U.S. patent application number 12/506794 was filed with the patent office on 2010-03-04 for template-fixed peptidomimetics with antibacterial activity.
This patent application is currently assigned to POLYPHOR LTD.. Invention is credited to Marc Kessler, Daniel Obrecht, John Anthony Robinson, Odile Sellier, Jan Wim Vrijbloed.
Application Number | 20100056432 12/506794 |
Document ID | / |
Family ID | 31896807 |
Filed Date | 2010-03-04 |
United States Patent
Application |
20100056432 |
Kind Code |
A1 |
Vrijbloed; Jan Wim ; et
al. |
March 4, 2010 |
TEMPLATE-FIXED PEPTIDOMIMETICS WITH ANTIBACTERIAL ACTIVITY
Abstract
Template-fixed .beta.-hairpin peptidomimetics of the general
formula (I) wherein Z is a template-fixed chain of 12 .alpha.-amino
acid residues which, depend on their positions in the chain
(counted starting from the N-terminal amino acid) are Gly, or Pro,
or of certain types which, as the remaining symbols in the above
formula, are defined in the description and the claims, and salts
thereof, have the property to selectively inhibit the growth of or
to kill microorganisms such as Pseudomonas aeruginosa and
Acinetobacter. They can be used as disinfectants for foodstuffs,
cosmetics, medicaments or other nutrient-containing materials, or
as medicaments to treat or prevent infections. In a specific
embodiment, the template is based on the D-Pro-L-Pro dipeptides.
These .beta.-hairpin peptidomimetics can be manufactured by
processes which are based on a mixed solid--and solution phase
synthetic strategy.
Inventors: |
Vrijbloed; Jan Wim; (Zurich,
CH) ; Obrecht; Daniel; (Battwil, CH) ;
Robinson; John Anthony; (Wermatswil, CH) ; Sellier;
Odile; (Sausheim, FR) ; Kessler; Marc;
(Bischheim, FR) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Assignee: |
POLYPHOR LTD.
Allschwil
CH
UNIVERSITAT ZURICH
ZURICH
CH
|
Family ID: |
31896807 |
Appl. No.: |
12/506794 |
Filed: |
July 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11062021 |
Feb 18, 2005 |
7582604 |
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12506794 |
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PCT/EP2002/009278 |
Aug 20, 2002 |
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11062021 |
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Current U.S.
Class: |
514/1.1 ;
530/317 |
Current CPC
Class: |
A61P 1/12 20180101; A61P
25/00 20180101; Y02A 50/473 20180101; A61P 13/00 20180101; A61P
13/08 20180101; A61P 19/00 20180101; A61P 19/08 20180101; A61P
31/18 20180101; A61P 17/02 20180101; A61P 35/00 20180101; A61P
29/00 20180101; A61P 11/06 20180101; A61P 13/02 20180101; C07K
5/06165 20130101; C07K 7/64 20130101; A61K 38/00 20130101; A61P
15/08 20180101; A61P 17/00 20180101; A61P 27/02 20180101; A61P
27/00 20180101; A61P 41/00 20180101; A61P 1/00 20180101; A61P 1/04
20180101; A61P 27/16 20180101; A61P 31/00 20180101; A61P 31/04
20180101; C07K 1/047 20130101; Y02A 50/30 20180101; A61P 9/00
20180101; A61P 11/00 20180101 |
Class at
Publication: |
514/9 ;
530/317 |
International
Class: |
A61K 38/12 20060101
A61K038/12; C07K 5/12 20060101 C07K005/12; A61P 11/00 20060101
A61P011/00; A61P 17/02 20060101 A61P017/02; A61P 1/00 20060101
A61P001/00; A61P 27/16 20060101 A61P027/16; A61P 35/00 20060101
A61P035/00 |
Claims
1. Compounds of the general formula ##STR00073## is a group of one
of the formulae ##STR00074## ##STR00075## ##STR00076## ##STR00077##
is the residue of an L-.alpha.-amino acid with B being a residue of
formula --NR.sup.20CH(R.sup.71)-- or the enantiomer of one of the
groups A1 to A69 as defined hereinafter; ##STR00078## is a group of
one of the formulae ##STR00079## ##STR00080## ##STR00081##
##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086##
##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091##
R.sup.1 is H; lower alkyl; or aryl-lower alkyl; R.sup.2 is H;
alkyl; alkenyl; --(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s SO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.3
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s SO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.4
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.s SO.sub.2R.sup.62; of
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.5
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s SO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.6
is H; alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s SO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.7
is alkyl; alkenyl; --(CH.sub.2).sub.q(CHR.sup.61).sub.sOR.sup.55;
--CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.r(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.8
is H; Cl; F; CF.sub.3; NO.sub.2; lower alkyl; lower alkenyl; aryl;
aryl-lower alkyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61)NR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOR.sup.64; R.sup.9 is alkyl;
alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.10
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.0(CHR.sup.61).sub.2NR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.11
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.12
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.r(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.13
is alkyl; alkenyl; --(CH.sub.2).sub.q(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.q(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.14
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSOR.sup.62; or
--(CH.sub.2).sub.q(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.15
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.16
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.17
is alkyl; alkenyl; --(CH.sub.2).sub.q(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.q(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.18
is alkyl; alkenyl; --(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.19
is lower alkyl; --(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.18
and R.sup.19 taken together can form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.20 is H;
alkyl; alkenyl; or aryl-lower alkyl; R.sup.21 is H; alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.0(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.22
is H; alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.0(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.0(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.23
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.24
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.25
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.26
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; or
R.sup.25and R.sup.26 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.rO(CH.sub.2).sub.r--;
--(CH.sub.2).sub.rS(CH.sub.2).sub.r--; or
--(CH.sub.2).sub.rNR.sup.57(CH.sub.2).sub.r--; R.sup.27 is H;
alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61
).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.35R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.28
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.s--OR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.29
is alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.30
is H; alkyl; alkenyl; or aryl-lower alkyl; R.sup.31 is H; alkyl;
alkenyl; --(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.32
is H; lower alkyl; or aryl-lower alkyl; R.sup.33 is H; alkyl,
alkenyl; --(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOR.sup.64;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--CONR.sup.58R.sup.59,
--CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8;
R.sup.34is H; lower alkyl; aryl, or aryl-lower alkyl; R.sup.33 and
R.sup.34 taken together can form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.35 is H;
alkyl; alkenyl; --(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.36
is H, alkyl; alkenyl; --CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.37
is H; F; Br; Cl; NO.sub.2; CF.sub.3; lower alkyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.38
is H; F; Br; Cl; NO.sub.2; CF.sub.3; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.39
is H; alkyl; alkenyl; or aryl-lower alkyl; R.sup.40 is H; alkyl;
alkenyl; or aryl-lower alkyl; R.sup.41 is H; F; Br; Cl; NO.sub.2;
CF.sub.3; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.42
is H; F; Br; Cl; NO.sub.2; CF.sub.3; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.43
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.44
is alkyl; alkenyl; --(CH.sub.2).sub.r(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.r(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.45
is H; alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.s(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.46
is H; alkyl; alkenyl; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.pC.sub.6H.sub.4R.sup.8;
R.sup.47is H; alkyl; alkenyl; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55; R.sup.48 is H; lower
alkyl; lower alkenyl; or aryl-lower alkyl; R.sup.49 is H; alkyl;
alkenyl; --(CHR.sup.61).sub.sCOOR.sup.57;
(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CHR.sup.61).sub.sSOR.sup.62; or
--(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.50 is H; lower
alkyl; or aryl-lower alkyl; R.sup.51 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.pPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.52
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.pPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.53
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.pPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.54
is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61)COOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; R.sup.55
is H; lower alkyl; lower alkenyl; aryl-lower alkyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.57;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--COR.sup.64;
--(CH.sub.2).sub.o(CHR.sup.61)COOR.sup.57; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59; R.sup.56
is H; lower alkyl; lower alkenyl; aryl-lower alkyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.57;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--COR.sup.64; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59; R.sup.57
is H; lower alkyl; lower alkenyl; aryl lower alkyl; or heteroaryl
lower alkyl; R.sup.58 is H; lower alkyl; lower alkenyl; aryl;
heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; R.sup.59
is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower
alkyl; or heteroaryl-lower alkyl; or R.sup.58 and R.sup.59 taken
together can form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.60 is H; lower
alkyl; lower alkenyl; aryl; or aryl-lower alkyl; R.sup.61 is alkyl;
alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower
alkyl; --(CH.sub.2).sub.mOR.sup.55;
--(CH.sub.2).sub.mNR.sup.33R.sup.34;
--(CH.sub.2).sub.mOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.mNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.oCOOR.sup.37; --(CH.sub.2).sub.oNR.sup.58R.sup.59;
or --(CH.sub.2).sub.oPO(COR.sup.60).sub.2; R.sup.62 is lower alkyl;
lower alkenyl; aryl, heteroaryl; or aryl-lower alkyl; R.sup.63 is
H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower alkyl;
heteroaryl-lower alkyl; --COR.sup.64; --COOR.sup.57;
--CONR.sup.58R.sup.59; --SO.sub.2R.sup.62; or
--PO(OR.sup.60).sub.2; R.sup.34and R.sup.63 taken together can
form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.64 is H; lower
alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl;
heteroaryl-lower alkyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.65;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.66; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
R.sup.65 is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;
heteroaryl-lower alkyl; --COR.sup.57; --COOR.sup.57; or
--CONR.sup.58R.sup.59; R.sup.66 is H; lower alkyl; lower alkenyl;
aryl; aryl-lower alkyl; heteroaryl-lower alkyl; or
--CONR.sup.58R.sup.59; m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is
1 or 2; s is 0 or 1; Z is a chain of 12 .alpha.-amino acid
residues, the positions of said amino acid residues in said chain
being counted starting from the N-terminal amino acid, whereby
these amino acid residues are, depending on their position in the
chain, Gly or Pro, or of formula -A-CO-, or of formula -B-CO-, or
of one of the types C: --NR.sup.20CH(R.sup.72)CO--; D:
--NR.sup.20CH(R.sup.73)CO--; E: --NR.sup.20CH(R.sup.74)CO--; F:
--NR.sup.20CH(R.sup.84)CO--; and H:
--NP.sup.20--CH(CO--)--(CH.sub.2).sub.4-7--CH(CO--)--NR.sup.20--;
--NR.sup.20--CH(CO--)--(CH.sub.2).sub.pSS(CH.sub.2).sub.p--CH(CO--)--NP.s-
up.20--;
--NR.sup.20--CH(CO--)--(--(CH.sub.2).sub.pNR.sup.20CO(CH.sub.2).s-
ub.p--CH(CO--)--NR.sup.20--; and
--NR.sup.20--CH(CO--)--(--(CH.sub.2).sub.pNR.sup.20CONR.sup.20(CH.sub.2).-
sub.p--CH(CO--)--NR.sup.20--; R.sup.71 is H; lower alkyl; lower
alkenyl; --(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.75; --(CH.sub.2)
.sub.pCONR.sup.58R.sup.59; --(CH.sub.2).sub.pPO(OR.sup.62).sub.2;
--(CH.sub.2).sub.pSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o--C.sub.6R.sup.67R.sup.68R.sup.69R.sup.70R.sup.76;
R.sup.72 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.85; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.85; R.sup.73 is
--(CH.sub.2).sub.oR.sup.77;
--(CH.sub.2).sub.rO(CH.sub.2).sub.oR.sup.77;
--(CH.sub.2).sub.rS(CH.sub.2).sub.oR.sup.77; or
--(CH.sub.2).sub.rNR.sup.20(CH.sub.2).sub.oR.sup.77; R.sup.74 is
--(CH.sub.2).sub.pNR.sup.78R.sup.79;
--(CH.sub.2).sub.pNR.sup.77R.sup.80;
--(CH.sub.2).sub.pC(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.sup.79,
--(CH.sub.2).sub.pNR.sup.80C(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pN.dbd.C(NR.sup.78R.sup.80)NR.sup.79R.sup.80;
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.77R.sup.80;
--(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.sup.-
79;
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80C(.dbd.NR.sup.80)NR.sup.78R.s-
up.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4N.dbd.C(NR.sup.78R.sup.80)NR.sup.79-
R.sup.80; --CH.sub.2).sub.rO(CH.sub.2).sub.mNR.sup.78R.sup.79;
--CH.sub.2).sub.rO(CH.sub.2).sub.mNR.sup.77R.sup.80;
--CH.sub.2).sub.rO(CH.sub.2).sub.pC(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.s-
up.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.mNR.sup.80C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.mN.dbd.C(NR.sup.78R.sup.80)NR.sup.79R.s-
up.80;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4CNR.sup.78R.sup.79-
;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NOR.sup.50)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NNR.sup.78R.sup.7-
9)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80C(.dbd.NR.sup.8-
0)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mNR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mNR.sup.77R.sup.80;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.s-
up.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mNR.sup.80C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mN.dbd.C(NR.sup.78R.sup.80)NR.sup.79R.s-
up.80;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4CNR.sup.78R.sup.79-
;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NOR.sup.50)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NNR.sup.78R.sup.7-
9)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80C(.dbd.NR.sup.8-
0)NR.sup.78R.sup.79; --(CH.sub.2).sub.pNR.sup.80COR.sup.64;
--(CH.sub.2).sub.pNR.sup.80COR.sup.77;
--(CH.sub.2).sub.pNR.sup.80CONR.sup.78R.sup.79; or
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80CONR.sup.78R.sup.79;
R.sup.75 is lower alkyl; lower alkenyl; or aryl-lower alkyl;
R.sup.33 and R.sup.75 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.75 and
R.sup.82 taken together can form: <CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.76 is H; lower
alkyl; lower alkenyl; aryl-lower alkyl;
--(CH.sub.2).sub.oOR.sup.72; --(CH.sub.2).sub.oSR.sup.72;
--(CH.sub.2).sub.oNR.sup.33R.sup.34;
--(CH.sub.2).sub.oOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.oCOOR.sup.75;
--(CH.sub.2).sub.oCONR.sup.58R.sup.59;
--(CH.sub.2).sub.oPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.pSO.sub.2R.sup.62; or
--(CH.sub.2).sub.oCOR.sup.64; R.sup.77 is
--C.sub.6R.sup.67R.sup.68R.sup.69R.sup.70R.sup.76; or a heteroaryl
group of one of the formulae ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## R.sup.78 is H; lower alkyl; aryl; or
aryl-lower alkyl; R.sup.78 and R.sup.82 taken together can form:
--(CH.sub.2).sub.2-6; --(CH.sub.2)O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.79 is H; lower
alkyl; aryl; or aryl-lower alkyl; or R.sup.78 and R.sup.79, taken
together, can be --(CH.sub.2).sub.2-7--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.80 is H; or
lower alkyl; R.sup.81 is H; lower alkyl; or aryl-lower alkyl;
R.sup.82 is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;
R.sup.33 and R.sup.82 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.83is H; lower
alkyl; aryl; or --NR.sup.78R.sup.79; R.sup.84 is
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOH;
--CH.sub.2).sub.pCONR.sup.78R.sup.79;
--(CH.sub.2).sub.pNR.sup.80CONR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4CONR.sup.78R.sup.79; or
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80CONR.sup.78R.sup.79;
R.sup.85 is lower alkyl; or lower alkenyl; with the proviso that in
said chain of 12 .alpha.-amino acid residues Z the amino acid
residues in positions 1 to 12 are: P1: of type C or of type D or of
type E or of type F, or the residue is Pro; P2: of type D; P3: of
type C, or of type D, or the residue is Pro; P4: of type C, or of
type D, or of type E; P5: of type E, or of type D, or of type C, or
of type F, or the residue is Gly or Pro; P6: of type E, or of type
For of formula -A-CO-, or the residue is Gly; P7: of type C, or of
type E or of type F or of formula -B-CO-; P8: of type D, or of type
C, or of type F, or the residue is Pro; P9: of type C, or of type E
or of type D or of type F; P10: of type F, or of type D or of type
C, or the residue is Pro; P11: of type E or of type D or of type C
or of type F; and P12; of type C or of type D or of type E or of
type F, or the residue is Pro; or P4 and P9 and/or P2 and P11,
taken together, can form a group of type H; and at P6 and P7 also
D-isomers being possible; with the further proviso that the amino
acid residue in P4 is of type C; and/or the amino acid residue in
P5 is of type F; and/or the amino acid residue in P7 is of type C;
and/or the amino acid residue in P8 is of type F; and/or the amino
acid residue in P9 is of type C; and/or the amino acid residue in
P10 is of type F; and/or the amino acid residue in P11 is of type C
or of type F; and pharmaceutically acceptable salts thereof.
2. Compounds according to claim 1 wherein ##STR00097## is a group
of formula (a1) or (a2).
3. Compounds according to claim 2 wherein A is a group of one of
the formulae A1 to A69; R.sup.1 is hydrogen or lower alkyl; R.sup.2
is H; lower alkyl; lower alkenyl; --(CH.sub.2).sub.mOR.sup.55
(where R.sup.55 is lower alkyl; or lower alkenyl);
--CH.sub.2).sub.mSR.sup.56 (where R.sup.56 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33 is
lower alkyl; or lower alkenyl; R.sup.34 is H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; of lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2l O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); (CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.3 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower alkyl; of
lower alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together and
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; of lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
<CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is
H; lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy). R.sup.4 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64(where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: is
H; or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where alkyl; or lower alkenyl);
or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where R.sup.8 is H; F;
Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower alkoxy). R.sup.5
is lower alkyl; lower alkenyl; --(CH.sub.2).sub.oR.sup.55 (where
R.sup.55 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower alkyl; or
lower alkenyl); (CH.sub.2).sub.oNR.sup.33R.sup.34 (where R.sup.33
is lower alkyl; or lower alkenyl; R.sup.34 is H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H
or lower alkyl)--(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is alkyl; alkenyl; aryl;
aryl-lower alkyl; or heteroaryl-lower alkyl);
--(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where
R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sup.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy): R.sup.6 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.7 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.qOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.qSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.qNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qN(R.sup.20)COR.sup.64(where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.qCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.rSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower
alkenyl; --(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; of lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2.sub.2; where R.sup.57 is H; or
lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82 (where
R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower alkyl; or
lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33 and
R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --
(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where R.sup.60 is lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oSO.sub.2R.sup.62 (where
R.sup.62 is lower alkyl; or lower alkenyl); or
--(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where R.sup.8 is H; F; Cl;
CF.sub.3; lower alkyl; lower alkenyl; or lower alkoxy); R.sup.9 is
lower alkyl; lower alkenyl; --(CH.sub.2).sub.oOR.sup.55 (where
R.sup.55 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where R.sup.33
is lower alkyl; or lower alkenyl; R.sup.34 is H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; of lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lowe alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.nN(R.sup.20)COR.sup.64(where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.10 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H is
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.11 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together and
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.r; of
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); or lower alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where
R.sup.57 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58 is lower
alkyl; or lower alkenyl; and R.sup.59 is H; lower alkyl; or
R.sup.58 and R.sup.59 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.12 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.rCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sup.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy): R.sup.13 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.qOR.sup.55 (where R.sup.55 is is lower alkyl; of
lower alkenyl); --(CH.sub.2).sub.qSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.qNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 arid R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lowe alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --CH.sub.2).sub.qN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.qCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.rSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.14 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl is R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.15 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lowe alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --NR.sup.20COlower alkyl (R.sup.20.circleincircle.H; or
lower alkyl); being particularly favoured;
--(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where
R.sup.58 is lower alkyl, or lower alkenyl; and R
.sup.59 is H; lower alkyl; or R.sup.58 and R.sup.59 taken together
are --(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or (CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy); R.sup.16 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--l where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lowe alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; or lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); and R.sup.17 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.qOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.qSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.qNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; of
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.qNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2)2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H; or
lower alkyl); --(CH.sub.2).sub.qN(R.sup.20)COR.sup.64(where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.qCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.rSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
of lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy).
4. Compounds according to claim 2 wherein A is a group of one of
the formulae A5 (with R.sup.2 being H); A8; A22; A25; A38 (with
R.sup.2 being H); A42; and A50.
5. Compounds according to claim 4 wherein A is a group of formula
##STR00098## wherein R.sup.20 is H or lower alkyl; and R.sup.64 is
alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower
alkyl.
6. Compounds according to claim 5 wherein R.sup.64 is n-hexyl;
n-heptyl; 4-(phenyl)benzyl; diphenylmethyl, 3-amino-propyl;
5-amino-pentyl; methyl; ethyl; isopropyl; isobutyl; n-propyl;
cyclohexyl; cyclohexylmethyl; n-butyl; phenyl; benzyl;
(3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl; or
n-nonyl.
7. Compounds according to claim 2 wherein A is a group of one of
the formulae A70 to A104; R.sup.20 is H; or lower alkyl; R.sup.18
is lower alkyl; R.sup.19 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.pSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2O(CH.sub.2).sub.2;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); (CH.sub.2).sub.pCOOR.sup.57 (where R.sup.57: lower alkyl;
or lower alkenyl); (CH.sub.2).sub.pCONR.sup.58R.sup.59 (where
R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.pSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or (CH.sub.2).sub.oC.sub.6H.sub.4R.sup.8 (where
R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy); R.sup.21 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2.sub.2O(CH.sub.2.sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOXONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; or lower alkenyl; R.sup.82 is H; or lower
alkyl; or R.sup.33 and R.sup.82 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.22 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF; lower alkyl; lower alkenyl; or
lower alkoxy); R.sup.23 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --NR.sup.20COlower alkyl (R.sup.20.dbd.H; or lower alkyl)
being particularly favoured; --(CH.sub.2).sub.oCOOR.sup.57 (where
R.sup.57 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58 is lower
alkyl, or lower alkenyl; and R.sup.59 is H; lower alkyl; or
R.sup.58 and R.sup.59 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); R.sup.24 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2.sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lowe alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --NR.sup.20COlower alkyl (R.sup.20.dbd.H; or lower alkyl)
being particularly favoured; --(CH.sub.2).sub.oCOOR.sup.57 (where
R.sup.57 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58 is lower
alkyl, or lower alkenyl; and R.sup.59 is H; lower alkyl; or
R.sup.58 and R.sup.59 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 (where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl;
lower alkenyl; or lower alkoxy); R.sup.25 is H; lower alkyl; lower
alkenyl; --(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower
alkyl; or lower alkenyl); --CH.sub.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl): --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); or lower alkoxy); R.sup.26 is H; lower alkyl;
lower alkenyl; --(CH.sub.2).sub.mOR.sup.55 (where R.sup.55 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkehyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or --(CH.sub.2
).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H; or lower
alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where R.sup.60 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oSO.sub.2R.sup.62
(where R.sup.62 is lower alkyl; or lower alkenyl); or
--(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where R.sup.8 is H; F; Cl;
CF.sub.3; lower alkyl; lower alkenyl; or lower alkoxy); or,
alternatively, R.sup.25 and R.sup.26 taken together are
--(CH.sub.2).sub.2-6--; --CH.sub.2).sup.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.34(CH.sub.2).sub.2--; R.sup.27 is H; lower
alkyl; lower alkenyl; --(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where
R.sup.56 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oNR.sup.33R.sup.34 (where R.sup.33 is lower alkyl;
or lower alkenyl; R.sup.34 is H; or lower alkyl; or R.sup.33 and
R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2_13 ;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy); R.sup.28 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); and R.sup.29 is lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oR.sup.55 (where R.sup.55 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33 is lower alkyl; or lower alkenyl; R.sup.34 is H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is II; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--l or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --NR.sup.20COlower-alkyl (R.sup.20.dbd.H; or lower alkyl)
being particularly favoured; --(CH.sub.2).sub.oCOOR.sup.57 (where
R.sup.57 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58 is lower
alkyl, or lower alkenyl; and R.sup.59 is H; lower alkyl; or
R.sup.58 and R.sup.59 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy).
8. Compounds according to claim 7 wherein R.sup.23, R.sup.24 and
R.sup.29 are --NR.sup.20--CO-lower alkyl where R.sup.20 is H; or
lower alkyl.
9. Compounds according to claim 7 wherein A is a group of one of
the formulae A74 (with R.sup.22 being H); a75; A76; A77 (with
R.sup.22 being H); A78; and A79.
10. Compounds according to claim 2 wherein B is a group of formula
--NR.sup.20CH(R.sup.71)-- or an enantiomer of one of the groups A5
(with R.sup.2 being H); A8; A22; A25; A38 (with R.sup.2 being H);
A42; A47; and A50.
11. Compounds according to claim 10 wherein B-CO is Ala; Arg; Asn;
Cys; Gin; Gly; His; Ile; Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp;
Tyr; Val; Cit; Orn; tBuA; Sar; t-BuG; 4AmPhe; 3AmPhe; 2AmPhe;
Phe(mC(NH.sub.2).dbd.NH; Phe(pC(NH.sub.2).dbd.NH; Phe(rnNHC
(NH.sub.2).dbd.NH; Phe(pNHC (NH.sub.2).dbd.NH; Phg; Cha; C.sub.4al;
C.sub.5al; Nlc; 2-Nal; 1-Nal; 4Cl-Phe; 3Cl-Phe; 2Cl-Phe;
3,4Cl.sub.2Phe; 4F-Phe; 3F-Phe; 2F-Phe; Tic; Thi; Tza; Mso; AcLys;
Dpr; A.sub.2Bu; Dbu; Abu; Aha; Aib; Y(Bzl); Bip; S(Bzl); T(Bzl);
hCha; hCys; hSer, hArg; hPhe; Bpa; Pip; OctG; MePhe; MeNle; MeAla;
MeIle; MeVal; or MeLeu.
12. Compounds according to claim 10 wherein B is a group, having
(L)-configuration, of formula ##STR00099## wherein R.sup.20 is H;
or lower alkyl; and R.sup.64 is alkyl; alkenyl; aryl; aryl-lower
alkyl; or heteroaryl-lower alkyl.
13. Compounds according to claim 12 wherein R.sup.64 is n-hexyl;
n-heptyl; 4-(phenyl)benzyl; diphenylmethyl, 3-amino-propyl;
5-amino-pentyl; methyl; ethyl; isopropyl; isobutyl; n-propyl;
cyclohexyl; cyclohexylmethyl; n-butyl; phenyl; benzyl;
(3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl; or
n-nonyl.
14. Compounds according to claim 1 wherein ##STR00100## is a group
of formula (b1) or (1); R.sup.1 is H; or lower alkyl; R.sup.20 is
H; or lower alkyl; R.sup.30 is H; or methyl; R.sup.31 is H; lower
alkyl; lower alkenyl; --(CH.sub.2).sub.pOR.sup.55 (where R.sup.55
is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33 is lower alkyl;
or lower alkenyl; R.sup.34 is H; or lower alkyl; or R.sup.33 and
R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sup.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.rC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); most preferably --CH.sub.2CONR.sup.58R.sup.59
(where R.sup.58 is H; or lower alkyl; and R.sup.59 is lower alkyl;
or lower alkenyl); R.sup.32 is H; or methyl; R.sup.33 is lower
alkyl; lower alkenyl; --(CH.sub.2).sub.mOR.sup.55 (where R.sup.55
is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.mNR.sup.34R.sup.63 (where R.sup.34 is lower alkyl;
or lower alkenyl; R.sup.63 is H; or lower alkyl; or R.sup.34 and
R.sup.63 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.75R.sup.82 (where
R.sup.75 is lower alkyl; or lower alkenyl; R.sup.82 is H; or lower
alkyl; or R.sup.75 and R.sup.82 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.78R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.78 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.78
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--l where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); R.sup.34 is H; or lower alkyl; R.sup.35: is H;
lower alkyl; lower alkenyl; (CH.sub.2).sub.mOR.sup.55 (where
R.sup.55: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33 is lower alkyl;
or lower alkenyl; R.sup.34 is H; or lower alkyl; or R.sup.33 and
R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl; or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); R.sup.36: lower alkyl; lower alkenyl; or
aryl-lower alkyl; R.sup.37 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33
is lower alkyl; or lower alkenyl; R.sup.34 is H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl);- (CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy); and R.sup.38 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55 is lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33
is lower alkyl; or lower alkenyl; R.sup.34 is H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together sre --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33 is H; or lower alkyl; or lower alkenyl; R.sup.75 is lower
alkyl; or R.sup.33 and R.sup.75 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20 is H; or lower alkyl; R.sup.33 is H; or lower
alkyl; or lower alkenyl; R.sup.82 is H; or lower alkyl; or R.sup.33
and R.sup.82 taken together are --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20 is H; or lower alkyl; R.sup.64 is lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57 is lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 is lower alkyl, or lower alkenyl; and R.sup.59 is
H; lower alkyl; or R.sup.58 and R.sup.59 taken together are
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57 is H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60 is lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62 is lower alkyl;
or lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8
(where R.sup.8 is H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
or lower alkoxy).
15. Compounds according to claim 14 wherein R.sup.1 is H; R.sup.20
is H; R.sup.30 is H; R.sup.31 is carboxymethyl; or lower
alkoxycarbonylmethyl; R.sup.32 is H; R.sup.35 is methyl; R.sup.36
is methoxy; R.sup.37 is H and R.sup.38is H.
16. Compounds according to claim 1 wherein the .alpha.-amino acid
residues in positions 1 to 12 of the chain Z are: P1: of type C or
of type D or of type E or of type F; P2: of type D; P3: of type C;
P4: of type E, or of type C; P5: of type E, or of type F; P6: of
type E, or of type F, or of formula -A-CO-; P7: of type E, or of
type F, or of formula -B-CO-; P8: of type D, or of type C, or of
Type F; P9: of type C, or of type E; P10: of type F, or of type D,
or of type C; P11: of type D, or of type C, or of type F; P12: of
type C or of type D or of type E or of type F; at P6 and P7 also
D-isomers being possible; with the proviso that the amino acid
residue in position P4 is of type C; and/or the amino acid residue
in position P5 is of type F; and/or the amino acid residue in
position P8 is of type F; and/or the amino acid residue in position
P9 is of type C; and/or the amino acid residue in position P10 is
of type F; and/or the amino acid residue in position P11 is of type
C or F.
17. Compounds according to claim 16 wherein the .alpha.-amino acid
residues in positions 1 to 12 of the chain Z are: P1: Arg; P2: Tip;
P3: Leu; P4: Lys or Val; P5: Lys; P6: Arg; P7: Arg; P8: Tip; P9:
Leu, Val or Lys; P10: Tyr, Thr or Gln; P11: Val, Leu, Tyr or Gin;
and P12: Arg; with the proviso that the amino acid residue in
position P4 is Val; and/or the amino acid residue in position P9 is
Leu or Val; and/or the amino acid residue in position P10 is Thr or
Gin; and/or the amino acid residue in position P11 is Val or Leu or
Gin.
18-19. (canceled)
20. A compound of formula I according to claim 1 wherein the
template is .sup.DPro-.sup.LPro and the amino acid residues in
position 1-12 are: P1: Arg; P2: Tip; P3: Leu; P4: Lys; P5: Lys; P6:
Arg; P7: Arg; P8: Tip; P9: Lys; P10: Thr; P11: Tyr; and P12:
Arg
21-24. (canceled)
25. Enantiomers of the compounds of formulae I as defined in claim
1.
26. Compounds according to claim 1 for use as therapeutically
active substances.
27. Compounds according to claim 26 having selective antimicrobial
activity being in particular against Pseudomonas aeruginosa or
Acinetobacter.
28. A pharmaceutical composition containing a compound according to
claim 1 and a pharmaceutically inert carrier.
29. Compositions according to claim 28 in a form suitable for oral,
topical, transdermal, injection, buccal, transmucosal, pulmonary or
inhalation administration.
30. Compositions according to claim 28 in form of tablets, dragees,
capsules, solutions, liquids, gels, plaster, creams, ointments,
syrup, slurries, suspensions, spray, nebuliser or
suppositories.
31. The use of compounds according to claim 1 for the manufacture
of a medicament for treating or preventing infections or diseases
related to such infections.
32. The use according to claim 31 wherein said infections are
related to respiratory diseases such as cystic fibrosis, emphysema
and asthma; related to skin or soft tissue diseases such as
surgical wounds, traumatic wounds or burn Wounds; related to
gastrointestinal diseases such as epidemic diarrhea, necrotizing
enterocolitis or typhlitis; related to eye diseases such as
keratitis or endophthalmitis; related to ear diseases such as
otitis; related to CNS diseases such as brain abscess or
meningitis; related to bone diseases such as osteochondritis or
osteomyelitis; related to cardiovascular diseases such as
endocartitis or pericarditis; related to gastrourinal diseases such
as epididymitis, prostatitis or urethritis; related to cancer; or
related to HIV.
33. The use of compounds according to claim 1 as disinfectants or
preservatives for foodstuffs, cosmetics, medicaments and other
nutrient-containing materials.
34. A process for the manufacture of compounds according to claim 1
which process comprises (a) coupling an appropriately
functionalized solid support with an appropriately N-protected
derivative of that amino acid Which in the desired end-product is
in position 5, 6 or 7, any functional group which may be present in
said N-protected amino acid derivative being likewise appropriately
protected; (b) removing the N-protecting group from the product
thus obtained; (c) coupling the product thus obtained with an
appropriately N-protected derivative of that amino acid which in
the desired end-product is one position nearer the N-terminal amino
acid residue, any functional group which may be present in said
N-protected amino acid derivative being likewise appropriately
protected; (d) removing the N-protecting group from the product
thus obtained; (e) repeating steps (c) and (d) until the N-terminal
amino acid residue has been introduced; (f) coupling the product
thus obtained with a compound of the general formula ##STR00101##
is as defined above and X is an N-protecting group or, if
##STR00102## is to be group (a1) or (a2), above, alternatively (fa)
coupling the product obtained in step (e) with an appropriately
N-protected derivative of an amino acid of the general formula
HOOC-B-H III or HOOC-A-H IV wherein B and A are as defined above,
any functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; (fb)
removing the N-protecting group from the product thus obtained; and
(fc) coupling the product thus obtained with an appropriately
N-protected derivative of an amino acid of the above general
formula IV and, respectively, III, any functional group which may
be present in said N-protected amino acid derivative being likewise
appropriately protected; (g) removing the N-protecting group from
the product obtained in step (f) or (fc); (h) coupling the product
thus obtained with an appropriately N-protected derivative of that
amino acid which in the desired end-product is in position 12, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; (i)
removing the N-protecting group from the product thus obtained; (j)
coupling the product thus obtained with an appropriately
N-protected derivative of that amino acid which in the desired
end-product is one position farther away from position 12, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; (k)
removing the N-protecting group from the product thus obtained; (l)
repeating steps (j) and (k) until all amino acid residues have been
introduced; (m) if desired, selectively deprotecting one or several
protected functional group(s) present in the molecule and
appropriately substituting the reactive group(s) thus liberated;
(o) detaching the product thus obtained from the solid support; (p)
cyclizing the product cleaved from the solid support; (q) if
desired, forming one or two interstrand lihkage(s) between
side-chains of appropriate amino acid residues at opposite
positions of the p-strand region; (r) removing any protecting
groups present on functional groups of any members of the chain of
amino acid residues and, if desired, any protecting group(s) which
may in addition be present in the molecule; and (s) if desired,
converting the product thus obtained into a pharmaceutically
acceptable salt or converting a pharmaceutically acceptable, or
unacceptable, salt thus obtained into the corresponding free
compound of formula I or into a different, pharmaceutically
acceptable, salt.
35. A process for the manufacture of compounds according to claims
1 which process comprises (a') coupling an appropriately
functionalized solid support with a compound of the general formula
##STR00103## is as defined above and X is an N-protecting group or,
if ##STR00104## is to be group (a1) or (a2), above, alternatively
(a'a) coupling said appropriately functionalized solid support with
an appropriately N-protected derivative of an amino acid of the
general formula HOOC-B-H III or HOOC-A-H IV wherein B and A are as
defined above, any functional group Which may be present in said
N-protected amino acid derivative being likewise appropriately
protected; (a'b) removing the N-protecting group from the product
thus obtained; and (a'c) coupling the product thus obtained with an
appropriately N-protected derivative of an amino acid of the above
general formula IV and, respectively, III, any functional group
which may be present in said N-protected amino acid derivative
being likewise appropriately protected; (b') removing the
N-protecting group from the product obtained in step (a') or (a'c);
(c') coupling the product thus obtained with an appropriately
N-protected derivative of that amino acid which in the desired
end-product is in position 12, any functional group which may be
present in said N-protected amino acid derivative being likewise
appropriately protected; (d') removing the N-protecting group from
the product thus obtained; (e') coupling the product thus obtained
with an appropriately N-protected derivative of that amino acid
which in the desired end-product is one position farther away from
position 12, any functional group which may be present in said
N-protected amino acid derivative being likewise appropriately
protected; (f) removing the N-protecting group from the product
thus obtained; (g') repeating steps (e') and (f') until all amino
acid residues have been introduced; (h) if desired, selectively
deprotecting one or several protected functional group(s) present
in the molecule and appropriately substituting the reactive
group(s) thus liberated; (i') detaching the product thus obtained
from the solid support; (j') cyclizing the product cleaved from the
solid support; (k') if desired forming one or two interstrand
linkage(s) between side-chains of appropriate amino acid residues
at opposite positions of the p-strand region; (l') removing any
protecting groups present on functional groups of any members of
the chain of amino acid residues and, if desired, any protecting
group(s) which may in addition be present in the molecule; and (m')
if desired, converting the product thus obtained into a
pharmaceutically acceptable salt or converting a pharmaceutically
acceptable, or unacceptable, salt thus obtained into the
corresponding free compound of formula I or into a different,
pharmaceutically acceptable, salt.
Description
[0001] The present invention provides template-fixed .beta.-hairpin
peptidomimetics incorporating a template-fixed chain of 12
.alpha.-amino acid residues which, depending on their positions in
the chain, are Gly or Pro, or of certain types, as defined herein
below. These template-fixed .beta.-hairpin mimetics have a
selective antimicrobial activity. In addition, the present
invention provides efficient synthetic processes by which these
compounds can, if desired, be made in parallel library-format.
These .beta.-hairpin peptidomimetics show improved efficacy,
bioavailability, half-life and most importantly a significantly
enhanced ratio between antibacterial activity on the one hand, and
hemolysis of red blood cells on the other.
[0002] The growing problem of microbial resistance to established
antibiotics has stimulated intense interest in developing novel
antimicrobial agents with new modes of action (H. Breithaupt, Nat.
Biotechnol. 1999, 17, 1165-1169). One emerging class of antibiotics
is based on naturally occurring cationic peptides (T. Ganz, R. I.
Lehrer, Mol. Medicine Today 1999, 5, 292-297; R. M. Epand, H. J.
Vogel, Biochim. Biophys. Acta 1999, 1462, 11-28). These include
disulfide-bridged .beta.-hairpin and .beta.-sheet peptides (such as
the protegrins [V. N. M.; O. V. Shamova, H. A. Korneva, R. I.
Lehrer, FEBS Lett. 1993, 327, 231-236], tachyplesins [T. Nakamura,
H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M. Niwa,
T. Takao, Y. Shimonishi, Y. J. Biol. Chem. 1988, 263, 16709-16713],
and the defensins [R. I. Lehrer, A. K. Lichtenstein, T. Ganz, Annu.
Rev. Immunol. 1993, 11, 105-128], amphipathic .alpha.-helical
peptides (e.g. cecropins, dermaseplins, magainins, and mellitins
[A. Tossi, L. Sandri, A. Giangaspero, Biopolymers 2000, 55, 4-30]),
as well as other linear and loop-structured peptides. Although the
mechanisms of action of antimicrobial cationic peptides are not yet
fully understood, their primary site of interaction is the
microbial cell membrane (H. W. Huang, Biochemistry 2000, 39,
8347-8352). Upon exposure to these agents, the cell membrane
undergoes permeabilization, which is followed by rapid cell death.
However, more complex mechanisms of action, for example, involving
receptor-mediated signaling, cannot presently be ruled out (M. Wu,
E. Maier, R. Benz, R. E. Hancock, Biochemistry 1999, 38,
7235-7242).
[0003] The antimicrobial activities of many of these cationic
peptides usually correlate with their preferred secondary
structures, observed either in aqueous solution or in membrane-like
environments (N. Sitaram, R. Nagaraj, Biochim. Biophys. Acta 1999,
1462, 29-54). Structural studies by nuclear magnetic resonance
(NMR) spectroscopy have shown that cationic peptides such as
protegrin 1 (A. Aumelas, M. Mangoni, C. Roumestand, L. Chiche, E.
Despaux, G. Grassy, B. Calas, A. Chavanieu, A. Eur. J. Biochem.
1996, 237, 575-583; R. L. Fahrner, T. Dieckmann, S. S. L. Harwig,
R. I. Lehrer, D. Eisenberg, J. Feigon, J. Chem. Biol. 1996, 3,
543-550) and tachyplesin I (K. Kawano, T. Yoneya, T. Miyata, K.
Yoshikawa, F. Tokunaga, Y. Terada, S. J. Iwanaga, S. J. Biol. Chem.
1990, 265, 15365-15367) adopt well defined .beta.-hairpin
conformations, due to the constraining effect of two disulfide
bridges. In protegrin analogues lacking one or both of these
disulfide bonds, the stability of the .beta.-hairpin conformation
is diminished, and the antimicrobial activity is reduced (J. Chen,
T. J. Falla, H. J. Liu, M. A. Hurst, C. A. Fujii, D. A. Mosca, J.
R. Embree D. J. Loury, P. A. Radel, C. C. Chang, L. Gu, J. C.
Fiddes, Biopolymers 2000, 55, 88-98; S. L. Harwig, A. Waring, H. J.
Yang, Y. Cho, L. Tan, R. I. Lehrer, R. J. Eur. J. Biochem. 1996,
240, 352-357; M. E. Mangoni, A. Aumelas, P. Charnet, C. Roumestand,
L. Chiche, E. Despaux, G. Grassy, B. Calas, A. Chavanieu, FEBS
Lett. 1996, 383, 93-98; H. Tamamura, T. Murakami, S. Noriuchi, K.
Sugihara, A. Otaka, W. Takada, T. Ibuka, M. Waki, N. Tamamoto, N.
Fujii, Chem. Pharm. Bull. 1995, 43, 853-858). Similar observations
have been made in analogues of tachyplesin I (H. Tamamura, R.
Ikoma, M. Niwa, S. Funakoshi, T. Murakami, N. Fujii, Chem. Pharm.
Bull. 1993, 41, 978-980) and in hairpin-loop mimetics of rabbit
defensin NP-2 (S. Thennarasu, R. Nagaraj, Biochem. Biophys. Res.
Comm. 1999, 254, 281-283). These results show that the
.beta.-hairpin structure plays an important role in the
antimicrobial activity and stability of these protegrin-like
peptides. In the case of the cationic peptides preferring a-helical
structures, the amphililic structure of the helix appears to play a
key role in determining antimicrobial activity (A. Tossi, L.
Sandri, A. Giangaspero, A. Biopolymers 2000, 55, 4-30). Gramicidin
S is a backbone-cyclic peptide with a well defined .beta.-hairpin
structure (S. E. Hull, R. Karlsson, P. Main, M. M. Woolfson, E. J.
Dodson, Nature 1978, 275, 206-275) that displays potent
antimicrobial activity against gram-positive and gram-negative
bacteria (L. H. Kondejewski, S. W. Farmer, D. S. Wishart, R. E.
Hancock, R. S. Hodges, Int. J. Peptide Prot. Res. 1996, 47,
460-466). The high hemolytic activity of gramicidin S has, however,
hindered its widespread use as an antibiotic. Recent structural
studies by NMR have indicated that the high hemolytic activity
apparently correlates with the highly amphipathic nature of this
cyclic .beta.-hairpin-like molecule, but that it is possible to
dissociate antimicrobial and hemolytic activities by modulating the
conformation and amphiphilicity (L. H. Kondejewski, M.
Jelokhani-Niaraki, S. W. Farmer, B. Lix, M. Kay, B. D. Sykes, R. E.
Hancock, R. S. Hodges, J. Biol. Chem. 1999, 274, 13181-13192; C.
McInnes L. H. Kondejewski, R. S. Hodges, B. D. Sykes, J. Biol.
Chem. 2000, 275, 14287-14294).
[0004] A new cyclic antimicrobial peptide RTD-1 was reported
recently from primate leukocytes (Y.-Q. Tang, J. Yuan, G. Osapay,
K. Osapay, D. Tran, C. J. Miller, A. J. Oellette, M. E. Selsted,
Science 1999, 286, 498-502. This peptide contains three disulfide
bridges, which act to constrain the cyclic peptide backbone into a
hairpin geometry. Cleavage of the three disulfide bonds leads to a
significant loss of antimicrobial activity. Analogues of protegrins
(J. P. Tam, C. Wu, J.-L. Yang, Eur. J. Biochem. 2000, 267,
3289-3300) and tachyplesins (J.-P. Tam, Y.-A. Lu, J.-L. Yang,
Biochemistry 2000, 39, 7159-7169; N. Sitaram, R. Nagaraij, Biochem.
Biophys. Res. Comm. 2000, 267, 783-790) containing a cyclic peptide
backbone, as well as multiple disulfide bridges to enforce a
amphiphilic hairpin structure, have also been reported. In these
cases, removal of all the cystine constraints does not always lead
to a large loss of antimicrobial activity, but does modulate the
membranolytic selectivity (J. P. Tam, C. Wu, J.-L. Yang, Eur. J.
Biochem. 2000, 267, 3289-3300).
[0005] A key issue in the design of new selective cationic
antimicrobial peptides are bioavailability, stability and reduced
haemolytic activity. The naturally occurring protegrins and
tachyplesins exert a significant hemolytic activity against human
red blood cells. This is also the case for protegrin analogues such
as IB367 (J. Chen, T. J. Falla, H. J. Liu, M. A. Hurst, C. A.
Fujii, D. A. Mosca, J. R. Embree, D. J. Loury, P. A. Radel, C. C.
Chang, L. Gu, J. C. Fiddes, Biopolymers 2000, 55, 88-98; C. Chang,
L. Gu, J. Chen, U.S. Pat. No. 5,916,872, 1999). This high hemolytic
activity essentially obviates its use in vivo, and represents a
serious disadvantage in clinical applications. Also, the antibiotic
activity of analogues often decreases significantly with increasing
salt concentration, such that under in vivo conditions (ca. 100-150
mM NaCl) the antimicrobial activity may be severely reduced.
[0006] Protegrin 1 exhibits potent and similar activity against
gram-positive and gram-negative bacteria as well as fungi in both
low- and high-salt assays. This broad antimicrobial activity
combined with a rapid mode of action, and their ability to kill
bacteria resistant to other classes of antibiotics, make them
attractive targets for development of clinically useful
antibiotics. The activity against gram-positive bacteria is
typically higher than against gram-negative bacteria. However,
protegrin 1 also exhibits a high hemolytic activity against human
red blood cells, and hence a low selectivity towards microbial
cells. Oriented CD experiments (W. T. Heller, A. J. Waring, R. I.
Lehrer, H. W. Huang, Biochemistry 1998, 37, 17331-17338) indicate
that protegrin 1 may exist in two different states as it interacts
with membranes, and these states are strongly influenced by lipid
composition. Studies of cyclic protegrin analogues (J.-P. Tam, C.
Wu, J.-L. Yang, Eur. J. Biochem. 2000, 267, 3289-3300) have
revealed, that an increase in the conformational rigidity,
resulting from backbone cyclization and multiple disulfide bridges,
may confer membranolytic selectivity that dissociates antimicrobial
activity from hemolytic activity, at least in the series of
compounds studied.
[0007] Protegrin 1 is an 18 residues linear peptide, with an
amidated carboxyl terminus and two disulfide bridges. Tachyplesin I
contains 17 residues, also has an amidated carboxyl terminus and
contains two disulfide bridges. Recently described backbone-cyclic
protegrin and tachyplesin analogues typically contain 18 residues
and up to three disulfide bridges (J. P. Tam, C. Wu, J.-L. Yang,
Eur. J. Biochem. 2000, 267, 3289-3300; J. P. Tam, Y.-A. Lu, J.-L.
Yang, Biochemistry 2000, 39, 7159-7169; N. Sitaram, R. Nagaraij,
Biochem. Biophys. Res. Comm. 2000, 267, 783-790).
[0008] Cathelicidin, a 37-residue linear helical-type cationic
peptide, and analogues are currently under investigation as inhaled
therapeutic agents for cystic fibrosis(CF) lung disease (L. Saiman,
S. Tabibi, T. D. Starner, P. San Gabriel, P. L. Winokur, H. P. Jia,
P. B. McGray, Jr., B. F. Tack, Antimicrob. Agents and Chemother.
2001, 45, 2838-2844; R. E. W. Hancock, R. Lehrer, Trends
Biotechnol. 1998, 16, 82-88). Over 80% of CF patients become
chronically infected with pseudomonas aeruginosa (C. A. Demko, P.
J. Biard, P. B. Davies, J. Clin. Epidemiol. 1995, 48, 1041-1049; E.
M. Kerem, R. Gold, H. Levinson, J. Pediatr. 1990, 116, 714-719).
Other antimicrobial peptides against Pseudomonads (Y. H. Yau, B.
Ho, N. S. Tan, M. L. Ng, J. L. Ding, Antimicrob. Agents and
Chemother. 2001, 45, 2820-2825 and herein cited references), like
FALL-39, SMAP-29, and lepidopteran cecropin display a few of the
desired attributes like potent antimicrobial activity over a wide
range of pH, rapid killing rate, and low hemolytic activity.
[0009] In the compounds described below, a new strategy is
introduced to stabilize .beta.-hairpin conformations in
backbone-cyclic cationic peptide mimetics exhibiting selective
antimicrobial activity. This involves transplanting the cationic
and hydrophobic hairpin sequence onto a template, whose function is
to restrain the peptide loop backbone into a hairpin geometry.
[0010] Template-bound hairpin mimetic peptides have been described
in the literature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv.
Med. Chem. 1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000,
4,429-441), but such molecules have not previously been evaluated
for development of selective antimicrobial peptides. However, the
ability to generate .beta.-hairpin peptidomimetics using
combinatorial and parallel synthesis methods has now been
established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A.
Robinson, Helv. Chim. Acta. 2000, 83, 3097-3112). These methods
allow the synthesis and screening of large hairpin mimetic
libraries, which in turn considerably facilitates
structure-activity studies, and hence the discovery of new
molecules with potent selective antimicrobial and very low
hemolytic activity to human red blood cells. The present strategy
allows to synthesize .beta.-hairpin peptidomimetics with novel
selectivities towards various multi-drug resistant pseudomonas--or
acinetobacter strains.
[0011] The .beta.-hairpin peptidomimetics of the present invention
are compounds of the general formula
##STR00001##
[0012] is a group of one of the formulae
##STR00002## ##STR00003## ##STR00004## ##STR00005##
[0013] is the residue of an L-.alpha.-amino acid with B being a
residue of formula --NR.sup.20CH(R.sup.71)-- or the enantiomer of
one of the groups A1 to A69 as defined hereinafter;
##STR00006##
[0014] is a group of one of the formulae
##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017## ##STR00018## ##STR00019## [0015] R.sup.1 is H; lower
alkyl; or aryl-lower alkyl; [0016] R.sup.2 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0017]
R.sup.3 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.6l).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0018]
R.sup.4 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0019]
R.sup.5 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0020]
R.sup.6 is H; alkyl; alkenyl;
--CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.67; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0021]
R.sup.7 is alkyl; alkenyl;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCONR.sup.5BR.sup.59;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.r(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0022]
R.sup.8 is H; Cl; F; CF.sub.3; NO.sub.2; lower alkyl; lower
alkenyl; aryl; aryl-lower alkyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61)NR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOR.sup.64; [0023] R.sup.9 is
alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R .sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0024]
R.sup.10 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0025]
R.sup.11 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.5BR.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0026]
R.sup.12 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.s(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0027]
R.sup.13 is alkyl; alkenyl;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.q(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0028]
R.sup.14 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSOR.sup.62; or
--(CH.sub.2).sub.q(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0029]
R.sup.15 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0030]
R.sup.16 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0031]
R.sup.17 is alkyl; alkenyl;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.q(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.q(CHR.sup.61).sub.sC.sub.6H.sub.4.sup.8; [0032]
R.sup.18 is alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0033]
R.sup.19 is lower alkyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; or
[0034] R.sup.18 and R.sup.19 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0035] R.sup.20 is
H; alkyl; alkenyl; or aryl-lower alkyl; [0036] R.sup.21 is H;
alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.6l).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0037]
R.sup.22 is H; alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sup.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2.sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0038]
R.sup.23 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0039]
R.sup.24 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0040]
R.sup.25 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0041]
R.sup.26 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; or
[0042] R.sup.25and R.sup.26 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.rO(CH.sub.2).sub.r--;
--(CH.sub.2).sub.rS(CH.sub.2).sub.r--; or
--(CH.sub.2).sub.rNR.sup.57(CH.sub.2).sup.r--; [0043] R.sup.27 is
H; alkyl; alkenyl; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34; [0044]
(CH.sub.2).sub.o (CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58
R.sup.59; --(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0045]
R.sup.28 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--OR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0046]
R.sup.29 is alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0047]
R.sup.30 is H; alkyl; alkenyl; or aryl-lower alkyl; [0048] R.sup.31
is H; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4 R.sup.8; [0049]
R.sup.32 is H; lower alkyl; or aryl-lower alkyl; [0050] R.sup.33 is
H; alkyl, alkenyl; --(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOR.sup.64;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--CONR.sup.58R.sup.59;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0051]
R.sup.34 is H; lower alkyl; aryl, or aryl-lower alkyl; [0052]
R.sup.33 and R.sup.34 taken together can form:
--(CH.sub.2).sub.2-6; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0053] R.sup.35 is
H; alkyl; alkenyl; --(CH.sub.2.sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0054]
R.sup.36 is H, alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.2NR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0055]
R.sup.37 is H; F; Br; Cl; NO.sub.2; CF.sub.3; lower alkyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0056]
R.sup.38 is H; F; Br; Cl; NO.sub.2; CF.sub.3; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0057]
R.sup.39 is H; alkyl; alkenyl; or aryl-lower alkyl; [0058] R.sup.40
is H; alkyl; alkenyl; or aryl-lower alkyl; [0059] R.sup.41 is H; F;
Br; Cl; NO.sub.2; CF.sub.3; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0060]
R.sup.42 is H; F; Br; Cl; NO.sub.2; CF.sub.3; alkyl; alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sub.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0061]
R.sup.43 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sub.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.5BR.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0062]
R.sup.44 is alkyl; alkenyl;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.r(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.r(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0063]
R.sup.45 is H; alkyl; alkenyl;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.s(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.s(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0064]
R.sup.46 is H; alkyl; alkenyl; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.pC.sub.6H.sub.4R.sup.8; [0065]
R.sup.47 is H; alkyl; alkenyl; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sOR.sup.55; [0066] R.sup.48 is
H; lower alkyl; lower alkenyl; or aryl-lower alkyl; [0067] R.sup.49
is H; alkyl; alkenyl; --(CHR.sup.61).sub.sCOOR.sup.57;
(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
(CHR.sup.61).sub.sPO(OR.sup.60).sub.2;
--(CHR.sup.61).sub.sSOR.sup.62; or
--(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0068] R.sup.50 is H;
lower alkyl; or aryl-lower alkyl; [0069] R.sup.51 is H; alkyl;
alkenyl; --(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sup.2).sub.o(CHR.sup.61).sub.pPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0070]
R.sup.52 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.pPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0071]
R.sup.53 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sSR.sup.56;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59;
--(CH.sub.2).sub.o(CHR.sup.61).sub.pPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sSO.sub.2R.sup.62; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0072]
R.sup.54 is H; alkyl; alkenyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.55;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61)COOR.sup.57;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sC.sub.6H.sub.4R.sup.8; [0073]
R.sup.55 is H; lower alkyl; lower alkenyl; aryl-lower alkyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.57;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--COR.sup.64;
--(CH.sub.2).sub.o(CHR.sup.61)COOR.sup.57; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59; [0074]
R.sup.56 is H; lower alkyl; lower alkenyl; aryl-lower alkyl;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOR.sup.57;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOCONR.sup.75R.sup.8;
--(CH.sub.2).sub.m(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.s--COR.sup.64; or
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCONR.sup.58R.sup.59; [0075]
R.sup.57 is H; lower alkyl; lower alkenyl; aryl lower alkyl; or
heteroaryl lower alkyl; [0076] R.sup.58 is H; lower alkyl; lower
alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower
alkyl; [0077] R.sup.59 is H; lower alkyl; lower alkenyl; aryl;
heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; or [0078]
R.sup.58 and R.sup.59 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0079] R.sup.60 is
H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl; [0080]
R.sup.61 is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;
heteroaryl-lower alkyl; --(CH.sub.2).sub.mOR.sup.55;
--(CH.sub.2).sub.mNR.sup.33R.sup.34;
--(CH.sub.2).sub.mOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.mNR.sup.20CONR.sup.78R.sup.82;
--(CH.sub.2).sub.oCOOR.sup.37; --(CH.sub.2).sub.oNR.sup.58R.sup.59;
or --(CH.sub.2).sub.oPO(COR.sup.60).sub.2; [0081] R.sup.62 is lower
alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower alkyl; [0082]
R.sup.63 is H; lower alkyl; lower alkenyl; aryl, heteroaryl;
aryl-lower alkyl; heteroaryl-lower alkyl; --COR.sup.64;
--COOR.sup.57; --CONR.sup.58R.sup.59; --SO.sub.2R.sup.62; or
--PO(OR.sup.60).sub.2; [0083] R.sup.34and R.sup.63 taken together
can form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0084] R.sup.64 is
H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl;
heteroaryl-lower alkyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.65;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.66; or
--(CH.sub.2).sub.p.sub.(CHR.sup.61).sub.sNR.sup.34R.sup.63;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.75R.sup.82;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.78R.sup.82;
[0085] R.sup.65 is H; lower alkyl; lower alkenyl; aryl, aryl-lower
alkyl; heteroaryl-lower alkyl; --COR.sup.57; --COOR.sup.57; or
--CONR.sup.58R.sup.59; [0086] R.sup.66 is H; lower alkyl; lower
alkenyl;;aryl; aryl-lower alkyl; heteroaryl-lower alkyl; or
--CONR.sup.58R.sup.59; [0087] m is 2-4; o is 0-4; p is 1-4; q is
0-2; r is 1 or 2; s is 0 or 1;
[0088] Z is a chain of 12 .alpha.-amino acid residues, the
positions of said amino acid residues in said chain being counted
starting from the N-terminal amino acid, whereby these amino acid
residues are, depending on their position in the chain, Gly or Pro,
or of formula -A-CO--, or of formula --B--CO--, or of one of the
types [0089] C: NR.sup.20CH(R.sup.72)CO--; [0090] D:
--NR.sup.20CH(R.sup.73)CO--; [0091] E: --NR.sup.20CH(R.sup.74)CO--;
[0092] F: --NR.sup.20CH(R.sup.84)CO--; [0093] H:
--NR.sup.20--CH(CO--)--(CH.sub.2).sub.4-7--CH(CO--)--NR.sup.20-- -;
--NR.sup.20--CH(CO--)--(CH.sub.2).sub.pSS(CH.sub.2).sub.p--CH(CO--)--NR-
.sup.20--;
--NR.sup.20--CH(CO--)--(--(CH.sub.2).sub.pNR.sup.20CO(CH.sub.2)-
.sub.p--CH(CO--)--NR.sup.20--; and
--NR.sup.20CH(CO--)--(--(CH.sub.2).sub.pNR.sup.20CONR.sup.20(CH.sub.2).su-
b.p--CH(CO--)--NR.sup.20--; [0094] R.sup.71 is H; lower alkyl;
lower alkenyl; --(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.33R.sup.34;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.o(CHR.sup.61).sub.sCOOR.sup.75;
--(CH.sub.2).sub.pCONR.sup.58R.sup.59;
--(CH.sub.2).sub.pPO(OR.sup.62).sub.2;
--(CH.sub.2).sub.pSO.sub.2R.sup.62; or
--(CH.sub.2).sub.o--C.sub.6R.sup.67R.sup.68R.sup.69R.sup.70R.sup.76;
[0095] R.sup.72 is H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.p(CHR.sup.61).sub.sOR.sup.85; or
--(CH.sub.2).sub.p(CHR.sup.61).sub.sSR.sup.85; [0096] R.sup.73 is
--(CH.sub.2).sub.oR.sup.77;
--(CH.sub.2).sub.rO(CH.sub.2).sub.oR.sup.77;
--(CH.sub.2).sub.rS(CH.sub.2).sub.oR.sup.77; or
--(CH.sub.2).sub.rNR.sup.20(CH.sub.2).sub.oR.sup.77; [0097]
R.sup.74 is --(CH.sub.2).sub.pNR.sup.78R.sup.79;
--(CH.sub.2).sub.pNR.sup.77R.sup.80;
--(CH.sub.2).sub.pC(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pNR.sup.80C(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pN.dbd.C(NR.sup.78R.sup.80)NR.sup.79R.sup.80;
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.77R.sup.80;
--(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.sup.-
79;
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80C(.dbd.NR.sup.80)NR.sup.78R.s-
up.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4N.dbd.C(NR.sup.78R.sup.80)NR.sup.79-
R.sup.80; --(CH.sub.2).sub.rO(CH.sub.2).sub.mNR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.mNR.sup.77R.sup.80;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.s-
up.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.mNR.sup.80C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.mN.dbd.C(NR.sup.78R.sup.80)NR.sup.79R.s-
up.80;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4CNR.sup.78R.sup.79-
;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NOR.sub.50)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NNR.sup.78R.sup.7-
9)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rO(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80C(.dbd.NR.sup.8-
0)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mNR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mNR.sup.77R.sup.80;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC(.dbd.NR.sup.80)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC(.dbd.NOR.sup.50)NR.sup.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC(.dbd.NNR.sup.78R.sup.79)NR.sup.78R.s-
up.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mNR.sup.80C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.mN.dbd.C(NR.sup.78R.sup.80)NR.sup.79R.s-
up.80;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4CNR.sup.78R.sup.79-
;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NR.sup.80)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NOR.sup.50)NR.sup-
.78R.sup.79;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4C(.dbd.NNR.sup.78R.sup.7-
9;
--(CH.sub.2).sub.rS(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80C(.dbd.NR.sup-
.80)NR.sup.78R.sup.79; --(CH.sub.2.sub.pNR.sup.80COR.sup.64;
--(CH.sub.2).sub.pNR.sup.80COR.sup.77;
--(CH.sub.2).sub.pNR.sup.80CONR.sup.78R.sup.79; or
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80CONR.sup.78R.sup.79;
[0098] R.sup.75 is lower alkyl; lower alkenyl; or aryl-lower alkyl;
[0099] R.sup.33 and R.sup.75 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0100] R.sup.75 and
R.sup.82 taken together can form: --(CH.sub.2).sub.2-6;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0101] R.sup.76 is
H; lower alkyl; lower alkenyl; aryl-lower alkyl;
--(CH.sub.2).sub.oOR.sup.72; --(CH.sub.2).sub.oSR.sup.72;
--(CH.sub.2).sub.oNR.sup.33R.sup.34;
--(CH.sub.2).sub.oOCONR.sup.33R.sup.75;
--(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82;
--(CH.sub.2).sub.oCOOR.sup.75;
--(CH.sub.2).sub.oCONR.sup.58R.sup.59;
--(CH.sub.2).sub.oPO(OR.sup.60).sub.2;
--(CH.sub.2).sub.pSO.sub.2R.sup.62; or
--(CH.sub.2).sub.oCOR.sup.64; [0102] R.sup.77 is
C.sub.6R.sup.67R.sup.68R.sup.69R.sup.70R.sup.76; or a heteroaryl
group of one of the formulae
[0102] ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## [0103] R.sup.78 is H; lower alkyl; aryl; or aryl-lower
alkyl; [0104] R.sup.78 and R.sup.82 taken together can form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0105] R.sup.79 is
H; lower alkyl; aryl; or aryl-lower alkyl; or [0106] R.sup.78 and
R.sup.79, taken together, can be --(CH.sub.2).sub.2-7--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0107] R.sup.80 is
H; or lower alkyl; [0108] R.sup.81 is H; lower alkyl; or aryl-lower
alkyl; [0109] R.sup.82 is H; lower alkyl; aryl; heteroaryl; or
aryl-lower alkyl; [0110] R.sup.33 and R.sup.82 taken together can
form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; [0111] R.sup.83 is
H; lower alkyl; aryl; or --NR.sup.78R.sup.79; [0112] R.sup.84 is
--(CH.sub.2).sub.m(CHR.sup.61).sub.sOH;
--(CH.sub.2).sub.pCONR.sup.78R.sup.79;
--(CH.sub.2).sub.pNR.sup.80CONR.sup.78R.sup.79;
--(CH.sub.2).sub.pC.sub.6H.sub.4CONR.sup.78R.sup.79; or
--(CH.sub.2).sub.pC.sub.6H.sub.4NR.sup.80CONR.sup.78R.sup.79;
[0113] R.sup.85 is lower alkyl; or lower alkenyl;
[0114] with the proviso that in said chain of 12 .alpha.-amino acid
residues Z the amino acid residues in positions 1 to 12 are: [0115]
P1: of type C or of type D or of type E or of type F, or the
residue is Pro; [0116] P2: of type D; [0117] P3: of type C, or of
type D, or the residue is Pro; [0118] P4: of type C, or of type D,
or of type E; [0119] P5: of type E, or of type D, or of type C, or
of type F, or the residue is Gly or Pro; [0120] P6: of type E, or
of type F Or of formula -A-CO--, or the residue is Gly; [0121] P7:
of type C, or of type E or of type F or of formula --B--CO--;
[0122] P8: of type D, or of type C, or of type F, or the residue is
Pro; [0123] P9: of type C, or of type E or of type D or of type F;
[0124] P10: of type F, or of type D or of type C, or the residue is
Pro; [0125] P11: of type E or of type D or of type C or of type F;
and [0126] P12: of type C or of type D or of type E or of type F,
or the residue is Pro; or [0127] P4 and P9 and/or P2 and P11, taken
together, can form a group of type H; and at P6and P7 also
D-isomers being possible;
[0128] with the further proviso that [0129] the amino acid residue
in P4 is of type C; and/or [0130] the amino acid residue in P5 is
of type F; and/or [0131] the amino acid residue in P7 is of type C;
and/or [0132] the amino acid residue in P8 is of type F; and/or
[0133] the amino acid residue in P9 is of type C; and/or [0134] the
amino acid residue in P10 is of type F; and/or [0135] the amino
acid residue in P11 is of type C or of type F;
[0136] and pharmaceutically acceptable salts thereof.
[0137] In accordance with the present invention these
.beta.-hairpin peptidomimetics can be prepared by a process which
comprises [0138] (a) coupling an appropriately functionalized solid
support with an appropriately N-protected derivative of that amino
acid which in the desired end-product is in position 5,6 or 7, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; [0139] (b)
removing the N-protecting group from the product thus obtained;
[0140] (c) coupling the product thus obtained with an appropriately
N-protected derivative of that amino acid which in the desired
end-product is one position nearer the N-terminal amino acid
residue, any functional group which may be present in said
N-protected amino acid derivative being likewise appropriately
protected; [0141] (d) removing the N-protecting group from the
product thus obtained; [0142] (e) repeating steps (c) and (d) until
the N-terminal amino acid residue has been introduced; [0143] (f)
coupling the product thus obtained with a compound of the general
formula
##STR00025##
[0144] is as defined above and X is an N-protecting group or,
if
##STR00026##
[0145] is to be group (a1) or (a2), above, alternatively. [0146]
(fa) coupling the product obtained in step (e) with an
appropriately N-protected derivative of an amino acid of the
general formula
[0146] HOOC--B--H III or HOOC--A-H IV [0147] wherein B and A are as
defined above, any functional group which may be present in said
N-protected amino acid derivative being likewise appropriately
protected; [0148] (fb) removing the N-protecting group from the
product thus obtained; and [0149] (fc) coupling the product thus
obtained with an appropriately N-protected derivative of an amino
acid of the above general formula IV and, respectively, III, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; [0150] (g)
removing the N-protecting group from the product obtained in step
(f) or (fc); [0151] (h) coupling the product thus obtained with an
appropriately N-protected derivative of that amino acid which in
the desired end-product is in position 12, any functional group
which maybe present in said N-protected amino acid derivative being
likewise appropriately protected; [0152] i) removing the
N-protecting group from the product thus obtained; [0153] j)
coupling the product thus obtained with an appropriately
N-protected derivative of that amino acid which in the desired
end-product is one position farther away from position 12, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; [0154] k)
removing the N-protecting group from the product thus obtained;
[0155] l) repeating steps (j) and (k) until all amino acid residues
have been introduced; [0156] (m) if desired, selectively
deprotecting one or several protected functional group(s) present
in the molecule and appropriately substituting the reactive
group(s) thus liberated; [0157] (o) detaching the product thus
obtained from the solid support; [0158] (p) cyclizing the product
cleaved from the solid support; [0159] (q) if desired, forming one
or two intetstrand linkage(s) between side-chains of appropriate
amino acid residues at opposite positions of the .beta.-strand
region; [0160] (r) removing any protecting groups present on
functional groups of any members of the chain of amino acid
residues and, if desired, any protecting group(s) which may in
addition be present in the molecule; and [0161] (s) if desired,
converting the product thus obtained into a pharmaceutical!y
acceptable salt or converting a pharmaceutically acceptable, or
unacceptable, salt thus obtained into the corresponding free
compound of formula 1 or into a different, pharmaceutically
acceptable, salt.
[0162] Alternatively, the peptidomimetics of the present invention
can be prepared by [0163] (a') coupling an appropriately
functionalized solid support with a compound of the general
formula
##STR00027##
[0164] is as defined above and X is an N-protecting group or,
if
##STR00028##
[0165] is to be group (al) or (a2), above, alternatively [0166]
(a'a) coupling said appropriately functionalized solid support with
an appropriately N-protected derivative of an amino acid of the
general formula
[0166] HOOC--B--H III or HOOC-A-H IV [0167] wherein B and A are as
defined above, any functional group which may be present in said
N-protected amino acid derivative being likewise appropriately
protected; [0168] (a'b) removing the N-protecting group from the
product thus obtained; and [0169] (a'c) coupling the product thus
obtained with an appropriately N-protected derivative of an amino
acid of the above general formula IV and, respectively, III, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; [0170] (b')
removing the N-protecting group from the product obtained in step
(a') or (a'c); [0171] (c') coupling the product thus obtained with
an appropriately N-protected derivative of that amino acid which in
the desired end-product is in position 12, any functional group
which may be present in said N-protected amino acid derivative
being likewise appropriately protected; [0172] (d') removing the
N-protecting group from the product thus obtained; [0173] (e')
coupling the product thus obtained with an appropriately
N-protected derivative of that amino acid which in the desired
end-product is one position farther away from position 12, any
functional group which may be present in said N-protected amino
acid derivative being likewise appropriately protected; [0174] (f)
removing the N-protecting group from the product thus obtained;
[0175] (g') repeating steps (e') and (f) until all amino acid
residues have been introduced; [0176] (h') if desired, selectively
deprotecting one or several protected functional group(s) present
in the molecule and appropriately substituting the reactive
group(s) thus liberated; [0177] (i') detaching the product thus
obtained from the solid support; [0178] (j') cyclizing the product
cleaved from the solid support; [0179] (k') if desired forming one
or two interstrand linkage(s) between side-chains of appropriate
amino acid residues at opposite positions of the p-strand region;
[0180] (l') removing any protecting groups present on functional
groups of any members of the chain of amino acid residues and, if
desired, any protecting group(s) which may in addition be present
in the molecule; and [0181] (m') if desired, converting the product
thus obtained into a pharmaceutically acceptable salt or converting
a pharmaceutically acceptable, or unacceptable, salt thus obtained
into the corresponding free compound of formula I or into a
different, pharmaceutically acceptable, salt.
[0182] The peptidomimetics of the present invention can also be
enantiomers of the compounds of formula I.
[0183] These enantiomers can be prepared by a modification of the
above processes in which enantiomers of all chiral starting
materials are used.
[0184] As used in this description, the term "alkyl", taken alone
or in combinations, designates saturated, straight-chain or
branched hydrocarbon radicals having up to 24, preferably up to 12,
carbon atoms. Similarly, the term "alkenyl" designates straight
chain or branched hydrocarbon radicals having up to 24, preferably
up to 12, carbon atoms and containing at least one or, depending on
the chain length, up to four olefinic double bonds. The term
"lower" designates radicals and compounds having up to 6carbon
atoms. Thus, for example, the term "lower alkyl" designates
saturated, straight-chain or branched hydrocarbon radicals having
up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl, tert.-butyl and the like. The term
"aryl" designates aromatic carbocyclic hydrocarbon radicals
containing one or two six-membered rings, such as phenyl or
naphthyl, which may be substituted by up to three substituents such
as Br, Cl, F, CF.sub.3, NO.sub.2, lower alkyl or lower alkenyl. The
term "heteroaryl" designates aromatic heterocyclic radicals
containing one or two five- and/or six-membered rings, at least one
of them containing up to three heteroatoms selected from the group
consisting of O, S and N and said ring(s) being optionally
substituted; representative examples of such optionally substituted
heteroaryl radicals are indicated hereinabove in connection with
the definition of R.sup.77.
[0185] The structural element -A-CO-- designates amino acid
building blocks which in combination with the structural element
--B--CO-- form templates (a1) and (a2). Templates (a) through (p)
constitute building blocks which have an N-terminus and a
C-terminus oriented in space in such a way that the distance
between those two groups may lie between 4.0-5.5 A. A peptide chain
Z is linked to the C-terminus and the N-terminus of the templates
(a) through (p) via the corresponding N- and C-termini so that the
template and the chain form a cyclic structure such as that
depicted in formula I. In a case as here where the distance between
the N- and C-termini of the template lies between 4.0-5.5 A the
template will induce the H-bond network necessary for the formation
of a .beta.-hairpin conformation in the peptide chain Z. Thus
template and peptide chain form a .beta.-hairpin mimetic.
[0186] The .beta.-hairpin conformation is highly relevant for the
antibiotic activity of the .beta.-hairpin mimetics of the present
invention. The .beta.-hairpin stabilizing conformational properties
of the templates (a) through (p) play a key role not only for the
selective antimicrobial activity but also for the synthesis process
defined hereinabove, as incorporation of the templates at the
beginning of the linear protected peptide precursors enhance
significantly cyclization yields.
[0187] Building blocks A1-A69 belong to a class of amino acids
wherein the N-terminus is a secondary amine forming part of a ring.
Among the genetically encoded amino acids only proline falls into
this class. The configuration of building block A1 through A69 is
(D), and they are combined with a building block --B--CO-- of
(L)-configuration. Preferred combinations for templates (a1)
are-.sup.DA1-CO--.sup.LB--CO-- to .sup.DA69-CO--.sup.LB--CO--.
Thus, for example, .sup.DPro-.sup.LPro constitutes the prototype of
templates (a1). Less preferred, but possible are combinations where
templates (a2) are -.sup.1.A1-CO--.sup.DB--CO-- to
.sup.LA69-CO--.sup.DB--CO--. Thus, for example, .sup.LPro-.sup.DPro
constitutes a less preferred prototype of template (a2).
[0188] It will be appreciated that building blocks-A1-CO-- to
-A69-CO-- in which A has (D)-configuration, are carrying a group
R.sup.1 at the .alpha.-position to the N-terminus. The preferred
values for R.sup.1 are H and lower alkyl with the most preferred
values for R.sup.1 being H and methyl. It will be recognized by
those skilled in the art, that A1-A69 are shown in
(D)-configuration which, for R.sup.1 being H and methyl,
corresponds to the (R)-configuration. Depending on the priority of
other values for R.sup.1 according to the Cahn, Ingold and
Prelog-rules, this configuration may also have to be expressed as
(S).
[0189] In addition to R.sup.1 building blocks -A1-CO-- to -A69-CO--
can carry an additional substituent designated as R.sup.2 to
R.sup.17. This additional substituent can be H, and if it is other
than H, it is preferably a small to medium-sized aliphatic or
aromatic group. Examples of preferred values for R.sup.2 to
R.sup.17 are: [0190] R.sup.2: H; lower alkyl; lower alkenyl;
(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); (CH.sub.2).sub.mSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); (CH.sub.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2)O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.57: H; or
lower alkyl); (CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where R.sup.33:
H; or lower alkyl; or lower alkenyl; R.sup.75: lower alkyl; or
R.sup.33 and R.sup.75 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl, R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2(where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0191] R.sup.3: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sup.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); (CH.sub.2).sub.oPO(OR.sup.60).sub.2 where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0192] R.sup.4: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;or lower
alkoxy). [0193] R.sup.5: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57; or
lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.57: where H;
or lower alkyl); (CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); (CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: alkyl; alkenyl; aryl; and
aryl-lower alkyl; heteroaryl-lower alkyl);
--(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where
R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or lower
alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2; where R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0194] R.sup.6: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 where
R.sup.60 : lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0195] R.sup.7: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.qOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.qSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.qNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2-; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
of lower alkyl); (CH.sub.2).sub.qR.sup.20CONR.sup.33R.sup.82 (where
R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower alkyl; or
lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33 and
R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.qCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2(where
R.sup.60 : lower alkyl; or lower alkenyl);
(CH.sub.2).sub.rSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;or lower
alkoxy). [0196] R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower
alkenyl; --(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl;
or lower alkenyl); (CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34
(where R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58 : lower alkyl; or lower alkenyl; and R.sup.59: H;
or lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--
; where R.sup.57: H; or lower alkyl);
--(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where R.sup.60: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oSO.sub.2R.sup.62 (where
R.sup.62: lower alkyl; or lower alkenyl); or
--(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where R.sup.8: H; F; Cl;
CF.sub.3; lower alkyl; lower alkenyl; or lower alkoxy). [0197]
R.sup.9: lower alkyl; lower alkenyl; --(CH.sub.2).sub.oR.sup.55
(where R.sup.55: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33; H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0198] R.sup.10: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl), --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2)2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2.sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0199] R.sup.11: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2)(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2)2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0200] R.sup.12: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.rCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0201] R.sup.13: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.qOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.qSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.qNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOO.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.qCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.rSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0202] R.sup.14: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sup.2).sub.mNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--;
--(CH.sub.(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or CH.sub.2).sub.2NR.sup.57
(CH.sub.2).sub.2--; where R.sup.57: H; or lower alkyl);
--(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where: R.sup.20: H; lower
alkyl; R.sup.64: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where
R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or lower
alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0203] R.sup.15: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); (CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); particularly favoured are NR.sup.20COlower alkyl
(R.sup.20.dbd.H; or lower alkyl); --(CH.sub.2).sub.oCOOR.sup.57
(where R.sup.57: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58: lower alkyl,
or lower alkenyl; and R.sup.59: H; lower alkyl; or R.sup.58 and
R.sup.59 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2
--; or --(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where
R.sup.57: H; or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2
(where R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0204] R.sup.16: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57: H; or lower alkyl);
--(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.75: lower alkyl; or R.sup.33 and
R.sup.75 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.5BR.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2O.sub.oPO(OR.sup.60).sub.2 where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6F.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0205] R.sup.17: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.qOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.qSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.qNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.qN(R.sup.20)COR.sup.64( where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.rCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.qCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.rPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.rSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy).
[0206] Among the building blocks A1 to A69 the following are
preferred: A5 with R.sup.2 being H, A8, A22, A25, A38 with R.sup.2
being H, A42, A47, and A50. Most preferred are building blocks of
type A8':
##STR00029##
[0207] wherein R.sup.20 is H or lower alkyl; and R.sup.64 is alkyl;
alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl;
especially those wherein R.sup.64 is n-hexyl (A8'-1); n-heptyl
(A8'-2); 4-(phenyl)benzyl (A8'-3); diphenylmethyl (A8'-4);
3-amino-propyl (A8'-5); 5-amino-pentyl (A8'-6); methyl (A8'-7);
ethyl (A8'-8); isopropyl (A8'-9); isobutyl (A8'-10); n-propyl
(A8'-11); cyclohexyl (A8'-12); cyclohexylmethyl (A8'-13); n-butyl
(A8'-14); phenyl (A8'-15); benzyl (A8'-16); (3-indolyl)methyl
(A8'-17); 2-(3-indolyl)ethyl (A8'-18); (4-phenyl)phenyl (A8'-19);
and n-nonyl (A8'-20).
[0208] Building block A70 belongs to the class of open-chained
.alpha.-substituted .alpha.-amino acids, building blocks A71 and
A72 to the corresponding .beta.-amino acid analogues and building
blocks A73-A104 to the cyclic analogues of A70. Such amino acid
derivatives have been shown to constrain small peptides in well
defined reverse turn or U-shaped conformations (C. M.
Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C
Sander, Biopolymers 1983, 22, 2577). Such building blocks or
templates are ideally suited for the stabilization of
.beta.-hairpin conformations in peptide loops (D. Obrecht, M.
Altorfer, J. A. Robinson, "Novel Peptide Mimetic Building Blocks
and Strategies for Efficient Lead Finding", Adv. Med Chem. 1999,
Vol. 4, 1-68; P. Balaram, "Non-standard amino acids in peptide
design and protein engineering", Curr. Opin. Struct. Biol. 1992, 2,
845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P.
Balaram, ".beta.-turn conformations in crystal structures of model
peptides containing .alpha.,.alpha.-disubstituted amino acids",
Biopolymers 1995, 35, 1-9; V. J. Hruby, F. Al-Obeidi, W.
Kazmierski, Biochem. J. 1990, 268, 249-262).
[0209] It has been shown that both enantiomers of building blocks
-A70-CO-- to A104-CO-- in combination with a building block
--B--CO-- of L-configuration can efficiently stabilize and induce
.beta.-hairpin conformations (D. Obrecht, M. Altorfer, J. A.
Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for
Efficient Lead Finding", Adv. Med Chem. 1999, Vol. 4, 1-68; D.
Obrecht, C. Spiegler, P. Schonholzer, K. Muller, H. Heimgartner, F.
Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D. Obrecht, U.
Bohdal, J. Daly, C. Lehmann, P. Schonholzer, K. Muller, Tetrahedron
1995, 51, 10883-10900; D. Obrecht, C. Lehmann, C. Ruffieux, P.
Schonholzer, K. Muller, Helv. Chim. Acta 1995, 78, 1567-1587; D.
Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.
Schonholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.
Obrecht, H. Karajiannis, C. Lehmann, P. Schonholzer, C. Spiegler,
Helv. Chim. Acta 1995, 78, 703-714).
[0210] Thus, for the purposes of the present invention templates
(a1) can also consist of -A70-CO-- to A104-CO-- where building
block A70 to A104 is of either (D)- or (L)-configuration, in
combination with a building block --B--CO-- of
(L)-configuration.
[0211] Preferred values for R.sup.20 in A70 to A104 are H or lower
alkyl with methyl being most preferred.
[0212] Preferred values for R.sup.18, R.sup.19 and
R.sup.21-R.sup.29 in building blocks A70 to A104 are the following:
[0213] R.sup.18: lower alkyl. [0214] R.sup.19: lower alkyl; lower
alkenyl; --(CH.sub.2).sub.pOR.sup.55 (where R.sup.55: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.pSR.sup.56 (where R.sup.56:
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34
(where R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.pCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.pSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.oC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0215] R.sup.21: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or (CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0216] R.sup.22: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF; lower alkyl; lower alkenyl; or lower
alkoxy). [0217] R.sup.23: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); particularly favoured are NR.sup.20COlower alkyl
(R.sup.20.dbd.H; or lower alkyl); --(CH.sub.2).sub.oCOOR.sup.57
(where R.sup.57: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58: lower alkyl,
or lower alkenyl; and R.sup.59: H; lower alkyl; or R.sup.58 and
R.sup.59 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2)2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy); [0218] R.sup.24: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.23).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); particularly favoured are NR.sup.20COlower alkyl
(R.sup.20.dbd.H; or lower alkyl); --(CH.sub.2).sub.oCOOR.sup.57
(where R.sup.57: lower alkyl; or lower alkenyl);
CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58: lower alkyl, or
lower alkenyl; and R.sup.59: H; lower alkyl; or R.sup.58 and
R.sup.59 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sup.2).sub.qC.sub.6H.sup.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy); [0219] R.sup.25: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 take together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where R.sup.60:
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.oSO.sub.2R.sup.62
(where R.sup.62: lower alkyl; or lower alkenyl); or
--(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where R.sup.8: H; F; Cl;
CF.sub.3; lower alkyl; lower alkenyl; or lower alkoxy). [0220]
R.sup.26: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2; where R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl);
or lower alkenyl); or --(CH.sub.2).sub.q
C.sub.6H.sub.4R.sup.8 (where R.sup.8: H; F; Cl; CF.sub.3; lower
alkyl; lower alkenyl; or lower alkoxy). [0221] Alternatively,
R.sup.25 and R.sup.26 taken together can be --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl). [0222] R.sup.27: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2(.sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0223] R.sup.28: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0224] R.sup.29: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64(where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); particularly favored are NR.sup.20COlower-alkyl
(R.sup.20.dbd.H; or lower alkyl); --(CH.sub.2).sub.oCOOR.sup.57
(where R.sup.57: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58: lower alkyl,
or lower alkenyl; and R.sup.59: H; lower alkyl; or R.sup.58 and
R.sup.59 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2.sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy).
[0225] For templates (b) to (p), such as (b1) and (c1), the
preferred values for the various symbols are the following: [0226]
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); (CH.sub.2).sub.oOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); -(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; or
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0227] R.sup.20: H; or lower alkyl. [0228] R.sup.30: H,
methyl. [0229] R.sup.31: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2`3;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); (--CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.rC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy); most preferred is --CH.sub.2CONR.sup.58R.sup.59 (R.sup.58:
H; or lower alkyl; R.sup.59: lower alkyl; or lower alkenyl). [0230]
R.sup.32: H, methyl. [0231] R.sup.33: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.14R.sup.63 (where R.sup.34:
lower alkyl; or lower alkenyl; R.sup.63: H; or lower alkyl; or
R.sup.34 and R.sup.63 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); (CH.sub.2).sub.mOCONR.sup.75R.sup.82(where
R.sup.75: lower alkyl; or lower alkenyl; R.sup.82: H; or lower
alkyl; or R.sup.75 and R.sup.82 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.78R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.78: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.78
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl). [0232] R.sup.34: H; or lower alkyl. [0233]
R.sup.35: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 take together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57: H; or lower alkyl). [0234] R.sup.36:
lower alkyl; lower alkenyl; or aryl-lower alkyl. [0235] R.sup.37:
H; lower alkyl; lower alkenyl; --(CH.sub.2).sub.pOR.sup.55 (where
R.sup.55: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33: lower alkyl;
or lower alkenyl; R.sup.34: H; or lower alkyl; or R.sup.33 and
R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower alkyl; R.sup.33: H; or lower alkyl; or
lower alkyl; R.sup.82: H; or lower alkyl; or R.sup.33 and R.sup.82
taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0236] R.sup.38: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.78 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
-(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0237] R.sup.39: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where: R.sup.20:
H; or lower alkyl; R.sup.64: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower alkyl; or
lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where
R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H; lower
alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl). [0238] R.sup.40: lower alkyl; lower alkenyl; or
aryl-lower alkyl. [0239] R.sup.41: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2.sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R
.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0240] R.sup.42: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl, or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sup.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.40: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0241] R.sup.43: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mSR.sup.56 (where R.sup.56 : lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oPO(OR.sup.60).sub.2 (where
R.sup.60: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oSO.sub.2R.sup.62 (where R.sup.62: lower alkyl; or
lower alkenyl); or --(CH.sub.2).sub.qC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0242] R.sup.44: lower alkyl; lower alkenyl;
--(CH.sub.2).sub.pOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.pNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; Or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.78 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.pN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.pCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); or --(CH.sub.2).sub.0C.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0243] R.sup.45: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.oOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.oNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.sOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.oN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); or --(CH.sub.2).sub.sC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0244] R.sup.46; H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.sOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.sSR.sup.56 (where R.sup.56: lower alkyl;
or lower alkenyl); --(CH.sub.2).sub.sNR.sup.33R.sup.34 (where
R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or lower
alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.sOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75: lower alkyl; or R.sup.33 and
R.sup.75 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.sNR.sup.20CONR.sup.33R.sup.82 (where
R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower alkyl; or
lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33 and
R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.sN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.oCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.oCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); or --(CH.sub.2).sub.sC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0245] R.sup.47: H; or OR.sup.55 (where R.sup.55: lower
alkyl; or lower alkenyl). [0246] R.sup.43: H; or lower alkyl.
[0247] R.sup.49: H; lower alkyl; --(CH.sub.2).sub.oCOOR.sup.57
(where R.sup.57: lower alkyl; or lower alkenyl);
--(CH.sub.2).sub.oCONR.sup.58R.sup.59 (where R.sup.58: lower alkyl;
or lower alkenyl; and R.sup.59: H; lower alkyl; or R.sup.58 and
R.sup.59 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); or (CH.sub.2).sub.sC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0248] R.sup.50: H; methyl. [0249] R.sup.51: H; lower
alkyl; lower alkenyl; --(CH.sub.2).sub.mOR.sup.55 (where R.sup.55:
lower alkyl; or lower alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34
(where R.sup.33: lower alkyl; or lower alkenyl; R.sup.34: H; or
lower alkyl; or R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); (CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2.sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.pCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59 : H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2.sub.2--; where R.sup.57: H; or
lower alkyl); or --(CH.sub.2).sub.rC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0250] R.sup.52: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; R.sup.57: H; or
lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.pCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.20(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); or --(CH.sub.2).sub.rC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0251] R.sup.53: H; lower alkyl; lower alkenyl;
--(CH.sub.2).sub.mOR.sup.55 (where R.sup.55: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.mNR.sup.33R.sup.34 (where R.sup.33:
lower alkyl; or lower alkenyl; R.sup.34: H; or lower alkyl; or
R.sup.33 and R.sup.34 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mOCONR.sup.33R.sup.75 (where
R.sup.33: H; or lower alkyl; or lower alkenyl; R.sup.75: lower
alkyl; or R.sup.33 and R.sup.75 taken together form:
--(CH.sub.2).sub.2-6--; --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mNR.sup.20CONR.sup.33R.sup.82
(where R.sup.20: H; or lower lower alkyl; R.sup.33: H; or lower
alkyl; or lower alkenyl; R.sup.82: H; or lower alkyl; or R.sup.33
and R.sup.82 taken together form: --(CH.sub.2).sub.2-6--;
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2--; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); --(CH.sub.2).sub.mN(R.sup.20)COR.sup.64 (where:
R.sup.20: H; or lower alkyl; R.sup.64: lower alkyl; or lower
alkenyl); --(CH.sub.2).sub.pCOOR.sup.57 (where R.sup.57: lower
alkyl; or lower alkenyl); --(CH.sub.2).sub.pCONR.sup.58R.sup.59
(where R.sup.58: lower alkyl; or lower alkenyl; and R.sup.59: H;
lower alkyl; or R.sup.58 and R.sup.59 taken together form:
--(CH.sub.2).sub.2-6--, --(CH.sub.2).sub.2O(CH.sub.2).sub.2--;
--(CH.sub.2).sub.2S(CH.sub.2).sub.2; or
--(CH.sub.2).sub.2NR.sup.57(CH.sub.2).sub.2--; where R.sup.57: H;
or lower alkyl); or --(CH.sub.2).sub.rC.sub.6H.sub.4R.sup.8 (where
R.sup.8: H; F; Cl; CF.sub.3; lower alkyl; lower alkenyl; or lower
alkoxy). [0252] R.sup.54: lower alkyl; lower alkenyl; or aryl-lower
alkyl.
[0253] Among the building blocks A70 to A104 the following are
preferred: A74 with R.sup.22 being H, A75, A76, A77 with R.sup.22
being H, A78 and A79.
[0254] The building block --B--CO-- within template (a1) and (a2)
designates an L-amino acid residue.
[0255] Preferred values for B are: --NR.sup.20CH(R.sup.71)-- and
enantiomers of groups A5 with R.sup.2 being H, A8, A22, A25, A38
with R.sup.2 being H, A42, A47, and A50. Most preferred are [0256]
Ala L-Alanine [0257] Arg L-Arginine [0258] Asn L-Asparagine [0259]
Cys L-Cysteine [0260] Gln L-Glutamine [0261] Gly Glycine [0262] His
L-Histidine [0263] Ile L-Isoleucine [0264] Leu L-Leucine [0265] Lys
L-Lysine [0266] Met L-Methionine [0267] Phe L-Phenylalanine [0268]
Pro L-Proline [0269] Ser L-Serine [0270] Thr L-Threonine [0271] Trp
L-Tryptophan [0272] Tyr L-Tyrosine [0273] Val L-Valine [0274] Cit
L-Citrulline [0275] Orn L-Ornithine [0276] tBuA L-t-Butylalanine
[0277] Sar Sarcosine [0278] t-BuG L-tert.-Butylglycine [0279]
4AmPhe L-para-Aminophenylalanine [0280] 3AmPhe
L-meta-Aminophenylalanine [0281] 2AmPhe L-ortho-Aminophenylalanine
[0282] Phe(mC(NH.sub.2).dbd.NH) L-meta-Amidinophenylalanine [0283]
Phe(pC(NH.sub.2).dbd.NH) L-para-Amidinophenylalanine [0284]
Phe(mNHC(NH.sub.2).dbd.NH) L-meta-Guanidinophenylalanine [0285]
Phe(pNHC(NH.sub.2).dbd.NH) L-para-Guanidinophenylalanine [0286] Phg
L-Phenylglycine [0287] Cha L-Cyclohexyl alanine [0288] C.sub.4al
L-3-Cyclobutylalanine [0289] C.sub.5al L-3-Cyclopentylalanine
[0290] Nle L-Norleucine [0291] 2-Nal L-2-Naphthylalanine [0292]
1-Nal L-1-Naphthylalanine [0293] 4Cl-Phe L-4-Chlorophenylalanine
[0294] 3Cl-Phe L-3-Chlorophenylalanine [0295] 2Cl-Phe
L-2-Chlorophenylalanine [0296] 3,4Cl.sub.2.Phe
L-3,4-Dichlorophenylalanine [0297] 4F-Phe L-4-Fluorophenylalanine
[0298] 3F-Phe L-3-Fluorophenylalanine [0299] 2F-Phe
L-2-Fluorophenylalanine [0300] Tic
L-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [0301] Thi
L-.beta.-2-Thienylalanine [0302] Tza L-2-Thiazolylalanine [0303]
Mso L-Methionine sulfoxide [0304] AcLys L-N-Acetyllysine [0305] Dpr
L-2,3-Diaminopropionic acid [0306] A.sub.2Bu L-2,4-Diaminobutyric
acid [0307] Dbu (S)-2,3-Diaminobutyric acid [0308] Abu
.gamma.-Aminobutyric acid (GABA) [0309] Aha .epsilon.-Aminohexanoic
acid [0310] Aib .alpha.-Aminoisobutyric acid [0311] Y(Bzl)
L-O-Benzyltyrosine [0312] Bip L-Biphenylalanine [0313] S(Bzl)
L-O-Benzylserine [0314] T(Bzl) L-O-Benzylthreonine [0315] hCha
L-Homo-cyclohexylalanine [0316] hCys L-Homo-cysteine [0317] hSer
L-Homo-serine [0318] hArg L-Homo-arginine [0319] hPhe
L-Homo-phenylalanine [0320] Bpa L-4-Benzoylphenylalanine [0321] Pip
L-Pipecolic acid [0322] OctG L-Octylglycine [0323] MePhe
L-N-Methylphenylalanine [0324] MeNle L-N-Methylnorleucine [0325]
MeAla L-N-Methylalanine [0326] MeIle L-N-Methylisoleucine [0327]
MeVal L-N-Methvaline [0328] MeLeu L-N-Methylleucine
[0329] In addition, the most preferred values for B also include
groups of type A8'' of (L)-configuration:
##STR00030##
[0330] wherein R.sup.20 is H or lower alkyl and R.sup.64 is alkyl;
alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl;
especially those wherein R.sup.64 is n-hexyl (A8''-21); n-heptyl
(A8''-22); 4-(phenyl)benzyl (A8''-23); diphenylmethyl (A8''-24);
3-amino-propyl (A8''-25); 5-amino-pentyl (A8''-26); methyl
(A8''-27); ethyl (A8''-28); isopropyl (A8''-29); isobutyl
(A8''-30); n-propyl (A8''-31); cyclohexyl (S8''-32);
cyclohexylmethyl (A8''-33); n-butyl (A8''-34); phenyl (A8''-35);
benzyl (A8''-36); (3-indolyl)methyl (A8''-37); 2-(3-indolyl)ethyl
(A8''-38); (4-phenyl)phenyl (A8''-39); and n-nonyl (A8''-40).
[0331] The peptidic chain Z of the .beta.-hairpin mimetics
described herein is generally defined in terms of amino acid
residues belonging to one of the following groups: [0332] Group C
--NR.sup.20CH(R.sup.72)CO--; "hydrophobic: small to medium-sized"
[0333] Group D --NR.sup.20CH(R.sup.73)CO--; "hydrophobic: large
aromatic or heteroaromatic" [0334] Group E
--NR.sup.20CH(R.sup.74)CO--; "polar-cationic" and "urea-derived"
[0335] Group F --NR.sup.20CH(R.sup.84)CO--; "polar-non-charged"
[0336] Group H
--NR.sup.20--CH(CO--)--(CH.sub.2).sub.4-7--CH(CO--)--NR.sup.20--;
--NR.sup.20--CH(CO--)--(CH.sub.2).sub.pSS(CH.sub.2).sub.p--CH(CO--)--NR.s-
up.20--;
--NR.sup.20--CH(CO--)--(--(CH.sub.2).sub.pNR.sup.20CO(CH.sub.2).s-
ub.p--CH(CO--)--NR.sup.20--; and
--NR.sup.20--CH(CO--)--(--(CH.sub.2).sub.pNR.sup.20CONR.sup.20(CH.sub.2).-
sub.p--CH(CO--)--NR.sup.20--; "interstrand linkage"
[0337] Furthermore, the amino acid residues in chain Z can also be
of formula -A-CO-- or of formula --B--CO-- wherein A and B are as
defined above. Finally, Gly can also be an amino acid residue in
chain Z, and Pro can be an amino acid residue in chain Z, too, with
the exception of positions where interstrand linkages (H) are
possible.
[0338] Group C comprises amino acid residues with small to
medium-sized hydrophobic side chain groups according to the general
definition for substituent R.sup.72. A hydrophobic residue refers
to an amino acid side chain that is uncharged at physiological pH
and that is repelled by aqueous solution. Furthermore these side
chains generally do not contain hydrogen bond donor groups, such as
(but not limited to) primary and secondary amides, primary and
secondary amines and the corresponding protonated salts thereof,
thiols, alcohols, phosphonates, phosphates, ureas or thioureas.
However, they may contain hydrogen bond acceptor groups such as
ethers, thioethers, esters, tertiary amides, alkyl- or aryl
phosphonates and phosphates or tertiary amines. Genetically encoded
small-to-medium-sized amino acids include alanine, isoleucine,
leucine, methionine and valine.
[0339] Group D comprises amino acid residues with aromatic and
heteroaromatic side chain groups according to the general
definition for substituent R.sup.73. An aromatic amino acid residue
refers to a hydrophobic amino acid having a side chain containing
at least one ring having a conjugated .pi.-elecrtron system
(aromatic group). In addition they may contain hydrogen bond donor
groups such as (but not limited to) primary and secondary amides,
primary and secondary amines and the corresponding protonated salts
thereof, thiols, alcohols, phosphonates, phosphates, ureas or
thioureas, and hydrogen bond acceptor groups such as (but not
limited to) ethers, thioethers, esters, tetriary amides, alkyl- or
aryl phosphonates -and phosphates or tertiary amines. Genetically
encoded aromatic amino acids include phenylalanine and
tyrosine.
[0340] A heteroaromatic amino acid residue refers to a hydrophobic
amino acid having a side chain containing at least one ring having
a conjugated 7i-system incorporating at least one heteroatom such
as (but not limited to) O, S and N according to the general
definition for substituent R.sup.77. In addition such residues may
contain hydrogen bond donor groups such as (but not limited to)
primary and secondary amides, primary and secondary amines and the
corresponding protonated salts thereof, thiols, alcohols,
phosphonates, phosphates, ureas or thioureas, and hydrogen bond
acceptor groups such as (but not limited to) ethers, thioethers,
esters, tetriary amides, alkyl- or aryl phosphonates--and
phosphates or tertiary amines. Genetically encoded heteroaromatic
amino acids include tryptophan and histidine.
[0341] Group E comprises amino acids containing side chains with
polar-cationic, acylamino- and urea-derived residues according to
the general definition for substituent R.sup.74. Polar-cationic
refers to a basic side chain which is protonated at physiological
pH. Genetically encoded polar-cationic amino acids include
arginine, lysine and histidine. Citrulline is an example for an
urea derived amino acid residue.
[0342] Group F comprises amino acids containing side chains with
polar-non-charged residues according to the general definition for
substituent R.sup.84. A polar-non-charged residue refers to a
hydrophilic side chain that is uncharged at physiological pH, but
that is not repelled by aqueous solutions. Such side chains
typically contain hydrogen bond donor groups such as (but not
limited to) primary and secondary amides, primary and secondary
amines, thiols, alcohols, phosphonates, phosphates, ureas or
thioureas. These groups can form hydrogen bond networks with water
molecules. In addition they may also contain hydrogen bond acceptor
groups such as (but not limited to) ethers, thioethers, esters,
tetriary amides, alkyl- or aryl phosphonates--and phosphates or
tertiary amines. Genetically encoded polar-non-charged amino acids
include asparagine, cysteine, glutamine, serine and threonine.
[0343] Group H comprises side chains of preferably (L)-amino acids
at opposite positions of the .beta.-strand region that can form an
interstrand linkage. The most widely known linkage is the disulfide
bridge formed by cysteines and homo-cysteines positioned at
opposite positions of the .beta.-strand. Various methods are known
to form disulfide linkages including those described by. J. P. Tarn
et al. Synthesis 1979, 955-957; Stewart et al., Solid Phase Peptide
Synthesis, 2d Ed., Pierce Chemical Company, III., 1984; Ahmed et
al. J. Biol. Chem. 1975, 250, 8477-8482 ; and Pennington et al.,
Peptides, pages 164-166, Giralt and Andreu, Eds., ESCOM Leiden, The
Netherlands, 1990. Most advantageously, for the scope of the
present invention, disulfide linkages can be prepared using
acetamidomethyl (Acm)-protective groups for cysteine. A well
established interstrand linkage consists in linking ornithines and
lysines, respectively, with glutamic and aspartic acid residues
located at opposite .beta.-strand positions by means of an amide
bond formation. Preferred protective groups for the side chain
amino-groups of ornithine and lysine are allyloxycarbonyl (Alloc)
and allylesters for aspartic and glutamic acid. Finally,
interstrand linkages can also be established by linking the amino
groups of lysine and ornithine located at opposite .beta.-strand
positions with reagents such as N,N-carbonylimidazole to form
cyclic ureas.
[0344] As mentioned earlier, positions for interstrand linkages are
positions P4 and P9; and/or P2 and P11 taken together. Such
interstrand linkages are known to stabilize the .beta.-hairpin
conformations and thus constitute an important structural element
for the design of .beta.-hairpin mimetics.
[0345] Most preferred amino acid residues in chain Z are those
derived from natural .alpha.-amino acids. Hereinafter follows a
list of amino acids which, or the residues of which, are suitable
for the purposes of the present invention, the abbreviations
corresponding to generally adopted Usual practice:
TABLE-US-00001 three letter code one letter code Ala L-Alanine A
Arg L-Arginine R Asn L-Asparagine N Asp L-Aspartic acid D Cys
L-Cysteine C Glu L-Glutamic acid E Gln L-Glutamine Q Gly Glycine G
His L-Histidine H Ile L-Isoleucine I Leu L-Leucine L Lys L-Lysine K
Met L-Methionine M Phe L-Phenylalanine F Pro L-Proline P .sup.DPro
D-Proline .sup.DP Ser L-Serine S Thr L-Threonine T Trp L-Tryptophan
W Tyr L-Tyrosine Y Val L-Valine V
[0346] Other .alpha.-amino acids which, or the residues of which,
are suitable for the purposes of the present invention include:
[0347] Cit L-Citrulline [0348] Orn L-Ornithine [0349] tBuA
L-t-Butylalanine [0350] Sar Sarcosine [0351] Pen L-Penicillamine
[0352] t-BuG L-tert.-Butylglycine [0353] 4AmPhe
L-para-Aminophenylalanine [0354] 3AmPhe L-meta-Aminophenylalanine
[0355] 2AmPhe L-ortho-Aminophenylalanine [0356]
Phe(mC(NH.sub.2).dbd.NH) L-meta-Amidinophenylalanine [0357]
Phe(pC(NH.sub.2).dbd.NH) L-para-Amidinophenylalanine [0358]
Phe(mNHC(NH.sub.2).dbd.NH) L-meta-Guanidinophenylalanine [0359]
Phe(pNHC(NH.sub.2).dbd.NH) L-para-Guanidinophenylalanine [0360] Phg
L-Phenylglycine [0361] Cha L-Cyclohexylalanine [0362] C.sub.4al
L-3-Cyclobutylalanine [0363] C.sub.5al L-3-Cyclopentylalanine
[0364] NIe L-Norleucine [0365] 2-Nal L-2-Naphthylalanine [0366]
1-Nal L-1-Naphthylalanine [0367] 4Cl-Phe L-4-Chlorophenylalanine
[0368] 3Cl-Phe L-3-Chlorophenylalanine [0369] 2Cl-Phe
L-2-Chlorophenylalanine [0370] 3,4Cl.sub.2-Phe
L-3,4-Dichlorophenylalanine [0371] 4F-Phe L-4-Fluorophenylalanine
[0372] 3F-Phe L-3-Fluorophenylalanine [0373] 2F-Phe
L-2-Fluorophenylalanine [0374] Tic
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid [0375] Thi
L-.beta.-2-Thienylalanine [0376] Tza L-2-Thiazolylalanine [0377]
Mso L-Methionine sulfoxide [0378] AcLys N-Acetyllysine [0379] Dpr
2,3-Diaminopropionic acid [0380] A.sub.2Bu 2,4-Diaminobutyric acid
[0381] Dbu (S)-2,3-Diaminobutyric acid [0382] Abu
.gamma.-Aminobutyric acid (GABA) [0383] Aha .epsilon.-Aminohexanoic
acid. [0384] Aib .alpha.-Aminoisobutyric acid [0385] Y(Bzl)
L-O-Benzyltyrosine [0386] Bip L-(4-phenyl)phenylalanine [0387]
S(Bzl) L-O-Benzylserine [0388] T(Bzl) L-O-Benzylthreonine [0389]
hCha L-Homo-cyclohexylalanine [0390] hCys L-Homo-cysteine [0391]
hSer L-Homo-serine [0392] hArg L-Homo-arginine [0393] hPhe
L-Homo-phenylalanine [0394] Bpa L-4-Benzoylphenylalanine [0395]
4-AmPyrr1 (2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid [0396]
4-AmPyrr2 (2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid [0397]
4-PhePyrr1 (2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid [0398]
4-PhePyrr2 (2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid [0399]
5-PhePyrr1 (2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid [0400]
5-PhePyrr2 (2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid [0401]
Pro(4-OH)1 (4S)-L-Hydroxyproline [0402] Pro(4-OH)2
(4R)-L-Hydroxyproline [0403] Pip L-Pipecolic acid [0404] .sup.DPip
D-Pipecolic acid [0405] OctG L-Octylglycine [0406] MePhe
L-N-Methylphenylalanine [0407] MeNle L-N-Methylnorleucine [0408]
MeAla L-N-Methylalanine [0409] MeIle L-N-Methylisoleucine [0410]
MeVal L-N-Methylvaline [0411] MeLeu L-N-Methylleucine
[0412] Particularly preferred residues for group C are: [0413] Ala
L-Alanine [0414] Ile L-Isoleucine [0415] Leu L-Leucine [0416] Met
L-Methionine [0417] Val L-Valine [0418] tBuA L-t-Butylalanine
[0419] t-BuG L-tert.-Butylglycine [0420] Cha L-Cyclohexylalanine
[0421] C.sub.4al L-3-Cyclobutylalanine [0422] C.sub.5al
L-3-Cyclopentylalanine [0423] Nle L-Norleucine [0424] hCha
L-Homo-cyclohexylalanine [0425] OctG L-Octylglycine [0426] MePhe
L-N-Methylphenylalanine [0427] MeNle L-N-Methylnorleucine [0428]
MeAla L-N-Methylalanine [0429] MeIle L-N-Methylisoleucine [0430]
MeVal L-N-Methylvaline [0431] MeLeu L-N-Methylleucine
[0432] Particularly preferred residues for group D are: [0433] His
L-Histidine [0434] Phe L-Phenylalanine [0435] Trp L-Tryptophan
[0436] Tyr L-Tyrosine [0437] Phg L-Phenylglycine [0438] 2-Nal
L-2-Naphthylalanine [0439] 1-Nal L-1-Naphthylalanine [0440] 4Cl-Phe
L-4-Chlorophenylalanine [0441] 3Cl-Phe L-3-Chlorophenylalanine
[0442] 2Cl-Phe L-2-Chlorophenylalanine [0443] 3,4Cl.sub.2-Phe
L-3,4-Dichlorophenylalanine [0444] 4F-Phe L-4-Fluorophenylalanine
[0445] 3F-Phe L-3-Fluorophenylalanine [0446] 2F-Phe
L-2-Fluorophenylalanine [0447] Thi L-.beta.-2-Thienylalanine [0448]
Tza L-2-Thiazolylalanine [0449] Y(Bzl) L-O-Benzyltyrosine [0450]
Bip L-Biphenylalanine [0451] S(Bzl) L-O-Benzylserine [0452] T(Bzl)
L-O-Benzylthreonine [0453] hPhe L-Homo-phenylalanine [0454] Bpa
L-4-Benzoylphenylalanine
[0455] Particularly preferred residues for group E are [0456] Arg
L-Arginine [0457] Lys L-Lysine [0458] Orn L-Omithine [0459] Dpr
L-2,3-Diaminopropionic acid [0460] A.sub.2Bu L-2,4-Diaminobutyric
acid [0461] Dbu (S)-2,3-Diaminobutyric acid [0462] Phe(pNH.sub.2)
L-para-Aminophenylalanine [0463] Phe(mNH.sub.2)
L-meta-Aminophenylalanine [0464] Phe(oNH.sub.2)
L-ortho-Aminophenylalanine [0465] hArg L-Homo-arginine [0466]
Phe(mC(NH.sub.2).dbd.NH) L-meta-Amidinophenylalanine [0467]
Phe(pC(NH.sub.2).dbd.NH) L-para-Amidinophenylalanine [0468]
Phe(mNHC(NH.sub.2).dbd.NH) L-meta-Guanidinophenylalanine [0469]
Phe(pNHC(NH.sub.2).dbd.NH) L-para-Guanidinophenylalanine [0470] Cit
L-Citrulline
[0471] Particularly preferred residues for group F are [0472] Asn
L-Asparagine [0473] Cys L-Cysteine [0474] Gln L-Glutamine [0475]
Ser L-Serine [0476] Thr L-Threonine [0477] Cit L-Citrulline [0478]
Pen L-Penicillamine [0479] AcLys L-N.sup.t-Acetyllysine [0480] hCys
L-Homo-cysteine [0481] hSer L-Homo-serine
[0482] Generally, the peptidic chain Z within the .beta.-hairpin
mimetics of the invention comprises 12 amino acid residues. The
positions P1 to P12 of each amino acid residue in the chain Z are
unequivocally defined as follows: P1 represents the first amino
acid in the chain Z that is coupled with its N-terminus to the
C-terminus of the templates (b)-(p) or of group --B--CO-- in
template (a1), or of group--A-CO-- in template a2, and P12
represents the last amino acid in the chain Z that is coupled with
its C-terminus to the N-terminus of the templates (b)-(p) or of
group -A-CO-- in template (a1) or of group --B--CO-- in template
(a2). Each of the positions P1 to P12 will preferably contain an
amino acid residue belonging to one of the above types C to F, or
of formula -A-CO-- or of formula --B--CO-- as follows: [0483] P1:
of type C or of type D or of type E or of type F; [0484] P2: of
type D; [0485] P3: of type C; [0486] P4: of type E, or of type C;
[0487] P5: of type E, or of type F; [0488] P6: of type E, or of
type F, or of formula -A-CO--; [0489] P7: of type E, or of type F,
or of formula --B--CO--; [0490] P8: of type D, or of type C, or of
Type F; [0491] P9: of type C, or of type E; [0492] P10: of type F,
Or of type D, or of type C; [0493] P11: of type D, or of type C, or
of type F; [0494] P12: of type C or of type D or of type E or of
type F;
[0495] at P6 and P7 also D-isomers being possible;
[0496] with the proviso that [0497] the amino acid residue in
position P4 is of type C; and/or [0498] the amino acid residue in
position P5 is of type F; and/or [0499] the amino acid residue in
position P8 is of type F; and/or [0500] the amino acid residue in
position P9 is of type C; and/or [0501] the amino acid residue in
position P10 is of type F; and/or [0502] the amino acid residue in
position P11 is of type C or F. [0503] Most preferably, the amino
acid residues in positions P1 to P12 are: [0504] P1: Arg; [0505]
P2: Trp; [0506] P3: Leu; [0507] P4: Lys or Val; [0508] P5: Lys;
[0509] P6: Arg; [0510] P7: Arg; [0511] P8: Trp; [0512] P9: Leu, Val
or Lys; [0513] P10: Tyr, Thr or Gln; [0514] P11: Val, Leu, Tyr or
Gln; and [0515] P12:Arg;
[0516] with the proviso that [0517] the amino acid residue in
position P4 is Val; and/or [0518] the amino acid residue in
position P9 is Leu or Val; and/or [0519] the amino acid residue in
position P10 is Thr or Gln; and/or [0520] the amino acid residue in
position P11 is Val or Leu or Gln.
[0521] Particularly preferred .beta.-peptidomimetics of the
invention include those described in Examples 1, to 8.
[0522] The processes of the invention can advantageously be carried
out as parallel array syntheses to yield libraries of
template-fixed .beta.-hairpin peptidomimetics of the above general
formula I. Such parallel syntheses allow one to obtain arrays of
numerous (normally 24 to 192, typically 96) compounds of general
formula I in high yields and defined purities, minimizing the
formation of dimeric and polymeric by-products. The proper choice
of the functionalized solid-support (i.e. solid support plus linker
molecule), templates and site of cyclization play thereby key
roles.
[0523] The functionalized solid support is conveniently derived
from polystyrene crosslinked with, preferably 1-5%, divinylbenzene;
polystyrene coated with polyethyleneglycol spacers
(Tentagel.sup.R); and polyacrylamide resins (see also Obrecht, D.;
Villalgordo, J.-M, "Solid-Supported Combinatorial and Parallel
Synthesis of Small-Molecular-Weight Compound Libraries",
Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier
Science, 1998).
[0524] The solid support is functionalized by means of a linker,
i.e. a bifunctional spacer molecule which contains on one end an
anchoring group for attachment to the solid support and on the
other end a selectively cleavable functional group used for the
subsequent chemical transformations and cleavage procedures. For
the purposes of the present invention the linker must be designed
to eventually release the carboxyl group under mild acidic
conditions which do not affect protecting groups present on any
functional group in the side-chains of the various amino acids.
Linkers which are suitable for the purposes of the present
invention form acid-labile esters with the carboxyl group of the
amino acids, usually acid-labile benzyl, benzhydryl and trityl
esters; examples of linker structures of this kind include
2-methoxy-4-hydroxymethylphenoxy (Sasrin.sup.R linker),
4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),
4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker),
trityl and 2-chlorotrityl.
[0525] Preferably, the support is derived from polystyrene
crosslinked with, most preferably 1-5%, divinylbenzene and
functionalized by means of the 2-chlorotrityl linker.
[0526] When carried out as a parallel array syntheses the processes
of the invention can be advantageously carried out as described
herein below but it will be immediately apparent to those skilled
in the art how these procedures will have to be modified in case it
is desired to synthesize one single compound of the above formula
I
[0527] A number of reaction vessels (normally 24 to 192, typically
96) equal to the total number of compounds to be synthesized by the
parallel method are loaded with 25 to 1000 mg, preferably 100 mg,
of the appropriate functionalized solid support, preferably 1 to 3%
cross linked polystyrene or tentagel resin.
[0528] The solvent to be used must be capable of swelling the resin
and includes, but is not limited to, dichloromethane (DCM),
dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane,
toluene, tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol
(TFE), isopropylalcohol and the like. Solvent mixtures containing
as at least one component a polar solvent (e. g. 20% TFE/DCM, 35%
THF/NMP) are beneficial for ensuring high reactivity and solvation
of the resin-bound peptide chains ( Fields, G. B., Fields, C. G.,
J. Am. Chem. Soc. 1991, 113, 4202-1207).
[0529] With the development of various linkers that release the
C-terminal carboxylic acid group under mild acidic conditions, not
affecting acid-labile groups protecting functional groups in the
side chain(s), considerable progresses have been made in the
synthesis of protected peptide fragments. The
2-methoxy-4-hydroxybenzylalcohol-derived linker (Sasrin.sup.R
linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008) is
cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) and
is stable to Fmoc deprotection conditions during the peptide
synthesis, Boc/tBu-based additional protecting groups being
compatible with this protection scheme. Other linkers which are
suitable for the process of the invention include the super acid
labile 4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink
linker, Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790), where the
removal of the peptide requires 10% acetic acid in DCM or 0.2%
trifluoroacetic acid in DCM; the
4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker
(HMPB-linker, Florsheimer & Riniker, Peptides 1991, 1990 131)
which is also cleaved with 1% TFA/DCM in order to yield a peptide
fragment containing all acid labile side-chain protective groups;
and, in addition, the 2-chlorotritylchloride linker (Barlos et al.,
Tetrahedron Lett. 1989, 30, 3943-3946), which allows the peptide
detachment using a mixture of glacial acetic
acid/trifluoroethanol/DCM (1:2:7) for 30 min.
[0530] Suitable protecting groups for amino acids and,
respectively, for their residues are, for example, [0531] for the
amino group (as is present e. g. also in the side-chain of lysine)
[0532] Cbz benzyloxycarbonyl [0533] Boc tert.-butyloxycarbonyl
[0534] Fmoc 9-fluorenylmethoxycarbonyl [0535] Alloc
allyloxycarbonyl [0536] Teoc trimethylsilylethoxycarbonyl [0537]
Tec trichloroethoxycarbonyl [0538] Nps o-nitrophenylsulfonyl;
[0539] Trt triphenymethyl or trityl [0540] for the carboxyl group
(as is present e. g. also in the side-chain of aspartic and
glutamic acid) by conversion into esters with the alcohol
components [0541] tBu tert.-butyl [0542] Bn benzyl [0543] Me methyl
[0544] Ph phenyl [0545] Pac Phenacyl [0546] Allyl [0547] Tse
trimethylsilylethyl [0548] Tce trichloroethyl; [0549] for the
guanidino group (as is present e. g. in the side-chain of arginine)
[0550] Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl [0551] Ts tosyl
(i. e. p-toluenesulfonyl) [0552] Cbz benzyloxycarbonyl [0553] Pbf
pentamethyldihydrobenzofuran-5-sulfonyl [0554] for the hydroxy
group (as is present e. g. in the side-chain of threonine and
serine) [0555] tBu tert.-butyl [0556] Bn benzyl [0557] Trt trityl
[0558] and for the mercapto group (as is present e. g. in the
side-chain of cysteine) [0559] Acm acetamidomethyl [0560] tBu
tert.-butyl [0561] Bn benzyl [0562] Trt trityl [0563] Mtr
4-methoxytrityl.
[0564] The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid
derivatives are preferably used as the building blocks for the
construction of the template-fixed .beta.-hairpin loop mimetics of
formula I. For the deprotection, i. e. cleaving off of the Fmoc
group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be
used.
[0565] The quantity of the reactant, i. e. of the amino acid
derivative, is usually 1 to 20 equivalents based on the
milliequivalents per gram (meq/g) loading of the functionalized
solid support (typically 0.1 to 2.85 meq/g for polystyrene resins)
originally weighed into the reaction tube. Additional equivalents
of reactants can be used if required to drive the reaction to
completion in a reasonable time. The reaction tubes, in combination
with the holder block and the manifold, are reinserted into the
reservoir block and the apparatus is fastened together. Gas flow
through the manifold is initiated to provide a controlled
environment, for example, nitrogen, argon, air and the like. The
gas flow may also be heated or chilled prior to flow through the
manifold. Heating or cooling of the reaction wells is achieved by
heating the reaction block or cooling externally with
isopropanol/dry ice and the like to bring about the desired
synthetic reactions. Agitation is achieved by shaking or magnetic
stirring (within the reaction tube). The preferred workstations
(without, however, being limited thereto) are Labsource's
Combi-chem station and MultiSyn Tech's-Syro synthesizer.
[0566] Amide bond formation requires the activation of the
.alpha.-carboxyl group for the acylation step. When this activation
is being carried out by means of the commonly used carbodiimides
such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am.
Chem. Soc. 1955, 77, 1067-1068) or diisopropylcarbodiimide (DIC,
Sarantakis et al Biochem. Biophys. Res. Commun.1976, 73, 336-342),
the resulting dicyclohexylurea is insoluble and, respectively,
diisopropylurea is soluble in the solvents generally used. In a
variation of the carbodiimide method 1-hydroxybenzotriazole (HOBt,
Konig & Geiger, Chem. Ber 1970, 103, 788-798) is included as an
additive to the coupling mixture. HOBt prevents dehydration,
suppresses racemization of the activated amino acids and acts as a
catalyst to improve the sluggish coupling reactions. Certain
phosphonium reagents have been used as direct coupling reagents,
such as benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP) (Castro et al., Tetrahedron Lett. 1975,
14, 1219-1222; Synthesis, 1976, 751-752), or
benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium
hexaflurophoshate (Py-BOP, Coste et al., Tetrahedron Lett. 1990,
31, 205-208), or
2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium
terafluoroborate (TBTU), or hexafluorophosphate (HBTU, Knorr et al,
Tetrahedron Lett. 1989, 30, 1927-1930); these phosphonium reagents
are also suitable for in situ formation of HOBt esters with the
protected amino acid derivatives. More recently diphenoxyphosphoryl
azide (DPPA) or
O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TATU) or
O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt,
Carpino et al., Tetrahedron Lett. 1994, 35, 2279-2281) have also
been used as coupling reagents.
[0567] Due to the fact that near-quantitative coupling reactions
are essential it is desirable to have experimental evidence for
completion of the reactions. The ninhydrin test (Kaiser et al.,
Anal. Biochemistry 1970, 34, 595), where a positive colorimetric
response to an aliquot of resin-bound peptide indicates
qualitatively the presence of the primary amine, can easily and
quickly be performed after each coupling step. Fmoc chemistry
allows the spectrophotometric detection of the Fmoc chromophore
when it is released with the base (Meienhofer et al., Int. J.
Peptide Protein Res. 1979, 73, 35-42).
[0568] The resin-bound intermediate within each reaction tube is
washed free of excess of retained reagents, of solvents, and of
by-products by repetitive exposure to pure solvents) by One of the
two following methods:
[0569] 1) The reaction wells are filled with solvent (preferably 5
ml), the reaction tubes, in combination with the holder block and
manifold, are immersed and agitated for 5 to 300 minutes,
preferably 15 minutes, and drained by gravity followed by gas
pressure applied through the manifold inlet (while closing the
outlet) to expel the solvent;
[0570] 2) The manifold is removed from the holder block, aliquots
of solvent (preferably 5 ml) are dispensed through the top of the
reaction tubes and drained by gravity through a filter into a
receiving vessel such as a test tube or vial.
[0571] Both of the above washing procedures are repeated up to
about 50 times (preferably about 10 times), monitoring the
efficiency of reagent, solvent, and byproduct removal by methods
such as TLC, GC, or inspection of the washings.
[0572] The above described procedure of reacting the resin-bound
compound with reagents within the reaction wells followed by
removal of excess reagents, by-products, and solvents is repeated
with each successive transformation until the final resin-bound
fully protected linear peptide has been obtained.
[0573] Before this fully protected linear peptide is detached from
the solid support, it is possible, if desired, to selectively
deprotect one or several protected functional group(s) present in
the molecule and to appropriately substitute the reactive group(s)
thus liberated. To this effect, the functional group(s) in question
must initially be protected by a protecting group which can be
selectively removed without affecting the remaining protecting
groups present. Alloc (allyloxycarbonyl) is an example for such a
protecting group for amino which can be selectively removed, e.g.
by means of Pd.sup.D and phenylsilane in CH.sub.2Cl.sub.2, without
affecting the remaining protecting groups, such as Fmoc, present in
the molecule. The reactive group thus liberated can then be treated
with an agent suitable for introducing the desired substituent.
Thus, for example, an amino group can be acylated by means of an
acylating agent corresponding to the acyl substituent to be
introduced.
[0574] Detachment of the fully protected linear peptide from the
solid support is achieved by immersion of the reaction tubes, in
combination with the holder block and manifold, in reaction wells
containing a solution of the cleavage reagent (preferably 3 to 5
ml). Gas flow, temperature control, agitation, and reaction
monitoring are implemented as described above and as desired to
effect the detachment reaction. The reaction tubes, in combination
with the holder block and manifold, are disassembled from the
reservoir block and raised above the solution level but below the
upper lip of the reaction wells, and gas pressure is applied
through the manifold inlet (while closing the outlet) to
efficiently expel the final product solution into the reservoir
wells. The resin remaining in the reaction tubes is then washed 2
to 5 times as above with 3 to 5 ml of an appropriate solvent to
extract (wash out) as much of the detached product as possible. The
product solutions thus obtained are combined, taking care to avoid
cross-mixing. The individual solutions/extracts are then
manipulated as needed to isolate the final compounds. Typical
manipulations include, but are not limited to, evaporation,
concentration, liquid/liquid extraction, acidification,
basification, neutralization or additional reactions in
solution.
[0575] The solutions containing fully protected linear peptide
derivatives which have been cleaved off from the solid support and
neutralized with a base, are evaporated. Cyclization is then
effected in solution using solvents such as DCM, DMF, dioxane, THF
and the like. Various coupling reagents which were mentioned
earlier can be used for the cyclization. The duration of the
cyclization is about 6-48 hours, preferably about 24 hours. The
progress of the reaction is followed, e. g. by RP-HPLC (Reverse
Phase High Performance Liquid Chromatography). Then the solvent is
removed by evaporation, the fully protected cyclic peptide
derivative is dissolved in a solvent which is not miscible with
water, such as DCM, and the solution is extracted with water or a
mixture of water-miscible solvents, in order to remove any excess
of the coupling reagent.
[0576] Before removing the protecting groups from the fully
protected cyclic peptide, it is possible, if desired, to form an
interstrand linkage between side-chains of appropriate amino acid
residues at opposite positions of the .beta.-strand region.
[0577] Interstrand linkages and their formation have been discussed
above, in connection with the explanations made regarding groups of
the type H which can, for example, be disulfide bridges formed by
cysteines and homocysteines at opposite positions of the
.beta.-strand, or glutamic and aspartic acid residues linking
ornithines and, respectively, lysines located at opposite
.beta.-strand positions by amide bond formation. The formation of
such interstrand linkages can be effected by methods well known in
the art.
[0578] Finally, the fully protected peptide derivative of type I is
treated with 95% TFA, 2.5% H.sub.2O, 2.5% TIS or another
combination of scavengers for effecting the cleavage of protecting
groups. The cleavage reaction time is commonly 30 minutes to 12
hours, preferably about 2 hours. Thereafter most of the TFA is
evaporated and the product is precipitated with ether/hexane (1:1)
or other solvents which are suitable therefor. After careful
removal of the solvent, the cyclic peptide derivative obtained as
end-product can be isolated. Depending on its purity, this peptide
derivative can be used directly for biological assays, or it has to
be further purified, for example by preparative HPLC.
[0579] As mentioned earlier, it is thereafter possible, if desired,
to convert a fully deprotected product thus obtained into a
pharmaceutically acceptable salt or to convert a pharmaceutically
acceptable, or unacceptable, salt thus obtained into the
corresponding free compound of formula I or into a different,
pharmaceutically acceptable, salt. Any of these operations can be
carried out by methods well known in the art.
[0580] The starting materials used in the process of the invention,
pre-starting materials therefore, and the preparation of these
starting and pre-starting materials will now be discussed in
detail.
[0581] Building blocks of type A can be synthesized according to
the literature methods described below. The corresponding amino
acids have been described either as unprotected or as Boc- or
Fmoc-protected racemates, (D)- or (L)-isomers. It will be
appreciated that unprotected amino acid building blocks can be
easily transformed into the corresponding Fmoc-protected amino acid
building blocks required for the present invention by standard
protecting group manipulations. Reviews describing general methods
for the synthesis of .alpha.-amino acids include: R. Duthaler,
Tetrahedron (Report) 1994, 349, I540-I650; R. M. Williams,
"Synthesis of optically active .alpha.-amino acids", Tetrahedron
Organic Chemistry Series, Vol. 7, J. E. Baldwin, P. D. Magnus
(Eds.), Pergamon Press., Oxford 1989. An especially useful method
for the synthesis of optically active .alpha.-amino acids relevant
for this invention includes kinetic resolution using hydrolytic
enzymes (M. A. Verhovskaya, I. A. Yamskov, Russian Chem. Rev. 1991,
60, 1163-1179; R. M. Williams, "Synthesis of optically active
.alpha.-amino acids", Tetrahedron Organic Chemistry Series, Vol. 7,
J. E. Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989,
Chapter 7, p. 257-279). Hydrolytic enzymes involve hydrolysis of
amides and nitriles by aminopeptidases or nitrilases, cleavage of
N-acyl groups by acylases, and ester hydrolysis by lipases or
proteases. It is well documented that certain enzymes will lead
specifically to pure (L)-enantiomers whereas others yield the
corresponding (D)-enantiomers (e.g.: R. Duthaler, Tetrahedron
Report 1994, 349, 1540-1650; R. M. Williams, "Synthesis of
optically active .alpha.-amino acids", Tetrahedron Organic
Chemistry Series, Vol. 7, J. E. Baldwin, P. D. Magnus (Eds.),
Pergamon Press., Oxford 1989).
[0582] A1: See D. Ben-Ishai, Tetrahedron 1977, 33, 881-883; K.
Sato, A. P. Kozikowski, Tetrahedron Lett. 1989, 30, 4073-4076; J.
E. Baldwin, C. N. Farthing, A. T. Russell, C. J. Schofield, A. C.
Spirey, Tetrahedron Lett. 1996, 37, 3761-3767; J. E. Baldwin, R. M.
Adlington, N. G. Robinson, J. Chem. Soc. Chem. Commun. 1987,
153-157; P. Wipf, Y. Uto, Tetrahedron Lett. 1999, 40, 5165-5170; J.
E. Baldwin, R. M. Adlington, A. O'Neil, A. C. Spirey, J. B.
Sweeney, J. Chem. Soc. Chem. Commun. 1989, 1852-1854 (for
R.sup.1.dbd.H, R.sup.2.dbd.H); T. Hiyama, Bull. Chem. Soc. Jpn.
1914, 47, 2909-2910; T. Wakamiya, K. Shimbo, T. Shiba, K. Nakajima,
M. Neya, K. Okawa, Bull. Chem. Soc. Jpn. 1982, 55, 3878-3881; I.
Shima, N. Shimazaki, K. Imai, K. Hemmi, M. Hashimoto, Chem. Pharm.
Bull. 1990, 38, 564-566; H. Han, J. Yoon, K. D. Janda, J. Org.
Chem. 1998, 63, 2045-2048 (R.sup.1.dbd.H, R.sup.2=Me); J. Legters,
G. H. Willems, L. Thijs, B. Zwannenburg, Reel. Trav. Chim. Pays-Bas
1992, 111, 59-68 (R.sup.1.dbd.H, R.sup.2=hexyl); J. Legters, L.
Thijs, B. Zwannenburg, Reel. Trav. Chim. Pays-Bas 1992, 111, 16-21;
G. A. Molander, P. J. Stengel, J. Org. Chem. 1995, 21, 6660-6661
(R.sup.1.dbd.H, R.sup.2=Ph); I. Funaki, L. Thijs, B. Zwannenburg,
Tetrahedron 1996, 52, 9909-9924 (R.sup.1.dbd.H, R.sup.2=Bn); A. S.
Pepito, D. C. Dittmer, J. Org. Chem. 1997, 62, 7920-7925;
(R.sup.1.dbd.H, R.sup.2.dbd.CH.sub.2OH); M. Egli, A. S. Dreiding,
Helv. Chim. Acta 1986, 69, 1442-1460
(R.sup.5.dbd.CH(OH)CH.sub.2OH); M. Carduccu, S. Fioravanti, M. A.
Loreto, L. Pellacani, P. A. Tardella, Tetrahedron Lett. 1996, 37,
3777-3778; F. J. Lakner, L. P. Hager, Tetrahedron: Asymmetry 1997,
21, 3547-3550 (R.sup.1=Me, R.sup.2.dbd.H, Me); G. A. Molander, P.
J. Stengel, Tetrahedron 1997, 26, 8887-8912; M. A. Loreto, F.
Pompei, P. A. Tardella, D. Tofani, Tetrahedron 1997, 53,
15853-15858 (R.sup.1=Me, R.sup.2.dbd.CH.sub.2SiMe.sub.3); H. Shao,
J. K. Rueter, M. Goodman, J. Org. Chem. 1998, 63, 5240-5244
(R.sup.1=Me, R.sup.2=Me).
[0583] A2: See A. Rao, M. K. Gurjar, V. Vivarr, Tetrahedron:
Asymmetry 1992, 3, 859-862; R. L. Johnson, G. Rayakumar, K.-L. Yu,
R. K. Misra, J. Med. Chem. 1986, 29, 2104-2107 (R.sup.1.dbd.H,
R.sup.2.dbd.H); J. E. Baldwin, R. M. Adlington, R. H. Jones, C. J.
Schofield, C. Zarcostas, J. Chem. Soc. Chem. Commun. 1985, 194-196;
J. E. Baldwin, R. M. Adlington, R. H. Jones, C. J. Schofield, C.
Zarcostas, Tetrahedron 1986, 42, 4879-4888 (R.sup.1.dbd.H,
R.sup.2.dbd.CH.sub.2OH, CH.sub.2CHO, CH.sub.2CH.sub.2COOH,
CH.sub.2CH.sub.2OH); A. P. Kozikowski, W. Tueckmantel, I. J.
Reynolds, J. T. Wroblewski, J. Med. Chem. 1990, 33, 1561-1571; A.
P. Kozikowski, W. Tueckmantel, Y. Liao, H. Manev, S. Ikonomovic J.
T. Wroblenski, J. Med. Chem. 1993, 36, 2706-2708 (R.sup.1.dbd.H,
R.sup.2.dbd.CH.sub.2OH, CHCONH.sub.2, CONHCH.sub.2COOH, COOtBu); D.
Seebach, T. Vettiger, H.-M. Muller, D. Plattner, W. Petter, Liebigs
Ann. Chem. 1990, 687-695 (R.sup.1=ArylCH(OH), R.sup.2.dbd.H); D.
Seebach, E. Dziadulewicz, L. Behrendt, S. Cantoreggi, R. Fitzi,
Liebigs Ann. Chem. 1989, 1215-1232 (R.sup.1=Me, Et,
R.sup.2.dbd.H).
[0584] A3: See A. P. Kozikowski, Y. Liao, W. Tueckmantel, S. Wang,
S. Pshsenichkin, Bioorg. Med. Chem. Lett. 1996, 6, 2559-2564
(R.sup.1.dbd.H; R.sup.2.dbd.CHCHO, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2COOH, COOH); Isono, J. Am. Chem. Soc, 1969, 91, 7490
(R.sup.1.dbd.H; R.sup.2=Et); P. J. Blythin, M. J. Green, M. J.
Mary, H. Shue, J. Org. Chem. 1994, 59, 6098-6100; S. Hanessian, N.
Bernstein, R.-Y. Yang, R. Maquire, Bioorg. Chem. Lett. 1994, 9,
1437-1442 (R.sup.1.dbd.H; R.sup.2=Ph).
[0585] A4: See G. Emmer, Tetrahedron 1992, 48, 7165-7172; M. P.
Meyer, P. L. Feldman, H. Rapoport, J. Org. Chem. 1985, 50,
5223-5230 (R.sup.1.dbd.H; R.sup.2.dbd.H); A. J. Bose, M. S. Manhas,
J. E. Vincent, I. F. Fernandez, J. Org. Chem. 1982, 47, 4075-4081
(R.sup.1.dbd.H; R.sup.2.dbd.NHCOCH.sub.2OPh); D. L. Boger, J. B.
Meyers, J. Org. Chem. 1991, 56, 5385-5390 (R.sup.1.dbd.H;
R.sup.2.dbd.NHCOCH.sub.2Ph); K.-D. Kampe. Tetrahedron Lett. 1969,
117-120 (R.sup.1.dbd.CH.sub.2OH; R.sup.2=Ph); M. D. Andrews, M. G.
Maloney, K. L. Owen, J. Chem. Soc. Perkin Trans. 1, 1996, 227-228
(R.sup.1.dbd.CH.sub.2OH; R.sup.2.dbd.H).
[0586] A5: See C. Bisang, C. Weber, J. Inglis, C. A. Schiffer, W.
F. van Gunsteren, J. A. Robinson J. Am. Chem. Soc. 1995, 117, 7904
(R.sup.1.dbd.CH.sub.3; R.sup.2.dbd.H); S. Takano, M. Morija, Y.
Iwabuki, K. Ogasawara, Tetrahedron Lett. 1989, 30, 3805-3806
(R.sup.1.dbd.H; R.sup.2.dbd.COOH); M. D. Bachi, R. Breiman, H.
Meshulam, J. Org. Chem. 1983, 48, 1439-1444 (R.sup.1.dbd.H;
R.sup.2.dbd.CH(Et)COOH); D. S. Kemp, T. P. Curran, Tetrahedron
Lett. 1988, 29, 4931-4934; D. S. Kemp, T. P. Curran, W. M. Davies,
J. Org. Chem. 1991, 56, 6672-6682 (R.sup.1.dbd.H;
R.sup.2.dbd.CH.sub.2OH); F. Manfre, J.-M. Kern, J.-F. Biellmann, J.
Org. Chem. 1992, 57, 2060-2065 (R.sup.1.dbd.H; R.sup.2.dbd.H,
CH.dbd.CH.sub.2, CCH); B. W. Bycroft, S. R. Chabra, J. Chem. Soc.
Chem. Commun. 1989, 423-425 (R.sup.1.dbd.H;
R.sup.2.dbd.CH.sub.2COOtBu; Y. Xu, J. Choi, M. I. Calaza, S.
Turner, H. Rapoport, J. Org. Chem. 1999, 64, 4069-4078
(R.sup.1.dbd.H; R.sup.2=3-pyridyl); E. M. Khalil, W. J. Ojala, A.
Pradham, V. D. Nair, W. B. Gleason, J. Med. Chem. 1999, 42,
628-637; E. M. Khalil, N. L. Subasinghe, R. L. Johnson, Tetrahedron
Lett. 1996, 37, 3441-3444 (R.sup.1=allyl; R.sup.2.dbd.H); A.
DeNicola, J.-L. Luche, Tetrahedron Lett. 1992, 33, 6461-6464; S.
Thaisrivongs, D. T. Pals, J. A. Lawson, S. Turner, D. W. Harris, J.
Med. Chem. 1987, 30, 536-541; E. M. Khalil, N. L. Subasinghe, R. L.
Johnson, Tetrahedron Lett. 1996, 37, 3441-3444; A. Lewis, J.
Wilkie, T. J. Rutherford, D. Gani, J. Chem. Soc. Perkin Trans. 1,
1998, 3711-1194 (R.sup.1=Me; R.sup.2.dbd.H); A. Lewis, J. Wilkie,
T. J. Rutherford, D. Gani, J. Chem. Soc. Perkin Trans. 1, 1998,
3777-3794 (R.sup.1.dbd.CH.sub.2COOMe; R.sup.2.dbd.H); N. L.
Subasinghe, E. M. Khalil, R. L. Johnson, Tetrahedron Lett. 1997,
38, 1317-1320 (R.sup.1.dbd.CH.sub.2CHO; R.sup.2.dbd.H); D. J.
Witter, S. J. Famiglietti, J. C. Gambier, A. L. Castelhano, Bioorg.
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Pradham, V. D. Nair, W. B. Gleason, J. Med. Chem. 1999, 42, 628-637
(R.sup.1.dbd.CH.sub.2CH.sub.2CHO; R.sup.2.dbd.H).
[0587] A6: See DeNardo, Farmaco Ed. Set. 1977, 32, 522-529
(R.sup.1.dbd.H; R.sup.3.dbd.H); P. J. T. Floris, N. Terhuis, H.
Hiemstra, N. W. Speckamp, Tetrahedron, 1993, 49, 8605-8628; S.
Kanemasa, N. Tomoshige, O. Tsuge, Bull. Chem. Soc. Jpn. 1989, 62,
3944-3949 (R.sup.1.dbd.H; R.sup.3.dbd.H); Sucrow, Chem. Ber. 1979,
112, 1719.
[0588] A7: See Fichter, J. Prakt. Chem. 1906, 74, 310 (R.sup.1=Me;
R.sup.4=Ph).
[0589] A8: See L. Lapantsanis, G. Milias, K. Froussios, M. Kolovos,
Synthesis 1983, 641-673; H. Nedev, H. Naharisoa, Tetrahedron Lett.
1993, 34, 4201-4204; D. Y. Jackson, C. Quan, D. R. Artis, T.
Rawson, B. Blackburn, J. Med. Chem. 1997, 40, 3359-3368; D.
Konopinska, H. Bartosz-Bechowski, G. Rosinski, W. Sobotka, Bull.
Pol. Acad. Sci. Chem. 1993, 41, 27-40; J. Hondrelis, G. Lonergan,
S. Voliotis, J. Matsukas, Tetrahedron 1990, 46, 565-576; T.
Nakamura, H. Matsuyama, H. Kanigata, M. Iyoda, J. Org. Chem. 1992,
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G. F. Swiss, B. R. Neustadt, E. H. Gold, J. A. Sommer, J. Med.
Chem. 1988, 31, 875-885; E. Rubini, C. Gilon, Z. Selinger, M.
Chorev, Tetrahedron 1986, 42, 6039-6045 (R.sup.1.dbd.H;
R.sup.5.dbd.OH); C. R. Noe, M. Knollmueller, H. Voelienkle, M.
Noe-Letschnig, A. Weigand, J. Muhl, Pharmazie, 1996, 51, 800-804
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N. Cammack, S. Dolan, D. N. Evans, J. Med. Chem. 1994, 37,
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Nakhle, H. D. Graham, T. L. Anstell, Tetrahedron 1995, 51,
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Tetrahedron Lett: 1986, 27, 151-154 (R.sup.1.dbd.H; R.sup.5=Ph); K.
Plucinska, T. Kataoka, M. Yodo, W. Cody, J. Med. Chem. 1993, 36,
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W. Cushman, J. R. Powell, J. Med. Chem. 1988, 31, 1148-1160
(R.sup.1.dbd.H; R.sup.5.dbd.SPh); A. J. Verbiscar, B. Witkop, J.
Org. Chem. 1970, 35, 1924-1927 (R.sup.1.dbd.H;
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R.sup.5.dbd.CH.sub.2COOBn).
[0590] A9: See Blake, J. Am. Chem. Soc. 1964, 86, 5293-5297; J.
Cooper, R. T. Gallagher, D. T. Knight, J. Chem. Soc. Chem. Perkin
Trans. 1, 1993, 1313-1318; D. W. Knight, A. W. Sibley, J. Chem.
Soc. Perkin Trans. 1, 1997, 2179, 2188 (R.sup.1.dbd.H;
R.sup.5.dbd.H); Blake, J. Am. Chem. Soc. 1964, 86, 5293-5297; Y.
Yamada, T. Ishii, M. Kimura, K. Hosaka, Tetrahedron Lett. 1981,
1353-1354 (R.sup.1.dbd.H; R.sup.5.dbd.OH); Y. Umio, Yakugaku
Zasshi, 1958, 78, 727 (R.sup.1.dbd.H; R.sup.5=iPr); Miyamoto,
Yakugaku Zasshi, 1957, 77, 580-584; Tanaka, Proc. Jpn. Acad. 1957,
33, 47-50 (R.sup.1.dbd.H;
R.sup.6.dbd.CH(CH.sub.3)CH.sub.2N(CH.sub.3).sub.2); L. E. Overman,
B. N. Rodgers, J. E. Tellew, W. C. Trenkle, J. Am. Chem. Soc. 1997,
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Bull. 1976, 24, 1362-1369 (R.sup.1.dbd.CH.sub.3;
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[0591] A10: See J. Mulzer, A. Meier, J. Buschmann, P. Luger,
Synthesis 1996, 123-132 (R.sup.1.dbd.H;
R.sup.7.dbd.CH.dbd.CH.sub.2); J. Cooper, P. T. Gallagher, D. W.
Knight, J. Chem. Soc. Chem. Commun. 1988, 509-510; E. Gotschi, C.
Jenny, P. Reindl, F. Ricklin, Helv. Chim. Acta 1996, 79, 2219-2234
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Fontaine, A. Chiaroni, C. Riche, P. Potier, Tetrahedron Lett. 1994,
35, 241-244 (R.sup.1.dbd.H; R.sup.7.dbd.COOH); R. Cotton, A. N. C.
Johnstone, M. North, Tetrahedron 1995, 51, 8525-8544
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E. W. Huber, J. S. Sabol, Tetrahedron Lett. 1996, 37, 4091-4094
(R.sup.1.dbd.H; R.sup.7=(4-BnO)C.sub.6H.sub.4); N. A. Sasaki, R.
Pauli, P. Potier, Tetrahedron Lett. 1994, 35, 237-240
(R.sup.1.dbd.H; R.sup.7.dbd.SO.sub.2Ph); R. J. Heffner, J. Jiang,
M. Jouillie, J. Am. Chem. Soc. 1992, 114, 10181-10189; U. Schmidt,
H. Griesser, A. Lieberknecht, J. Hausler, Angew. Chem. 1981, 93,
272-273 (R.sup.1.dbd.H; R.sup.7.dbd.OAryl); H. Mosberg, A. L.
Lomize, C. Wang, H. Kroona, D. L. Heyl, J. Med. Chem. 1994, 37,
4371-4383 (R.sup.1.dbd.H; R.sup.7=4-OHC.sub.6H.sub.4); S. A.
Kolodziej, G. V. Nikiforovich, R. Sceean, M.-F. Lignon, J.
Martinez, G. R. Marshall, J. Med. Chem. 1995, 38, 137-149
(R.sup.1.dbd.H; R.sup.7.dbd.SCH.sub.2(4-Me)C.sub.6H.sub.4).
[0592] A11: See Kuhn, Osswald, Chem. Ber. 1956, 89, 1423-1434;
Patchett, Witkop, J. Am. Chem. Soc. 1957, 79, 185-189; Benz, Helv.
Chim. Acta 1974, 57, 2459-2475; P. Wessig, Synlett, 1999, 9,
1465-1467; E. M. Smit, G. F. Swiss, B. R. Neustadt, E. H. Gold, J.
A. Sommer, J. Med. Chem. 1988, 31, 875-885; J. Krapcho, C. Turk, D.
W. Cushman, J. R. Powell, J. M. DeForrest, J. Med. Chem. 1988, 31,
1148 (R.sup.1.dbd.H; R.sup.6.dbd.H); D. BenIshai, S. Hirsh,
Tetrahedron 1988, 44, 5441-5450 (R.sup.1.dbd.H;
R.sup.6.dbd.CH.sub.3); M. W. Holladay, C. W. Lin, C. S. Garvey, D.
G. Witte, J. Med. Chem. 1991, 34, 455-457 (R.sup.1.dbd.H;
R.sup.6=allyl); P. Barralough, P. Hudhomme, C. A. Spray, D. W.
Young, Tetrahedron 1995, 51, 4195-4212 (R.sup.1.dbd.H; R.sup.6=Et);
J. E. Baldwin, M. Rudolf, Tetrahedron Lett. 1994, 35, 6163-6166; J.
E. Baldwin, S. J. Bamford, A. M. Fryer, M. Rudolf, M. E. Wood,
Tetrahedron 1997, 53, 5233-5254 (R.sup.1.dbd.H;
R.sup.6.dbd.CH.sub.2COOtBu); P. Gill, W. D. Lubell, J. Org. Chem.
1995, 60, 2658-2659 (R.sup.1.dbd.H; R.sup.6.dbd.CH.sub.3; Bn;
allyl; CH.sub.2COOMe); M. J. Blanco, F. J. Sardina, J. Org. Chem.
1998, 63, 3411-3466 (R.sup.1.dbd.H; R.sup.6.dbd.OCH.sub.2OMe).
[0593] A12: See Ahmed, Cheeseman, Tetrahedron 1977, 33, 2255-2257;
J. S. New, J. P. Yevich, J. Heterocycl. Chem. 1984, 27, 1355-1360;
R. Kikumoto, Y. Tamao, K. Ohkubo, T. Tezuka, S. Tonomura, J. Med.
Chem. 1980, 23, 1293-1299; C. J. Blankley, J. S. Kaltenbronn, D. E.
DeJohn, A. Werner, L. R. Bennett, J. Med. Chem. 1987, 30, 992-998;
S. Klutcho, C. J. Blankley, R. W. Fleming, J. M. Hinkley, R. E.
Werner, J. Med. Chem. 1986, 29, 1953-1961 (R.sup.1.dbd.H;
R.sup.8.dbd.H); L. J. Beeley, C. J. M. Rockwell, Tetrahedron Lett.
1990, 31, 417-420 (R.sup.1.dbd.COOEt; R.sup.8.dbd.H).
[0594] A13: See G. Flouret, W. Brieher, T. Majewski, K. Mahan, J.
Med. Chem. 1991, 43, 2089-2094; G. Galiendo, P. Grieco, E.
Perissuti, V. Santagada, Farmaco, 1996, 51, 197-202; D. F.
McComsey, M. J. Hawkins, P. Andrade-Gordon, M. F. Addo, B. E.
Maryanoff, Bioorg. Med. Chem. Lett. 1999, 9, 1423-1428; G. B.
Jones, S. B. Heaton, B. J. Chapman, M. Guzel, Tetrahedron:
Asymmetry 1997, 8, 3625-3636; M. Asami, H. Watanabe, K. Honda, S.
Inoue, Tetrahedron: Asymmetry 1998, 9, 4165-4174; K. Gross, Y. M.
Yun, P. Beak, J. Org. Chem. 1997, 62, 7679-7689 (R.sup.1.dbd.H;
R.sup.6.dbd.H; R.sup.8.dbd.H); K. Gross, Y. M. Yun, P. Beak, J.
Org. Chem. 1997, 62, 7679-7689 (R.sup.1.dbd.H; R.sup.6.dbd.H;
R.sup.8=6-Cl); Ch. Noe, M. Knollmueller, C. Schoedl, M. L. Berger,
Sci. Pharm. 1996, 64, 577-590; E. Reiman, W. Erdle, H. Unger,
Pharmazie, 1994, 54, 418-421 (R.sup.1.dbd.H;
R.sup.6.dbd.CH.sub.2COOH; R.sup.8.dbd.H); V. Collot, M. Schmitt, A.
K. Marwah, B. Norberg, J.-J. Bourgignon, Tetrahedron Lett. 1997,
38, 8033-8036 (R.sup.1.dbd.H; R.sup.6=Ph; R.sup.8.dbd.H); L. V.
Dunkerton, H. Chen, B. P. McKillican, Tetrahedron Lett. 1988, 29,
2539-2542 (R.sup.1.dbd.C(CH.sub.3).sub.2CH.dbd.CH.sub.2;
R.sup.6.dbd.H; R.sup.8.dbd.H); E. J. Corey, J. Am. Chem. Soc. 1970,
92, 2476-2488; Neunhoeffer, Lehmann, Chem. Ber. 1961, 94, 2960-2963
(R.sup.1.dbd.CH.sub.3; R.sup.6.dbd.H; R.sup.8.dbd.H).
[0595] A14: Amino acids of type A14 can be made according to Scheme
1.
##STR00031##
[0596] A15: See D. S. Perlow, J. M. Erb, N. P. Gould, R. D. Tung, R
M. Freidinger, J. Org. Chem. 1992, 57, 4394-4400; D. Y. Jackson, C.
Quan, D. R. Artis, T. Rawson, B. Blackburn, J. Med. Chem. 1997, 40,
3359-3368 (R.sup.1.dbd.H; R.sup.3.dbd.H); H. H. Wasserman, K.
Rodrigues, K. Kucharczyk, Tetrahedron Lett. 1989, 30, 6077-6080
(R.sup.1.dbd.H; R.sup.2.dbd.COOH).
[0597] A16: See Beyerman, Boekee, Recl. Trav. Chim. Pays-Bas, 1959,
78, 648-653; M. E. Freed, A. R. Day, J. Org. Chem. 1960, 25,
2105-2107; D. R. Adams, P. D. Bailey, I. D. Collier, J. D.
Heferman, S. Slokes, J. Chem. Soc. Chem. Commun. 1996, 349-350; J.
E. Baldwin, R. M. Adlington, C. R. A. Godfrey, D. W. Collins, J. D.
Vaughan, J. Chem. Soc. Chem. Commun. 1993, 1434-1435; Y. Matsumura,
Y. Takeshima, H. Ohita, Bull Chem. Soc. Jpn. 1994, 67, 304-306
(R.sup.1.dbd.H; R.sup.6.dbd.H); C. Herdeis, W. Engel, Arch. Pharm.
1991, 324, 670 (R.sup.1.dbd.COOMe; R.sup.6.dbd.CH.sub.3).
[0598] A17, A18: See C. R. Davies, J. S. Davies, J. Chem. Soc.
Perkin Trans 1, 1976, 2390-2394; K. Bevan, J. Chem. Soc. C, 1971,
514-522; K. Umezawa, K. Nakazawa, Y. Ikeda, H. Naganawa, S. Kondo,
J. Org. Chem. 1999, 64, 3034-3038 (R.sup.1.dbd.R.sup.3.dbd.H); P.
D. Williams, M. G. Bock, R. D. Tung, V. M. Garsky, D. S. Parlow, J.
Med. Chem, 1992, 35, 3905-3918; K. Tamaki, K. Tanzawa, S. Kurihara,
T. Oikawa, S. Monma, Chem. Pharm. Bull. 1995, 43, 1883-1893
(R.sup.1.dbd.R.sup.5.dbd.H; R.sup.3.dbd.COOBn); K. J. Hale, J. Cai,
V. Delisser, S. Manaviazar, S. A. Peak, Tetrahedron 1996, 52,
1047-1068; M. H. Chen, O. P. Goel, J.-W. Hyun, J. Magano, J. R.
Rubin, Bioorg. Med. Chem. Lett. 1999, 9, 1587-1592
(R.sup.1.dbd.R.sup.5.dbd.H; R.sup.3.dbd.COOtBu); R. Baenteli, I.
Brun, P. Hall, R. Metternich, Tetrahedron Lett. 1999, 40, 2109-2112
(R.sup.1.dbd.R.sup.5.dbd.H; R.sup.3.dbd.COR); K. J. Hale, N.
Jogiya, S. Manaviazar, Tetrahedron 1998, 39, 7163-7166
(R.sup.1.dbd.H; R.sup.3.dbd.COOBn; R.sup.5.dbd.OBn); T. Kamenecka,
S. J. Danishewsky, Angew. Chem. Int. Ed. Engl. 1998, 37, 2995-2998
(R.sup.1.dbd.H; R.sup.3.dbd.COO(CH.sub.2).sub.2SiMe.sub.3;
R.sup.5.dbd.OSiMe.sub.2tBu.
[0599] A19: See Beilstein, Registry Number 648833
(R.sup.1.dbd.R.sup.4.dbd.R.sup.8.dbd.H). Compounds of this type can
be prepared according to Scheme 2.
##STR00032##
[0600] A20: See D. Hagiwara, H. Miyake, N. Igari, M. Karino, Y.
Maeda, J. Med. Chem. 1994, 37, 2090-2099 (R.sup.1.dbd.H;
R.sup.9.dbd.OH); Y. Arakawa, M. Yasuda, M. Ohnishi, S. Yoshifuji,
Chem. Pharm. Bull. 1997, 45, 255-259 (R.sup.1.dbd.H;
R.sup.9.dbd.COOH); P. J. Murray, I. D. Starkey, Tetrahedron Lett.
1996, 37, 1875-1878 (R.sup.1.dbd.H;
R.sup.9.dbd.(CH.sub.2).sub.2NHCOCH.sub.2Ph); K. Clinch, A. Vasella,
R. Schauer, Tetrahedron Lett. 1987, 28, 6425-6428 (R.sup.1.dbd.H;
R.sup.9.dbd.NHAc).
[0601] A21: See A. Golubev, N. Sewald, K. Burger, Tetrahedron Lett.
1995, 36, 2037-2040; F. Machetti, F. M. Cordero, F. DeSario, A.
Guarna, A. Brandi, Tetrahedron Lett. 1996, 37, 4205-4208; P. L.
Ornstein, D. D. Schoepp, M. B. Arnold, J. D. Leander, D. Lodge, J.
Med. Chem. 1991, 34, 90-97; R.sup.1.dbd.R.sup.6.dbd.H); P. D.
Leeson, B. J. Williams, R. Baker, T. Ludduwahetty, K. W. Moore, M.
Rowley, J. Chem. Soc. Chem. Commun. 1990, 1578-1580; D. I. C.
Scopes, N. F. Hayes, D. E. Bays, D. Belton, J. Brain, J. Med. Chem.
1992, 35, 490-501; H. Kessler, M. Kuehn, T. Loschner, Liebigs Ann.
Chem. 1986, 1-20 (R.sup.1.dbd.R.sup.6.dbd.H); C. Herdeis, W. Engel,
Arch. Pharm. 1992, 7, 419-424 (R.sup.1.dbd.R.sup.6=Bn); C. Herdeis,
W. Engel, Arch. Pharm. 1992, 411-418 (R.sup.1.dbd.COOMe;
R.sup.6.dbd.H); C. Herdeis, W. Engel, Arch. Pharm. 1992, 419-424
(R.sup.1.dbd.COOMe; R.sup.6=Bn).
[0602] A22: See P. D. Leeson, B. J. Williams, R. Baker, T.
Ladduwahetty, K. W. Moore, M. Rowley, J. Chem. Soc. Chem. Comm.
1990, 1578-1580 (R.sup.1.dbd.H; R.sup.10.dbd.NHOBn).
[0603] A23: See Beyerman, Boekee, Recl. Trav. Chim. Pays-Bas 1959,
78, 648-653; D. R. Adams, P. D. Bailey, I. D. Collier, J. D.
Hefferman, S. Stokes J. Chem. Soc. Chem. Commun. 1996, 349-350; J.
E. Baldwin, R. M. Adlington, C. Godfrey, D. W. Collins, J. G.
Vaughan, J. Chem. Soc. Chem. Comm. 1993, 1434-1435
(R.sup.1.dbd.R.sup.6.dbd.H); C. Herdeis, W. Engel, Arch. Pharm.
1993, 297-302 (R.sup.1.dbd.COOMe; R.sup.6.dbd.H).
[0604] A24: See Plieninger, Leonhauser, Chem. Ber. 1959, 92,
1579-1584; D. W. Knight, N. Lewis, A. C. Share, D. Haigh, J. Chem.
Soc. Perkin Trans. 1 1998, 22, 3673-3684; J. Drummond, G. Johnson,
D. G. Nickell, D. F. Ortwine, R. F. Bruns, B. Welbaum, J. Med.
Chem. 1989, 32, 2116-2128; M. P. Moyer, P. L Feldman, H. Rapoport,
J. Org. Chem. 1985, 50, 5223-5230 (R.sup.1.dbd.R.sup.6.dbd.H);
McElvain, Laughton, J. Am. Chem. Soc. 1951, 73, 448-451
(R.sup.1.dbd.H; R.sup.6=Ph); McElvain, Laughton, J. Am. Chem. Soc.
1951, 73, 448-451 (R.sup.1=Ph; R.sup.6.dbd.H);
[0605] A25: See L.-Y. Hu, T. R. Ryder, S. S. Nikam, E. Millerman,
B. G. Szoke, M. F. Rafferty, Bioorg. Med. Chem. Lett. 1999, 9,
1121-1126; W. C. Lumma, R. D. Hartman, W. S. Saari, E. L.
Engelhardt, V. J. Lotti, C. A. Stone, J. Med. Chem. 1981, 24,
93-101; N. Hosten, M. J. O. Antenuis, Bull. Soc. Chim. Belg. 1988,
97, 48-50; C. F. Bigge, S. J. Hays, P. M. Novak, J. T. Drummond, G.
