# US 5,703,093 A · Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

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- Number: US 5,703,093 A
- Document ID: US5703093A
- Status: Granted
- Kind: A
- Application number: 08/454,748
- Filed: 1995-05-31
- Granted: 1997-12-30
- Earliest claimed: 1995-05-31
- Assignees: Cytomed, Inc.
- Inventors: Xiong Cai; Aberra Fura; Changgeng Qian
- Web page: https://patentgrep.com/patent/US5703093A

## CPC

- C07D 471/04: Ortho-condensed systems
- C07D 307/14: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Tetrahydrofurans, tetrahydrothiophenes, pyrrolidines and cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. It has been determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds.

## Claims

### Claim 1

A compound of formula: ##STR30## wherein: Ar is an aryl or heteroaryl group that is optionally substituted with halo, lower alkoxy, lower aryloxy, W, cyano, or R.sup.3 ;
m is 0 or 1;
n is 1-6;
W is independently --AN(OM)C(O)N(R.sup.3)R.sup.4, --N(OM)C(O)N(R.sup.3)R.sup.4, --AN(R.sup.3)C(O)N(OM)R.sup.4, --N(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4, --N(OM)C(O)R.sup.4 --, AC(O)N(OM)R.sup.4, --C(O)N(OM)R.sup.4, --C(O)NHA;
A is lower alkylene, lower alkenylene, lower alkynylene, alkylarylene or aryl alkylene, or a hetero derivative thereof, wherein one or more carbons optionally can be replaced by O, N, or S (with valence completed with hydrogen or oxygen as necessary), however, --Y--A--, --A--, and --AW-- must not include two adjacent heteroatoms;
M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;
X is O, S, S(O), S(O).sub.2, NR.sup.3, or CHR.sup.5 ;
Y is O, S, S(O), S(O).sub.2, NR.sup.3, or CHR.sup.5 ;
Z is O, S, S(O), S(O).sub.2, NR.sup.3 ;
R.sup.1 and R.sup.2 are independently hydrogen, lower alkyl, cyclopropylmethyl, ethyl, isopropyl, butyl, pentyl hexyl, and C.sub.3-8 cycloalkyl, for example, cyclopentyl; halo lower alkyl, halo; or --COOH;
R.sup.3 and R.sup.4 are independently hydrogen or alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, C.sub.1-6 alkoxy-C.sub.1-10 alkyl, C.sub.1-6 alkylthio-C.sub.1-10 alkyl, heteroaryl, or heteroarylalkyl-;
R.sup.5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkylaryl, --AN(OM)C(O)N(R.sup.3)R.sup.4, --AN(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4, --AC(O)N(OM)R.sup.4, --AS(O)xR.sup.3, --AS(O).sub.x H.sub.2 C(O)R.sup.3, --AS(O)xCH.sub.2 CH(OH)R.sup.3, or --AC(O)NHR.sup.3 ;
wherein x is 0-2.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Ar is selected from the group consisting of phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl, difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl, and thienyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Ar is 4-fluorophenyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Z is O.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Z is S.

### Claim 6 (depends on 1)

The compound of claim 1, wherein --(Y).sub.m W is selected from the group consisting of: ##STR31##

### Claim 7 (depends on 1)

The compound of claim 1, wherein --(Y).sub.m W is selected from the group consisting of: ##STR32##

### Claim 8 (depends on 1, 2, 3, 4, 5, 6)

The compound of claim 1, 2, 3, 4, 5, 6, or 7 in at least 97% enantiomerically enriched form.

### Claim 9

A compound selected from the group consisting of 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-protectedoxy-1-butynyl)tetrahyd rofuran and 2S,5R-cis-2-(4-fluorophenoxymethly)-5-(4-protectedoxy-1-butynyl) tetrahydr ofuran.

### Claim 10 (depends on 1)

The compound of claim 1 that is 2S,5-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butyl)tetrahy drofuran.

### Claim 11 (depends on 1)

The compound of claim 1 that is 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)tetr ahydrofuran.

### Claim 12 (depends on 1)

The compound of claim 1 that is 2R,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butyl)tetrah ydrofuran.

### Claim 13 (depends on 1)

The compound of claim 1 that is 2R,5R-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)tetr ahydrofuran.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising an effective antiinflammatory amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 15 (depends on 10, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory mount of the compound of claim 10 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 16 (depends on 11, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory amount of the compound of claim 11 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 17 (depends on 12, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory amount of the compound of claim 12 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 18 (depends on 13, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory mount of the compound of claim 13 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 19 (depends on 2, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory mount of the compound of claim 2 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 20 (depends on 3, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory amount of the compound of claim 3 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 21 (depends on 6, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory mount of the compound of claim 6 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

### Claim 22 (depends on 7, 14)

The pharmaceutical composition of claim 14 that an effective antiinflammatory amount of the compound of claim 7 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.