JP-2022534578-A5 -

Dates

Publication Date

20230525

Application Date

20200525

Description

Unnatural variant isotopic forms containing radioisotopes can be used, for example, in tissue distribution studies of drugs and/or substrates. Radioisotopes tritium, i.e., 3H , and carbon-14, i.e., 14C , are particularly useful for this purpose, given their easy uptake and readily available detection methods. Unnatural variant isotopic forms incorporating deuterium, i.e., 2H or D, may offer certain therapeutic benefits resulting from higher metabolic stability, e.g., increased in vivo half-life or reduced required dose, and are therefore preferable in certain situations. Furthermore, unnatural variant isotopic forms incorporating positron-emitting isotopes such as 11C , 18F , 15O , and 13N may be prepared, which would be useful in positron emission tomography (PET ) studies to investigate substrate receptor occupancy. In one embodiment, the compound of the present invention is of formula I, where Z is -NR 4a R 4b and R 4a is as described above, or of any one of formulas IIIa to IVp, where R 4b is a 5-6 membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from N, O, and S, and is substituted with one or more independently selected C 1-4 alkyl groups. In a particular embodiment, R 4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, flazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridadinyl, or pyrimidinyl, each substituted with one or more independently selected C 1-4 alkyl groups. In another specific embodiment, R 4b is a 5- to 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, and substituted with one C1-4 alkyl group. In yet another specific embodiment, R 4b is a 5- to 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, and substituted with one or more independently selected -CH3 , -CH2CH3 , or -CH( CH3 ) 2 . In a more specific embodiment, R 4b is an imidazolyl, pyrazolyl, or pyrimidinyl, each substituted with one or more independently selected C1-4 alkyl groups. In another, more specific embodiment, R 4b is a 5- to 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, and substituted with one -CH3 . In yet another, more specific embodiment, R 4b is pyrrolyl, furanyl, thiophenyl, imidazolyl, flazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridadinyl, or pyrimidinyl, each substituted with one C1-4 alkyl. In yet another, more specific embodiment, R 4b is a 5- to 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, and substituted with one -CH3, -CH2CH3 , or -CH ( CH3 ) 2 . In a more specific embodiment, R 4b is an imidazolyl, pyrazolyl, or pyrimidinyl, each substituted with one C1-4 alkyl group. In yet another even more specific embodiment, R 4b is an imidazolyl, pyrazolyl, or pyrimidinyl, each substituted with one or more -CH3 , -CH2CH3 , or -CH( CH3 ) 2 groups. In yet another even more specific embodiment, R 4b is a pyrrolyl, furanil, thiophenyl, imidazolyl, furazanil, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridadinyl, or pyrimidinyl, each substituted with one or more -CH3 groups . In a further, more specific embodiment, R 4b is pyrrolyl, furanyl , thiophenyl, imidazolyl , fluzanyl, oxazolyl , oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridadinyl, or pyrimidinyl, each substituted with one -CH3, -CH2CH3, or -CH( CH3 ) 2 . In a further, more specific embodiment, R 4b is a 5- to 6-membered monocyclic heteroaryl containing one, two, or three heteroatoms independently selected from N, O, and S, and substituted with one -CH3. In the most specific embodiment, R 4b is imidazolyl, pyrazolyl, or pyrimidinyl, each substituted with one -CH3 . In one embodiment, the compounds of the present invention are co-administered with other therapeutic agents for the treatment and/or prevention of autoimmune diseases, and specific agents include, but are not limited to, glucocorticoids, cell proliferation inhibitors (e.g., purine analogs), alkylating agents (e.g., nitrogen mustard (cyclophosphamide), nitrosourea , platinum compounds, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), and cytotoxic antibiotics (e.g., dactinomycin, ant). Examples include racycline, mitomycin C, bleomycin, and mitramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atogum® and Thymoglobulin®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferon (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycop