Small molecule inhibitors of shared epitope-calreticulin interactions and methods of use
View Patent ↗This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a triazole-methyl-piperidinyl-pyrolyl-propenone structure which function as modulators of shared epitope (SE)-calreticulin (CRT) binding and/or interaction, and their use as therapeutics for the treatment of immunoregulatory abnormalities (e.g., autoimmune diseases, inflammatory diseases (e.g., chronic inflammatory disease), and bone erosive diseases) by selectively inhibiting SE-CRT interactions and/or signal transduction pathways commonly overactive or dysregulated in arthritic and/or other diseases or conditions.
1. A compound encompassed within Formulas I, II, III, and IV:
and pharmaceutically acceptable salts thereof;
wherein R 1 is selected from the group consisting of
wherein R 2 is selected from the group consisting of CH 3 ,
wherein R 3 is selected from the group consisting of hydrogen or fluorine.
2. The compound of claim 1 , wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. A pharmaceutical composition comprising a compound of claim 1 .
4. A method of treating, or ameliorating an immunoregulatory abnormality in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 3 ,
wherein the immunoregulatory abnormality is selected from the group consisting of Paget's disease of bone, chronic rheumatoid arthritis, rheumatoid arthritis, osteoporosis, and periodontitis.
5. A method of suppressing the immune system in a mammalian patient in need of immunosuppression comprising administering to the patient an immunosuppressing effective amount of the pharmaceutical composition of claim 3 .
6. A method of treating[H] or ameliorating a disease or condition characterized with bone erosion and/or bone loss in a patient comprising administering to the patient a pharmaceutical composition of claim 3 in an amount that is effective for treating, ameliorating the bone erosion and/or bone loss disease or condition.
7. The method of claim 6 , wherein the disease or condition is one or more of rheumatoid arthritis, a bone destroying arthritic condition, periodontal disease, osteoporosis, osteomyelitis, bone metastasis, bone fracture healing.
8. The method of claim 6 , wherein the treating, ameliorating, or preventing enhances and/or maintains bone density, bone mass, and/or bone structure in the patient.
9. The method of claim 6 , further comprising administering to said patient one or more anti-inflammatory and/or anti-rheumatic compositions.
10. A kit comprising a medicament comprising a compound of claim 1 and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament for treating or delaying progression of bone erosion and/or bone loss in a mammalian patient.
11. A process for preparing a compound having the formula:
comprising:
(a) starting with piperidin-3-ylmethanol, N-benzyl protecting and converting the alcohol to the mesylate to prepare a compound having the structure:
(b) displacing the mesylate with azide to prepare the intermediate:
(c) cyclization with substituted alkyne to prepare:
(d) debenzylation to prepare:
(e) coupling of carboxylic acid analogs to prepare:
and
(f) removing the Boc protecting group to prepare
wherein Bz is benzyl,
wherein OMs is methanesulfonate,
wherein Boc is tert-butoxycarbonyl,
wherein R 1 is hydrogen, and
wherein R 2 is methyl.