Short acting benzothiazepine calcium channel blockers and uses thereof
Inventors
Maguire, Martin P. • Herbart, Dominik • Leighton, Harry J.
Assignees
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Publication Number
US-8501727-B2
Publication Date
2013-08-06
Expiration Date
Abstract
The present invention relates to short-acting calcium channel blocking compounds and their use to treat ischemic heart conditions, cardiac arrhythmias, hypertensive crisis in an emergency room setting, hypertension in general, hypertension been.) fore, during, or after surgery, no-reflow phenomenon following reperfusion, and diseases associated with decreased skeletal muscle blood flow. The invention also relates to pharmaceutical compositions formulated for use in such methods and to kits for such methods.
Core Innovation
The invention relates to short-acting calcium channel blocker compounds having a structure according to Formulas (I), (I-a), (I-a-1), and (I-a-2), including pharmaceutically acceptable acid addition salts and benzothiazepine analog structures. The compounds are defined by specific linker selections and substituent patterns, and are associated with rapid, serum esterase-sensitive inactivation and esterase-mediated hydrolysis.
The disclosed compounds are short-acting L-type calcium channel-blocking benzothiazepine derivatives defined by a benzothiazepine core with linkers a through e and f and substituents R1 through R9. The compounds are defined by structural constraints including allowed linker types, an integer parameter n where n is 2, 3, or 4, and an at least one carboxylate-related motif selected from (single bond)-CO2R9, O-(lower alkyl substituted with CO2R9), or O-(lower alkoxyalkyl substituted with CO2R9).
The compounds are described as stereochemically pure forms or as mixtures, including a single enantiomer, a single diastereomer, a racemate, and mixtures of enantiomers and/or diastereomers. The invention additionally includes pharmaceutical formulation and administration routes, including prompt release and sustained release considerations, and pharmaceutically acceptable acid addition salts.
Claims Coverage
The provided independent claims cover pharmaceutical compositions defined by a specific compound structural scaffold with constrained linkers and substituent groups, and a required carboxylate-related motif. Across the consolidated claim coverage, the independent claim framework includes multiple structural variations, with dependent coverage adding stereochemical and formulation limitations and a therapeutic use method.
Pharmaceutical composition defined by a constrained structural scaffold
A pharmaceutical composition comprising a compound having a structure according to the stated formula, or a pharmaceutically acceptable addition salt thereof, with each linker a, b, c, d, and e independently being CH2, O, S, or a single bond; linker f being C(O) or a single bond; and n being 2, 3, or 4 with defined allowances for substitution on methylene groups.
Allowed substituent sets for R1-R9 with conditional single-bond linkage
Substituents R1, R2, R3, R4, and R5 are independently H, F, Cl, Br, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxyalkyl, or CO2R9; R6 and R7 are independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxyalkyl; R8 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower alkoxyalkyl; and R9 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl, with the condition that when any R1-R5 is H, F, Cl, or Br, the corresponding linker is a single bond.
Requirement for at least one carboxylate-related motif containing CO2R9
At least one of a-R1, b-R2, c-R3, d-R4, or e-R5 is (single bond)-CO2R9, or at least one of a-R1, b-R2, c-R3, d-R4, or e-R5 is O-(lower alkyl substituted with CO2R9), or at least one of a-R1, b-R2, c-R3, d-R4, or e-R5 is O-(lower alkoxyalkyl substituted with CO2R9).
Stereochemical restrictions at C2 and C3
Dependent coverage specifies cis relationship at C2 and C3 and S-configuration at C2 and C3 in some embodiments.
Hydrochloric acid addition salt form
Dependent coverage further includes the hydrochloric acid addition salt of the compound.
Parenteral administration formulation
The pharmaceutical composition is formulated for parenteral administration.
Treatment of hypertension and prevention of no-reflow after reperfusion
A method of treating hypertension and/or preventing no-reflow after reperfusion is provided by administering a therapeutically effective amount of a compound having a structure according to a defined claim to a patient before, during, or after surgery.
Overall, the claims focus on a pharmaceutical composition containing a compound defined by a specific scaffold with constrained linkers a through e and f, constrained substitution patterns for R1 through R9 and n, a conditional single-bond relationship when R1 through R5 is H, F, Cl, or Br, and a required carboxylate-related motif involving CO2R9. Dependent coverage further narrows stereochemistry at C2 and C3, specifies hydrochloric acid addition salt, limits formulation to parenteral administration, and includes therapeutic use for hypertension and prevention of no-reflow after reperfusion.
Stated Advantages
Reduces accumulation via rapid, serum esterase-sensitive inactivation to inactive metabolites.
Improves dose-duration predictability for calcium channel blockade.
Characterized by L-type calcium channel binding inhibition.
Human plasma stability ranking is used to assess hydrolysis sensitivity of calcium channel blocker analogs.
Documented Applications
Treating calcium-regulation disorders including pulmonary hypertension.
Treating stroke and migraine.
Treating bronchial asthma.
Treating peripheral vascular disease.
Treating mild congestive heart failure.
Treating hypertrophic subaortic stenosis.
Providing ischemic injury protection.
Treating tumor resistance to anti-neoplastic drugs.
Treating achalasia and esophageal spasms.
Treating premature labor.
Treating dysmenorrhea.
Enhancement of success in renal transplantation.
Administration routes described as sublingual, buccal, transdermal, intranasal, inhalation/aerosol, topical, and parenteral (including intravenous and intramuscular).
Treating ischemic heart conditions, including stable/unstable/vasospastic angina.
Treating cardiac arrhythmias including atrial fibrillation, atrial flutter, and PSVT, among others.
Treating hypertensive crisis, including an emergency room setting.
Treating hypertension before, during, or after surgery.
Preventing no-reflow after reperfusion.
Treating diseases with decreased skeletal muscle blood flow, including Raynaud’s phenomenon and intermittent claudication.
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