Macrocyclic compounds useful as pharmaceuticals
Inventors
Boivin, Roch • Chiba, Kenichi • Chow, Jesse • Du, Hong • Eguchi, Yoshihito • Fujita, Masanori • Goto, Masaki • Gusovsky, Fabian • Harmange, Jean-Christophe • Inoue, Atsushi • Jiang, Yimin • Kawada, Megumi • Kawai, Takatoshi • Kawakami, Yoshiyuki • Kimura, Akifumi • Kotake, Makoto • Kuboi, Yoshikazu • LEMELIN CHARLES-ANDRE, null • Lemelin, Charles-André • Li, Xiang-Yi • Matsushima, Tomohiro • Mizui, Yoshiharu • Muramoto, Kenzo • Sakurai, Hideki • Shen, Yong-Chun • Shirota, Hiroshi • Spyvee, Mark • Tanaka, Isao • Wang, John (Yuan) • Yamamoto, Satoshi • Yoneda, Naoki
Assignees
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Publication Number
US-7799827-B2
Publication Date
2010-09-21
Expiration Date
Abstract
The present invention provides compounds having formula (I):and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of various disorders including inflammatory or autoimmune disorders, and disorders involving malignancy or increased angiogenesis, wherein R1-R11, X, Y, Z, and n are as defined herein.
Core Innovation
The disclosure concerns chemically defined compounds and compound families presented as formula-based or substituent-variable-defined structures, including pharmaceutically acceptable salt, ester, or salt of ester forms. The compounds are characterized by detailed R-group definitions, heteroatom and connectivity variables X, Y, and Z, and allowed bonding arrangements between Y and Z, together with optional protecting groups and substitutions such as hydroxyl, protected hydroxyl, alkyloxy, amino, protected amino, alkylamino, aminoalkyl, and halogen.
The material also describes related polycyclic scaffold compounds and closely related structural variants, including compounds with phenolic OH groups, an ester or carboxylate motif, ether or protected-O substituents, and variable halogens, methoxy/alkoxy groups, amino-containing substituents, and stereochemical definitions. Several labeled compound series are shown, including NF2433–NF2561, the 509-HD series, and related ER-, NY-, TM-, YE-, MK-, and 557-MS-labeled intermediates and derivatives.
Where synthetic sequences are shown, the content presents intermediate-to-intermediate relationships and conversions leading to protected derivatives, later intermediates, and named final compounds. The documents consistently present the compounds as members of defined structural families and depict their derivatized and stereochemically varied forms.
Claims Coverage
The consolidated claim coverage includes four independent claims: clm-00001, clm-00002, clm-00027, and clm-00029. Across these claims, the invention is primarily structural, defining compounds by substituent variables and connectivity constraints, with pharmaceutically acceptable salt and ester forms included; two independent claims are also formula-defined.
Substituent-defined compound structure
A compound of the structure, or a pharmaceutically acceptable salt, ester, or salt of ester thereof, defined by R1–R13 and X, Y, Z, where R2 is methyl; R3 and R4 are hydrogen or halogen in one claim set; R5 is hydrogen or a protecting group; R6 is hydrogen, hydroxyl, or protected hydroxyl; n is 0–2; R8 is hydrogen, halogen, hydroxyl, protected hydroxyl, or alkyloxy; R9 is NR12R13; R10 is hydroxyl, protected hydroxyl, or amino; R11 is hydrogen; X is O, NH, or N-alkyl; Y is CHR17, O, CR17, or NR17; Z is CHR18, C=O or CR18; and Y and Z are connected by a single or double bond.
Substituent-defined compound structure with constrained R1 options
A compound of the structure, or a pharmaceutically acceptable salt, ester, or salt of ester thereof, where R1 is hydrogen, straight or branched C1-6 alkyl, straight or branched C1-6 heteroalkyl, or aryl, optionally substituted with halogen, hydroxyl, or protected hydroxyl, and the remaining variables follow the stated hydrogen, halogen, protecting-group, and connectivity options.
General formula compound
A compound of the formula, or a pharmaceutically acceptable salt, ester, or salt of ester thereof.
Specific formula compound
A compound of the formula, or a pharmaceutically acceptable salt, ester, or salt of ester thereof.
The independent claims collectively define structurally specified compounds and formula-defined compounds, each including pharmaceutically acceptable salt and ester forms. The claim scope is centered on detailed substituent-variable definitions, connectivity between Y and Z, and optional protecting-group and substitution patterns.
Stated Advantages
Inhibiting NF-κB activation.
Producing an anti-inflammatory effect.
Treating psoriasis.
Reducing skin photodamage.
Anti-inflammatory/immunosuppressive activity.
Antiangiogenic activity.
Inhibitors of NF-κB activation and AP-1 activation.
Protein kinase inhibitors, including MEKK1, MEK1, VEGFr, and PDGFr.
Documented Applications
Pharmaceutical compositions for inhibiting NF-κB activation.
Pharmaceutical compositions for producing an anti-inflammatory effect.
Pharmaceutical compositions for treating psoriasis.
Pharmaceutical compositions for reducing skin photodamage.
Pharmaceutical compositions containing macrocyclic compounds of formula (I).
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