1. A compound of Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is selected from hydrogen or
R2 is selected from hydrogen,
O1 is the phenolic oxygen present in the unbound form of p-OH mexiletine;
X is (\u2014NH\u2014), (\u2014O\u2014), or absent;
each occurrence of RAA is independently a natural or non-natural amino acid side chain;
n1 is an integer selected from 0 to 16;
each occurrence of n2 is independently an integer selected from 1 to 9;
each occurrence of R3 is independently selected from hydrogen, or an optionally substituted alkyl group;
each occurrence of R4 and R5 is independently selected from hydrogen,
or an optionally substituted alkyl group;
wherein in the case of a double bond occurring in the carbon chain defined by n1, R4 is present and R5 is absent on the carbons that form the double bond; provided that
at least R1 is
or alternatively,
at least R2 is either
and provided that the compound is not one of the following compounds: HBr.glycine-(rac)mexiletine; AcOH.asparagine-(rac)mexiletine; TFA.tryptophan-(rac)mexiletine; HBr.alanine-(rac)mexiletine; AcOH.asparagine-(rac)mexiletine; HBr.glycine-(rac)mexiletine; AcOH-phenylalanine-(rac)mexiletine; or TFA.tryptophan-(rac)mexiletine.H2O.
2. The compound of claim 1, wherein R1 is hydrogen and R2 is
3. The compound of claim 2, wherein R2 is
4. The compound of claim 1, wherein R2 is hydrogen and R1 is
5. The compound of in any of claims 1 to 4, wherein each occurrence of R3 is hydrogen.
6. The compound of any of claims 1 to 4, wherein each occurrence of R3 is independently selected from an unsubstituted C1-6 alkyl.
7. The compound of any of claims 1 to 4, wherein R4 is hydrogen or C1-4 alkyl at each occurrence.
8. The compound of any of claims 1 to 4, wherein R5 is hydrogen or C1-4 alkyl at each occurrence,
9. The compound of claim 8, wherein each R5 is hydrogen at each occurrence.
10. The compound of any of claims 1 to 4, wherein the compound of Formula (I) is not one of the following compounds:
alanine-(rac)mexiletine amide;
\u03b2-methoxy aspartic acid-(rac)mexiletine amide;
\u03b1-methoxy aspartic acid-(rac)mexiletine amide;
asparagine-(rac)mexiletine amide;
glycine-(rac)mexiletine amide;
leucine-(rac)mexiletine amide;
methionine-(rac)mexiletine amide;
(rac)methionine-(rac)mexiletine amide;
phenylalanine-(rac)mexiletine amide; or
alanine glycine glycine-(rac)mexiletine amide;
or tryptophan(rac)mexiletine.
11. The compound of any of claims 1 to 4, wherein the compound of Formula (I) has one prodrug moiety, and the prodrug moiety wherein each occurrence of n2 is 1, 2 or 3.
12. The compound of any of claims 1 to 4, wherein each occurrence of RAA is independently an amino acid side chain, wherein an amino acid residue comprises from 1 to 20 carbon atoms, or the residue is hydrogen.
13. The compound of claim 12, wherein RAA is a naturally occurring amino acid.
14. The compound of claim 1, where in the compound is selected from the group consisting of:
mexiletine sarcosine amide;
mexiletine threonine amide;
mexiletine histidine amide;
mexiletine serine amide;
mexiletine 2-methyl \u03b2 alanine amide;
mexiletine glycine amide;
mexiletine glutamine amide;
mexiletine cyclopropyl glycine amide;
mexiletine \u03b2 amino alanine amide;
mexiletine nicotinic acid amide;
mexiletine citrulline amide;
mexiletine isonicotinic acid amide;
mexiletine homoarginine amide;
mexiletine arginine amide;
mexiletine glutamic acid amide; and
mexiletine S-methyl-methionine chloride amide.
15. A method for treating a subject with pain, arrhythmia, or a combination thereof comprising administering to a subject in need thereof an effective amount of the compound or salt according to claim 1, wherein the compound or salt exhibits a reduced adverse gastrointestinal side effect as compared to an equivalent dose of mexiletine alone.
16. The method of claim 15, wherein the gastrointestinal side effect associated with administration of mexiletine is selected from the group consisting of: emesis, nausea, and abdominal discomfort.
17. A composition comprising a compound of claim 1 and one or more pharmaceutical excipients
18. A compound of Formula (IA)
or a pharmaceutically acceptable salt thereof,
wherein,
R1 is
R2 is selected from hydrogen or
each occurrence of RAA is independently a natural or non-natural amino acid side chain containing from 1 to 20 carbon atoms or hydrogen;
n2 is an integer selected from 1, 2 or 3;
R3 is selected from hydrogen, or an optionally substituted c1-4 alkyl group;
provided that the compound is not one of the following compounds: HBr.glycine-(rac)mexiletine; AcOH.asparagine-(rac)mexiletine; TFA.tryptophan-(rac)mexiletine; HBr.alanine-(rac)mexiletine; AcOH.asparagine-(rac)mexiletine; HBr.glycine-(rac)mexiletine; AcOH-phenylalanine-(rac)mexiletine; or TFA.tryptophan-(rac)mexiletine.H2O.
19. The compound of claim 18, wherein n2 is 1.
20. The compound of claim 18 or 19 wherein RAA is a natural amino acid side chain.
21. The compound of claim 18, wherein the compound is selected from the group consisting of mexiletine pipecolic amide and mexiletine dimethylglycine amide.
22. A method for treating a subject with pain, arrhythmia, or a combination thereof comprising administering to a subject in need thereof an effective amount of the compound or salt according to claim 18.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A packaged green tea beverage with a concentrate of a green tea extract mixed therein, comprising:
(a) 0.05 to 0.5 wt. % of non-polymer catechins in which the weight ratio (A)(B) of (A) non-epicatechins to (B) epicatechins is from 0.54 to 9.0;
(b) 10 to 30 mgkg of aluminum ions; and
(c) 10 to 30 mgkg of silicon ions.
2. A process for the production of a packaged green tea beverage containing non-polymer catechins at a concentration of 0.05 to 0.5 wt. %, which comprises bringing an aluminosilicate, which has an iron release rate of not greater than 0.8 mgkg to a catechin-containing solution, into contact with a green tea mixture of a green tea extract and a concentrate of green tea extract.
3. The process for the production of a packaged green tea beverage according to claim 2, wherein the aluminosilicate is added in the proportion of 0.05 to 0.5 wt % based on the green tea mixture.
4. The process for production of a packaged green tea beverage according to claim 2, wherein the packaged green tea beverage is the packaged green tea beverage according to claim 1.
5. The process for the production of a packaged green tea beverage according to claim 3, wherein the packaged green tea beverage is the packaged green tea beverage according to claim 1.