Compounds and methods for inhibiting production of trimethylamine

Patent metadata

Field	Value
Publication number	US-10213407-B2
Application number	US-201615366940-A
Country	US
Kind code	B2
Filing date	Dec 1, 2016
Priority date	Dec 1, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The invention provides a method of inhibiting the conversion of choline or carnitine to trimethylamine (TMA) and lowering TMAO in an individual comprising administering to the individual a composition comprising a compound set forth in FORMULA (I):

The invention also provides for a method of inhibiting the production of TMA by bacteria comprising administering to the individual a composition comprising a compound set forth in FORMULA (I) wherein the compound is administered in an amount effective to inhibit formation of trimethylamine (TMA) from choline or carnitine in the individual.

First claim

What is claimed is:

1. A method of inhibiting the conversion of choline or carnitine to trimethylamine (TMA) by a bacterium comprising: contacting the bacterium with a compound as set forth in Formula (I):

wherein
Y + is selected from a quaternary nitrogen; X − is an anion; n is selected from 1, 2 or 3; R 2 and R 3 are independently selected from C1-4 alkyl or bound together forming an aliphatic, aromatic or heterocyclic ring system;
R 4 is selected from C1-4 alkyl, alkenyl, alkynyl, alkoxy carbonyl, alkoxy dicarbonyl, acrylic, alkoxy, alkoxy alkyl, aryloxy alkyl, alkyl carboxylate as part of a betaine, inner salt, or Zwitterion form, halo alkyl, hydroxy alkyl, nitrile, or propargyl;
R 6 is selected from C1-4 alkyl, alkoxy, hydroxy, alkoxy alkyl, hydroxy alkyl, or epoxy; and
including any acceptable salts or solvates thereof.

2. The method of claim 1 , wherein the compound is at least one of N-(2-Phenoxyethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate, N-(2-isothiocyanatoethyl)-N,N-dimethylprop-2-yn-1-aminium bromide, 3-Isothiocyanato-N,N-diethyl-N-methylpropanaminium iodide, and N-(2-isothiocyanatoethyl)-2-(methoxycarbonyl)-N,N-dimethylprop-2-en-1-aminium bromide, or pharmaceutically acceptable salts thereof.

3. The method of claim 1 , wherein the compound is at least one of N,N-Diethyl-2-isothiocyanato-N-methylpropanaminium iodide, N-(2-Bromoethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate, N-(Ethoxypropyl-2,3-dione)-3-isothiocyanato-N,N-diethylpropan-1-aminium bromide, or pharmaceutically acceptable salts thereof.

4. The method of claim 1 further comprising contacting the bacterium with a second agent that is at least one of Omega 3 oil, salicylic acid, dimethylbutanol, garlic oil, olive oil, krill oil, Co enzyme Q-10, a probiotic, a prebiotic, dietary fiber, psyllium husk, bismuth salts, phytosterols, grape seed oil, green tea extract, vitamin D, an antioxidant, turmeric, curcumin, resveratrol, activated charcoal, or copper chlorophyllin.

5. The method of claim 1 , wherein conversion of choline or carnitine to trimethylamine (TMA) is inhibited by from about 1% to about 100%.

6. The method of claim 1 , wherein conversion of choline or carnitine to trimethylamine (TMA) is inhibited by at least 50%.

7. The method of claim 1 , wherein the bacterium is at least one of Proteus mirabilis, Desulfovibrio alaskensis, Clostridium ljungdahlii, C. scindens, C. aldenense, C. aminobutyricum, Collinsella tanakaei, Anaerococcus vaginalis, Streptococcus dysgalactiae, Desultitobacterium hafniense, Klebsiella variicola, K pneumonia, Proteus penneri, Eggerthella lenta, Edwardsiella tarda, Escherichia coli , or E. fergusonii.

8. A method of inhibiting the conversion of choline to trimethylamine (TMA) by a bacterium comprising: contacting the bacterium with a compound set forth in Formula (II):

wherein R 1 is H, C 1 -C 4 alkoxy, Br, Cl, F, I, or is selected from

Y + is selected from a quaternary nitrogen; X − is an anion; n is selected from 1, 2 or 3; R 2 and R 3 are independently selected from C1-4 alkyl or bound together forming an aliphatic, aromatic or heterocyclic ring system;
Z is O, CH 2 , or H, H;
m is 0, 1 or 2;
R 5 is hydroxyl, or hydroxyl alkyl; and
R 7 is H, or C 1-4 alkyl; and
including any acceptable salts or solvates thereof.

