sGC stimulators
Inventors
Kim, Charles • Nakai, Takashi • Lee, Thomas Wai-Ho • Moore, Joel • Perl, Nicholas Robert • Rohde, Jason • Iyengar, Rajesh R • Mermerian, Ara • Fretzen, Angelika
Assignees
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Publication Number
US-8748442-B2
Publication Date
2014-06-10
Expiration Date
Abstract
Compounds of Formula I are described. They are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds may be useful for treating, preventing or managing various disorders that are herein disclosed.
Core Innovation
The invention relates to a compound according to Formula I, or a pharmaceutically acceptable salt thereof, defined by a broad poly-heteroaromatic scaffold with variable ring B, ring D, and ring C elements. Ring B is a phenyl or a 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms, with integer n selected from 0 to 3, and independently selected substituent positions defined by JB and RB options. The framework further specifies X selected from N, C-JD or C-H, and o selected from 0 to 3, together with extensive JD, RD, Rd, Rf, R5, JC, RH, R7, and R8 definitions.
The invention further defines alternative linkage patterns that form 4 to 8-membered heterocyclic rings or 5-membered heteroaryl rings, and fused ring D structures from vicinal ring D atoms. Ring C is selected from a phenyl ring, a monocyclic 5 or 6-membered heteroaryl ring, a bicyclic 8 to 10-membered heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphatic ring, or a monocyclic 4 to 10-membered heterocycle, with heteroatom count constraints and optional substitution by up to 3 instances of JC. The monocyclic 5 or 6-membered heteroaryl ring is not a 1,3,5-triazinyl ring.
Claims Coverage
The consolidated content identifies one independent claim, clm-00001, which defines a broad class of Formula I compounds (or pharmaceutically acceptable salts) through variable ring systems, atom/position variables, substituent sets, and ring-forming linkage alternatives. The inventive coverage centers on a single structurally parameterized compound class.
Formula I compound scaffold with variable ring B
A compound according to Formula I, or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl or a 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms in the ring, n is an integer selected from 0 to 3, each JB is independently selected from halogen, —CN, —NO2, a C1-6 aliphatic, —ORB or a C3-8 cycloaliphatic group, and each RB is independently selected from hydrogen, a C1-6 aliphatic or a C3-8 cycloaliphatic group, each optionally substituted with up to 3 instances of R3.
Ring D positional selection and substituent set
X is selected from N, C-JD or C-H, o is an integer selected from 0 to 3, and each JD is independently selected from halogen, —NO2, —ORD, —SRD, carbonyl-containing groups, —CN, —N(RD)2, sulfonyl-containing groups, a C1-6 aliphatic, a C3-8 cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-membered heterocyclic ring, or a 5 to 10-membered heteroaryl ring, with optional substitution limits.
Alternative linkage formations creating heterocycles and fused ring D
Alternative linkage patterns are provided in which two instances of RD linked to the same nitrogen atom of JD form a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring, one instance of RD linked to a carbon, oxygen or sulfur atom of JD and one instance of Rd linked to a nitrogen atom of the same JD form a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring, and two JD groups attached to vicinal ring D atoms form a 5 to 7-membered heterocycle resulting in a fused ring D.
Ring C selection and substitution limits
RC is selected from —CN, C1-6 alkyl or a ring C, wherein ring C is a phenyl ring, a monocyclic 5 or 6-membered heteroaryl ring, a bicyclic 8 to 10-membered heteroaryl ring, a monocyclic 3 to 10-membered cycloaliphatic ring, or a monocyclic 4 to 10-membered heterocycle, with heteroatom count constraints and optional substitution by up to 3 instances of JC.
Specific proviso for an unsubstituted phenyl/pyrimidinyl combination
A proviso restricts the selection when ring B is unsubstituted phenyl and ring D is unsubstituted pyrimidinyl (X is N and o is zero), specifying that RC is not methyl or ethyl.
Claim clm-00001 broadly covers Formula I compounds (or pharmaceutically acceptable salts) by combining variable ring B, ring D, and ring C definitions with extensive substituent sets and alternative ring-forming linkages, while including a specific proviso for one unsubstituted ring combination.
Stated Advantages
Compounds are NO-independent, heme-dependent activators of soluble guanylate cyclase (sGC).
Compounds increase cGMP.
Positioned as relevant to cardiovascular and urogenital disorders including pulmonary hypertension and erectile dysfunction.
Positioned as an approach relative to NO-dependent therapies.
Documented Applications
Treatment and/or prophylaxis of pulmonary hypertension-related conditions.
Treatment and/or prophylaxis of erectile dysfunction.
Use in connection with cardiovascular disorders and endothelial dysfunction.
Examples and tables describe specific compound structures to support chemical-space coverage of the claimed Formula I scaffold.
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