sGC stimulators
Inventors
Perl, Nicholas • Nakai, Takashi • Lee, Thomas Wai-Ho • RENNIE, Glen Robert • Renhowe, Paul Allan • Iyengar, Rajesh R.
Assignees
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Publication Number
US-10047095-B2
Publication Date
2018-08-14
Expiration Date
Abstract
The present patent application discloses at least the compounds according to Formula I′ shown below, or pharmaceutically acceptable salts thereof, wherein ring D, ring A, ring E, ring F, JB, n, JD, J, o, RC1, RC2, W, JE, r, JF, s, Z1, Z2 and Z3 are as defined herein.
Core Innovation
The patent describes compounds according to Formula I, or pharmaceutically acceptable salts thereof, as soluble guanylate cyclase stimulators acting via the NO/cGMP pathway. The core chemical concept is a structurally complex scaffold built from ring A, ring D, and a fused or bicyclic arrangement incorporating ring E and ring F, with optional ring B defined under the variable W and extensive explicit structural definitions for heteroatom content and permissible substituent patterns.
Ring A is a 5-membered heteroaryl ring, and ring D is a 6-membered heteroaryl ring with Z1 and Z2 independently selected from N or C(JD) or CH, including that at least one instance of Z2 is a nitrogen and that a maximum of three instances of Z1 and Z2 combined can simultaneously be N. The disclosure provides detailed options for substituent JD and additional variable groups with substitution and heteroatom-count limits.
Ring E is selected from a tetrahydropyridine, a piperazine, a pyrroline, or an imidazolidine ring, and ring F is a 5- or 6-membered heteroaryl ring containing up to 4 heteroatoms independently selected from N, O, and S. The fused or bicyclic relationship is defined by the selection of ring E and the placement of Z3, together with further constraints through variables such as JE, JF, Y, and R9.
Claims Coverage
The consolidated material identifies one independent claim directed to a compound according to Formula I, or a pharmaceutically acceptable salt thereof. The inventive features are the defined heterocyclic core and the constrained substituent and ring-system parameters across ring A, ring D, the W/JB options, and the fused or bicyclic E/F system.
Formula I compound with ring A heteroaryl constraints
A compound according to Formula I, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl ring formed from independently selected X as C or N with single or double bonds, with a minimum of two and a maximum of three instances of X simultaneously being N.
Defined W substitution pattern and J/B connectivity options
W is either absent with JB connected directly to the carbon atom bearing two J groups, or W is ring B selected from phenyl, a 5- or 6-membered heteroaryl ring, a C3-7 cycloalkyl ring, or a 4- to 7-membered heterocyclic ring containing 1 to 3 ring heteroatoms selected from N, O or S, with corresponding constraints on J and JB.
Ring D heteroaryl definition with Z1/Z2 nitrogen-count constraints
Ring D is a 6-membered heteroaryl ring with Z1 and Z2 independently selected from N or C(JD) or CH, with a maximum of three instances of Z1 and Z2 combined simultaneously being N and at least one instance of Z2 being a nitrogen; Z3 is selected from C or N, and JD is either absent or a substituent on any available C atom of ring D independently selected from the defined substituent set.
Fused or bicyclic E/F ring system with defined ring E selection and ring F heteroatom limits
Ring E is selected from a tetrahydropyridine, a piperazine, a pyrroline, or an imidazolidine ring; ring F is a 5- or 6-membered heteroaryl ring containing up to 4 heteroatoms independently selected from N, O, and S; and the fused or bicyclic relationship is defined according to the selected ring E, with further constraints through JF, Y, r, and s.
The independent claim defines a Formula I scaffold with a constrained heteroaryl ring A, a 6-membered heteroaryl ring D with nitrogen-count limits and a defined JD substituent system, optional W/ring B connectivity, and a fused or bicyclic ring E/F system governed by ring selection and substitution variables.
Stated Advantages
Provides extensive therapeutic disease-area coverage for sGC stimulation via NO/cGMP pathways.
Includes multiple formulation and delivery options including sterile injectable solutions/suspensions, depot microencapsulated polymer formulations, liposomes/microemulsions, and multiple non-injectable routes.
Supports combination therapy and co-administration concepts involving NO/cGMP pathway-related agents and other listed drug classes.
Documented Applications
Treatment of diseases mediated by sGC stimulation via NO/cGMP pathways.
Cardiovascular disorders including hypertension, coronary disease, heart failure, and pulmonary hypertension.
Ischemia/thromboembolic and inflammatory/fibrotic conditions.
CNS and sexual dysfunctions.
Wound healing and bone fracture healing.
Drug-device delivery concepts such as drug-eluting stents and gel delivery.
Rectal/vaginal suppositories/pessaries and other non-injectable routes, including topical/transdermal, ophthalmic, and nasal aerosol/inhalation.
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