9. The method of claim 8 , wherein the compound is at least one of N-(2-Phenoxyethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate, N-(2-isothiocyanatoethyl)-N,N-dimethylprop-2-yn-1-aminium bromide, 3-Isothiocyanato-N,N-diethyl-N-methylpropanaminium iodide, and N-(2-isothiocyanatoethyl)-2-(methoxycarbonyl)-N,N-dimethylprop-2-en-1-aminium bromide, or pharmaceutically acceptable salts thereof.

10. The method of claim 8 , wherein the compound is at least one of N,N-Diethyl-2-isothiocyanato-N-methylpropanaminium iodide, N-(2-Bromoethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate, N-(Ethoxypropyl-2,3-dione)-3-isothiocyanato-N,N-diethylpropan-1-aminium bromide, or pharmaceutically acceptable salts thereof.

11. The method of claim 8 further comprising contacting the bacterium with a second agent that is at least one of Omega 3 oil, salicylic acid, dimethylbutanol, garlic oil, olive oil, krill oil, Co enzyme Q-10, a probiotic, a prebiotic, dietary fiber, psyllium husk, bismuth salts, phytosterols, grape seed oil, green tea extract, vitamin D, an antioxidant, turmeric, curcumin, resveratrol, activated charcoal, or copper chlorophyllin.

12. The method of claim 8 , wherein conversion of choline or carnitine to trimethylamine (TMA) is inhibited by from about 1% to about 100%.

13. The method of claim 8 , wherein conversion of choline or carnitine to trimethylamine (TMA) is inhibited by at least 50%.

14. The method of claim 8 , wherein the bacterium is at least one of Proteus mirabilis, Desulfovibrio alaskensis, Clostridium ljungdahlii, C. scindens, C. aldenense, C. aminobutyricum, Collinsella tanakaei, Anaerococcus vaginalis, Streptococcus dysgalactiae, Desultitobacterium hafniense, Klebsiella variicola, K pneumonia, Proteus penneri, Eggerthella lenta, Edwardsiella tarda, Escherichia coli , or E. fergusonii.

15. A compound:

wherein R 1 is, C 1 -C 4 alkoxy, Br, Cl, F, I, or is selected from

Y + is selected from a quaternary nitrogen; X − is an anion; n is selected from 1, 2 or 3; R 2 and R 3 are independently selected from C1-4 alkyl or bound together forming an aliphatic, aromatic or heterocyclic ring system;
Z is O, CH 2 , or H, H;
m is 0, 1 or 2;
R 5 is hydroxyl, or hydroxyl alkyl; and
R 7 is H, or C 1-4 alkyl and
including any acceptable salts or solvates thereof.

16. The compound of claim 15 , wherein the compound is at least one compound selected from N-(Ethoxycarbonylethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium bromide; N-(Ethoxycarbonylethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium bromide; N-(Ethoxypropyl-2,3-dione)-2-isothiocyanato-N,N-dimethylethan-1-aminium bromide; N-(Ethoxypropyl-2,3-dione)-3-isothiocyanato-N,N-diethylpropan-1-aminium bromide; N-(2-Bromoethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate; N-Cyanomethyl-2-isothiocyanato-N,N-diethylethan-1-aminium bromide; N-Cyanomethyl-3-isothiocyanato-N,N-diethylpropan-1-aminium bromide, N-(2-Phenoxyeth y)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate; N-(2-Benzyloxyethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate; N-(2-Benzyloxyethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate; N-(2-Phenoxyethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate; N-(2-Bromoethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate; N-(Oxiranylmethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate; N-(Oxiranylmethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate; N-(2-Methoxyethyl)-2-isothiocyanato-N,N-dimethylethan-1-aminium triflate; N-(2-Methoxyethyl)-3-isothiocyanato-N,N-diethylpropan-1-aminium triflate; N-(2-Ethoxyethyl)-

Assignees

• Procter & Gamble
• Cleveland Clinic Found

Inventors

• Garcia-Garcia Jose Carlos
• HAZEN Stanley Leon
• Wos John August

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K31/452

  Piperidinium derivatives (pancuronium A61K31/58) · CPC title

• C07D213/30

  Oxygen atoms · CPC title

• A61K31/145

  having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) (isothiourea A61K31/155) · CPC title

• A61K31/325

  Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145) · CPC title