US 9,540,323 B2 · 7-hydroxy-indolinyl antagonists of P2Y1 receptor

Abstract

The present invention provides compounds of Formula (I): Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are antagonists of P2Y1 receptor which may be used medicaments.

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Claims9

Dependent claims

A compound of Formula (I):

or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:
X is independently CH or N;
ring A is independently selected from C3-6 carbocycle substituted with 0-3 R5 and a heterocycle substituted with 0-2 R5;
wherein said heterocycle is selected from thienyl, thiazolyl, thiadiazolyl, pyridyl,
R1 is independently selected from H, halogen and OH;
R2 is independently H or halogen;
R3 is independently selected from a ring moiety substituted with 0-3 R6 and selected from the group consisting of C3-6 cycloalkyl, phenyl;
R4 and R4a are, independently at each occurrence, selected from C1-6 alkyl, CO2(C1-4 alkyl) and C1-6 haloalkyl;
R5 is, independently at each occurrence, selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, CO2(C1-4 alkyl), NO2, and
R6 is, independently at each occurrence, selected from halogen, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, CH2OH, CN, CO2(C1-4 alkyl), NH(C1-4 alkyl), CH2N(C1-4 alkyl)2, and morpholinylmethyl;
R7 is independently selected from C1-6 alkyl, C1-6 haloalkyl, CO(C1-4 alkyl), —(CH2)1-2—C3-6 cycloalkyl, and COCF3;
and
R8 is independently selected from H, halogen and CN.

10 more elements

Dependencies are inferred from the claim text.

Description39,965 words

Summary1,332 words

#The present invention provides novel 7-hydroxy-indolinyl compounds, and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.

#Purinoreceptors bind to and are activated by a variety of both ribosylated (nucleotide) and non-ribosylated (nucleoside) purines. This distinction has been used to classify these receptors into two broad groups: the P1 receptors (A1, A2a, A2b, and A3), which bind to and are activated by the nucleoside adenosine, and the P2 receptors, which comprise a second, more diverse class of receptors which are activated by a wide variety of nucleotides including ATP, ADP, UTP, and UDP. The P2 receptors can be further subdivided into two distinct types of receptors; the ionotropic P2X receptors that mediate cation flux across cellular membranes in response to ATP and the metabotropic P2Y family of receptors which are G-protein coupled receptors. In humans, the P2Y family of receptors is generally considered to consist of seven distantly related members; P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, and P2Y13 (Boeynaems, J. M. et al., Drug Development Research, 52:187-189 (2001)). In addition, an eighth receptor, P2Y14, has been considered by some to be a member of this class although it does not respond to ribosylated nucleotides and is activated by UDP-glucose (Abbracchio, M. P. et al., Trends Pharmacol. Sci., 24:52-55 (2003)).

#Several studies have suggested that modulators of specific members of the P2Y family of receptors could have therapeutic potential for the treatment of a variety of disorders (for review see Burnstock, G. et al., J. Pharm. Exp. Ther., 295:862-869 (2000)), including diabetes, cancer, CF, and treatment of ischemia-reperfusion injury (Abbracchio M. P. et al., Pharmacol. Ther., 64:445-475 (1994)). P2Y1 receptors, almost ubiquitous among human organs (Janssens, R. et. al., Biochem, Biophys, Res. Comm., 221:588-593 (1996) have been identified on microglia (Norenberg, W. et al., Br. J. Pharmacol., 111:942-950 (1994)) and on astrocytes (Salter, M. W. et al., J. Neurosc., 15:2961-2971 (1995)). Extracellular ATP activates microglial and/or astrocytes via P2Y receptors and leads directly to the release of inflammatory mediators. Microglia and astrocytes are believed to play a role in the progression of Alzheimer's disease and other CNS inflammatory disorders such as stroke and multiple sclerosis.

Detailed description38,633 words

#I. Compounds of the Invention

#In a first aspect, the present invention provides, inter alia, a compound of Formula (I):

#or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof, wherein:

Facts

Application

14/418,023Filed 30 Jul 2013 · us provisional application

Priority

1 Aug 2012

Published

US 2015/0259286 A117 Sep 2015

Granted

10 Jan 2017

Term ends

30 Jul 2033

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification19 codes

C07D 209/26
Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals: with…
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
C07D 209/14
With substituted hydrocarbon radicals attached to carbon atoms of the hetero ring: radicals substituted by nitrogen atoms, not forming part of a…
C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond

7-hydroxy-indolinyl antagonists of P2Y1 receptor

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7-hydroxy-indolinyl antagonists of P2Y1 receptor

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Life of this patent

Abstract

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Claims9

Description39,965 words

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Classification19 codes

Life of this patent

Description39,965 words