Johnson, T. P. Bobovski, Tetrahedron Lett. 1989, 30, 5193-5191; B.
Aebischer, P. Frey, H.-P. Haerter, P. L. Herrling, W. Muller, Helv.
Chim. Acta 1989, 72, 1043-1051; W. J. Hoeckstra, B. E. Maryanoff,
B. P. Damiano, P. Andrade-Gordon, J. H. Cohen, M. J. Constanzo, B.
J. Haertlein, L. R. Hecker, B. L. Hulshizer, J. A. Kauffman, P.
Keane, J. Med. Chem. 1999, 42, 5254-5265 (R.sup.1.dbd.H;
R.sup.11.dbd.H); B. D. Dorsey, R. B. Levin, S. L. McDaniel, J. P.
Vacca, J. P. Guare, J. Med. Chem. 1994, 57, 3443-3451; M. Cheng, B.
De, S. Pikul, N. G. Almstaed, M. G. Natchus, M. V. Anastasio, S. J.
McPhail, C. J. Snider, Y. O. Taiwo, L. Chen, C. M. Dunaway, J. Med.
Chem. 2000, 43, 369-380; R. Kuwano, Y. Ito, J. Org. Chem. 1999, 64,
1232-1237 (R.sup.1.dbd.H; R.sup.11.dbd.COOtBu); J. Kitchin, R. C.
Bethell, N. Cammack, S. Dolan, D. N. Evans, J. Med. Chem. 1994, 37,
3707-3716 (R.sup.1.dbd.H; R.sup.11.dbd.COOPh); C. F. Bigge, S. J.
Hays, P. M. Novak, J. T. Drummond, G. Johnson, T. P. Bobovski, J.
Med. Chem. 1990, 33, 2916-2924 (R.sup.1.dbd.H; R.sup.11.dbd.COOtBu;
(CH.sub.2).sub.3COOEt; (CH.sub.2).sub.3PO(Me)OH;
CH.sub.2PO(OH).sub.2; (CH.sub.2).sub.2PO(OEt).sub.2;
(CH.sub.2).sub.2PO(OH).sub.2).
[0606] Compounds of type A25 can also be prepared according to
Scheme 3:
##STR00033##
[0607] A26: See Koegel, J. Biol. Chem. 1953, 201, 547
(R.sup.1.dbd.R.sup.12.dbd.H).
[0608] A27: See G. Makara, G. R. Marshall, Tetrahedron Lett. 1997,
55, 5069-5072; R. N. Patel, A. Banerjee, R L. Hanson, D. B.
Brzozowski, L. W. Parker, L. J. Szarka, Tetrahedron: Asymmetry
1999, 10, 31-36 (R.sup.1.dbd.H; R.sup.13.dbd.OH, OtBu); J. E.
Johanson, B. D. Christie, H. Rapoport, J. Org. Chem. 1981, 46,
4914-4920; N. Moss, J.-S. Duceppe, J.-M Ferland, J. Gauthier, J.
Med. Chem. 1996, 39, 2178-2187 (R.sup.1.dbd.H;
R.sup.13.dbd.CONHMe); G. M. Makara, G. R Marshall, Tetrahedron
Lett. 1997, 38, 5069-5072 (R.sup.1.dbd.H;
R.sup.13.dbd.SCH.sub.2(4-MeO)C.sub.6H.sub.4).
[0609] A28: See A. Golubev, N. Sewald, K. Burger, Tetrahedron Lett.
1995, 36, 2037-2040; P. L. Ornstein, D. D. Schoepp, M. B. Arnold,
J. D. Leander, D. Lodge, J. Med. Chem. 1991, 34, 90-97
(R.sup.1.dbd.R.sup.6.dbd.H); P. D. Leeson, B. J. Williams, R.
Baker, T. Ladduwahetty, K. W. Moore, M. Rowley, J. Chem. Soc. Chem.
Commun. 1990, 22, 1578-1580; C. Herdeis, W. Engel, Arch. Pharm.
1991, 324, 670 (R.sup.1.dbd.H; R.sup.6=Me); C. Herdeis, W. Engel,
Arch. Pharm. 1991, 324, 670 (R.sup.1.dbd.COOMe; R.sup.6.dbd.H,
Me).
[0610] A29: See Kawase, Masami, Chem. Pharm. Bull. 1997, 45,
1248-1253; I. G. C. Coutts, J. A. Hadfield, P. R. Huddleston, J.
Chem. Res. Miniprint, 1987, 9, 2472-2500; I. G. C. Coutts, J. A.
Hadfield, P. R. Huddleston, J. Chem. Res. Miniprint. 1987, 9,
2472-2500; V. J. Hrubi, W. L. Cody, A. M. Castrucci, M. E. Hadley,
Collect. Czech. Chem. Commun. 1988, 53, 2549-2573; R. T. Shuman, R.
B. Rothenberger, C. S. Campbell, G. F. Smith, D. S. Gifford-Moore,
P. D. Gesellchen, J. Med. Chem. 1993, 36, 314-319; M. Kawase, Y.
Okada, H. Miyamae, Heterocycles, 1998, 48, 285-294
(R.sup.1.dbd.R.sup.8.dbd.H); Kawase, Masami, Chem. Pharm. Bull.
1997, 45, 1248-1253 (R.sup.1.dbd.H; R.sup.8=6,7-(MeO.sub.2); D. F.
Ortwine, T. C. Malone, C. F. Bigge, J. T. Drummond, C. Humblet, J.
Med. Chem. 1992, 35, 1345-1370 (R.sup.1.dbd.H;
R.sup.8=7-CH.sub.2PO(OEt).sub.2); E. J. Corey, D. Y. Gin,
Tetrahedron Lett. 1996, 37, 7163-7166
(R.sup.1.dbd.CH.sub.2SCOOtBu); P. Dostert, M. Varasi, A.
DellaTorre, C. Monti, V. Rizzo, Eur. J. Med. Chim. Ther. 1992, 27,
57-59 (R.sup.1=Me; R.sup.8=6,7-(OH).sub.2); Z. Czarnocki, D. Suh,
D. B. McLean, P. G. Hultin, W. A. Szarek, Can. J. Chem. 1992, 70,
1555-1561; B. Schonenberger, A. Brossi, Helv. Chim. Acta 1986, 69,
1486-1497 (R.sup.1=Me; R.sup.8=6-OH; 7-MeO); Hahn, Stiel, Chem.
Ber. 1936, 69, 2627; M. Chrzanowska, B. Schonenberger, A. Brossi,
J. L. Flippen-Anderson, Helv. Chim. Acta 1987, 70, 1721-1731; T.
Hudlicky, J. Org. Chem. 1981, 46, 1738-1741 (R.sup.1=Bn;
R.sup.8=6,7-(OH).sub.2); A. I. Meyers, M. A. Gonzalez, V. Struzka,
A. Akahane, J. Guiles, J. S. Warmus, Tetrahedron Lett. 1991, 32,
5501-5504 (R.sup.1.dbd.CH.sub.2(3,4-methylenedioxy)C.sub.6H.sub.3;
R.sub.8=6,7-(OMe).sub.2).
[0611] A30 and A31 can be prepared according to Schemes 4 and
5.
##STR00034##
##STR00035##
[0612] A32 can be prepared according to P. W. Schiller, G.
Weltrowska, T. M.-D. Nguyen, C. Lemieux, N. Nga, J. Med. Chem.
1991, 34, 3125-3132; V. S. Goodfellow, M. V. Marathe, K. G.
Kuhlman, T. D. Fitzpatrick, D. Cuadrato, J. Med. Chem. 1996, 39,
1472-1484; G. Caliendo, F. Fiorino, P. Grieco, E. Perissutti, S.
DeLuca, A. Guiliano, G. Santelli, D. Califano, B. Severino, V.
Santagada, Farmacao, 1999, 54, 785-790; V. S. Goodfellow, M. V.
Marathe, K. G. Kuhlman, T. D. Fitzpatrick, D. Cuadro, J. Med. Chem.
1996, 39, 1472-1484 (R.sup.1.dbd.R.sup.8.dbd.H); D. Tourwe, E.
Mannekens, N. T. Trang, P. Verheyden, H. Jaspers, J. Med. Chem.
1998, 41, 5167-5176; A.-K. Szardenings, M. Gordeev, D. V. Patel,
Tetrahedron Lett. 1996, 37, 3635-3638; W. Wiczk, K. Stachowiak, P.
Skurski, L. Lankiewicz, A. Michniewicz, A. Roy, J. Am. Chem. Soc.
1996, 118, 8300-8307; K. Verschuren, G. Toth, D. Tourwe, M. Lebl.,
G. van Binst, V. Hrubi, Synthesis 1992, 458-460 (R.sup.1.dbd.H;
R.sup.8=6-OH); P. L. Ornstein, M. B. Arnold, N. K. Augenstein, J.
W. Paschal, J. Org. Chem. 1991, 56, 4388-4392 (R.sup.1.dbd.H;
R.sup.8=6-MeO); D. Ma, Z. Ma, A. P. Kozikowski, S. Pshenichkin, J.
T. Wroblenski, Bioorg. Med. Lett. 1998, 8, 2447-2450
(R.sup.1.dbd.H; R.sup.8=6-COOH); U. Schollkopf, R. Hinrichs, R.
Lonsky, Angew. Chem. 1987, 99, 137-138 (R.sup.1=Me; R.sup.8.dbd.H);
B. O. Kammermeier, U. Lerch, C. Sommer, Synthesis 1992, 1157-1160
(R.sup.1.dbd.COOMe; R.sup.8.dbd.H); T. Gees, W. B. Schweizer, D.
Seebach, Helv. Chim. Acta 1993, 76, 2640-2653 (R.sup.1=Me;
R.sup.8=6,7-(MeO.sub.2).
[0613] A33: See Hinton, Mann, J. Chem. Soc. 1959, 599-608.
[0614] A34: See G. P. Zecchini, M. P. Paradisi, J. Heterocycl.
Chem. 1979, 16, 1589-1597; S. Cerrini, J. Chem. Soc. Perkin Trans.
1, 1979, 1013-1019; P. L. Ornstein, J. W. Paschal, P. D.
Gesellchen, J. Org. Chem. 1990, 55, 738-741; G. M. Ksander, A. M.
Yan, C. G. Diefenbacher, J. L. Stanton, J. Med. Chem. 1985, 28,
1606-1611; J. A. Robl, D. S. Karanewsky, M. M. Asaad, Tetrahedron
Lett. 1995, 36, 1593-1596; S. Katayama, N. Ae, R. Nagata,
Tetrahedron: Asymmetry 1998, 9, 4295-4300
(R.sup.1.dbd.R.sup.8.dbd.H); K. Hino, Y. Nagai, H. Uno, Chem.
Pharm. Bull. 1988, 36, 2386-2400 (R.sup.1=Me; R.sup.8.dbd.H).
[0615] A35: See Beilstein Registry Numbers: 530775, 883013
(R.sup.1.dbd.R.sup.8.dbd.H).
[0616] A36: See R. W. Carling, P. D. Leeson, A. M. Moseley, R.
Baker, A. C. Foster, J. Med. Chem. 1992, 35, 1942-1953; S. Kano, T.
Ebata, S. Shibuya, J. Chem. Soc. Perkin Trans. 1, 1980, 2105-2111
(R.sup.1.dbd.R.sup.8.dbd.H); R. W. Carling, P. D. Leeson, A. M.
Moseley, R. Baker, A. C. Foster, J. Med. Chem. 1992, 35, 1942-1953
(R.sup.1.dbd.H; R.sup.8=5-Cl; 7-Cl).
[0617] A37: See Nagarajan, Indian J. Chem. 1973, 11, 112
(R.sup.1.dbd.CH.sub.2COOMe; R.sup.8.dbd.H).
[0618] A38: See R. Pauly, N. A. Sasaki, P. Potire, Tetrahedron
Lett. 1994, 35, 237-240; J. Podlech, D. Seebach, Liebigs Ann. Org.
Bioorg. Chem. 1995, 7, 1217-1228; K. C. Nicolaou, G.-Q. Shi, K.
Namoto, F. Bernal, J. Chem. Soc. Chem. Commun. 1998, 1757-1758
(R.sup.1.dbd.H; R.sup.2.dbd.H).
[0619] A39: See Beilstein, Registry Number 782885.
[0620] A40: See F. P. J. C. Rutjes, N. M. Terhuis, H. Hiemstra, N.
W. Speckamp, Tetrahedron 1993, 49, 8605-8628 (R.sup.1.dbd.H;
R.sup.3=Bn); compounds of this type can be prepared according to
Scheme 6.
##STR00036##
[0621] A41: Compounds of this type can be prepared according to
Scheme 7.
##STR00037##
[0622] A42 to A46: Compounds of this type can be prepared according
to Schemes 8 to 12. Key intermediate 34 and .alpha.-amino acid
synthesis involving this building block include: R. M. Williams,
M.-N. Im, Tetrahedron Lett. 1988, 29, 6079-6082; R. M. Williams,
M.-N. Im, J. Am. Chem. Soc.1991, 113, 9276-9286; J. F. Dellaria, B.
D. Santarsiero, Tetrahedron Lett. 1988, 29, 6079-6082; J. F.
Dellaria, B. D. Santarsiero, J. Org. Chem. 1989, 54, 3916-3926; J.
E. Baldwin, V. Lee, C. J. Schofield, Synlett 1992, 249-251; J. E.
Baldwin, V. Lee, C. J. Schofield, Heterocycles 1992, 34,
903-906.
##STR00038##
##STR00039##
##STR00040##
##STR00041##
##STR00042##
[0623] A47: See P. Barraclough, R. D. Farrant, D. Kettle, S. Smith,
J. Chem. Res. Miniprint 1991, 11, 2876-2884
(R.sup.1.dbd.R.sup.11.dbd.H, Bn,
(CH.sub.2).sub.2PO(OEt).sub.2).
[0624] A48: See A. Nouvet, M. Binard, F. Lamaty, J. Martinez, R.
Lazaro, Tetrahedron 1999, 55, 4685-4698
(R.sup.1.dbd.R.sup.12.dbd.H).
[0625] A49: See M. Y. Kolleganov, I. G. Kolleganova, M. D.
Mitrofanova, L. I. Martynenko, P. P. Nazarov, V. I. Spitsyn, Bull.
Acad. Sci. USSR Div. Chem. Sci (Engl. Trans.) 1983, 32, 1293-1299;
Izv. Akad. Nauk SSSR Ser. Khim. 1983, 6, 1293-1299; V. P. Vasilev,
T. D. Orlova, S. F. Ledenkov, J. Gen. Chem. USSR (Engl. Trans.
1989, 59, 1629-1634; Zh. Obshch. Khim. 1989, 59, 1828-1833
(R.sup.1.dbd.H; R.sup.12.dbd.CH(COOH)CH.sub.2COOH). Compounds of
type A49 can also be prepared according to Scheme 13.
##STR00043##
[0626] A50 and A51: Compounds of these types can be prepared
according to Schemes 14 and 15.
##STR00044##
##STR00045##
[0627] A53: See P. Barraclough, R. D. Farrant, D. Kettle, S. Smith,
J. Chem. Res. Miniprint 1991, 11, 2876-2884
(R.sup.1.dbd.R.sup.11.dbd.H; R.sup.1.dbd.H; R.sup.11=Bn;
(CH.sub.2).sub.3PO(OH).sub.2); (CH.sub.2).sub.3PO(Et).sub.2); J. I.
Levin, J. F. DiJoseph, L. M. Killar; A. Sung, T. Walter, Bioorg.
Med. Chem. Lett. 1998, 5, 2657-2662 (R.sup.1.dbd.H;
R.sup.11=4CF.sub.3OC.sub.6H.sub.4CO).
[0628] A 52 and A54: Compounds of this type can be prepared
according to Schemes 16 and 17.
##STR00046##
##STR00047##
[0629] A55 and A56: Compounds of this type can be prepared
according to Schemes 18 and 19.
##STR00048##
##STR00049##
[0630] A57: Compounds of this type can be prepared according to
Scheme 20.
##STR00050##
[0631] A58: See C.-H. Lee, H. Kohn, J. Org. Chem. 1990, 55,
6098-6104 (R.sup.1.dbd.R.sup.8.dbd.H).
[0632] A59. can be prepared according to Scheme 21.
##STR00051##
[0633] A60: Compounds of this type can be prepared according to
Scheme 22.
##STR00052##
[0634] A61: See D. R. Armour, K. M. Morriss, M. S. Congreve, A. B.
Hawcock, Bioorg. Med. Chem. Lett. 1997, 7, 2037-2042
(R.sup.1.dbd.R.sup.12.dbd.H).
[0635] A62. Compounds of this type can be prepared according to
Scheme 23.
##STR00053##
[0636] A63: See S. E. Gibson, N. Guillo, R. J. Middleton, A.
Thuilliez, M. J. Tozer, J. Chem. Soc. Perkin Trans. 1, 1997, 4,
447-456; S. E. Gibson, N. Guillo, S. B. Kalindjan, M. J. Tozer,
Bioorg. Med. Chem. Lett, 1997, 7, 1289-1292 (R.sup.1.dbd.H;
R.sup.8.dbd.H); Beilstein Registry Number: 459155 (R.sup.1.dbd.H;
R.sup.8=4,5-MeO.sub.2).
[0637] A64: Compounds of this type can be prepared according to
Scheme 24.
##STR00054##
[0638] A65 and A 67: Compounds of these types can be prepared
according to Schemes 25 and 26.
##STR00055##
##STR00056##
[0639] A66: See G. L. Grunewald, L. H. Dahanukar, J. Heterocycl.
Chem. 1994, 31, 1609-1618 (R.sup.1.dbd.H; R.sup.8.dbd.H,
8-NO.sub.2; C(1)=O).
[0640] A68: See Griesbeck, H. Mauder, I. Muller, Chem. Ber. 1992,
11, 2467-2476; (R.sup.1.dbd.R.sup.8.dbd.H; C(1)=O).
[0641] A69: R. Kreher, W. Gerhardt, Liebigs Ann. Chem. 1981,
240-247 (R.sup.1.dbd.R.sup.8.dbd.H).
[0642] As explained above, building blocks A70 belong to the class
of open-chain .alpha.-substituted .alpha.-amino acids, A71 and A72
to the class of the corresponding .beta.-amino acid analogues and
A73-A104 to the class of the cyclic analogues of A70.
[0643] Building blocks of types A70 and A73-A104 have been
synthesized by several different general methods: by [2+2]
cycloaddition of ketenes with imines (I. Ojima, H. J. C. Chen, X.
Quin, Tetrahedron Lett. 1988, 44, 5307-5318); by asymmetric aldol
reaction (Y. Ito, M. Sawamura, E. Shirakawa, K. Hayashikazi, T.
Hayashi, Tetrahedron Lett. 1988, 29, 235-238; by the oxazolidinone
method (J. S. Amato, L. M. Weinstock, S. Karady, U.S. Pat. No.
4,508,921 A; M. Gander-Coquoz, D. Seebach, Helv. Chim. Acta 1988,
71, 224-236; A. K. Beck, D. Seebach, Chimia 1988, 42, 142-144; D.
Seebach, J. D. Aebi, M. Gander-Coquoz, R. Naef, Helv. Chim. Acta
1987, 70, 1194-1216; D. Seebach, A. Fadel, Helv. Chim. Acta 1995,
68, 1243-1250; J. D. Aebi, D. Seebach, Helv. Chim. Acta 1985, 68,
1507-1518; A. Fadel, J. Salaun, Tetrahedron Lett. 1987, 28,
2243-2246); by Schmidt-rearrangement of
.alpha.,.alpha.-disubstituted .alpha.-ketoesters (G. I. Georg, X.
Guan, J. Kant, Tetrahedron Lett. 1988, 29, 403-406); asymmetric
synthesis via chiral Ni(II)-derived Schiff-bases (Y. N. Belokon, V.
I. Bakhmutov, N. I. Chemoglazova, K. A. Kochetov, S. V. Vitt, N. S.
Garbalinskaya, V. M. Belikov, J. Chem. Soc. Perkin Trans. 1, 1988,
305-312; M. Kolb, J. Barth, Liebigs Ann. Chem. 1983, 1668-1688); by
the bis-lactim ether synthesis (U. Schollkopf, R. Hinrichs, R.
Lonsky, Angew. Chem. 1987, 99, 137-138); by microbial resolution
(K. Sakashita, I. Watanabe, JP 62/253397 A2) and by the hydantoin
method combined with resolution of theracemic amino acids with
chiral auxiliaries derived from L-phenylalanine amides (D. Obrecht,
C. Spiegler, P. Schonholzer, K. Muller, H. Heimgartner, F. Stierli,
Helv. Chim. Acta 1992, 75, 1666-1696; D. Obrecht, U. Bohdal, J.
Daly, C. Lehmann, P. Schonholzer, K. Muller, Tetrahedron 1995, 51,
10883-10900; D. Obrecht, C. Lehmann, C. Ruffieux, P. Schonholzer,
K. Muller, Helv. Chim. Acta 1995, 78, 1567-1587; D. Obrecht, U.
Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schonholzer,
C. Spiegler, Helv. Chim. Ada 1995, 78, 563-580; D. Obrecht, H.
Karajiannis, C. Lehmann, P. Schonholzer, C. Spiegler, Helv. Chim.
Acta 1995, 78, 703-714; D. Obrecht, M. Altorfer, C. Lehmann, P.
Schonholzer, K. Muller, J. Org. Chem. 1996, 61, 4080-4086; D.
Obrecht, C. Abrecht, M. Altorfer, U. Bohdal, A. Grieder, P.
Pfyffer, K. Muller, Helv. Chim. Acta 1996, 79, 1315-1337). The
latter method has been especially useful in preparing both
enantiomers of building blocks of type A70 (see Scheme 27) and
A73-A104 (see Scheme 28) in pure form.
##STR00057## ##STR00058##
[0644] The method depicted in Scheme 27 consists in treatment of
the appropriate ketones 126 with KCN, (NH.sub.4).sub.2CO.sub.3 in a
mixture of ethanol/water (E. Ware, J. Chem. Res. 1950, 46, 403; L.
H. Goodson, I. L. Honigberg, J. J. Lehmann, W. H. Burton, J. Org.
Chem. 1960, 25, 1920; S. N. Rastogi, J. S. Bindra, N. Anand, Ind.
J. Chem. 1971, 1175) to yield the corresponding hydantoins 127,
which were hydrolyzed with Ba(OH).sub.2 in water at 120-140.degree.
(R. Sarges, R. C. Schur, J. L. Belletire, M. J. Paterson, J Med.
Chem. 1988, 31, 230) to give 128 in high yields. Schotten-Baumann
acylation (Houben-Weyl, `Methoden der Organischen Chemie`, Volume
XI/2, Stickstoff-Verbindungen II und III', Georg Tieme Verlag,
Stuttgart, pp 339) followed by cyclization with N,N'-dicyclohexyl
carbodiimide gave azlactones 129 (D. Obrecht, U. Bohdal, C. Broger,
D. Bur, C. Lehmann, R. Ruffieux, P. Schonholzer, C. Spiegler, Helv.
Chim. Ada 1995, 78, 563-580; D. Obrecht, C. Spiegler, P.
Schonholzer, K. Muller, H. Heimgartner, F. Stierli, Helv. Chim.
Acta 1992, 75, 1666-1696). Alternatively, azlactones 129 could also
be prepared starting from amino acids 130 and 131, Schotten-Baumann
acylation and cyclization with N,N'-dicyclohexyl carbodiimide to
azlactones 132 and 133 and alkylation to yield 129 (D. Obrecht, U.
Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schonholzer,
C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D. Obrecht, C.
Spiegler, P. Schonholzer, K. Muller, H. Heimgartner, F. Stierli,
Helv. Chim. Acta 1992, 75, 1666-1696) (see Scheme 1). Treatment of
129 with L-phenylalanine cyclohexylamide (D. Obrecht, U. Bohdal, C.
Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schonholzer, C.
Spiegler, Helv. Chim. Acta 1995, 78, 563-580) gave diastereomeric
peptides 134 and 135, which could be conveniently separated by
flash-chromatography or crystallisation. Treatment of 134 and 135
with methanesulphonic acid in methanol at 80.degree. gave esters
136a and 136b which were converted into the corresponding
Fmoc-protected final building blocks 137a and 137b.
##STR00059##
[0645] According to the general method described in Scheme 28 (D.
Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.
Schonholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.
Obrecht, C. Spiegler, P. Schonholzer, K. Muller, H. Heimgartner, F.
Stierli, Helv. Chim. Acta 1992, 75, 1666-1696) A73-A104 can be
prepared starting from the corresponding ketones 138, hydantoin
formation (139) (E. Ware, J. Chem. Res. 1950, 46, 403; L. H.
Goodson, I. L. Honigberg, J. J. Lehmann, W. H. Burton, J. Org.
Chem. 1960, 25, 1920; S. N. Rastogi, J. S. Bindra, N. Anand, Ind.
J. Chem. 1971, 1175; D. Obrecht, U. Bohdal, C. Broger, D. Bur, C.
Lehmann, R. Ruffieux, P. Schonholzer, C. Spiegler, Helv. Chim. Acta
1995, 78, 563-580) and saponification (Ba(OH).sub.2) to yield the
racemic amino acids 140, which upon Schotten-Baumann-acylation and
cyclization with N,N'-dicyclohexylcarbodiimide gave azlactones 141.
Reaction with L-phenylalanine cyclohexylamide (D. Obrecht, U.
Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schonholzer,
C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580) gave the
diastereomeric peptides 142 and 143, which were separated by
flash-chromatography or crystallization. Treatment of 142 and 143
with methanesulphonic acid in methanol at 80.degree. gave esters
144a and 144b which were converted into the corresponding suitably
protected amino acid precursors 145a and 145b, ready for peptide
synthesis.
[0646] A71: Amino acid building blocks of this type (see formula
147) can be conveniently prepared from the corresponding
disubstituted succinates 146 by Cumus-rearrangement as shown in
Scheme 29.
##STR00060##
[0647] A71: See D. Seebach, S. Abele. T. Sifferlen, M. Haenggi, S.
Gruner, P. Seiler, Helv. Chim. Acta 1998, 81, 2218-2243 (R.sup.18
and R.sup.19form: --(CH.sub.2).sub.2--; --(CH.sub.2).sub.3--;
--(CH.sub.2).sub.4--; --(CH.sub.2).sub.5--; R.sup.20.dbd.H); L.
Ducrie, S. Reinelt, P. Seiler, F. Diederich, D. R. Bolin, R. M.
Campbell, G. L. Olson, Helv. Chim. Acta 1999, 82, 2432-2447; C. N.
C. Drey, R. J. Ridge, J. Chem. Soc. Perkin Trans. 1, 1981,
2468-2471; U. P. Dhokte, V. V. Khau, D. R. Hutchinson, M. J.
Martinelli, Tetrahedron Lett. 1998, 39, 8771-8774
(R.sup.18.dbd.R.sup.19=Me; R.sup.20.dbd.H); D. L. Varie, D. A. Hay,
S. L. Andis, T. H. Corbett, Bioorg. Med. Chem. Lett. 1999, 9,
369-374 (R.sup.18.dbd.R.sup.19=Et); Testa, J. Org. Chem. 1959, 24,
1928-1936 (R.sup.18=Et; R.sup.19=Ph); M. Haddad, C. Wakselman, J.
Fluorine Chem. 1995, 73, 57-60 (R.sup.18=Me; R.sup.19.dbd.CF.sub.3;
R.sup.20.dbd.H); T. Shono, K. Tsubata, N. Okinaga, J. Org. Chem.
1984, 49, 1056-1059 (R.sup.18.dbd.R.sup.19.dbd.R.sup.20=Me); K.
Ikeda, Y. Terao, M. Sekiya, Chem. Pharm. Bull. 1981, 29, 1747-1749
(R.sup.18 and R.sup.19 form: --(CH.sub.2).sub.5--; R.sup.20=Me).
Amino acid building blocks of type A72 can be conveniently prepared
by Arndt-Eisteri Cl-homologation of compounds of type A70 according
to Scheme 30.
##STR00061##
[0648] A72: See Y. V. Zeifman, J. Gen. Chem. USSR (Engl. Trans.)
1967, 37, 2355-2363 (R.sup.18.dbd.R.sup.19.dbd.CF.sub.3); W. R.
Schoen, J. M. Pisano, K. Pendergast, M. J. Wyvratt, M. H. Fisher,
J. Med. Chem. 1994, 37, 897-906; S. Thaisrivongs, D. T. Pals, D. W.
DuCharme, S. Turner, G. L. DeGraaf, J. Med. Chem. 1991, 34,
655-642; T. K. Hansen, H. Thoegersen, B. S. Hansen, Bioorg. Med.
Chem. Lett. 1997, 7, 2951-2954; R. J. DeVita, R. Bochis, A. J.
Frontier, A. Kotliar, M. H. Fisher, J. Med. Chem. 1998, 41,
1716-1728; D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo,
Helv. Chim. Acta 1996, 79, 2043-2066; R. P. Nargund, K. H. Barakat,
K. Cheng, W. Chan, B. R. Butler, A. A. Patchett, Bioorg. Med. Chem.
Lett. 1996, 6, 1265-1270 (R.sup.18.dbd.R.sup.19=Me); E. Altmann, K.
Nebel, M. Mutter, Helv. Chim. Acta 1991, 74, 800-806 (R.sup.18=Me;
R.sup.19.dbd.COOMe).
[0649] A73: Compounds of this type can be prepared according to C.
Mapelli, G. Tarocy, F. Schwitzer, C. H. Stammer, J. Org. Chem.
1989, 54, 145-149 (R.sup.21=4-OHC.sub.6H.sub.4); F. Elrod, E. M.
Holt, C. Mapelli, C. H. Stammer, J. Chem. Soc. Chem. Commun. 1988,
252-253 (R.sup.21.dbd.CH.sub.2COOMe); R. E. Mitchell, M. C.
Pirrung, G. M. McGeehan, Phytochemistry 1987, 26, 2695
(R.sup.21.dbd.CH.sub.2OH), J. Bland, A. Batolussi, C. H. Stammer,
J. Org. Chem. 1988, 53, 992-995 (R.sup.21.dbd.CH.sub.2NH.sub.2).
Additional derivatives of A73 have been described by T. Wakamiya,
Y. Oda, H. Fujita, T. Shiba, Tetrahedron Lett. 1986, 27, 2143-2134;
U. Schollkopf, B. Hupfeld, R. Gull, Angew. Chem. 1986, 98, 755-756;
J. E. Baldwin, R. M. Adlington, B. J. Rawlings, Tetrahedron Lett.
1985, 26, 481-484; D. Kalvin, K. Ramalinggam, R. Woodard, Synth.
Comm. 1985, 15, 267-272 and L. M. Izquierdo, I. Arenal, M. Bernabe,
E. Alvarez, Tetrahedron Lett. 1985, 41, 215-220.
[0650] A74: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding cyclobutanones.
[0651] A75 and A76: Compounds of this type can be prepared using
the following methods: P. Hughes, J. Clardy, J. Org. Chem. 1988,
53, 4793-4796; E. A. Bell, M. Y. Qureshi, R. J. Pryce, D. H.
Janzen, P. Lemke, J. Clardy, J. Am. Chem. Soc. 1980, 102, 1409; Y.
Gaoni, Tetrahedron Lett. 1988, 29, 1591-1594; R. D. Allan, J. R.
Haurahan, T. W. Hambley, G. A. R. Johnston, K. N. Mewett, A. D.
Mitrovic, J. Med. Chem. 1990, 33, 2905-2915 (R.sup.23.dbd.COOH); G.
W. Fleet, J. A. Seijas, M. Vasquez Tato, Tetrahedron 1988, 44,
2077-2080 (R.sup.23.dbd.CH.sub.2OH).
[0652] A77: Compounds of this type can be prepared according to J.
H. Burckhalter, G. Schmied, J. Pharm. Sci. 1966, 55, 443-445
(R.sup.23=aryl).
[0653] A78: Compounds of this type can be prepared according to J.
C. Watkins, P. Kroosgard-Larsen, T. Honore, TIPS 1990, 11, 25-33;
F. Trigalo, D. Brisson, R. Azerad, Tetrahedron Lett. 1988, 29, 6109
(R.sup.24.dbd.COOH).
[0654] A79: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding pyrrolidine-3-ones.
