;
- and
- a compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R4;
- p is an integer from 1 to 6;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety;
- m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Ra, for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently hydrogen, hydroxy, SO2Rd, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently hydrogen, —N(Re)2, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic;
- with the proviso that the compound does not have one of the following structures:
- wherein R4A is hydrogen, methyl, wherein p and R4 are as defined above methoxy, chloro or —NO2
15 more elements
A method for:
- agonizing HGF/SF activity;
- agonizing c-met;
- stimulating cell proliferation;
- promoting angiogenic activity,
- promoting the formation of new blood vessels;
- inducing proliferation of epithelial cells, neuronal cells, Schwann cells or oligodendrocyte cells;
- promoting axonal growth;
- inducing myelin production;
- and/or
- reducing fibrosis;
- in a subject comprising:
- administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R4;
- p is an integer from 1 to 6;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety;
- m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Ra, for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently hydrogen, hydroxy, SO2Rd, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently hydrogen, —N(Re)2, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic.
22 more elements
A method for protecting from cell apoptosis in a subject comprising:
- administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein Cy is an N-linked 5- to 10-membered heterocyclic or heteroaryl group other than an optionally substituted homopiperidinyl group, wherein Cy is optionally substituted with p occurrences of R4;
- p is an integer from 1 to 6;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, or acyl moiety;
- m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Ra, for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently hydrogen, hydroxy, SO2Rd, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently hydrogen, —N(Re)2, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic;
- with the proviso that the compound does not have the following structure:
12 more elements
A method for:
- agonizing HGF/SF activity;
- agonizing c-met;
- stimulating cell proliferation;
- promoting angiogenic activity,
- promoting the formation of new blood vessels;
- inducing proliferation of epithelial cells, neuronal cells, Schwann cells or oligodendrocyte cells;
- promoting axonal growth;
- inducing myelin production;
- and/or
- reducing fibrosis;
- in a subject comprising:
- administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- R2 and R3 are independently hydrogen, hydroxyl, —NH2, an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic or acyl moiety;
- Ra, for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently selected from the group consisting of hydrogen;
- hydroxy;
- SO2Rd;
- and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently selected from the group consisting of hydrogen;
- —N(Re)2;
- aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic.
25 more elements
A method for protecting from cell apoptosis in a subject comprising:
- administering to a subject in need thereof a therapeutically effective amount of a compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- R2 and R3 are independently hydrogen, hydroxyl, —NH2, an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRe, —C(═O)Ra or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic or acyl moiety;
- Ra, for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently selected from the group consisting of hydrogen;
- hydroxy;
- SO2Rd;
- and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently selected from the group consisting of hydrogen;
- —N(Re)2;
- aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic;
- with the proviso that the compound does not have one of the following structures:
15 more elements
A method for treating or lessening the severity of fibrotic liver disease, hepatic ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease or lung (pulmonary) fibrosis, multiple sclerosis or a neurodegenerative disease in a subject comprising administering to a subject in need thereof, optionally with a pharmaceutically acceptable carrier, adjuvant or vehicle, a therapeutically effective amount of a compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- R2 and R3 are independently hydrogen, hydroxyl, —NH2, an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic or heteroaromatic or acyl moiety;
- or R2 and R3 taken together with the nitrogen to which they are attached form an optionally substituted heteroaromatic or heterocyclic group other than an optionally substituted homopiperidinyl group comprising 4-10 ring members and 0-3 additional heteroatoms selected from the group consisting of O, N and S;
- the heteroaromatic or heterocyclic group optionally further substituted with one or more optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl groups;
- Rb and Rc, for each occurrence, are independently selected from the group consisting of hydrogen;
- hydroxy;
- SO2Rd;
- and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently selected from the group consisting of hydrogen;
- —N(Re)2;
- aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic;
- with the proviso that the compound does not have one of the following structures:
15 more elements
A method for treating or lessening the severity of liver disease, lung disease, fibrotic disease, renal fibrosis, renal fibrosis secondary to renal obstruction, renal trauma, liver fibrosis, lung fibrosis, idiopathic pulmonary fibrosis, radiocontrast nephropathy, promotion of vascularization of organs, peripheral vascular disease, liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions (stones in the bile duct), cholangiopathies (primary biliary cirrhosis and sclerosing cholangitis), autoimmune liver disease, or inherited metabolic disorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency), comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure:
An isolated compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein Cy is an N-linked pyrrolyl group optionally substituted with p occurrences of R4;
- p is 1, 3, or 4;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Ra, for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently hydrogen, hydroxy, SO2Rd, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently hydrogen, —N(Re)2, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic.
10 more elements
An isolated compound having the structure:
- or pharmaceutically acceptable salt, ester, or salt of such an ester thereof;
- wherein Cy is an N-linked pyrrolyl group optionally substituted with p occurrences of R4;
- p is 2;
- each occurrence of R4 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted C2-20 aliphatic moiety, an optionally substituted alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- m is an integer from 1 to 4;
- each occurrence of R1 is independently hydrogen, halogen, hydroxyl, —NO2, —NH2, —CN, —CONH2, —SO2OH, an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, —ORR, —S(═O)nRd, —NRbRc, —C(═O)Ra, —OPO2ORa or —C(═O)ORa;
- wherein n is 0-2, RR is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Ra, for each occurrence, is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or heteroaromatic moiety;
- Rb and Rc, for each occurrence, are independently hydrogen, hydroxy, SO2Rd, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety;
- Rd, for each occurrence, is independently hydrogen, —N(Re)2, or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;
- and
- Re, for each occurrence, is independently hydrogen or aliphatic.
10 more elements
Dependencies are inferred from the claim text.