# US 10,117,879 B2 · Treating and preventing disease with TMA and TMAO lowering agents

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- Number: US 10,117,879 B2
- Document ID: US10117879B2
- Status: Granted
- Kind: B2
- Application number: 15/610,145
- Filed: 2017-05-31
- Published: 2017-09-21
- Granted: 2018-11-06
- Earliest claimed: 2014-09-26
- Assignees: The Cleveland Clinic Foundation
- Applicants: The Cleveland Clinic Foundation
- Inventors: Stanley L. Hazen
- Web page: https://patentgrep.com/patent/US10117879B2

## CPC

- A61K 31/616: by carboxylic acids, e.g. acetylsalicylic acid
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/133: having hydroxy groups, e.g. sphingosine
- A61K 31/205: Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
- A61K 31/409: having four such rings, e.g. porphine derivatives, bilirubin, biliverdine (hemin, hematin A61K31/555)
- A61K 31/4164: 1,3-Diazoles
- A61K 31/43: Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems
- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 33/44: Elemental carbon, e.g. charcoal, carbon black
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/12: of the kidneys
- G01N 33/492: {Determining multiple analytes}
- G01N 2800/32: Cardiovascular disorders
- G01N 2800/34: Genitourinary disorders
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided herein are compositions, systems, and methods for treating a disease, such as kidney and/or cardiovascular disease, with an agent that reduces the production of trimethylamine (TMA) or trimethylamine-n-oxide (TMAO) in a subject. In certain embodiments, the agent is: i) 3,3-dimethyl-1-butanol (DMB) or a DMB derivative or related compound, ii) acetylsalicylic acid or derivative thereof (e.g., with an enteric coating for delivery to the colon and/or cecum); iii) a flavin monooxygenase 3 (FMO3) inhibitor; iv) a gut TMA lyase inhibitor; v) an antibiotic or antimicrobial; vi) a probiotic or prebiotic; vii) an antiplatelet agent; or viii) a TMA and/or TMAO sequestering agent.

## Claims

### Claim 1

A method of treating a subject with symptoms of kidney and/or cardiovascular disease comprising:
treating a subject with a gut TMA lyase inhibitor, wherein said subject has symptoms of kidney and/or cardiovascular disease, and wherein said gut TMA lyase inhibitor comprises
a morpholine compound with one of the following structures:
wherein, for said morpholine compound: X is H, F, Cl, Br, or I; and Y is Cl, Br, or I.

### Claim 2 (depends on 1)

The method of claim 1, wherein a sample from said subject is assayed to determine levels of eGFR, eCrCl, Cystatin C, KIM1, elevated urine albumin/Creatinine ratio, trimethylamine N-oxide (TMAO), TMA, and/or a TMA-containing compound prior to and/or after said treating.

### Claim 3 (depends on 2)

The method of claim 2, wherein said sample is selected from whole blood, serum, plasma, urine, and saliva.

### Claim 4 (depends on 1)

The method of claim 1, wherein said morpholine compound has the following structure:

### Claim 5 (depends on 1)

The method of claim 1, wherein said morpholine compound has the following structure:

### Claim 6 (depends on 1)

The method of claim 1, wherein, for said morpholine compound: X is H or F.

### Claim 7 (depends on 1)

The method of claim 1, wherein, for said morpholine compound: X is Cl or Br.

### Claim 8 (depends on 1)

The method of claim 1, wherein, for said morpholine compound: X is I and/or Y is Cl.

### Claim 9 (depends on 1)

The method of claim 1, wherein, for said morpholine compound: Y is Br, or I.

### Claim 10 (depends on 1)

The method of claim 1, wherein said morpholine compound is N-methyl-N-(2-hydroxyethyl)morpholine.

### Claim 11 (depends on 1)

The method of claim 1, wherein said subject has symptoms of cardiovascular disease.

### Claim 12 (depends on 1)

The method of claim 1, wherein said subject has symptoms of kidney disease.

### Claim 13 (depends on 1)

The method of claim 1, wherein said morpholine compound has the following structure:
and wherein X is Cl and Y is I.