[0655] A80-A82: Compounds of this type can be prepared according to
D. M. Walker, E. W. Logusch, Tetrahedron Lett. 1989, 30, 1181-1184;
Y. Morimoto, K. Achiwa, Chem. Pharm. Bull. 1989, 35, 3845-3849; J.
Yoshimura, S. Kondo, M. Ihara, H. Hashimoto, Carbohydrate Res.
1982, 99, 129-142.
[0656] A83: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding pyrazoline-4-ones.
[0657] A84. Compounds of this type can be prepared according to R.
M. Pinder, B. H. Butcher, D. H. Buxton, D. J. Howells, J. Med.
Chem. 1971, 14, 892-893; D. Obrecht, U. Bohdal, C. Broger, D. Bur,
C. Lehmann, R. Ruffieux, P. Schonholzer, C. Spiegler, Helv. Chim.
Acta 1995, 78, 563-580.
[0658] A85: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding indane-1,3-diones.
[0659] A86: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding indane-2-ones.
[0660] A87: Compounds of this type and analogues thereof can be
prepared according to C. Cativiela, M. D. Diaz de Villegas, A.
Avenoza, J. M. Peregrina, Tetrahedron 1993, 47, 10987-10996; C.
Cativiela, P. Lopez, J. A. Mayoral, Tetrahedron Assymmetry 1990, 1,
379; C. Cativiela, J. A. Mayoral, A. Avenoza, M. Gonzalez, M. A.
Rey, Synthesis 1990, 1114.
[0661] A87 and A88: Compounds of this type can be prepared
according to L. Munday, J. Chem. Soc. 1961, 4372; J. Ansell, D.
Morgan, H. C. Price, Tetrahedron Lett. 1978, 47, 4615-4616.
[0662] A89: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding piperidine-3-ones.
[0663] A90: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding tetrahydrothiapyran-3-ones.
[0664] A91. Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding tetrahydropyran-3-ones.
[0665] A92: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding piperidine-2,5-diones.
[0666] A93: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding cyclohexanones.
[0667] A94: Compounds of this type can be prepared according to J.
Org. Chem. 1990, 55, 4208.
[0668] A95: Compounds of this type can be prepared according to N.
J. Lewis, R. L. Inloes, J. Hes, R. H. Matthews, G. Milo, J. Med.
Chem. 1978, 21, 1070-1073.
[0669] A96: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding tetrahydropyran-4-ones.
[0670] A97: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding piperidine-2,4-diones.
[0671] A98: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding 1-tetralones (D. Obrecht, C. Spiegler, P.
Schonholzer, K. Muller, H. Heimgartner, F. Stierli, Helv. Chim.
Acta 1992, 75, 1666-1696).
[0672] A99: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding tetraline-1,4-dione mono-diethylacetals.
[0673] A100: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding tetrahydroquinolin-4-ones.
[0674] A101: Compounds of this type can be prepared according to
general method described in Scheme 28 starting from the
corresponding tetrahydroquinoline-2,4-diones.
[0675] A102: Compounds of this type can be prepared according to K.
Ishizumi, N. Ohashi, N. Tanno, J. Org. Chem. 1987, 52, 4477-4485;
D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux,
P. Schonholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.
Obrecht, C. Spiegler, P. Schonholzer, K. Muller, H. Heimgartner, F.
Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D. R. Haines, R. W.
Fuller, S. Ahmad, D. T. Vistica, V. E. Marquez, J. Med. Chem. 1987,
30, 542-547; T. Decks, P. A. Crooks, R. D. Waigh, J. Pharm. Sci
1984, 73, 457-460; I. A. Blair, L. N. Mander, Austr. J. Chem. 1979,
32, 1055-1065.
[0676] Overviews dealing with building blocks of types (b)-(p) are:
S. Hanessian, G. McNaughton-Smith, H.-G. Lombart, W. D. Lubell,
Tetrahedron 1997, 38, 12789-12854; D. Obrecht, M. Altorfer, J. A.
Robinson, "Novel Peptide Mimetic Building Blocks and Strategies for
Efficient Lead Finding", Adv. Med. Chem. 1999, Vol, 4, 1-68
[0677] Templates of type (b1) can be prepared according to Schemes
31 and 32.
##STR00062## [0678] i: Treatment of 150 with a dehydrating reagent
such as thionylchloride in methanol at an elevated temperature,
conveniently at reflux. [0679] ii: Introduction of Boc, e.g. using
di-tert.-butyl dicarbonate and triethylamine in a suitable solvent
such as dichloromethane; any other suitable N-protecting group (not
shown in Reaction Scheme 31) can be introduced in an analogous
manner. [0680] iii: Reaction of formed product with phthalimide,
diethyl diazodicarboxylate and triphenylphoshine under standard
Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T. J. J. Am.
Chem. Soc. 1972, 94, 672) to conveniently yield 151. [0681] iv:
Treatment of 151 with trifluoracetic acid in dichloromethane.
[0682] v: 152 is coupled under standard peptide coupling conditions
with Cbz-Asp(tBu)OH in DMF with reagents such as HBTU and
1-hydroxybenztriazole (HOBt) with a base such as
diisopropylethylamine to yield 153. [0683] vi: Removal of the
Cbz-group, conveniently by hydrogenation using H.sub.2 and a
catalyst such as Palladium on charcoal, in solvents such as
ethanol, DMF and ethyl acetate. [0684] vii: The phthalimide group
is cleaved off from the resulting product, conveniently by
treatment with hydrazine in a suitable solvent such as ethanol at
an elevated temperature, suitably at about 80.degree. C. and
cleavage of the formed product with trifluoracetic acid in
CH.sub.2Cl.sub.2. [0685] viii: The formed amino acid is
conveniently protected with reagents such as
9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl
succinimide using a base such as sodium carbonate or triethylamine
in a suitable solvent or mixture of solvents such as dioxane and
water, or dichloromethane to yield 154 as described by Bisang, C;
Weber, C; Robinson, J. A. Helv. Chim. Acta 1996, 79, 1825-1842.
[0685] ##STR00063## [0686] i: Treatment of 150 with a dehydrating
reagent such as thionyl chloride in a suitable solvent such as
methanol at an elevated temperature, conveniently at reflux. [0687]
ii: The resulting amino acid ester is N-protected under standard
conditions for introducing the Cbz-group, e.g. using
benzyloxycarbonyl chloride and triethylamine in a suitable solvent
such as dichloromethane. [0688] iii: The Cbz-protected amino acid
methyl ester is treated with trimethylsilylchloride and a base such
as triethylamine in a solvent such as tetrahydrofuran, cooled,
conveniently to about -78.degree. C., followed by reaction with a
strong base such as lithium diisopropylamide or lithium
hexamethyldisilylazide and tert.-butyl bromoacetate yielding 155 as
a mixture of diastereomers as described by Bisang, C; Jiang, L.;
Freund, E.; Emery, F.; Bauch, C; Matile, H.; Pluschke, G.;
Robinson, J. A. J. Am. Chem. Soc. 1998, 120, 7439-7449; Emery, F.;
Bisang, C.; Favre, M.; Jiang, L.; Robinson, J. A. J. Chem. Soc.
Chem. Commun. 1996, 2155-2156. [0689] iv: Reaction of 155 with
phthalimide, diethyl diazodicarboxylate and triphenylphosphine
under standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano,
T. J. J. Am. Chem. Soc. 1972, 94, 672). [0690] v: The resulting
product is hydrogenated using H.sub.2 and a suitable catalyst such
as palladium on charcoal in a solvent such as ethyl acetate, DMF or
ethanol; subsequently separation of diastereomers takes place and
yields 156. [0691] vi: 156 is coupled with Fmoc-Asp(allyl)OH under
standard peptide coupling conditions using reagents such as HATU,
HOAt and a base such as diisopropylethylamine in a suitable solvent
such as DMF. [0692] vii: Cyclization, conveniently with DBU in DMF
to yield 157. [0693] viii: The phthalimide group is cleaved off
from resulting product, conveniently by hydrazinolysis, e.g.
treatment with methylhydrazine in a suitable solvent such as DMF.
[0694] ix: The formed product is conveniently protected with
reagents such as 9-fluorenylmethoxcarbonyl chloride or
9-fluorenylmethoxcarbonyl succinimide using a base such as sodium
carbonate or triethylamine in a suitable solvent or mixture of
solvents such as dioxane and water, or dichloromethane to yield
158. [0695] x: Standard removal of an allyl ester group using e.g.
palladium(0) as catalyst gives 159.
[0696] Templates of type (b2) can be prepared according to Scheme
33.
##STR00064## [0697] i: 160 (obtainable from Vitamin C as described
by Hubschwerlen, C. (Synthesis 1986, 962) is treated with
phthalimide, diethyl diazodicarboxylate and triphenylphoshine under
standard Mitsunobu conditions (Mitsunobu, O.; Wada, M.; Sano, T. J.
J. Am. Chem. Soc. 1972, 94, 672). [0698] ii: The phthalimide group
is cleaved off from the product, conveniently by hydrazinolysis,
e.g. by treatment with methylhydrazine in a suitable solvent such
as DMF. [0699] iii: The amino group is protected by treatment with
a benzoylating reagent such as benzoic acid anhydride or
benzoylchloride and a base such as triethylamine or
4-dimethylaminopyridine in a suitable solvent such as
dichloromethane or DMF. [0700] iv. Removal of the
2,4-dimethoxybenzyl group, e.g. with K.sub.2S.sub.2O.sub.8 and
Na.sub.2HPO.sub.4 in aqueous acetonitrile at an elevated
temperature, e.g. at about 80.degree. C. [0701] v: Introduction of
a tert-butoxycarbonyl group using e.g. di-tert.-butyloxycarbonyl
dicarbonate, triethylamine and a catalytic amount of
4-dimethylaminopyridine in a suitable solvent such as
dichloromethane. [0702] vi: Reaction with aqueous sodium carbonate
in tetrahydrofuran followed by acidification. [0703] vii:
Esterification of the carboxylic acid group, conveniently with
diazomethane in a suitable solvent such as diethylether yielding
161. [0704] viii Removal of the Cbz-group, conveniently by
hydrogenation with H.sub.2 in the presence of a catalyst such as
palladium on charcoal in a solvent such as DMF to yield 161 as
described by Pfeifer, M.; Robinson, J. A. J. Chem. Soc. Chem.
Commun. 1998, 1977. [0705] ix: 161 is coupled under standard
peptide coupling conditions with Cbz-Asp(tBu)OH in DMF with
reagents such as HBTU and 1-hydroxybenztriazole with a base such as
diisopropylethylamine to yield 162 as described by Pfeifer, M.;
Robinson, J. A. J. Chem. Soc. Chem. Commun. 1998, 1977. [0706] x:
Removal of the Cbz-group, e.g. by hydrogenation using H.sub.2 and a
catalyst such as palladium on charcoal under standard conditions,
yields 163 as described by Pfeifer, M.; Robinson, J. A. J. Chem.
Soc. Chem. Commun. 1998, 1977. [0707] xi: Cleavage of the
tert.-butyl ester and tert.-butyloxycarbonyl groups, conveniently
using trifluoracetic acid in dichloromethane or 4N hydrochloric
acid in dioxane. [0708] xii: The intermediate free amino acid
formed is conveniently protected with reagents such as
9-fluorenylmethoxcarbonyl Chloride or 9-fluorenylmethoxcarbonyl
succinimide using a base such as sodium carbonate or triethylamine
in a suitable solvent or mixture of solvents such as dioxane and
water, or dichloromethane to yield 164 as described by Pfeifer, M.;
Robinson, J. A. J. Chem. Soc. Chem. Commun. 1998, 1977.
[0709] Templates of type (c1) can be prepared according to Schemes
34 to 37.
##STR00065## [0710] i: 166 can be synthesized from 165 according to
P. Waldmeier, "Solid-supported synthesis of highly substituted
xanthene-derived templates for the synthesis of .beta.-turn
stabilized cyclic peptide libraries", PhD-thesis, University of
Zurich, 1996. For cleaving the phthalimide group 166 is
conveniently submitted to hydrazinolysis, e.g. by treatment with
hydrazine hydrate in a suitable solvent such as ethanol at an
elevated temperature, e.g. at about 80.degree. C. [0711] ii: The
intermediate aminonitrile is saponified, conveniently under basic
conditions, e.g. with aqueous sodium hydroxide in a suitable
solvent such as ethanol at an elevated temperature, conveniently
under reflux, to yield 167. [0712] iii: The intermediate free amino
acid formed is conveniently protected with reagents such as
9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl
succintmide using a base such as sodium carbonate or triethylamine
in a suitable solvent or mixture of solvents such as dioxane and
water, or dichloromethane to yield 168 as described by P.
Waldmeier, "Solid-supported synthesis of highly substituted
xanthene-derived templates for the synthesis of .beta.-turn
stabilized cyclic peptide libraries", PhD-thesis, University of
Zurich, 1996. [0713] iv: Regioselective bromination of 167 is
performed preferably with bromine in acetic acid and
dichloromethane. In a similar fashion R.sup.37.dbd.NO.sub.2 can be
introduced by treatment with HNO.sub.3 in acetic acid and
R.sup.37.dbd.CH.sub.2--NPht by treatment with hydroxymethyl
phthalimide in H.sub.2SO.sub.4. [0714] v: The amino group is
conveniently Cbz-protected with reagents such as benzyloxycarbonyl
chloride or succinimide in a suitable solvent such as dioxane in
presence of a base such as aqueous sodium hydroxide. [0715] vi: The
carboxylic acid group is esterified, preferably with DBU and methyl
iodide in DMF to yield 169. [0716] vii: Introduction of lower
alkyl, substituted lower alkyl and aryl substituents (R.sup.37),
conveniently by palladium(0)-catalyzed Stille--(Stille, J. K.
Angew. Chem. 1986, 68, 504) and Suzuki-couplings (Oh-e, T.;
Mijaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201). Any other
functionalization known for aryl bromides can be employed for
introduction of substituents R.sup.37. [0717] viii: Removal of the
Cbz-group, e.g. by hydrogenation using H.sub.2 and a catalyst such
as palladium on charcoal in a suitable solvent such as ethanol, DMF
and ethyl acetate. [0718] ix: Hydrolysis of the ester group,
conveniently under acidic conditions, e.g. with 25% aqueous
hydrochloric acid in a suitable solvent such as dioxane at an
elevated temperature, preferably at about 100.degree. C. [0719] x:
The intermediate free amino acid formed is conveniently protected
with reagents such as 9-fluorenylmethoxcarbonyl chloride or
9-fluorenylmethoxcarbonyl succinimide using a base such as sodium
carbonate or triethylamine in a suitable solvent or mixture of
solvents such as dioxane and water, or dichloromethane to yield
170.
[0719] ##STR00066## [0720] i: Double ortho-bromination of 171 is
performed preferably with excess bromine in acetic acid and
dichloromethane. In a similar fashion
R.sup.37.dbd.R.sup.38.dbd.NO.sub.2 can be introduced by treatment
with HNO.sub.3 in acetic acid and
R.sup.37.dbd.R.sup.38.dbd.CH.sub.2--NPht by treatment with
hydroxymethyl phthalimide in H.sub.2SO.sub.4. [0721] ii: The amino
group is protected, conveniently Cbz-protected, with reagents such
as benzyloxycarbonyl chloride or succinimide in a suitable solvent
such as dioxane in the presence of a base such as aqueous sodium
hydroxide. [0722] iii: The carboxylic acid group is esterified,
preferably with DBU and methyl iodide in DMF to yield 172. [0723]
iv: Introduction of lower alkyl, substituted lower alkyl and aryl
substituents (R.sup.37.dbd.R.sup.38), e.g. by
palladium(0)-catalyzed Stille--(Stille, J. K. Angew. Chem. 1986,
68, 504) and Suzuki-couplings (Oh-e, T.; Mijaura, N.; Suzuki, A. J.
Org. Chem. 1993, 55, 2201). Any other functionalization known for
aryl bromides can be employed for introduction of substituents
R.sup.37 and R.sup.38. [0724] v: Removal of the Cbz-group of 173,
e.g. by hydrogenation using H.sub.2 and a catalyst such as
palladium on charcoal in a suitable solvent such as ethanol, DMF or
ethyl acetate. [0725] vi: Hydrolysis of the ester group,
conveniently under acidic conditions, e.g. with 25% aqueous
hydrochloric acid in a suitable solvent such as dioxane at an
elevated temperature, conveniently at about 100.degree. C. [0726]
vii: The intermediate free amino acid formed is conveniently
protected with reagents such as 9-fluorenylmethoxcarbonyl chloride
or 9-fluorenylmethoxcarbonyl succinimide using a base such as
sodium carbonate or triethylamine in a suitable solvent or mixture
of solvents such as dioxane and water, or dichloromethane to yield
174.
[0726] ##STR00067## [0727] i: Cleavage of the methoxy groups of
166, preferably by treatment with an excess of boron tribromide in
a suitable solvent such as dichloromethane. [0728] ii: Hydrolysis
of the cyano group under acidic conditions, preferably with 25%
aqueous hydrochloric acid in a suitable solvent such as dioxane at
an elevated temperature, conveniently at about 100.degree. C.
[0729] iii: The resulting acid is treated with a dehydrating agent
such as thionyl chloride in a suitable solvent such as dioxane to
yield 175. [0730] iv: Treatment of 175 with an appropriate
triflating reagent, preferably trifluoromethanesulfonic acid
anhydride in the presence of a base such as
2,6-di-tert.-butyl-pyridine in a suitable solvent such as
dichloromethane. [0731] v: Heating of the intermediate,
conveniently in a suitable solvent such as methanol. [0732] vi:
Introduction of lower alkyl or aryl-lower alkyl (R.sup.35) by
alkylation to yield 177. Any other functionalization known for
phenol groups can be employed for introduction of substituents
R.sup.35. [0733] vii: Introduction of lower alkyl or aryl
(R.sup.36), conveniently by palladium(0)-catalyzed Suzuki-coupling
(Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201) to
yield 178. Any other functionalization known for aryl bromides can
be employed for introduction of substituents R.sup.36. [0734] viii:
Hydrolysis of the ester group under acidic conditions, conveniently
with 25% aqueous hydrochloric acid in a suitable solvent such as
dioxane at an elevated temperature, e.g. at about 100.degree. C.
[0735] ix: Cleavage of the phthalimido group, conveniently by
hydrazinolysis, e.g. with hydrazine hydrate in a suitable solvent
such as ethanol. [0736] x: The intermediate free amino acid formed
is conveniently protected with reagents such as
9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl
succinimide using a base such as sodium carbonate or triethylamine
in a suitable solvent or mixture of solvents such as dioxane and
water, or dichloromethane to yield 179.
[0736] ##STR00068## [0737] i: Bromination of 175 using reagents
such as bromine in a mixture of acetic acid and dichloromethane at
temperatures ranging from about 0.degree. C. to about room
temperature, [0738] ii: Benzoylation of the hydroxy group using an
appropriate acylating agent such as benzoyl chloride or benzoic
acid anhydride, a base such as pyridine or triethylamine and a
suitable solvent such as dichloromethane to yield 180. [0739] iii:
180 is treated with methanol and a catalytic amount of an acidic
catalyst such as camphor sulfonic acid under heating. [0740] iv:
Introduction of lower alkyl or aryl-lower alkyl (R.sup.35) by
alkylation using a base such as sodium hydride or potassium
tert.-butoxide in a solvent such as tetrahydrofuran,
dimethoxyethane or DMF gives 181. [0741] v: Lower alkyl,
substituted lower alkyl and aryl substituents (R.sup.38) are
introduced, e.g. by palladium(0)-catalyzed Stille--(Stille, J. K.
Angew. Chem. 1986, 68, 504) and Suzuki-couplings (Oh-e, T.;
Mijaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201). Any other
functionalization known for aryl bromides can be employed for
introduction of substituents R.sup.38. [0742] vi: For cleaving the
benzyloxy group the intermediate is conveniently heated with sodium
cyanide adsorbed on aluminum oxide and methanol. [0743] vii:
Treatment with an appropriate triflating reagent, preferably
trifluoromethanesulfonic acid anhydride, in the presence of a base
such as 2,6-di-tert.-butyl-pyridine in a suitable solvent such as
dichloromethane. [0744] viii: Introduction of lower alkyl and aryl
substituents (R.sup.36), e.g. by palladium(0)-catalyzed
Stille--(Stille, J. K. Angew. Chem 1986, 68, 504) and
Suzuki-couplings (Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org. Chem.
1993, 58, 2201) yields 182. Any other functionalization known for
aryl bromides can be employed for introduction of substituents
R.sup.36. [0745] ix: Bromination under standard conditions such as
using bromine in acetic acid and dichloromethane at temperatures
ranging from about 0.degree. C. to about room temperature. [0746]
x: Lower alkyl, substituted lower alkyl and aryl substituents
(R.sup.37) are introduced, e.g. by palladium(0)-catalyzed
Stille--(Stille, J. K. Angew. Chem. 1986, 68, 504) and
Suzuki-couplings (Oh-e, T.; Mijaura, N.; Suzuki, A. J. Org. Chem.
1993, 58, 2201) to yield 184. Any other functionalization known for
aryl bromides can be employed for introduction of substituents
R.sup.37. [0747] xi: The ester group is hydrolyzed under acidic
conditions, conveniently with 25% aqueous hydrochloric acid in a
suitable solvent such as dioxane at an elevated temperature, e.g.
at about 100.degree. C. [0748] xii: The phthalimido group is
cleaved, e.g. by hydrazinolysis, conveniently with hydrazine
hydrate in a suitable solvent such as ethanol. [0749] xiii: The
intermediate free amino acid formed is conveniently protected with
reagents such as 9-fluorenylmethoxcarbonyl chloride or
9-fluorenylmethoxcarbonyl succinimide using a base such as sodium
carbonate or triethylamine in a suitable solvent or mixture of
solvents such as dioxane and water, or dichloromethane to yield
185.
[0750] Templates of type (c2) can be prepared as shown in Schemes
38 and 39.
##STR00069## [0751] i: 3,7-Dimethoxyphenothiazine 186 is prepared
and converted into 187 according to Muller, K.; Obrecht, D.;
Knierzinger, A.; Spiegler, C; Bannwarth, W.; Trzeciak, A.; Englert,
G.; Labhardt, A.; Schonholzer, P. Perspectives in Medicinal
Chemistry, Editor Testa, B.; Kyburz, E.; Fuhrer, W.; Giger, R.,
Weinheim, N.Y., Basel, Cambridge: Verlag Helvetica Chimica Acta,
1993, 513-531; Bannwarth, W.; Gerber, F.; Grieder, A.; Knierzinger,
A.; Muller, K.; Obrecht. D.; Trzeciak, A. Can. Pat. Appl. CA2101599
(131 pages). The benzyl group is cleaved off from 187 conveniently
by hydrogenation, e.g. with H.sub.2 and a catalyst such as
palladium on charcoal in a suitable solvent such as ethanol, DMF or
ethyl acetate, [0752] ii: Introduction of lower alkyl (R.sup.43) by
alkylation using an appropriate alkylating agent (R.sup.43--X';
X'.dbd.OTf, Br, I) and strong bases such as sodium amide in liquid
ammonia or sodium hydride in tetrahydrofuran, dioxan or DMF in the
presence of a phase transfer catalyst such as TDA-I. In a similar
manner substituted lower alkyl (R.sup.43) can be introduced; thus,
for example R.sup.43.dbd.CH.sub.2COOR.sup.55 and
CH.sub.2CH.sub.2COOR.sup.55 can be introduced by treatment with the
appropriate 2-halo acetic and, respectively, 3-halo propionic acid
derivatives. Any other functionalization known for diarylamines can
be employed for introduction of substituents R.sup.43. [0753] iii:
Cleavage of the methoxy groups of 188, conveniently by treatment
with an excess of boron tribromide in a suitable solvent such as
dichloromethane at temperatures ranging from about -20.degree. C.
to about room temperature. [0754] iv: For the introduction of lower
alkyl, substituted lower alkyl or aryl-lower alkyl substituents
(R.sup.39 and R.sup.40) the intermediate bis-phenol derivative is
conveniently reacted with a reagent of the formula R.sup.39-- and
R.sup.40--X' (X'.dbd.OTf, Br, I) in the presence of strong bases
such as sodium hydride in tetrahydrofuran, dioxan or DMF in the
presence of a phase transfer catalyst such as TDA-I. Any other
functionalization known for phenol groups can be employed for
introduction of substituents R.sup.39 and R.sup.40. [0755] v: The
cyano group of 188 and, respectively, 189 is hydrolyzed,
conveniently under acidic conditions, e.g. with 25% aqueous
hydrochloric acid in a suitable solvent such as dioxane at an
elevated temperature, e.g. at about 100.degree. C. [0756] vi: The
phthalimide group of the intermediate is cleaved, conveniently by
hydrazinolysis, e.g. with hydrazine hydrate in a suitable solvent
such as ethanol. [0757] vii: The free amino group is conveniently
protected with reagents such as 9-fluorenylmethoxcarbonyl chloride
or 9-fluorenylmethoxcarbonyl succinimide using a base such as
sodium carbonate or triethylamine in a suitable solvent or mixture
of solvents such as dioxane and water, or dichloromethane to yield
190 and, respectively, 191.
[0757] ##STR00070## [0758] i: The cyano group of 188 is hydrolyzed,
conveniently under acidic conditions, e.g. with 25% aqueous
hydrochloric acid in a suitable solvent such as dioxane at an
elevated temperature, e.g. at about 100.degree. C. [0759] ii: The
phthalimide group of the intermediate is cleaved, conveniently by
hydrazinolysis, e.g. with hydrazine hydrate in a suitable solvent
such as ethanol to yield 192. [0760] iii: Double ortho-bromination
of 192 is performed preferably with excess bromine in acetic acid
and dichloromethane. In a similar fashion
R.sup.41.dbd.R.sup.42.dbd.NO.sub.2 can be introduced by treatment
with HNO.sub.3 in acetic acid and
R.sup.41.dbd.R.sup.42.dbd.CH.sub.2--NPht by treatment with
hydroxymethyl phthalimide in H.sub.2SO.sub.4. Any other
functionalization by electrophilic aromatic substitution known can
be employed for introduction of substituents R.sup.41 and R.sup.42.
[0761] iv: The amino group is protected, conveniently
Cbz-protected, with reagents such as benzyloxycarbonyl chloride or
succinimide in a suitable solvent such as dioxane in the presence
of a base such as aqueous sodium hydroxide. [0762] v: The
carboxylic acid group is esterified, preferably with DBU and methyl
iodide in DMF to yield 193. [0763] vi: Regioselective bromination
of 192 is performed preferably with bromine in acetic acid and
dichloromethane. In a similar fashion R.sup.41.dbd.NO.sub.2 can be
introduced by treatment with HNO.sub.3 in acetic acid and
R.sup.41.dbd.CH.sub.2--NPt by treatment with hydroxymethyl
phthalimide in H.sub.2SO.sub.4. Any other functionalization by
electrophilic aromatic substitution known can be employed for
introduction of substituents R.sup.41. [0764] vii: The amino group
is conveniently Cbz-protected with reagents such as
benzyloxycarbonyl chloride or succinimide in a suitable solvent
such as dioxane in presence of a base such as aqueous sodium
hydroxide. [0765] viii: The carboxylic acid group is esterified,
preferably with DBU and methyl iodide in DMF to yield 194. [0766]
ix: Introduction of lower alkyl, substituted lower alkyl and aryl
substituents (R.sup.41) for 194 and (R.sup.41 and R.sup.42) for
193, conveniently by palladium(0)-catalyzed Stille--(Stille, J. K.
Angew. Chem. 1986, 68, 504) and Suzuki-couplings (Oh-e, T.;
Mijaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201). Any other
functionalization known for aryl bromides can be employed for
introduction of substituents R.sup.41 and R.sup.42. [0767] x:
Removal of the Cbz-group, e.g. by hydrogenation using H.sub.2 and a
catalyst such as palladium on charcoal in a suitable solvent such
as ethanol, DMF and ethyl acetate. [0768] xi: Hydrolysis of the
ester group, conveniently under acidic conditions, e.g. with 25%
aqueous hydrochloric acid in a suitable solvent such as dioxane at
an elevated temperature, preferably at about 100.degree. C. [0769]
xii: The intermediate free amino acid formed is conveniently
protected with reagents such as 9-fluorenylmethoxcarbonyl chloride
or 9-fluorenylmethoxcarbonyl succinimide using a base such as
sodium carbonate or triethylamine in a suitable solvent or mixture
of solvents such as dioxane and water, or dichloromethane to yield
195 and 196.
[0770] Templates of type (c3) can be prepared as shown in Schemes
40 and 41.
##STR00071## [0771] i: 197 can be prepared from commercial
resorufin and coverted into 198 according to Muller, K.; Obrecht,
D.; Knierzinger, A.; Spiegler, C; Bannwarth, W.; Trzeciak, A.;
Englert, G.; Labhardt, A.; Schonholzer, P. Perspectives in
Medicinal Chemistry, Editor Testa, B.; Kyburz, E.; Fuhrer, W.;
Giger, R., Weinheim, N.Y., Basel, Cambridge: Verlag Helvetica
Chimica Acta, 1993, 513-531; Bannwarth, W.; Gerber, F.; Grieder,
A.; Knierzinger, A.; Muller, K.; Obrecht. D.; Trzeciak, A. Can.
Pat. Appl. CA2101599 (131 pages). For splitting off the benzyl
group 198 is conveniently hydrogenated e.g. with H.sub.2 and a
catalyst such as palladium on charcoal in a suitable solvent such
as ethanol, DMF or ethyl acetate. [0772] ii: Introduction of lower
alkyl (R.sup.43) by alkylation with R.sup.43--X' (X'.dbd.OTf, Br,
I) using strong bases such as sodium amide in liquid ammonia or
sodium hydride in tetrahydrofuran, dioxan or DMF in the presence of
a phase transfer catalyst such as TDA-I to yield 199. In a similar
manner substituted lower alkyl (R.sup.43) can be introduced; thus,
for example, R.sup.43.dbd.CH.sub.2COOR.sup.55 and
CH.sub.2CH.sub.2COOR.sup.55 can be introduced by treatment with the
appropriate 2-halo acetic and, respectively, 3-halo propionic acid
derivatives. Any other functionalization of diarylamino groups
known can be employed for introduction of substituents R.sup.43.
[0773] iii: Cleavage of the methoxy groups of 199, conveniently by
treatment with excess boron tribromide in dichloromethane at
temperatures ranging from about -20.degree. to about room
temperature. [0774] iv: The intermediate bis-phenol derivative is
preferably reacted with R.sup.39 and R.sup.40--X' (X'.dbd.OTf, Br,
I) in the presence of strong bases such as sodium hydride in
tetrahydrofuran, dioxan or DMF in the presence of a phase transfer
catalyst such as TDA-I. Any other functionalization for phenol
groups can be employed for introduction of substituents R.sup.39
and R.sup.40. [0775] v: The cyano group of 199 and, respectively,
200 is hydrolyzed under acidic conditions, e.g. with 25% aqueous
hydrochloric acid in a suitable solvent such as dioxane at an
elevated temperature, conveniently at about 100.degree. C. [0776]
vi: The phthalimide group is cleaved, conveniently by
hydrazinolysis, e.g. with hydrazine hydrate in suitable solvent
such as ethanol. [0777] vii: The free amino group is conveniently
protected with reagents such as 9-fluorenylmethoxcarbonyl chloride
or 9-fluorenylmethoxcarbonyl succinimide using a base such as
sodium carbonate or triethylamine in suitable solvent or mixture of
solvents such as dioxane and water, or dichloromethane to yield 201
and, respectively, 202.
[0777] ##STR00072## [0778] i: The cyano group of 199 is hydrolyzed,
conveniently under acidic conditions, e.g. with 25% aqueous
hydrochloric acid in a suitable solvent such as dioxane at an
elevated temperature, e.g. at about 100.degree. C. [0779] ii: The
phthalimide group of the intermediate is cleaved, conveniently by
hydrazinolysis, e.g. with hydrazine hydrate in a suitable solvent
such as ethanol to yield 203. [0780] iii: Double ortho- bromination
of 203 is performed preferably with excess bromine in acetic acid
and dichloromethane. In a similar fashion
R.sup.41.dbd.R.sup.42.dbd.NO.sub.2 can be introduced by treatment
with HNO.sub.3 in acetic acid and
R.sup.41.dbd.R.sup.42.dbd.CH.sub.2--NPht by treatment with
hydroxymethyl phthalimide in H.sub.2SO.sub.4. Any other
functionalization by electrophilic aromatic substitution can be
employed for introduction of substituents R.sup.41 and R.sup.42.
