Claims
- 1. A compound of Formula (I): ##STR5## R.sub.1 is independently hydrogen, NH.sub.2, OH, SH, CN, CO.sub.2 H or hydrogen;
- R.sub.2 is independently hydrogen, C.sub.1-4 alkylC(O)R.sub.5, C.sub.1-4 alkyl or R.sub.2 is benzyl which is optionally substituted by one or two C.sub.1-4 alkyl, C.sub.1-4 alkoxy, F, C1, I, Br, OH, or N(R.sub.4).sub.2 ;
- R.sub.3 is independently hydrogen, C.sub.1-5 alkyl, C.sub.1-5 alkylenehydroxy, C.sub.1-5 alkyleneCO.sub.2 H,
- (CH.sub.2).sub.y N(R.sub.4).sub.2, (CH.sub.2).sub.m C(O)N(R.sub.4).sub.2, C.sub.1-5 alkyleneSH, CH.sub.2 Ar, ##STR6## R.sub.4 is independently hydrogen, C.sub.1-5 alkyl or benzyl; Ar is independently phenyl or indolyl optionally substituted by one or two R.sub.7 groups;
- Q is bicyclo[3.3.0]octanyl, xylyl, benzophenonyl or 1,2,3,4-tetrahydronaphthyl; all of which are unsubstituted or substituted by one or two substituents chosen from: C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, mono or di C.sub.1-4 alkylamino, or --(CH.sub.2).sub.n --COR.sub.6 ;
- R.sub.5 is --OR.sub.6, --N(R.sub.6).sub.2, or --SR.sub.6 ;
- R.sub.6 is hydrogen, C.sub.1-4 alkyl or benzyl;
- R.sub.7 is halogen, R.sub.5 or R.sub.6 ;
- n is independently an integer from 0 to 3;
- m is independently an integer from 1 to 3;
- s is independently 0 or 1; and
- y is independently an integer from 2 to 4;
- provided that n is not 0 when s is 1 and further provided that the compound of Formula (I) is not:
- [(S),(S)]-N,N'-(1,4-xylenediyl)bis[2-acetamido-6,7,8,8a-tetrahydropyrrolo[1,2-.alpha.]pyrazine-1,4(2H, 3H)-dione];
- [(R),(R)]-2,2'-(1,2-xylenediyl)bis[6,7,8,8a-tetrahydropyrrolo[1,2-.alpha.]pyrazine-1,4(2H,3H-dione]; or
- [(S),(S)]-2,2'-(1,3-xylenediyl)bis[6,7,8,8a-tetrahydropyrrolo[1,2-.alpha.]pyrazine-1,4(2H,3H-dione];
- or a pharmaceutically acceptable salt thereof.
- 2. A compound of claim 1 wherein R.sub.1 is OH or H; R.sub.3 is CH.sub.2 OH or H; and Q is xylyl or bicyclo[3.3.0.]octanyl.
- 3. A compound of claim 1 wherein R.sub.1, R.sub.2 and R.sub.3 are hydrogen and Q is xylyl.
- 4. A compound of claim 1 which is:
- [3(S),3'(S),8a(S)]-N,N'-(1,4-xylenediyl)bis[acetamido)-3-(hydroxymethyl)-6,7,8,8a-tetrahydropyrrolo[1,2-.alpha.]pyrazine-1,4(2H,3H)-dione] or
- [(S),(S),2,2'-(1,2-xylenediyl)bis[6,7,8,8a-tetrahydropyrrolo[1,2-.alpha.]pyrazine-1,4(2H,3H-dione]
- [(S),(S),2,2'-(1,2-xylenediyl)bis[6,7,8,8a-tetrahydropyrrolo[1,2-.alpha.]pyrazine-1(2H,3H, 4H)-one].
- 5. A method of preventing or treating bacterial infections which comprises administering to an animal in need thereof, an effective amount of a compound of claim 1.
- 6. A method of preventing or treating sepsis which comprises administering to an animal in need thereof, an effective amount of a compound of claim 1.
- 7. A process for preparing a compound of claim 1 which comprises:
- a) For compounds wherein A is tetrahydropyrrolopyrazinedione, coupling two equivalents of a compound of Formula (II): ##STR7## in which R.sub.1 and R.sub.3 are as defined in claim 1 or a group convertible thereto by removal of a protecting group; with a suitable diamine of Formula (IV):
- HN(R.sub.2)--Q--(R.sub.2)NH (IV)
- in which R.sub.2 and Q are as defined in claim 1;
- with a coupling agent in a suitable solvent and removing any protecting groups; or
- b) For compounds wherein A is tetrahydropyrrolopyrazinone, alkylating a compound of Formula (V): ##STR8## wherein R.sub.1 and R.sub.3 are as defined in claim 1 or a group convertible thereto by removal of a protecting group,
- with one half equivalent of a suitable dihalide of Formula (VI):
- X--Q--X (VI)
- in which X is Cl, F or I and Q is defined in Formula (I), followed if necessary by:
- i) removing any protecting groups; and/or
- ii) salt formation.
Parent Case Info
This application claims the benefit of U.S. Provisional Application Nos. 60/006,641, filed Nov. 13, 1995 and 60/015,537, filed Apr. 17, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US96/18247 |
11/12/1996 |
|
|
11/23/1998 |
11/23/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/18214 |
5/22/1997 |
|
|
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
4499081 |
Laerum et al. |
Feb 1985 |
|
5760003 |
Bhatnagar et al. |
Jun 1998 |
|
Non-Patent Literature Citations (4)
Entry |
DeMarsh et al., J. Infect.Dis.,173,p. 203-211, 1996. |
Pelus et al., Exp.Hematol.,22,p. 239-247, 1994. |
DeMarsh et al., Immunopharmacology,27, p. 199-206, 1994. |
Tomiyasu et al., Chemical Abstracts, vol. 97, No. 145258, 1982. |