# US 5,346,893 A · Rapamycin 42-sulfonates and 42-(N-carbalkoxy) sulfamates useful as immunosuppressive agents

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- Number: US 5,346,893 A
- Document ID: US5346893A
- Status: Granted
- Kind: A
- Application number: 08/065,107
- Filed: 1993-05-19
- Granted: 1994-09-13
- Earliest claimed: 1992-03-19
- Assignees: American Home Products Corporation
- Inventors: Amedeo Failli; Wenling Kao; Robert J. Steffan; Robert L. Vogel
- Web page: https://patentgrep.com/patent/US5346893A

## CPC

- C07D 498/18: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention concerns compounds of formula (I) ##STR1## where R.sup.1 is alkyl, haloalkyl, alkenyl, or alkynyl containing 1 to 6 carbon atoms; or an aromatic moiety selected from phenyl, naphthyl and 4-(phenylaza) phenyl wherein said aromatic group is optionally substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di-(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, (C.sub.1 -C.sub.6) thioalkyl, halo, cyano, nitro, trifuluoromethyl, trifluoromethoxy or R.sup.1 is a heteroaromatic group of 5 to 10 ring atoms containing oxygen, nitrogen and/or sulfur as heteroatom(s) wherein said heteroaromatic group is optionally substituted by one or more substituents selected form C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di-(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, (C.sub.1 -C.sub.6) thioalkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy or R.sup.1 is NHCO.sub.2 R.sup.2 wherein R.sup.2 is lower alkyl containing 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof, which compounds are useful in the treatment of transplantation rejection, host versus graft disease, autoimmune diseases and diseases of inflammation.

## Claims

### Claim 1

A compound of formula (I) ##STR6## where R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 haloalkyl, C.sub.2 -C.sub.6 alkenyl, or C.sub.2 -C.sub.6 alkynyl; or an aromatic moiety selected from phenyl, naphthyl and 4-(phenylaza) phenyl wherein said aromatic group is optionally substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di-(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, (C.sub.1 -C.sub.6) thioalkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy or R.sup.1 is a heteroaromatic group of 5 to 10 ring atoms containing oxygen, nitrogen or sulfur as heteroatom wherein said heteroaromatic group is optionally substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di-(C.sub.1 -C.sub.6)alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, (C.sub.1 -C.sub.6) thioalkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy or R.sup.1 is NHCO.sub.2 R.sup.2 wherein R.sup.2 is lower alkyl containing 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1 wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 haloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl; or an aromatic moiety selected from phenyl, naphthyl and 4-(phenylaza)phenyl wherein said aromatic group is optionally substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di(C.sub.1 -C.sub.6) alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, thioalkyl (C.sub.1 -C.sub.6), halo, cyano, nitro, trifluoromethyl, trifluoromethoxy or R.sup.1 is a heteroaromatic moiety selected from thienyl, quinolinyl and isoquinolinyl wherein said heteroaromatic group is optionally substituted by one or more substituents selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, amino, mono- or di(C.sub.1 -C.sub.6) alkylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, C.sub.2 -C.sub.7 alkanoyl, thioalkyl (C.sub.1 -C.sub.6), halo, cyano, nitro, trifluoromethyl, trifluoromethoxy or R.sup. 1 is NHCO.sub.2 R.sup.2 wherein R.sup.2 is lower alkyl containing 1 to 6 carbon atoms or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 5-(dimethylamino)-1-naphthyl or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 4-methylphenyl or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 2-thiophenyl or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 4-[[4-(dimethylamino)phenyl]aza]phenyl or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 1-naphthyl or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 8-quinolinyl or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A compound of claim 1 wherein R.sup.1 is methyl or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A compound of claim 1 wherein R.sup.1 is 2,2,2-trifluoroethyl or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A compound of claim 1 wherein R.sup.1 is [methoxycarbonyl]amino or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A process for preparing a compound of formula I as shown and defined in claim 1, which comprises:
a) reacting rapamycin with a compound of formula
R.sup.1 SO.sub.2 hal (II)
or
(R.sup.1 SO.sub.2).sub.2 O (III)
wherein R.sup.1 is as defined in claim 1 and hal is a halogen;
b) reacting rapamycin with a compound of formula
R.sup.2 OCON.sup.- SO.sub.2 N.sup.+ (alkyl).sub.3 (IV)
wherein R.sup.2 is as defined in claim 1 to give a corresponding compound of formula I where R.sup.1 is NHCO.sub.2 R.sup.2 where R.sup.2 is as defined above and if desired after each of the abovementioned processes isolating the compound of formula I in the form of a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 1)

A method of treating transplantation rejection, host versus graft disease, autoimmune diseases, and diseases of inflammation in a mammal by administering an effective amount of a compound of formula I as shown and defined in claim 1.