# US 5,347,029 A · Dialkyl (dialkoxyphosphinyl)methyl phosphates as anti-inflammatory agents

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 5,347,029 A
- Document ID: US5347029A
- Status: Granted
- Kind: A
- Application number: 08/168,441
- Filed: 1993-12-16
- Granted: 1994-09-13
- Earliest claimed: 1991-06-19
- Assignees: The Upjohn Company
- Inventors: Roy A. Johnson
- Web page: https://patentgrep.com/patent/US5347029A

## CPC

- C07F 9/657181: {the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative}
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07F 9/4006: {Esters of acyclic acids which can have further substituents on alkyl}
- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07F 9/58: Pyridine rings
- C07F 9/6506: having the nitrogen atoms in positions 1 and 3
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are novel dialkyl (dialkoxyphosphinyl)methyl phosphates of formula ##STR1## which am useful as anti-inflammatory and anti-arthritic agents. The compounds are synthesized from the reaction of tetraethyl oxiranylidenebisphosphonate and unsubstituted or alkyl-amines. Representative compounds include 2-(benzylamino)-1-(diethoxyphosphinyl)ethyl phosphonic acid diethyl ester, 1-(diethoxyphosphinyl)-2-[2'-(1', 2', 3', 4'-tetrahydro)napthylamino]ethyl phosphonic acid diethyl ester, 2-(3-fluorobenzylamino)-1-(diethoxyphosphinyl)ethyl phosphonic acid diethyl ester, and 5,5 -dimethyl-2-[2-(3-fluorobenzyl)amino-1-[(5,5-dimethyl-1,3,2-dioxaphosphori nan-2-yl)oxy]ethyl]-1,3,2-dioxaphosphorinane P,2-dioxide.

## Claims

### Claim 1

A compound of formula
wherein
R.sub.1 is independent and selected from the group consisting of hydrogen, C.sub.1 -C.sub.10 alkyl, --C.sub.6 H.sub.5 ;
adjacent R.sub.1 taken together may be --CH.sub.2 (CH.sub.2).sub.n CH.sub.2 --or --CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 --;
R.sub.2 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.7 cycloalkyl, --CH.sub.2 CH.dbd.CH.sub.2, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 (CH.sub.2).sub.n Ar, --CH.sub.2 CH.sub.2 OCH.sub.2 Ar, --CH(C.sub.6 H.sub.5).sub.2, and 1 '- or 2 '-(1',2',3',4'-tetrahydro)naphthylene;
R.sub.3 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.10 alkyl, --CO(CH.sub.2).sub.m CH.sub.3, --CO.sub.2 CH.sub.2 Ar, and --COAr;
n is 0, 1, or 2;
m is 0 thru 9;
Ar is selected from the group consisting of
(a) phenyl, 1- or 2-naphthyl, 3-indolyl, 2-, 3-, or 4-pyridinyl, or 1-imidazolyl,
(b) phenyl optionally substituted with 1 thru 5 --F or --Cl,
(c) phenyl optionally substituted with 1 thru 3 --Br, --I, --CF.sub.3, --R.sub.4, or --OR.sub.4,
(d) phenyl substituted with --COOR.sub.4, --OCOR.sub.4, --SO.sub.2 NH.sub.2, --NHSO.sub.2 R.sub.4, and --NHCOR.sub.4 ;
R.sub.4 is C.sub.1 -C.sub.5 alkyl;
provided, however, when R.sub.1 is --C.sub.2 H.sub.5, neither R.sub.2 nor R.sub.3 may be --C.sub.3 H.sub.7 ;
and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein
R.sub.1 is independent and selected from the group consisting of C.sub.1 -C.sub.10 alkyl;
R.sub.2 is selected from the group consisting of C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.7 cycloalkyl, --CH.sub.2 CH.dbd.CH.sub.2, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 (CH.sub.2).sub.n Ar, --CH.sub.2 CH.sub.2 OCH.sub.2 Ar, --CH(C.sub.6 H.sub.5).sub.2 and 1'- or 2'-(1',2',3',4'-tetrahydro)naphthylene; and
R.sub.3 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.10 alkyl, --CO.sub.2 CH.sub.2 Ar, and --COAr.

### Claim 3 (depends on 2)

A compound according to claim 2 wherein
R.sub.2 is selecled from the group consisting of C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.7 cycloalkyl, --CH.sub.2 CH.dbd.CH.sub.2, --CH.sub.2 CH.sub.2 OH, --CH(C.sub.6 H.sub.5).sub.2, and 1'- or 2'-(1', 2', 3', 4'-tetrahydro)naphthylene; and
R.sub.3 is hydrogen.

