# US 10,370,335 B2 · Xanthurenic acid derivative pharmaceutical compositions and methods related thereto

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- Number: US 10,370,335 B2
- Document ID: US10370335B2
- Status: Granted
- Kind: B2
- Application number: 14/249,802
- Filed: 2014-04-10
- Published: 2014-10-16
- Granted: 2019-08-06
- Earliest claimed: 2004-12-29
- Assignees: Naturon, Inc.
- Applicants: Naturon, Inc.
- Inventors: Neal S. Bricker; Stewart Shankel; Christopher D. Cain; Mark A. Mitchnick; Michael Schmertzler
- Web page: https://patentgrep.com/patent/US10370335B2

## CPC

- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4706: 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/12: for electrolyte homeostasis
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- G01N 33/5308: {for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites}
- G06K 19/02: characterised by the selection of materials, e.g. to avoid wear during transport through the machine
- G06K 19/07749: {the record carrier being capable of non-contact communication, e.g. constructional details of the antenna of a non-contact smart card}
- G06K 19/0776: {the adhering arrangement being a layer of adhesive, so that the record carrier can function as a sticker}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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)
- G06K: GRAPHICAL DATA READING (image or video recognition or understanding G06V); PRESENTATION OF DATA; RECORD CARRIERS; HANDLING RECORD CARRIERS

## Abstract

The present invention relates to diuretic pharmaceutical compositions and methods and in particular to certain derivatives of the formula I wherein R1, R2, R3, R5, R6 and R7 are independently X3R where R is selected from the group consisting of H, halo; optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; —P(O)(ORa)(ORb) and —NRaRb, where Ra and Rb are independently H, optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; X1, X2 and X3 are independently —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, —OS(O)y—, —S(O)y—, —O—, —NHC(O)—, —NHC(O)O—, —S(O)2NH—, a bond or absent; where y is an integer from 0 to 3; and R4 and R8 are independently H, (═O); hydroxy; or optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or —P(O)(ORa)(ORb) or —NRaRb, where Ra and Rb are independently H, or optionally substituted aliphatic, cycloalkyl or heterocycloalkyl, aryl or heteroaryl; or a prodrug or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

## Claims

### Claim 1

A pharmaceutical formulation comprising in unit dosage form a therapeutically effective amount of an acid or base salt of a freeze-dried, non-steroidal naturietic compound of formula (I):
wherein R1, R2, R3, R5, R6 and R7 are independently X3R where R is selected from the group consisting of H, halo; optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; —P(O)(ORa)(ORb) and —NRaRb, where Ra and Rb are independently H, optionally substituted aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
X1, and X3 are independently —C(O)O—, —OC(O)—, —C(O)NH—, —NHC(O)—, OC(O)NH—, —NHC(O)O—, —OS(O)y—, —S(O)y—, —O—, —NHC(O)—, —NHC(O)O—, —S(O)2NH—, a bond or absent; where y is an integer from 0 to 3; and
R4 is H, (═O); hydroxy; or optionally substituted saccharide, aliphatic, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or —P(O)(ORa)(ORb) or NRaRb, where Ra and Rb are independently H, or optionally substituted aliphatic, cycloalkyl or heterocycloalkyl, aryl or heteroaryl;
X2 is —O— and R8 is an optionally substituted saccharide; or X2 is OS(O)y— or S(O)y—, where y is an integer from 0 to 3, and R8 is H or optionally substituted aliphatic;
and a pharmaceutically acceptable carrier.

### Claim 2 (depends on 1)

The formulation of claim 1 wherein R1, R3, R5, R6 and R7 are independently H or halogen.

### Claim 3 (depends on 2)

The formulation of claim 2 wherein X1 is absent or a bond and R4 is hydroxy or (═O).

### Claim 4 (depends on 3)

The formulation of claim 3 wherein R2 is —C(O)OR.

### Claim 5 (depends on 4)

The formulation of claim 4 wherein R2 is —C(O)OH.

### Claim 6 (depends on 1)

The formulation of claim 1 wherein R8 is an optionally substituted saccharide.

### Claim 7 (depends on 6)

The formulation of claim 6 wherein X2 is —O— and R8 is an optionally substituted monosaccharide.

### Claim 8 (depends on 7)

The formulation of claim 7 wherein R8 is an aldohexopyranose, aldopentopyranose, aldopentofuranose or ketose.

### Claim 9 (depends on 8)

The formulation of claim 8 wherein R8 is a glucoside.

### Claim 10 (depends on 1)

The formulation of claim 1 wherein the compound of formula I is xanthurenic acid 8-O-β-D-glucoside.

### Claim 11 (depends on 1)

The formulation of claim 1 wherein X3 is —OS(O)y—.

### Claim 12 (depends on 1)

The formulation of claim 1 wherein the compound of formula I is xanthurenic acid 8-O-sulfate.

### Claim 13 (depends on 1)

The formulation of claim 1, further comprising a diuretic compound selected from the group consisting of a loop diuretic, thiazide diuretic, potassium-sparing diuretic, carbonic anhydrase inhibitor and osmotic diuretic.

### Claim 14 (depends on 13)

The formulation of claim 13, wherein the diuretic compound is selected from furosemide, bumetanide, torsemide, ethacrynic acid, chlorothiazide, hydrochlorothiazide, spironolactone, amiloride, triamterene, acetazolamide, methazolamide, dichlorphenamide, hydroflumethiazide, methyclothiazide, indapamide, metolazone, polythiazide, chlorthalidone, dorzolamide, brinzolamide, glycerol, mannose and urea.

### Claim 15 (depends on 14)

The formulation of claim 14, wherein the diuretic compound is furosemide.

### Claim 16 (depends on 1)

The formulation of claim 1, further comprising a cardiovascular agent selected from the group consisting of an angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist and beta-adrenergic blocker.

### Claim 17 (depends on 16)

The formulation of claim 16, wherein the cardiovascular agent is lisinopril, moexipril, enalapril, irbesartan, valsartan, losartan, nadolol, propranolol, atenolol, timolol or bisoprolol.

### Claim 18 (depends on 1)

A method of treating or controlling hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure or nephrotic syndrome in a mammal, comprising administering a formulation of claim 1, orally or intravenously.

### Claim 19 (depends on 1)

A method for effecting diuresis in a patient in need thereof, comprising administering a formulation of claim 1, orally or intravenously.

### Claim 20 (depends on 19)

The method of claim 19, where said patient has one or more of the following conditions: hypertension, edema, acute renal failure, congestive heart failure, chronic renal failure, ascites, increased intra-ocular pressure or nephrotic syndrome.