# US 10,869,871 B2 · Compositions and methods of modulating short-chain dehydrogenase activity

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- Number: US 10,869,871 B2
- Document ID: US10869871B2
- Status: Granted
- Kind: B2
- Application number: 15/785,259
- Filed: 2017-10-16
- Published: 2019-12-05
- Granted: 2020-12-22
- Earliest claimed: 2013-10-15
- Assignees: Case Western Reserve University; Board of Regents, The University of Texas System
- Applicants: Case Western Reserve University; Board of Regents of the University of Texas System
- Inventors: Sanford Markowitz; James K.V. Wilson; Bruce Posner; Joseph Ready; Monika Antczak; Yongyou Zhang; Amar Desai; Stanton Gerson; William Greenlee; Sung Yeun Yang; KiBeom Bae
- Web page: https://patentgrep.com/patent/US10869871B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- 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
- 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 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/06: Antihyperlipidemics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- 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 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 15/10: for impotence
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/14: for baldness or alopecia
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 39/02: Antidotes
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 495/04: Ortho-condensed systems
- 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

Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors described herein.

## Claims

### Claim 1

A pharmaceutical composition comprising a compound having the formula (V):
or a pharmaceutically acceptable salt thereof;
wherein n=1;
R1 is selected from the group consisting of
R3 is selected from the group consisting of H, alkyl, —CO2H, —CO2alkyl, —CONH2, —CONH(alkyl), —CON(alkyl)2,
R2 is N or CH;
R4 is H or NH2;
R5 is a branched or linear alkyl or
wherein n2=0-6 and X is any of the following: CFyHz (y+z=3), CClyHz (y+z=3), OH, OAc, OMe, CN, or
(n3=0-5, m=1-5);
each R6 is the same or different and is independently one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano (—CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C1-C24 alkyl amino substituted with hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate ester, and combinations thereof;
R3 is not hydrogen if R1 is an unsubstituted thiazole and R5 is butyl; or R3 is not an unsubstituted phenyl if R1 is an unsubstituted thiazole and R5 is (CH2)n5(CH3)(n5=0-5).

### Claim 2 (depends on 1)

The composition of claim 1, wherein R1 is a substituted or unsubstituted thiazole, oxazole, imidazole, pyrimidine or pyridine.

### Claim 3 (depends on 1)

The composition of claim 1, wherein R3 is selected from the group consisting of H, substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, alkyl, —CO2H, —CO2alkyl, —CONH2, —CONH(alkyl), and —CON(alkyl)2.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the compound has formula (V1)
or a pharmaceutically acceptable salt thereof;
wherein n=1;
R3 is selected from the group consisting of H, alkyl, —CO2H, —CO2alkyl, —CONH2, —CONH(alkyl), —CON(alkyl)2,
R2 is N or CH;
R4 is selected from the group consisting of H and NH2;
R5 is a branched or linear alkyl or
wherein n2=0-6 and X is any of the following: CFyHz (y+z=3), CClyHz (y+z=3), OH, OAc, OMe, CN, or
(n3=0-5, m=1-5);
each R6 is the same or different and is independently one or more substituent selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano (—CN), isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate ester, and combinations thereof;
R3 is not hydrogen if R5 is butyl; or R3 is not an unsubstituted phenyl if R5 is (CH2)n5(CH3)(n5=0-5).

### Claim 5 (depends on 4)

The composition of claim 4, wherein R3 is selected from the group consisting of H, substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, alkyl, —CO2H, —CO2alkyl, —CONH2, —CONH(alkyl), and —CON(alkyl)2.

### Claim 6 (depends on 1)

The composition of claim 1, the compound having a formula selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 1)

The composition of claim 1, the compound having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The composition of claim 1, the compound having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The composition of claim 1, the compound having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The composition of claim 1, the compound consisting essentially of the (+) optical isomer of a compound of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The composition of claim 1, the compound inhibiting the activity of a 15-PGDH enzyme.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 1 μM.

### Claim 13 (depends on 1)

The composition of claim 1, including an amount of the compound effective to increase prostaglandin levels in tissue of a subject when administered to a subject.

### Claim 14

A compound having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The compound of claim 14 having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 14)

The compound of claim 14 having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 14)

The compound of claim 14 consisting essentially of the (+) optical isomer of a compound of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The composition of claim 1, wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 250 nM.

### Claim 19 (depends on 1)

The composition of claim 1, wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 50 nM.

### Claim 20 (depends on 1)

The composition of claim 1, wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 10 nM.

### Claim 21 (depends on 1)

The composition of claim 1, wherein the compound inhibits the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 5 nM.