The present disclosure relates generally to therapeutic agents that may be useful as modulators of Integrated Stress Response (ISR) pathway.

The present invention relates to a new compound that can inhibit an anoctamin 6 protein, a composition comprising the compound, a method for preparing the compound, and a method for using the compound or composition.

The present invention relates to a new compound that can inhibit an anoctamin 6 protein, a composition comprising the compound, a method for preparing the compound, and a method for using the compound or composition.

The present disclosure provides methadone prodrugs, pharmaceutical compositions, and their methods of use, where the pharmaceutical compositions comprise a methadone prodrug that provides enzymatically-controlled release of methadone, and an optional enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of methadone from the prodrug so as to attenuate enzymatic cleavage of the prodrug.

The present disclosure provides methadone prodrugs, pharmaceutical compositions, and their methods of use, where the pharmaceutical compositions comprise a methadone prodrug that provides enzymatically-controlled release of methadone, and an optional enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of methadone from the prodrug so as to attenuate enzymatic cleavage of the prodrug.

Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “” represents either or both the R and S form of the compound): ##STR00001##
where A, B, C, Y.sub.1, Y.sub.2, Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, W.sub.1, n, p and q are as defined herein.

Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “” represents either or both the R and S form of the compound): ##STR00001##
where A, B, C, Y.sub.1, Y.sub.2, Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, W.sub.1, n, p and q are as defined herein.

The present disclosure is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises:

(a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The disclosure is also related to novel intermediates:

##STR00001##

wherein R, R′ and X are as described in the specification.

The present disclosure is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises:

(a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The disclosure is also related to novel intermediates:

##STR00001##

wherein R, R′ and X are as described in the specification.

A compound of formula (Ie′): ##STR00001##
wherein Ar′, R.sub.1, R.sub.4e and Y are as defined herein and a method of controlling pests using the compound.