# US 8,569,259 B2 · Adenosine analogs and their use

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- Number: US 8,569,259 B2
- Document ID: US8569259B2
- Status: Granted
- Kind: B2
- Application number: 12/515,033
- Filed: 2007-11-16
- Published: 2011-09-29
- Granted: 2013-10-29
- Earliest claimed: 2006-11-17
- Assignees: Microdose Therapeutx, Inc.
- Applicants: Efrat Ben-Zeev; Vincent Jacques; Yael Marantz; A. Sekar Reddy; Zhaoda Zhang; Oren Becker; Dilara McCauley; Pini Orbach; Sharon Shacham; Ashis K. Saha; Michael Xie
- Inventors: Efrat Ben-Zeev; Vincent Jacques; Yael Marantz; A. Sekar Reddy; Zhaoda Zhang; Oren Becker; Dilara McCauley; Pini Orbach; Sharon Shacham; Ashis K. Saha; Michael Xie
- Web page: https://patentgrep.com/patent/US8569259B2

## CPC

- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 31/7034: attached to a carbocyclic compound, e.g. phloridzin
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/10: Laxatives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 27/16: Otologicals
- C07H 15/203: Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/16: Purine radicals
- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- 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)

## Abstract

Provided are adenosine analog compounds of the general formula that act as P2Y receptors, e.g., the P2Y2 receptor, including pharmaceutical compositions; and uses thereof to treat or prevent diseases associated with that receptor, e.g., disorders relating to mucus secretion, such as cystic fibrosis, chronic obstructive pulmonary disorder (COPD), asthma, constipation, chronic idiopathic constipation, dry mouth (xerostomia), gum disease, and gastrointestinal problems caused by radiation and chemotherapy for cancer.

## Claims

### Claim 1

A compound of formula IA:
or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or pharmaceutically acceptable salts thereof, wherein:
Ar is an aryl, alkyl, cycloalkyl, aralkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, imino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl;
X is a bond or is selected from the group consisting of O, S, S(O), S(O2), N(R′), —C(O)N(R′)—, and —(CH2)mX1—;
X1 is O, S, S(O), S(O2), or N(R′);
R′ is H, alkyl, or aralkyl;
Q is selected from the group consisting of H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino; and lower dialkylamino group;
U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; methylene; or mono- or dihalomethylene;
Y1, Y2, and Y3 each represent independently for each occurrence O−, S−; or substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy groups;
Z is O, NH, or a lower alkylamino diradical;
m and n are independently 0, 1 or 2;
W is P.

### Claim 2

A compound of formula IIA:
or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or pharmaceutically acceptable salts thereof, wherein:
A, D, and E are independently N, C(R5), or CH;
F is N or C(R4);
R1 is an H, oxo, lower alkoxy, lower alkylamino, lower dialkylamino, imino, lower alkyl-substituted imino, lower thioalkyl, aryl, substituted or unsubstituted lower alkyl, or lower alkyl-substituted aryl group;
R2 is absent or is selected from the group consisting of a lower alkyl, lower alkoxy, lower alkyl-substituted aryl, aralkyl, and cycloalkyl group;
R3 and R4 are independently an H, lower thioalkyl, substituted lower alkyl, or unsubstituted lower alkyl group;
R5 is a lower alkyl, lower alkoxy, lower alkyl-substituted aryl, aralkyl, or cycloalkyl group;
Ar is an aryl, alkyl, cycloalkyl, arylalkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl;
X is a bond or is selected from the group consisting of O, S, S(O), S(O2), N(R′), —C(O)N(R′)—, and —(CH2)mX1—;
X1 is O, S, S(O), S(O2), or N(R′);
R′ is H, alkyl, or aralkyl;
Q represents independently for each occurrence an H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino, or lower dialkylamino group;
U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; methylene; or mono- or dihalomethylene;
Y2 and Y3 each represent independently for each occurrence O−, S−; or a substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy group;
M is H or a salt-forming cation;
Z represents independently for each occurrence O, NH, or a lower alkylamino diradical;
m and n are independently 0, 1 or 2; and
W is P.

### Claim 3 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-1:

### Claim 4 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-2:

### Claim 5 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-3:

### Claim 6 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-4:

### Claim 7 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-5:

### Claim 8 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-6:

### Claim 9 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-7:
wherein R6 represents independently for each occurrence a halo, hydroxy, alkyl, alkoxy, carboxyl, cyano, nitro, sulfonamide, sulfonate, amino, alkylamino, or di-alkylamino group; and t is 1, 2, or 3.

