# US 10,369,133 B2 · Immunosuppressive compounds and therapeutics

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- Number: US 10,369,133 B2
- Document ID: US10369133B2
- Status: Granted
- Kind: B2
- Application number: 14/907,015
- Filed: 2014-07-23
- Published: 2016-06-23
- Granted: 2019-08-06
- Earliest claimed: 2013-07-23
- Assignees: University of Tennessee Research Foundation
- Applicants: University of Tennessee Research Foundation; Rxbio, Inc.
- Inventors: Duane Douglas Miller; Charles Ryan Yates; Jayaprakash Pagadala; Ram Mahato; Hao Wu
- Web page: https://patentgrep.com/patent/US10369133B2

## CPC

- A61K 31/365: Lactones
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/661: Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos}
- A61K 31/665: having oxygen as a ring hetero atom, e.g. fosfomycin
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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

## Abstract

Here provided are new immunosuppressive compounds and novel therapeutics for improving tissue transplantation.

## Claims

### Claim 1

A method for improving survival and function of a transplanted tissue, comprising administering to the tissue a therapeutically-effective amount of a compound of Formula II or Formula III:
Wherein:
(i) X is S or P;
(ii) Y1 and Y2 are each independently O or N; and
(iii) R1, R2 and R10 are each independently selected from the group consisting of:
a) H or OH;
b) a straight- and branched-chain alkyl having one to twelve carbon atoms;
c) an alkylidene that is a divalent radical having one to twelve carbon atoms;
d) an alkenyl that is straight- and branched-chain alkenyl groups having from two to twelve carbon atoms;
e) an alkynyl that is straight- and branched-chain alkynyl groups having from two to twelve carbon atoms;
f) a cycloalkyl that is saturated or partially unsaturated carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures;
g) a heterocycloalkyl that is a saturated or partially unsaturated monocyclic radical containing carbon atoms, preferably with 4 or 5 ring carbon atoms, and with at least one heteroatom selected from nitrogen, oxygen (e.g., monosaccharide) and sulfur;
h) an aryl or heteroaryl that have monocyclic and polycyclic unsaturated or aromatic ring structures, with “aryl” referring to those that are carbocycles and “heteroaryl” referring to those that are heterocycles;
i) an alkoxy that is a radical —O-alkyl;
j) an aryloxy;
k) a cycloalkoxyl;
l) an alkylthio;
m) an alkylamino;
n) an arylthio;
o) an arylamino;
p) a cycloalkylthio;
q) a cycloalkylamino;
r) a heteroarylthio;
s) a heteroarylamino;
t) a halogen;
wherein every member in each group can be taken independently or combined via covalent bond in any order with some or all members of any group defined above to the extent that these combinations give rise to chemically feasible entities; and
wherein each of the groups ‘b’ through ‘s’ can contain or be substituted by any one or more functional groups taken from the functional group pool listed below either singularly, in plurality or in combination with other members of the functional group, which functional group pool is consisting of ether, thioether, amine, nitro, nitrile, sulfoxides, sulfones, ester, amide, hydroxamic acid, sulfonamides, sulfamide, ureas, sulfimines, sulfonylureas, carbamates, thiocarbamates, carbonates and hydroxyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein the alkyl is selected from the group consisting of methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl, and isohexyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the alkyl is an alkyl having from 1 to 8 carbon atoms.

### Claim 4 (depends on 1)

The method of claim 1, wherein the alkyl is a substituted alkyl selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein the alkylidene is selected from the group consisting of CH2, CHCH3, and (CH3)2.

### Claim 6 (depends on 1)

The method of claim 1, wherein the alkenyl is selected from the group consisting of prop-2-enyl, but-3-enyl, hex-3-enyl, 2-methylprop-2-enyl, and hept-2-enyl.

### Claim 7 (depends on 1)

The method of claim 1, wherein the cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein the aromatic ring structures in the aryl or heteroaryl is selected from the group consisting of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and a fused-ring structure or bridge.

### Claim 9 (depends on 8)

The method of claim 8, wherein a fused-ring structure or bridge is OCH2.

### Claim 10 (depends on 1)

The method of claim 1, wherein the alkoxy is selected from the group consisting of methoxy, ethoxy, propoxy.

### Claim 11 (depends on 1)

The method of claim 1, wherein the halogen is selected from the group consisting of chlorine, fluorine, bromine and iodine.

### Claim 12 (depends on 1)

The method of claim 1, wherein Formula II refers to a compound of Formula IV

### Claim 13 (depends on 12)

The method of claim 12, wherein the compound of Formula IV is in a mono or di salt form.

### Claim 14 (depends on 1)

The method of claim 1, wherein Formula III refers to a compound of Formula V

### Claim 15 (depends on 14)

The method of claim 14, wherein the compound of Formula V is in a mono or di salt form.