# US 2020/0399302 A1 · Uridine nucleoside derivatives, compositions and methods of use

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- Number: US 2020/0399302 A1
- Document ID: US20200399302A1
- Status: Published application
- Kind: A1
- Application number: 16/773,406
- Filed: 2020-01-27
- Published: 2020-12-24
- Earliest claimed: 2013-03-13
- Assignees: Tufts University
- Applicants: Tufts University
- Inventors: Philip G. Haydon; Jinbo Lee
- Web page: https://patentgrep.com/patent/US20200399302A1

## CPC

- C07H 19/06: Pyrimidine radicals
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07H 19/067: with ribosyl as the saccharide radical
- 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)
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This disclosure relates to uridine nucleoside derivatives, compositions comprising therapeutically effective amounts of those nucleoside derivatives and methods of using those nucleoside derivatives or compositions in treating disorders that are responsive to ligands, such as agonists, of P2Y6 receptor, e.g., neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease) and traumatic CNS injury, pain, Down Syndrome (DS), glaucoma and inflammatory conditions.

## Claims

### Claim at position 1

-225. (canceled)

### Claim 226

A pharmaceutical composition, comprising a compound of formula I:
or a salt thereof, wherein:
A is a bicyclic aromatic ring selected from:
wherein the bicyclic aromatic ring is independently and optionally substituted with one or more R7;
X is selected from:
—H, —C(O)R5, and —C(O)OR5;
Y is a bond or a (C1-C5)-aliphatic group independently and optionally substituted with one or more R4;
Z and W are each independently selected from ═O, ═S, ═N(R5), and ═NOR5;
R1 is selected from: —H, bromine, iodine, methyl, ethyl or —CF3;
R2 and R3 are each independently selected from —OR5, —SR5, —NR5R6, —OC(O)R5,
—OC(O)NR5R6, and —OC(O)OR5;
each occurrence of R4 is independently selected from:
halogen, —OR5, —NO2, —CN, —CF3, —OCF3, —R5, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R5)2, —SR5, —SOR5, —SO2 R5, —SO2N(R5)2, —SO3R5, —C(O)R5, —C(O)C(O)R5, —C(O)CH2C(O)R5, —C(S)R5, —C(S)OR5, —C(O)OR5, —C(O)C(O)OR5, —C(O)C(O)N(R5)2, —OC(O)R5, —C(O)N(R5)2, —OC(O)N(R5)2, —C(S)N(R5)2, —(CH2)0-2NHC(O)R5, —N(R5)N(R5)COR5, —N(R5)N(R5)C(O)OR5, —N(R5)N(R5)CON(R5)2, —N(R5)SO2R5, —N(R5)SO2N(R5)2, —N(R5)C(O)OR5, —N(R5)C(O)R5, —N(R5)C(S)R5, —N(R5)C(O)N(R5)2, —N(R5)C(S)N(R5)2, —N(COR5)COR5, —N(OR5)R5, —C(═NH)N(R5)2, —C(O)N(OR5)R5, —C(═NOR5)R5, —OP(O)(OR5)2, —P(O)(R5)2, —P(O)(OR5)2, and —P(O)(H)(OR5);
each occurrence of R5 is independently selected from:
H-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, and
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein two R5 groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, O, S, SO, and SO2, wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; and
wherein each R5 group is independently and optionally substituted with one or more R7;
R6 is selected from:
—R5, —C(O)R5, —C(O)OR5, —C(O)N(R5)2 and —S(O)2R5;
each occurrence of R7 is independently selected from:
halogen, —OR8, —NO2, —CN, —CF3, —OCF3, —R8, oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R8)2, —SR8, —SOR8, —SO2 R8, —SO2N(R8)2, —SO3R8, —C(O)R8, —C(O)C(O)R8, —C(O)CH2C(O)R8, —C(S)R8, —C(S)OR8, —C(O)OR8, —C(O)C(O)OR8, —C(O)C(O)N(R8)2, —OC(O)R8, —C(O)N(R8)2, —OC(O)N(R8)2, —C(S)N(R8)2, —(CH2)0-2NHC(O)R8, —N(R8)N(R8)COR8, —N(R8)N(R8)C(O)OR8, —N(R8)N(R8)CON(R8)2, —N(R8)SO2R8, —N(R8)SO2N(R8)2, —N(R8)C(O)OR8, —N(R8)C(O)R8, —N(R8)C(S)R8, —N(R8)C(O)N(R8)2, —N(R8)C(S)N(R8)2, —N(COR8)COR8, —N(OR8)R8, —C(═NH)N(R8)2, —C(O)N(OR8)R8, —C(═NOR8)R8, —OP(O)(OR8)2, —P(O)(R8)2, —P(O)(OR8)2, and —P(O)(H)(OR8);
each occurrence of R8 is independently selected from:
H- and (C1-C6)-aliphatic-;
and an acceptable carrier, adjuvant or excipient.

### Claim 227 (depends on 226)

The pharmaceutical composition of claim 226, wherein X of the compound of formula I is —H or —C(O)R5.

### Claim 228 (depends on 226)

The pharmaceutical composition of claim 226, wherein R1 is —H.

### Claim 229 (depends on 226)

The pharmaceutical composition of claim 226, wherein Z of the compound of formula I is ═O or ═S.

### Claim 230 (depends on 226)

The pharmaceutical composition of claim 226, wherein Z is ═O.

### Claim 231 (depends on 226)

The pharmaceutical composition of claim 226, wherein W of the compound of formula I is ═O or ═S.

### Claim 232 (depends on 226)

The pharmaceutical composition of claim 226, wherein W is ═O.

### Claim 233 (depends on 226)

The pharmaceutical composition of claim 226, wherein Y of the compound of formula I is a C1-aliphatic group optionally substituted with one or more R4.

### Claim 234 (depends on 226)

The pharmaceutical composition of claim 226, wherein Y is —CH2—.

### Claim 235 (depends on 226)

The pharmaceutical composition of claim 226, wherein Y of the compound of formula I is a C2-aliphatic group optionally substituted with one or more R4.

### Claim 236 (depends on 226)

The pharmaceutical composition of claim 226, wherein Y is —CH2—C(R4)2—.

### Claim 237 (depends on 226)

The pharmaceutical composition of claim 226, wherein Y is —CH2—CH2—.

### Claim 238 (depends on 226)

The pharmaceutical composition of claim 226, wherein each occurrence of R4 is independently selected from halogen.

### Claim 239 (depends on 226)

The pharmaceutical composition of claim 226, wherein both occurrences of R4 are —F.

### Claim 240 (depends on 226)

The pharmaceutical composition of claim 226, wherein each occurrence of R4 is independently a (C1-C3)-aliphatic group.

### Claim 241 (depends on 226)

The pharmaceutical composition of claim 226, wherein both occurrences of R4 are —CH3.

### Claim 242 (depends on 226)

The pharmaceutical composition of claim 226, wherein R2 of the compound of formula I is —OR5.

### Claim 243 (depends on 226)

The pharmaceutical composition of claim 226, wherein R2 is —OH.

### Claim 244 (depends on 226)

The pharmaceutical composition of claim 226, wherein R3 of the compound of formula I is —OR5.

### Claim 245 (depends on 226)

The pharmaceutical composition of claim 226, wherein R3 is —OH.