### Claim 10 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-8:
wherein:
R1 is a H, oxo, lower alkoxy, lower alkylamino, lower dialkylamino, imino, lower alkyl-substituted imino, lower thioalkyl, aryl, substituted or unsubstituted lower alkyl, or lower alkyl-substituted aryl group;
R2 is absent or is a lower alkyl, lower alkoxy, lower alkyl-substituted aryl, aralkyl, or cycloalkyl group;
R6 represents independently for each occurrence a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group; and
t is 1, 2, or 3.

### Claim 11 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-9:
wherein:
R1a is absent or is H or alkyl;
R1b is H or alkyl;
R2 is absent or is a lower alkyl, lower alkoxy, lower alkyl-substituted aryl, aralkyl, or cycloalkyl group;
R6 represents independently for each occurrence a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group; and
t is 1, 2, or 3.

### Claim 12 (depends on 2)

The compound of claim 2, which is a compound of formula IIA-10:
wherein:
R1a is absent or is H or C1-5alkyl;
R1b is H or C1-5alkyl;
R2 is absent or C1-5alkyl;
R6 represents independently for each occurrence C1-5alkyl or C1-5alkoxy; and
t is 1 or 2.

### Claim 13

A compound of Formula IIB:
or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or a pharmaceutically acceptable salt thereof, wherein:
Ar is an aryl, alkyl, cycloalkyl, arylalkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl;
X is a bond or is selected from the group consisting of O, S, S(O), S(O2), N(R′), —C(O)N(R′)—, and —(CH2)mX1—;
X1 is O, S, S(O), S(O2), or N(R′);
R′ is H, alkyl, or aralkyl;
Q represents independently for each occurrence an H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino; or lower dialkylamino group;
U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; a lower dialkylamino diradical; methylene; or mono- or dihalomethylene;
Y1 is CH2 or NH;
Y2 and Y3 each represent independently for each occurrence O−, S−; or a substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy group;
M is H or a salt-forming cation;
Z represents independently for each occurrence O, NH, or a lower alkylamino diradical;
m and n are independently 0, 1 or 2;
W is P.

### Claim 14

A compound of Formula IIIA:
or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, amorphous forms, or a crystalline forms, non-crystalline forms, amorphous forms, or a pharmaceutically acceptable salt thereof, wherein:
is phenyl or pyridyl;
X1 is O, NH, N(alkyl), —N(alkyl)-C(O)—, —C(O)N(alkyl)-, —N(alkyl)-CH2—, —CH2—N(alkyl)-, —CH2N(alkyl)-C(O)—, or —C(O)N(alkyl)-CH2—;
R′ represents independently for each occurrence a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group; and
t is 0, 1, 2, or 3.

### Claim 15 (depends on 14)

The compound of claim 14, wherein the compound is a compound of Formula IIIB:
or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or a pharmaceutically acceptable salt thereof.

### Claim 16

A compound of Formula IV:
or enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures, crystalline forms, non-crystalline forms, amorphous forms, or a pharmaceutically acceptable salt thereof, wherein:
Ar is an aryl, alkyl, cycloalkyl, aralkyl, or a heteroaryl or fused heteroaryl group containing 1-4 heteroatoms; each of which is optionally substituted with one or more of a halo, hydroxy, alkyl, alkoxy, carboxy, cyano, nitro, sulfonamido, sulfonate, amino, alkylamino, or di-alkylamino group or groups; provided that when X is O, Ar is neither unsubstituted phenyl, anilino, nor 4-nitrophenyl;
X is O, S, S(O), S(O2), N(R′), —C(O)N(R′)—, or —(CH2)mX1—;
X1 is O, S, S(O), S(O2), or N(R′);
R′ is H, alkyl, or aralkyl;
Q represents independently for each occurrence an H; OH; lower alkoxy; halo; mono-, di- or trihalomethyl; amino; lower alkylamino; or lower dialkylamino group;
U and V each represent independently for each occurrence O; NH; a lower alkylamino diradical; a lower dialkylamino diradical; methylene; or mono- or dihalomethylene;
Y2 and Y3 each represent independently for each occurrence O−, S−; or a substituted or unsubstituted lower alkoxy, aryloxy, aralkyloxy, or cycloalkyloxy group;
M is H or a salt-forming cation;
Z represents independently for each occurrence O, NH, or a lower alkylamino diradical;
m and n are independently 0, 1 or 2; and
W is P.

### Claim 17

A compound represented by one of the following:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The compound of claim 17, wherein the compound is represented by one of the following:

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)

A pharmaceutical composition, comprising a compound of any one of claims 1-18, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 2)

A method of treating constipation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 2.

### Claim 21 (depends on 20)

The method of claim 20, wherein the subject is a human.