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Development of factor D inhibitor BCX1470 halted due to lack of specificity and short half-life of the compound
Method used
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[0463] Compounds of the invention are prepared from, for example, a central core. In one embodiment, the central core structure 1 is, for example, an N-protected amino acid, where X 1 is nitrogen and PG = protecting group. In one embodiment, the central core is coupled to an amine to generate an amide of structure 2 (where L-B includes a C(O)N moiety). Structure 2 can then be deprotected to generate Structure 3 . Structure 3 is coupled to structure 4 (A-COOH) to generate a second amide bond to form a compound of formula I. This chemistry is schematically shown in Scheme 1.
[0466] In an alternative embodiment, the central core structure 5 is reacted with a heterocyclic or heteroaryl compound to generate a compound of structure 6. In one embodiment, structure 6 is deprotected to generate the carboxylic acid (structure 7). In one embodiment, structure 7 is coupled to an amine to generate a compou...
[0508] In one embodiment, deuterated L-proline synthons are disclosed. Deuterated synthons include, but are not limited to, compounds such as:
[0509]
[0510] Structure A can be treated with deuteriumoxide to generate structure B. See Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO 2014 / 037480 (p. 103). Structure B can be reduced to generate structure C. See Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. Structure C can be treated with Mitsunobu reaction conditions to generate structure D. Structure B can be processed with DAST to generate structure E. See WO 2014 / 037480. Structure A can be treated with sodium borodeuteride to generate structure F. See Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Compound F can be u...
Embodiment 3
[0511] Example 3: Preparation of Center-L-B Synthon
[0512]
[0513] Routes 1a, 1b and 1c
[0514] In Scheme 1a, (4S)-5-azaspiro[2.4]heptane-4,5-dicarboxylic acid, 5-(1,1-dimethylethyl)ester (CAS209269-08-9) can be Prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144. In step 2, the protected azaspiro[2.4]heptane is coupled to an amine in the presence of an organic solvent, base and couplingreagent to generate an amide bond: moiety L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the couplingreagent is HATU. In step 3, the protecting group is removed. In one embodiment, the starting material is reacted with the acid in the presence of an organic solvent. In one embodiment, the acid is 4N hydrochloric acid. In one embodiment, the organic solvent is dioxane.
[0515] In Scheme 1b, (4S) 4...
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Abstract
Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R12 or R13 on the A group is an amidesubstituent (R32) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.
Description
[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 61 / 944,189, filed February 25, 2014, U.S. Provisional Application No. 62 / 022,916, filed July 10, 2014, and U.S. Provisional Application No. 62, filed September 5, 2014 / Interest in No. 046,783. The entire content of each of these applications is incorporated herein by reference in its entirety. Background technique [0003] The complement system is a part of the innate immune system that does not change with changes in the life course of the host, but is recruited and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to clear pathogens. This complex regulatory pathway enables rapid responses to pathogenic organisms while protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagoc...
Claims
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