Beta-lactamyl phenylalanine, cysteine, and serine vasopressin antagonists
Inventors
Koppel, Gary A. • Miller, Marvin J.
Assignees
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Publication Number
US-8048874-B2
Publication Date
2011-11-01
Expiration Date
Abstract
Substituted 2-(azetidin-2-on-1-yl)alkoxyalkylalkanoic acids and 2-(azetidin-2-on-1-yl)arylalkylalkanoic acids, and analogs and derivatives thereof are described. Methods for using the described compounds, and pharmaceutical compositions thereof, to treat disease states responsive to antagonism of one or more vasopressin receptors are also described.
Core Innovation
The invention relates to vasopressin (V1a, V1b, V2) receptor antagonists and to compounds of formulae (I)–(III) and related analogs and derivatives. The compounds include substituted 2-(azetidin-2-on-1-yl)alkoxyalkylalkanoic acids and 2-(azetidin-2-on-1-yl)arylalkylalkanoic acids, with variable substituents including oxygen, sulfur, oxidized sulfur, amino or nitrogen-containing heterocycles attached at a nitrogen, and optional substitutions across aromatic and heterocyclic groups. The disclosure further includes stereoisomerism at C(3) and C(4).
The described work includes synthetic preparation of representative imines and azetidinone/imidazolidinone intermediates that lead to compounds of formulae (I)–(III). The synthetic schemes include cyclization transformations such as oxidative cyclization of acylhydroxamates, with formation of acyloxyazetidinone intermediates, and alkylation/acylation of azetidinone acetic acid derivatives to introduce substituent groups, including introduction of R1 and carboxylic acid side chains. Sulfur-containing variants are accessed using protecting groups and in oxidized forms, including disulfide substitutions.
The disclosure further describes pharmaceutical compositions comprising the compounds and therapeutic uses for disorders responsive to vasopressin antagonism. The therapeutic uses described include stress-related mental illnesses, cardiovascular/heart failure, and water homeostasis/renal function, and the compounds are described as potentially crossing the blood-brain barrier. Extensive worked examples are provided showing preparation of intermediates and achieved structures using analytical characterization such as NMR/MS, together with example IC50/Ki tables and receptor binding and functional readouts.
Claims Coverage
The partial content includes four independent claims. Two independent claims are directed to multi-parameter structural formulas for azetidinone-containing compounds, and two independent claims are directed to core compound formulas defined by Q or Aryl and variable substituent selections. The claims collectively emphasize broad substituent classes, parameter ranges, and pharmaceutically acceptable salts.
Substituted azetidin-2-on alkoxyalkylalkanoic acid scaffold with variable q and n
A compound having a formula in which Q is oxygen, sulfur, -S(O)-, or -SO2-; n is 1 or 2; A is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; and R1-R15 are defined by specific allowed groups and classes of substituents, including optional stereochemical considerations and pharmaceutically acceptable salts, hydrates, and solvates, with an added proviso when Q is oxygen.
Substituted azetidin-2-on arylalkylalkanoic acid scaffold defined by aryl and integer m
A compound having a formula in which Aryl is an optionally substituted monocyclic or polycyclic aromatic group; m is 1, 2, or 3; A is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; and R1-R4 and the remaining substituent groups are defined by specific allowed groups and classes, with pharmaceutically acceptable salts.
Multi-parameter compound formula with q and heterocycle a
A compound of the formula wherein Q is oxygen, sulfur, -S(O)-, or -SO2-; n is 1 or 2; A is monosubstituted amino, disubstituted amino, or an optionally substituted nitrogen-containing heterocycle attached at a nitrogen; R1 is hydrogen or C1-C6 alkyl; and R2 is hydrogen or a specified set of groups including -CO2R8, -CONR8R8′, and -NR8(COR9).
Defined substituent framework for r3, r4, and r5′
R3 is selected from the defined substituent options; R4 is selected from specified alkyl, alkenyl, alkynyl and aryl-containing options; and R5′ is selected from -SR15, C1-C6 alkyl, C3-C8 cycloalkyl, (C1-C4 alkoxy)-(C1-C4 alkyl), optionally-substituted arylalkyl, heterocyclyl, heterocyclyl(C1-C4 alkyl), and R6′R7′N-(C2-C4 alkyl), with heterocyclyl options including tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl.
Conditional restriction when q is oxygen and variable substituent groups
R6′ is hydrogen or alkyl, and R7′ is alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R6′ and R7′ together form a heterocycle; R8 and R8′ are independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, or together form an optionally substituted heterocycle; R9 is selected from a specified set including alkyl- and aryl-containing options; and R13′ and R15 are selected from specified groups, with the proviso that when Q is oxygen, n is 2 and R5′ is not -SR15.
Defined substituent framework for r3, r4, r8/r8′ and r9 with pharmaceutically acceptable salts
R3 is selected from the defined substituent options; R4 is selected from specified alkyl, alkenyl, alkynyl and aryl-containing options; R8 and R8′ are independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl, or together form a heterocycle selected from optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and homopiperazinyl; and R9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R8R8′N-(C1-C4 alkyl), with pharmaceutically acceptable salts thereof.
Overall, the claim coverage centers on azetidin-2-on-containing vasopressin receptor antagonist compounds defined by structural formulas with multiple variable substituents and constrained parameter choices. The first two independent claims emphasize the Q/n-dependent selection of the scaffold and the Aryl-based variant, while the other two claims specify broad substituent classes and a proviso restricting the oxygen case, with pharmaceutically acceptable salts covered where stated.
Stated Advantages
The compounds are described as potentially crossing the blood-brain barrier.
Documented Applications
Therapeutic use for disorders responsive to vasopressin antagonism, including stress-related mental illnesses, cardiovascular/heart failure, and water homeostasis/renal function.
Use in vasopressin receptor binding and functional antagonism assays, including receptor binding and functional readouts.
Receptor and functional assay context for oxytocin and tachykinin receptor binding.
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