e.g. 3-((2-(di-t-butyloxycarbonylamino)pyridin-4-yl)methyl)-4-oxoazetidine-2-carboxylic acid; tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, Factor XIa inhibitor; urokinase-type plasminogen activator; antiallergen; chronic asthma, allergic rhinitis, and thrombotic disorders
Inventors
Bannister, Thomas • Celatka, Cassandra • Chandrakumar, Nizal S. • Deng, Hongfeng • Guo, Zihong • Jin, Lei • Lazarova, Tsvetelina • Lin, Jian • Moe, Scott T. • Nagafuji, Pamela • Navia, Manuel • Ripka, Amy • Rynkiewicz, Michael J. • Spear, Kerry L. • Stickler, James E. • Xie, Roger
Assignees
Daiichi Asubio Medical Research Laboratories LLC • Exithera Pharmaceuticals Inc • Cadrenal Therapeutics Inc
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Publication Number
US-7501404-B2
Publication Date
2009-03-10
Expiration Date
Abstract
Compounds are provided which have the structure Wherein A, B, C, D, m, Y, Ra, Rc, Rd, and Rd′ are as described herein, and which are useful as inhibitors of tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, Factor XIa, and urokinase-type plasminogen activator and may be employed in preventing and/or treating asthma, chronic asthma, allergic rhinitis, and thrombotic disorders.
Core Innovation
The disclosure provides a family of β-lactam compounds having an azetidinone core and defined structural variables A, B, C, D, m, X, Y, Ra, Rc, Rd, and Rd'. The scaffold is represented by a defined structure in which A is selected from CR1R2, O, and S, B is selected from unsubstituted alkyl, —S—, and —O—, m is an integer selected from 0 to 2, and C is selected from a bond and —O—. X is selected from S and O, while Y is selected from a bond, C=O, and SO2.
The compounds further include substituent group selections for D, Rc, Rd, and related substituents, including guanidine, amidinohydrazone, amine, and aminopyridine options, together with defined options for substituents Ra and R8 via NR7R8 and substituted and unsubstituted heteroaryl. Rc is selected from H and substituted or unsubstituted alkyl, and Rd is selected from R16 and (CR14R15)p with p=1, where R16 is selected from C(O)R18, OH, and R18 groups selected from OR21, NR19R20, and NR19SO2R20.
The disclosure describes provisos that restrict combinations when Y is selected from C=O and SO2, ABC in combination form unsubstituted alkyl, and when D is substituted or unsubstituted guanidine. Under those provisos, Rc cannot be selected from CH3 and CH2CH3, and Rd and Rd' cannot be members selected from H and COOR1a; and H and CONR19R20. The disclosure also specifies that R1a, R19, and R20 have defined selections, including optional joining to form a 6 membered ring for R19 and R20 with the atoms to which they are attached.
Claims Coverage
The document contains one independent claim directed to a defined β-lactam compound structure with extensive variable substituent options and specific structural provisos that limit allowable combinations, particularly when Y and D take certain selections. Dependent claims refine the structural scope and include downstream claims covering pharmaceutical compositions and treatment methods; however, only the independent claim text provided here can be extracted precisely.
Defined β-lactam azetidinone scaffold with variable substituents
A compound according to a structure in which A is selected from CR1R2, O, and S; B is selected from unsubstituted alkyl, —S—, and —O—; m is an integer selected from 0 to 2; C is selected from a bond and —O—; X is selected from S and O; Y is selected from a bond, C=O, and SO2; Ra is selected from NR7R8 and substituted and unsubstituted heteroaryl; Rc is selected from H and substituted or unsubstituted alkyl; Rd is selected from R16 and (CR14R15)p where p=1 and R14 and R15 are H and R16 is selected from C(O)R18, OH; and R18 groups are selected from OR21, NR19R20, and NR19SO2R20 with defined selections for R21, R19, and R20, and where R19 and R20 can optionally be joined to form a 6 membered ring.
Structural provisos restricting specific substituent combinations
A proviso for the compound, or salts thereof, that if Y is selected from C=O and SO2; ABC, in combination, form unsubstituted alkyl; and D is substituted or unsubstituted guanidine, then Rc cannot be selected from CH3 and CH2CH3; and Rd and Rd' cannot be members selected from H and COOR1a; and H and CONR19R20, where R1a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted aryl, and where R19 and R20 are selected as defined.
The independent claim defines a β-lactam/azetidinone compound family by combining broad structural variable selections for ring linkages and substituents (including A, B, C, D, m, X, Y, Ra, Rc, Rd/Rd' and associated R-group definitions) with explicit provisos that prohibit certain substituent combinations under defined conditions relating to Y, ABC, and D.
Stated Advantages
Provides compounds that inhibit multiple serine proteases/coagulation enzymes including tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, and Factor XIa.
Provides compounds that inhibit urokinase-type plasminogen activator.
Supports therapeutic use for preventing or treating asthma and chronic asthma.
Supports therapeutic use for preventing or treating allergic rhinitis.
Supports therapeutic use for preventing or treating thrombotic disorders.
Documented Applications
Thrombolysis/thrombosis in connection with Factor XIa (FXIa) and tryptase inhibition.
As a pharmaceutical context for asthma and chronic asthma, including allergic rhinitis, connected to Factor XIa (FXIa) and tryptase inhibition.
The document transitions into pharmaceutical composition and broad treatment indications for the invention’s compounds, including chronic asthma, allergic rhinitis, and thrombotic events.
Preventing and treating asthma and chronic asthma.
Preventing and treating allergic rhinitis.
Preventing and treating thrombotic disorders.
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