T-type calcium channel modulator and uses thereof

Inventors

Zamponi, Gerald WernerDiaz, Philippe

Assignees

UTI LPUniversity of Montana Missoula

Publication Number

US-10227332-B2

Publication Date

2019-03-12

Expiration Date

2035-10-15

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Abstract

The present invention provides T-type calcium channel modulators and methods for producing and using the same. In some embodiments, compounds of the invention are of the formula: where R1 is selected from the group consisting of alkyl, alkenyl, polyether, alkoxy and cycloalkyl;X is selected from the group consisting of methylene, —C(═O)—[NR4]a—, —C(═S)—, and —S(═O)b;R2 is selected from the group consisting of heterocycloalkyl and heteroaryl;R3 is selected from the group consisting of alkyl, alkenyl, polyether, alkoxy, cycloalkyl, —NR5R6, —C(═O)NR5R6, —C(═O)ORa (where Ra is alkyl, typically C1-C8 alkyl, often C2-C6 alkyl, and in one particular embodiment Ra is tert-butyl), and —SO2NR5R6;R4 is hydrogen, alkyl, or a nitrogen protecting group;each of R5 and R6 are independently selected from the group consisting of hydrogen and alkyl;a is 0 or 1;b is 1 or 2;n=1 to 3; andm=0 to 1.

Core Innovation

The invention provides T-type calcium channel modulators, specifically novel compounds of defined chemical structure, and methods for making and using them. These compounds are characterized by a general formula in which various substituents are described, including alkyl, alkenyl, polyether, alkoxy, cycloalkyl, methylene, carbonyl- or sulfur-containing linkages, heterocycloalkyl, and heteroaryl groups. The modulators can exhibit selective inhibition of Cav3.2 T-type calcium channels and, in some embodiments, have minimal or no cannabinoid receptor activity.

The problem addressed by the invention is the lack of effective, selective modulators of T-type calcium channels, which are known regulators of neuronal and cardiac pacemaker activity and are implicated in disorders such as arrhythmia, epilepsy, and pain. Prior compounds with T-type calcium channel antagonist activity often also engage cannabinoid receptors, which can result in undesirable side effects. Therefore, there is a need for compounds that modulate T-type calcium channels selectively, with reduced interaction with cannabinoid receptors.

The invention discloses that compounds with a carbazole scaffold, a substituted tertiary amine, and specific variations in linker length or ring structures are effective T-type calcium channel blockers. Notably, certain embodiments result in potent analgesic activity in animal models of inflammatory and neuropathic pain, with observed specificity for Cav3.2 channels, as demonstrated by lack of efficacy in Cav3.2 null mice and lack of significant motor impairment. Methods of use include treating conditions associated with T-type calcium channel activation by administering a therapeutically effective amount of these compounds.

Claims Coverage

There are two independent claims covering the core inventive features of the patent: one for novel compounds of a defined structure, and another for methods of treating clinical conditions associated with T-type calcium channel activation using the compounds.

Novel compound of specified general formula as a T-type calcium channel modulator

A compound defined by a formula in which: - R1 is selected from alkyl, alkenyl, polyether, alkoxy, or cycloalkyl; - X is selected from methylene, —C(═O)—[NR4]a—, —C(═S)—, or —S(═O)b—; - R2 is heterocycloalkyl or heteroaryl; - R3 is alkyl, alkenyl, polyether, alkoxy, cycloalkyl, —NR5R6, —C(═O)NR5R6, —C(═O)ORa, or —SO2NR5R6; - R4 is hydrogen, alkyl, or a nitrogen protecting group; - R5 and R6 are each independently hydrogen or alkyl; - a is 0 or 1; - b is 1 or 2; - n is 1 to 3; - m is 0 or 1; where further subsets and preferred substituents are described. These compounds include carbazole derivatives with substituted tertiary amines and variations in chain length and ring structure, encompassing a variety of specific chemical entities.

Method for treating clinical conditions associated with T-type calcium channel activation using the claimed compound

A method comprising: 1. Administering a therapeutically effective amount of the compound defined above to a subject in need of treatment for a clinical condition associated with T-type calcium channel activation. 2. The method does not embrace preventing the disease, but focuses on treating existing conditions. 3. The conditions specified include acute inflammatory pain, tactile allodynia, diabetic neuropathy, pulmonary hypertension, chemotherapeutic induced neuropathy, chronic pain, diabetes, epilepsy, visceral pain, cancer pain, cardiac hypertrophy, or a combination thereof. The method claim covers the use of these novel compounds specifically for therapeutic modulation of disorders linked to T-type calcium channel activity.

The inventive features include new chemical entities of defined structural scope for modulating T-type calcium channels and therapeutic methods for using these compounds to treat medical conditions linked to channel activation.

Stated Advantages

Provides selective and potent T-type calcium channel blockers with reduced affinity for cannabinoid receptors, minimizing unwanted side effects.

Enables treatment of pain, including acute inflammatory and neuropathic pain, via mechanisms specific to Cav3.2 channel inhibition.

Exhibits significant analgesic effects in animal models without causing significant motor deficits.

Documented Applications

Treatment of clinical conditions associated with T-type calcium channel activation, including acute inflammatory pain, tactile allodynia, diabetic neuropathy, pulmonary hypertension, chemotherapeutic induced neuropathy, chronic pain, diabetes, epilepsy, visceral pain, cancer pain, and cardiac hypertrophy.

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