### Claim 4 (depends on 3)

A compound according to claim 3 selected from the group consisting of
2-(cyclohexylamino)-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester,
1-(diethoxyphosphinyl)-2-[(2'-hydroxy)ethylamino]ethyl phosphoric acid diethyl ester,
1-(diethoxyphosphinyl)-2-[2'-(1',2',3',4'-tetrahydro)naphthylamino]ethyl phosphoric acid diethyl ester,
1-(diethoxyphosphinyl)-2-(2'-propen-1'-ylamino)ethyl phosphoric acid diethyl ester, and
1-(diethoxyphosphinyl)-2-(diphenylmethylamino)ethyl phosphoric acid diethyl ester.

### Claim 5 (depends on 2)

A compound according to claim 2 wherein
R.sub.2 is --CH.sub.2 (CH.sub.2).sub.n Ar;
R.sub.3 is hydrogen;
Ar is selected from the group consisting of
(a) phenyl,
(b) phenyl substituted with 1 thru 5 --F or --Cl,
(c) phenyl substituted with 1 thru 3 --Br, --I, --CF.sub.3, --R.sub.4, or --OR.sub.4,
(d) phenyl substituted with --COOR.sub.4, --OCOR.sub.4, --SO.sub.2 NH.sub.2, --NHSO.sub.2 R.sub.4, and --NHCOR.sub.4 ; and
R.sub.4 is C.sub.1 -C.sub.5 alkyl.

### Claim 6 (depends on 5)

A compound according to claim 5 selected from the group consisting of
2-(benzylamino)-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester,
2-[(3'-fluoro)benzylamino]-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester, and
(1RS,1'R)-1-(diethoxyphosphinyl)-2-[(1'-phenyl)ethylamino]ethyl diethyl ester.

### Claim 7 (depends on 6)

A compound according to claim 6 which is 2-(benzylamino)-1-(dicthoxyphosphinyl)ethyl phosphoric acid diethyl ester.

### Claim 8 (depends on 6)

A compound according to claim 6 which is 2-[(3'-fluoro)benzylamino]1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester.

### Claim 9 (depends on 2)

A compound according to claim 2 wherein
R.sub.2 is --CH.sub.2 (CH.sub.2).sub.n Ar;
R.sub.3 is hydrogen; and
Ar is selected from the group consisting of 1- or 2-naphthyl, 3-indolyl, 2-, 3-, or 4-pyridinyl, or 1-imidazolyl.

### Claim 10 (depends on 9)

A compound according to claim 9 selected from the group consisting of
1-(diethoxyphosphinyl)-2-[(3'-pyridyl)methylamino]ethyl phosphoric acid diethyl ester,
1-(diethoxyphosphinyl)-2-[2'-(3'-indolyl)ethylamino]ethyl phosphoric acid diethyl ester, and
1-(diethoxyphosphinyl)-2-[3'-(1'-imidazolyl)propylamino]ethyl phosphoric acid diethyl ester.

### Claim 11 (depends on 10)

A compound according to claim 10 which is 1-(diethoxyphosphinyl)-2-[(3'-pyridyl)methylamino]ethyl phosphoric acid diethyl ester.

### Claim 12 (depends on 2)

A compound according to claim 2 wherein
R.sub.2 is selected from the group consisting of --CH.sub.2 CH.dbd.CH.sub.2, --CH.sub.2 (CH.sub.2).sub.n Ar, and --CH.sub.2 CH.sub.2 OCH.sub.2 Ar;
R.sub.3 is selected from the group consisting of --CO.sub.2 CH.sub.2 Ar, --CO(CH.sub.2).sub.m CH.sub.3, and --COAr;
Ar is selected from the group consisting of
(a) phenyl,
(b) phenyl optionally substituted with 1 thru 5 --F or --Cl, and
(c) phenyl optionally substituted with 1 thru 3 --Br, --I, --CF.sub.3, --R.sub.4, or --OR.sub.4,
R.sub.4 is C.sub.1 -C.sub.5 alkyl.

### Claim 13 (depends on 12)

A compound according to claim 12 selected from the group consisting of
2-[acetyl(3'-fluoro)benzylamino]-1-(diethoxyphosphinyl)ethyl phosphoric acid diethyl ester, and
2-[benxyloxyformyl(2'-propen-1'-yl)amino]-1-(diethoxyphosphiny)ethyl phosphoric acid diethyl ester.

### Claim 14 (depends on 1)

A compound according to claim 1 wherein
adjacent R.sub.1 taken together are --CH.sub.2 (CH.sub.2).sub.n CH.sub.2 --or --CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 --.

### Claim 15 (depends on 14)

A compound according to claim 14 selected from the group consisting of
5,5-dimethyl-2-[2-(3-fluorobenzyl)amino-1-[(5,5-dimethyl-1,3,2-dioxaphoshor inan-2-yl) oxy]ethyl]-1,3,2-dioxaphosphorinane P,2-dioxide, and
5,5-dimethyl-2-[2-(2-phenyl)ethylamine-1-[(5,5-dimethyl-1,3,2-dioxaphosphor inan-2-yl) oxy]ethyl]-1,3,2-dioxaphosphorinane P,2-dioxide.