[0781] iv: The amino group is protected, conveniently
Cbz-protected, with reagents such as benzyloxycarbonyl chloride or
succinimide in a suitable solvent such as dioxane in the presence
of a base such as aqueous sodium hydroxide. [0782] v: The
carboxylic acid group is esterified, preferably with DBU and methyl
iodide in DMF to yield 204. [0783] vi: Regioselective bromination
of 203 is performed preferably with bromine in acetic acid and
dichloromethane. In a similar fashion R.sup.41.dbd.NO.sub.2 can be
introduced by treatment with HNO.sub.3 in acetic acid and
R.sup.41.dbd.CH.sub.2--NPht by treatment with hydroxymethyl
phthalimide in H.sub.2SO.sub.4. [0784] vii: The amino group is
conveniently Cbz-protected with reagents such as benzyloxycarbonyl
chloride or succinimide in a suitable solvent such as dioxane in
presence of a base such as aqueous sodium hydroxide. [0785] viii:
The carboxylic acid group is esterified, preferably with DBU and
methyl iodide in DMF to yield 205. [0786] ix: Introduction of lower
alkyl, substituted lower alkyl and aryl substituents (R.sup.41) for
205 and (R.sup.41 and R.sup.42) for 204, conveniently by
palladium(0)-catalyzed Stille--(Stille, J. K. Angew. Chem. 1986,
68, 504) and Suzuki-couplings (Oh-e, T.; Mijaura, K; Suzuki, A. J.
Org. Chem. 1993, 58, 2201). Any other functionalization known for
aryl bromides can be employed for introduction of substituents
R.sup.41 and R.sup.42. [0787] x: Removal of the Cbz-group, e.g. by
hydrogenation using H.sub.2 and a catalyst such as palladium on
charcoal in a suitable solvent such as ethanol, DMF and ethyl
acetate, [0788] xi: Hydrolysis of the ester group, conveniently
under acidic conditions, e.g. with 25% aqueous hydrochloric acid in
a suitable solvent such as dioxane at an elevated temperature,
preferably at about 100.degree. C. [0789] xii: The intermediate
free amino acid formed is conveniently protected with reagents such
as 9-fluorenylmethoxcarbonyl chloride or 9-fluorenylmethoxcarbonyl
succinimide using a base such as sodium carbonate or triethylamine
in a suitable solvent or mixture of solvents such as dioxane and
water, or dichloromethane to yield 206 and 207.
[0790] Templates(d) can be prepared according to D. Obrecht, U.
Bohdal, C. Lehmann, P. Schonholzer, K. Muller, Tetrahedron 1995,
51, 10883; D. Obrecht, C. Abrecht, M. Altorfer, U. Bohdal, A.
Grieder, M. Kleber, P. Pfyffer, K. Muller, Helv. Chim. Acta 1996,
79, 1315-1337.
[0791] Templates (e1) and (e2): See R. Mueller, L. Revesz,
Tetrahedron Lett. 1994, 35, 4091; H.-G. Lubell, W. D. Lubell, J.
Org. Chem. 1996, 61, 9437; L. Colombo, M. DiGiacomo, G. Papeo, O.
Carugo, C. Scolastico, L. Manzoni, Tetrahedron Lett. 1994, 55,
4031.
[0792] Templates (e3): See S. Hanessian, B. Ronan, A. Laoui,
Bioorg. Med. Chem. Lett. 1994, 4, 1397.
[0793] Templates (e4): See S. Hanessian, G. McNaughton-Smith,
Bioorg. Med. Chem. Lett. 1996, 6, 1567.
[0794] Templates (f): See T. P. Curran, P. M. McEnay, Tetrahedron
Lett. 1995, 36, 191-194.
[0795] Templates (g): See D. Gramberg, C. Weber, R. Beeli, J.
Inglis, C. Brans, J. A. Robinson, Helv. Chem. Acta 1995, 78,
1588-1606; K. H. Kim, J. P. Dumas, J. P. Germanas, J. Org. Chem.
1996, 61, 3138-3144.
[0796] Templates (b). See S. de Lombart, L. Blanchard, L. B.
Stamford, D. M. Sperbeck, M. D. Grim, T. M. Jenson, H. R.
Rodriguez, Tetrahedron Lett. 1994, 35, 7513-7516.
[0797] Templates (i1): See J. A. Robl, D. S. Karanewski, M. M.
Asaad, Tetrahedron Lett. 1995, 5, 773-758.
[0798] Templates (i2): See T. P. Burkholder, T.-B. Le, E. L.
Giroux, G. A. Flynn, Bioorg. Med. Chem. Lett. 1992, 2, 579.
[0799] Templates (i3) and (i4): See L. M. Simpkins, J. A. Robl, M.
P. Cimarusti, D. E. Ryono, J. Stevenson, C.-Q. Sun, E. W. Petrillo,
D. S. Karanewski, M. M. Asaad, J. E. Bird, T. R. Schaeffer, N. C.
Trippodo, Abstracts of papers, 210.sup.th Am. Chem. Soc Meeting,
Chicago, Ill., MEDI 064 (1995).
[0800] Templates (k): See D. BenIshai, A. R. McMurray, Tetrahedron
1993, 49, 6399.
[0801] Templates (l): See E. G. von Roedem, H. Kessler, Angew.
Chem. Int. Ed. Engl. 1994, 33, 687-689.
[0802] Templates (m): See R. Gonzalez-Muniz, M. J. Dominguez, M. T.
Garcia-Lopez, Tetrahedron 1992, 45, 5191-5198.
[0803] Templates (n): See F. Esser, A. Carpy, H. Briem, H. Koppen,
K.-H. Pook, Int. J. Pept. Res. 1995, 45, 540-546.
[0804] Templates (o): See N. De la Figuera, I. Alkorta, T.
Garcia-Lopez, R. Herranz, R. Gonzalez-Muniz, Tetrahedron 1995, 51,
7841.
[0805] Templates (p): See U. Slomcynska, D. K. Chalmers, F.
Cornille, M. L. Smythe, D. D. Benson, K. D. Moeller, G. R.
Marshall, J. Org. Chem. 1996, 61, 1198-1204.
[0806] The .beta.-hairpin peptidomimetics of the invention can be
used in a wide range of applications in order to inhibit the growth
of or to kill microorganisms. In particular they can be used to
selectively inhibit the growth of or to kill microorganisms such as
Pseudomonas aeruginosa and Acinetobacter.
[0807] They can be used for example as disinfectants or as
preservatives for materials such as foodstuffs, cosmetics,
medicaments and other nutrient-containing materials. The
.beta.-hairpin peptidomimetics of the invention can also be used to
treat or prevent diseases related to microbial infection in plants
and animals.
[0808] For use as disinfectants or preservatives the .beta.-hairpin
peptidomimetics can be added to the desired material singly, as
mixtures of several .beta.-hairpin peptidomimetics or in
combination with other antimicrobial agents. The .beta.-hairpin
peptidomimetics may be administered per se or may be applied as an
appropriate formulation together with carriers, diluents or
excipients well known in the art.
[0809] When used to treat or prevent infections or diseases related
to such infections, particularly infections related to respiratory
diseases such as cystic fibrosis, emphysema and asthma, infections
related to skin or soft tissue diseases such as surgical wounds,
traumatic wounds and burn wounds, infections related to
gastrointestinal diseases such as epidemic diarrhea, necrotizing
enterocolitis and typhlitis, infections related to eye diseases
such as keratitis and endophthalmitis, infections related to ear
diseases such as otitis, infections related to CNS diseases such as
brain abscess and meningitis, infections related to bone diseases
such as osteochondritis and osteomyelitis, infections related to
cardiovascular diseases such as endocartitis and pericarditis,
infections related to gastrourinal diseases such as epididymitis,
prostatitis and urethritis, the .beta.-hairpin peptidomimetics can
be administered singly, as mixtures of several .beta.-hairpin
peptidomimetics, in combination with other antimicrobial or
antibiotic agents, or anti cancer agents, or antiviral (e. g.
anti-HIV) agents, or in combination with other pharmaceutically
active agents. The .beta.-hairpin peptidomimetics can be
administered per se or as pharmaceutical compositions.
[0810] Pharmaceutical compositions comprising .beta.-hairpin
peptidomimetics of the invention may be manufactured by means of
conventional mixing, dissolving, granulating, coated tablet-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes. Pharmaceutical compositions may be formulated in
conventional manner using one or more physiologically acceptable
carriers, diluents, excipients or auxiliaries which facilitate
processing of the active .beta.-hairpin peptidomimetics into
preparations which can be used pharmaceutically. Proper formulation
depends upon the method of administration chosen.
[0811] For topical administration the .beta.-hairpin
peptidomimetics of the invention may be formulated as solutions,
gels, ointments, creams, suspensions, etc. as are well-known in the
art.
[0812] Systemic formulations include those designed for
administration by injection, e.g. subcutaneous, intravenous,
intramuscular, intrathecal or intraperitoneal injection, as well as
those designed for transdermal, transmucosal, oral or pulmonary
administration.
[0813] For injections, the .beta.-hairpin peptidomimetics of the
invention may be formulated in adequate solutions, preferably in
physiologically compatible buffers such as Hink's solution,
Ringer's solution, or physiological saline buffer. The solution may
contain formulatory agents such as suspending, stabilizing and/or
dispersing agents. Alternatively, the .beta.-hairpin
peptidomimetics of the invention may be in powder form for
combination with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0814] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation as known in
the art.
[0815] For oral administration, the compounds can be readily
formulated by combining the active .beta.-hairpin peptidomimetics
of the invention with pharmaceutically acceptable carriers well
known in the art. Such carriers enable the .beta.-hairpin
peptidomimetics of the invention to be formulated as tablets,
pills, dragees, capsules, liquids, gels, syrups, slurries,
suspensions etc., for oral ingestion of a patient to be treated.
For oral formulations such as, for example, powders, capsules and
tablets, suitable excipients include fillers such as sugars, such
as lactose, sucrose, mannitol and sorbitol; cellulose preparations
such as maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl
cellulose, sodium carboxymethylcellulose, and/or
polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
If desired, desintegrating agents may be added, such as
cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt
thereof, such as sodium alginate. If desired, solid dosage forms
may be sugar-coated or enteric-coated using standard
techniques.
[0816] For oral liquid preparations such as, for example,
suspensions, elixirs and solutions, suitable carriers, excipients
or diluents include water, glycols, oils, alcohols, etc. In
addition, flavoring agents, preservatives, coloring agents and the
like may be added.
[0817] For buccal administration, the composition may take the form
of tablets, lozenges, etc. formulated as usual.
[0818] For administration by inhalation, the .beta.-hairpin
peptidomimetics of the invention are conveniently delivered in form
of an aeorosol spray from pressurized packs or a nebulizer, with
the use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluromethane, carbon dioxide or another suitable gas. In
the case of a pressurized aerosol the dose unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of e.g. gelatin for use in an inhaler or insufflator may
be formulated containing a powder mix of the .beta.-hairpin
peptidomimetics of the invention and a suitable powder base such as
lactose or starch.
[0819] The compounds may also be formulated in rectal or vaginal
compositions such as suppositories together with appropriate
suppository bases such as cocoa butter or other glycerides.
[0820] In addition to the formulations described previously, the
.beta.-hairpin peptidomimetics of the invention may also be
formulated as depot preparations. Such long acting formulations may
be administered by implantation (e.g. subcutaneously or
intramuscularly) or by intramuscular injection. For the manufacture
of such depot preparations the .beta.-hairpin peptidomimetics of
the invention may be formulated with suitable polymeric or
hydrophobic materials (e.g. as an emulsion in an acceptable oil) or
ion exchange resins, or as sparingly soluble salts.
[0821] In addition, other pharmaceutical delivery systems may be
employed such as liposomes and emulsions well known in the art.
Certain organic solvents such as dimethylsulfoxide also may be
employed. Additionally, the .beta.-hairpin peptidomimetics of the
invention may be delivered using a sustained-release system, such
as semipermeable matrices of solid polymers containing the
therapeutic agent. Various sustained-release materials have been
established and are well known by those skilled in the art.
Sustained-release capsules may, depending on their chemical nature,
release the compounds for a few weeks up to over 100 days.
Depending on the chemical nature and the biological stability of
the therapeutic agent, additional strategies for protein
stabilization may be employed.
[0822] As the .beta.-hairpin pepdidomimetics of the invention may
contain charged residues, they may be included in any of the
above-described formulations as such or as pharmaceutically
acceptable salts. Pharmaceutically acceptable salts tend to be more
soluble in aqueous and other protic solvents than are the
corresponding free base forms.
[0823] The .beta.-hairpin peptidomimetics of the invention, or
compositions thereof, will generally be used in an amount effective
to achieve the intended purpose. It is to be understood that the
amount used will depend on a particular application.
[0824] For example, for use as a disinfectant or preservative, an
antimicrobially effective amount of a .sym.-hairpin peptidomimetic
of the invention, or a composition thereof, is applied or added to
the material to be desinfected or preserved. By antimicrobially
effective amount is meant an amount of a .beta.-hairpin
peptidomimetic of the invention or composition that inhibits the
growth of, or is lethal to, a target microbe population. While the
antimicrobially effective amount will depend on a particular
application, for use as desinfectants or preservatives the
.beta.-hairpin peptidomimetics of the invention, or compositions
thereof, are usually added or applied to the material to be
desinfected or preserved in relatively low amounts. Typically, the
.beta.-hairpin peptidomimetics of the invention comprise less than
about 5% by weight of a desinfectant solution or material to be
preserved, preferably less than 1% by weight and more preferably
less than 0.1% by weight. An ordinary skilled expert will be able
to determine antimicrobially effective amounts of particular
.beta.-hairpin pepdidomimetics of the invention for particular
applications without undue experimentation using, for example, the
in vitro assays provided in the examples.
[0825] For use to treat or prevent microbial infections or diseases
related to such infections, the .beta.-hairpin pepidomimetics of
the invention, or compositions thereof, are administered or applied
in a therapeutically effective amount. By therapeutically effective
amount is meant an amount effective in ameliorating the symptoms
of, or in ameliorating, treating or preventing microbial infections
or diseases related thereto. Determination of a therapeutically
effective amount is well within the capacities of those skilled in
the art, especially in view of the detailed disclosure provided
herein.
[0826] As in the case of desinfectants and preservatives, for
topical administration to treat or prevent bacterial infections a
therapeutically effective dose can be determined using, for
example, the in vitro assays provided in the examples. The
treatment may be applied while the infection is visible, or even
when it is not visible. An ordinary skilled expert will be able to
determine therapeutically effective amounts to treat topical
infections without undue experimentation.
[0827] For systemic administration, a therapeutically effective
dose can be estimated initially from in vitro assays. For example,
a dose can be formulated in animal models to achieve a circulating
.beta.-hairpin peptidomimetic concentration range that includes the
IC.sub.50 as determined in the cell culture (i.e. the concentration
of a test compound that is lethal to 50% of a cell culture), the
MIC, as determined in cell culture (i.e. the concentration of a
test compound that is lethal to 100% of a cell culture). Such
information can be used to more accurately determine useful doses
in humans.
[0828] Initial dosages can also be determined from in vivo data,
e.g. animal models, using techniques that are well known in the
art. One having ordinary skills in the art could readily optimize
administration to humans based on animal data.
[0829] Dosage amount for applications as antimicrobial agents may
be adjusted individually to provide plasma levels of the
.beta.-hairpin peptidomimetics of the invention which are
sufficient to maintain the therapeutic effect. Therapeutically
effective serum levels may be achieved by administering multiple
doses each day.
[0830] In cases of local administration or selective uptake, the
effective local concentration of the .beta.-hairpin peptidomimetics
of the invention may not be related to plasma concentration. One
having the skills in the art will be able to optimize
therapeutically effective local dosages without undue
experimentation.
[0831] The amount of .beta.-hairpin peptidomimetics administered
will, of course, be dependent on the subject being treated, on the
subject's weight, the severity of the affliction, the manner of
administration and the judgement of the prescribing physician.
[0832] The antimicrobial therapy may be repeated intermittently
while infections are detectable or even when they are not
detectable. The therapy may be provided alone or in combination
with other drugs, such as for example antibiotics or other
antimicrobial agents.
[0833] Normally, a therapeutically effective dose of the
.beta.-hairpin peptidomimetics described herein will provide
therapeutic benefit without causing substantial toxicity.
[0834] Hemolysis of red blood cells is often employed for
assessment of toxicity of related compounds such as protegrin or
tachyplesin. Values are given as %-lysis of red blood cells
observed at a concentration of 100 .mu.g/ml. Typical values
determined for cationic peptides such as protegrin and tachyplesin
range between 30-40% with average MIC-values of 1-5 .mu.g/ml over a
wide range of pathogens. Normally, .beta.-hairpin peptidomimetics
of the invention will show hemolysis in a range of 0.5-10%, often
in a range of 1-5%, at activity levels comparable to those
mentioned above for protegrin and tachyplesin. Thus preferred
compounds exhibit low MIC-values and low %-hemolysis of red blood
cells observed at a concentration of 100 .mu.g/ml.
[0835] Toxicity of the .beta.-hairpin peptidomimetics of the
invention herein can be determined by standard pharmaceutical
procedures in cell cultures or experimental animals, e.g., by
determining the LD.sub.50 (the dose lethal to 50% of the
population) or the LD.sub.100 (the dose lethal to 100% of the
population). The dose ratio between toxic and therapeutic effect is
the therapeutic index. Compounds which exhibit high therapeutic
indices are preferred. The data obtained from these cell culture
assays and animal studies can be used in formulating a dosage range
that is not toxic for use in humans. The dosage of the
.beta.-hairpin peptidomimetics of the invention lies preferably
within a range of circulating concentrations that include the
effective dose with little or no toxicity. The dosage may vary
within the range depending upon the dosage form employed and the
route of administration utilized. The exact formulation, route of
administration and dose can be chosen by the individual physician
in view of the patient's condition (see, e.g. Fingl et al. 1975,
In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).
[0836] The following Examples illustrate the invention in more
detail but are not intended to limit its scope in any way. The
following abbreviations are used in these Examples: [0837] HBTU:
1-benzotriazol-1-yl-tetramethylurounium hexafluorophosphate (Knorr
et al. Tetrahedron Lett. 1989, 30, 1927-1930); [0838] HOBt: 1
-hydroxybenzotriazole; [0839] DIEA: diisopropylethylamine; [0840]
HOAT: 7-aza-1-hydroxybenzotriazole; [0841] HATU:
O-(7-aza-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronoium
hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,
2279-2281).
EXAMPLES
1. Peptide Synthesis
[0842] Coupling of the First Protected Amino Acid Residue to the
Resin
[0843] 0.5 g of 2-chlorotritylchloride resin (Barlos et al.
Tetrahedron Lett. 1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol)
was filled into a dried flask. The resin was suspended in
CH.sub.2Cl.sub.2 (2.5 ml) and allowed to swell at room temperature
under constant stirring for 30 min. The resin was treated with
0.415 mMol (1 eq) of the first suitably protected amino acid
residue (see below) and 284 .mu.l (4 eq) of diisopropylethylamine
(DIEA) in CH.sub.2Cl.sub.2 (2.5 ml), the mixture was shaken at
25.degree. C. for 4 hours. The resin colour changed to purple and
the solution remained yellowish. The resin was shaken
(CH.sub.2Cl.sub.2/MeOH/DIEA: 17/2/1), 30 ml for 30 min; then washed
in the following order with CH.sub.2Cl.sub.2(1.times.), DMF
(1.times.), CH.sub.2Cl.sub.2(1.times.), MeOH (1.times.),
CH.sub.2Cl.sub.2(1.times.), MeOH (1.times.), CH.sub.2Cl.sub.2
(2.times.), Et.sub.2O (2.times.) and dried under vacuum for 6
hours.
[0844] Loading was typically 0.6-0.7 mMol/g.
[0845] The following preloaded resin was prepared:
Fmoc-ProO-chlorotritylresin.
[0846] Synthesis of the Fully Protected Peptide Fragment
[0847] The synthesis was carried out using a Syro-peptide
synthesizer (Multisyntech) using 24 to 96reaction vessels. In each
vessel was placed 60 mg (weight of the resin before loading) of the
above resin. The following reaction cycles were programmed and
carried out:
TABLE-US-00002 Step Reagent Time 1 CH.sub.2Cl.sub.2, wash and swell
(manual) 3 .times. 1 min. 2 DMF, wash and swell 1 .times. 5 min 3
40% piperidine/DMF 1 .times. 5 min. 4 DMF, wash 5 .times. 2 min. 5
5 equiv. Fmoc amino acid/DMF + 5 eq. HBTU + 1 .times. 120 min. 5
eq. HOBt + 5 eq. DIEA 6 DMF, wash 4 .times. 2 min. 7
CH.sub.2Cl.sub.2, wash (at the end of the synthesis) 3 .times. 2
min. Steps 3 to 6 are repeated to add each amino-acid.
[0848] Cleavage of the Fully Protected Peptide Fragment
[0849] After completion of the synthesis, the resin was suspended
in 1 ml (0.39 mMol) of 1% TFA in CH.sub.2Cl.sub.2 (v/v) for 3
minutes, filtered and the filtrate was neutralized with 1 ml (1.17
mMol, 3 eq.) of 20% DIEA in CH.sub.2Cl.sub.2 (v/v). This procedure
was repeated twice to ensure completion of the cleavage. The
filtrate was evaporated to dryness and the product was fully
deprotected [cleavage mixture containing 95% trifluoroacetic acid
(TFA), 2.5% water and 2.5% triisopropylsilane (TIS)] to be analyzed
by reverse phase-HPLC (column C.sub.18) and ESI-MS to monitor the
efficiency of the linear peptide synthesis.
[0850] Cyclization of the Linear Peptide
[0851] 100 mg of the fully protected linear peptide were dissolved
in DMF (9 ml, cone. 10 mg/ml). Then 41.8 mg (0.110 mMol, 3 eq.) of
HATU, 14.9 mg (0.110 mMol, 3 eq) of HOAt and 1 ml (0.584 mMol) of
10% DIEA in DMF (v/v) were added and the mixture vortexed at
20.degree. C. for 16 hours and subsequently concentrated under high
vacuum. The residue was partitioned between CH.sub.2Cl.sub.2 and
H.sub.2O/CH.sub.3CN (90/10: v/v). The CH.sub.2Cl.sub.2 phase was
evaporated to yield the fully protected cyclic peptide.
[0852] Deprotection and Purification of the Cyclic Peptide:
[0853] The cyclic peptide obtained was dissolved in 1 ml of the
cleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5%
water and 2.5% triisopropylsilane (TIS). The mixture was left to
stand at 20.degree. C. for 2.5 hours and then concentrated under
vacuum. The residue was dissolved in a solution of H.sub.2O/acetic
acid (75/25: v/v) and the mixture extracted with
di-isopropylether.
[0854] The water phase was dried under vacuum and then the product
purified by preparative reverse phase HPLC.
[0855] After lyophilisation products were obtained as a white
powder and analysed by ESI-MS. The analytical data comprising HPLC
retention times and ESI-MS are shown in table 1.
[0856] Analytical HPLC retention times (RT, in minutes) were
determined using a VYDAC 218MS5215 column with the following
solvents A (H.sub.2O+0.02% TFA) and B (CH.sub.3CN) and the
gradient: 0 min: 92% A, 8% B; 8 min: 62% A 38% B; 9-12 min: 0% A,
100% B.
[0857] Examples 1-7 (n=12) are shown intable 1. The peptides were
synthesized starting with the amino acid Pro which was grafted to
the resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which
was prepared as described above. The linear peptides were
synthesized on solid support according to procedure described above
in the following sequence:
Resin-Pro-.sup.oPro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1, cleaved
from the resin, cyclized, deprotected and purified as
indicated.
[0858] HPLC-retention times (minutes) were determined using the
gradient described above:
[0859] Ex.1 (5.73; 6.29)*; Ex.2 (5.13; 5.51; 5.75)*; Ex.3 (4.83;
5.37)*; Ex.4 (4.79; 5.43)*; Ex.5 (5.27; 5.85)* Ex.6 (5.31; 6.03);
Ex.7 (4.59).
[0860] * double peaks which show both correct MS and chiral amino
acid analysis. At 60.degree. only one peak is observed.
TABLE-US-00003 TABLE 1 Examples (Ex) Ex. SEQ ID P1 P2 P3 P4 P5 P6
P7 P8 P9 P10 P11 P12 Template Purity %.sup.a) [m/z], z = 2 1 SEQ ID
NO: 1 Arg Trp Leu Lys Lys Arg Arg Trp Leu Tyr Tyr Arg
.sup.DPro.sup.LPro 100 1000.3 2 SEQ ID NO: 2 Arg Trp Leu Lys Lys
Arg Arg Trp Lys Tyr Val Arg .sup.DPro.sup.LPro 100 976.1 3 SEQ ID
NO 3 Arg Trp Leu Lys Lys Arg Arg Trp Lys Thr Tyr Arg
.sup.DPro.sup.LPro 54 977.0 4 SEQ ID NO 4 Arg Trp Leu Lys Lys Arg
Arg Trp Lys Gln Tyr Arg .sup.DPro.sup.LPro 100 991.1 5 SEQ ID NO: 5
Arg Trp Leu Val Lys Arg Arg Trp Lys Tyr Tyr Arg .sup.DPro.sup.LPro
100 993.4 6 SEQ ID NO: 6 Arg Trp Leu Lys Lys Arg Arg Trp Val Tyr
Tyr Arg .sup.DPro.sup.LPro 100 993.5 7 SEQ ID NO: 7 Arg Trp Leu Lys
Lys Arg Arg Trp Lys Tyr Gln Arg .sup.DPro.sup.LPro 100 991.2 8 SEQ
ID NO: 8 Arg Trp Leu Lys Lys Arg Arg Trp Lys Tyr Leu Arg
.sup.DPro.sup.LPro 24 983.1 .sup.a)%-puritity of compounds after
prep. HPLC.
[0861] 2. Biological Methods
[0862] 2.1. Preparation of the Peptides.
[0863] Lyophilized peptides were weighed on a Microbalance (Mettler
MT5) and dissolved in sterile water containing 0.01% acetic
acid.
[0864] 2.2. Antimicrobial Activity of the Peptides.
[0865] The selective antimicrobial activities of the peptides were
determined by the standard NCCLS broth microdilution method (see
ref 1, below) examined in sterile 96-wells plates (Nunclon
polystyrene microtiter plates) in a total volume of 100 .mu.l.
Innocula of the microorganisms were prepared with 0.5 Mcfarland
standard and then diluted into Mueller-Hinton (MH) broth to give
appr. 10.sup.6 colony forming units (CFU)/ml for bacteria Aliquots
(50 .mu.l) of the innocula were added to 50 .mu.l of MH broth
containing the peptide in serial twofold dilutions. For the
screening of the peptides displaying selectivity, the following
microorganisms were used: Escherichia coli (ATCC 25922),
Pseudomonas aeruginosa (P. aeruginosa) (ATCC 27853), Staphylococcus
aureus (ATCC 29213 and ATCC 25923), and clinical isolates of
Pseudomonas aeruginosa (P. aeruginosa) V02 16085 and Acinetobacter
(Acinetobacter V04 19905/1, Acinetobacter V12 21143/1 and
Acinetobacter V12 21193/1). Antimicrobial activities of the
peptides were expressed as the minimal inhibitory concentration
(MIC) in .mu.g/ml at which no visible growth was observed after
18-20 hours of incubation of the microtiter plates at 37.degree.
C.
[0866] 2.3. Antimicrobial Activity of the Peptides in 0.9%
Saline
[0867] Salt sensitivity of the peptides was tested by the
microtiter serial dilution assay as described above. Only MH broth
was replaced by MH broth containing 0.9% NaCl.
[0868] 2.4. Antimicrobial Activity of the Peptides in Human
Serum
[0869] Serum binding of the peptides was tested by the microtiter
serial dilution assay as described above. Only MH broth was
replaced by MH broth containing 90% human serum (BioWhittaker).
[0870] 2.5. Hemolysis
[0871] The peptides were tested for their hemolytic activity
against human red blood cells (hRBC). Fresh hRBC were washed three
times with phosphate buffered saline (PBS) by centrifugation for 10
min at 2000.times.g. Peptides at a concentration of 100 .mu.g/ml
were incubated with 20% v/v hRBC for 1 hour at 37.degree. C. The
final erythrocyte concentration was appr. 0.9.times.10.sup.9/ml. A
value of 0% resp. 100% cell lysis was determined by incubation of
the hRBC in the presence of PBS alone and resp. 0.1% Triton X-100
in H.sub.2O. The samples were centrifuged and the supernatant was
20 fold diluted in PBS buffer and the optical density (OD) of the
sample at 540 nM was measured. The 100% lysis value
(OD.sub.540H.sub.2O) gave an OD of approximately 1.6-2.0. Percent
hemolysis was calculated as follows:
(OD.sub.540peptide/OD.sub.540H.sub.2O).times.100%.
[0872] 2.6. Results
[0873] The results of the experiments described above are indicated
in Table 2 and Table 3, herein below.
REFERENCES
[0874] 1. National Committee for Clinical Laboratory Standards.
1993. Methods for dilution antimicrobial susceptibility tests for
bacteria that grow aerobically, 3rd ed. Approved standard M7-A3.
National Committee for Clinical laboratory standards, Villanova,
Pa.
[0875] 2. Mossman T. J Immunol Meth 1983, 65, 55-63
[0876] 3. Berridge M V, Tan A S. Archives of Biochemistry &
Biophysics 1993, 303, 474-482
TABLE-US-00004 TABLE 2 Minimal inhibitory concentrations (MIC in
.mu.g/ml) in Mueller-Hinton broth and percentage hemolyses at a
concentration of 100 .mu.g/ml of peptide Escherichia Escherichia
Staphylococcus Staphylococcus coli ATCC coli ATCC aureus ATCC
aureus ATCC P. aeruginosa P. aeruginosa Acinetobacter Acinetobacter
Hemolysis at Ex. 25922 43827 29213 25923 ATCC 27853 VO216085
V1221143/1 V1221193/1 100 .mu.g/ml 1 25 25 25 50 12.5 9.4 6.2 6.2
0.5 2 50 100 100 100 3.1 3.1 6.2 6.2 0.5 3 100 200 100 100 6.2 6.2
25 100 1.5 4 100 100 100 200 3.1 3.1 6.2 12.5 0.6 5 25 n.d. 100 100
6.2 n.d. n.d. n.d. 0.5 6 12.5 n.d. 100 100 6.2 n.d. n.d. n.d. 0.5 7
100 n.d. 200 25 9.4 n.d. n.d. n.d 0.7 8 50 n.d. 100 100 6.2 n.d.
n.d. n.d. 0.4 n.d.: not determined
TABLE-US-00005 TABLE 3 Minimal inhibitory concentrations (MIC in
.mu.g/ml) in Mueller-Hinton broth containing 0.9% NaCl Escherichia
coli Escherichia coli P. aeruginosa P. aeruginosa Acinetobacter
Acinetobacter Ex. ATCC 25922 ATCC 43827 ATCC 278853 VO216085 V12
21143/1 V12 21193/1 1 100 200 50 50 6.2 6.2 2 100 100 9.4 6.2 12.5
25 3 200 200 200 9.4 25 100 4 100 200 6.2 3.1 12.5 25
Sequence CWU 1
1
8114PRTArtificial Sequenceantimicrobial cyclic peptide sequence
based on Protegrin 1 peptide 1Arg Trp Leu Lys Lys Arg Arg Trp Leu
Tyr Tyr Arg Pro Pro1 5 10214PRTArtificial Sequenceantimicrobial
cyclic peptide sequence based on Protegrin 1 peptide 2Arg Trp Leu
Lys Lys Arg Arg Trp Lys Tyr Val Arg Pro Pro1 5 10314PRTArtificial
Sequenceantimicrobial cyclic peptide sequence based on Protegrin 1
peptide 3Arg Trp Leu Lys Lys Arg Arg Trp Lys Thr Tyr Arg Pro Pro1 5
10414PRTArtificial Sequenceantimicrobial cyclic peptide sequence
based on Protegrin 1 peptide 4Arg Trp Leu Lys Lys Arg Arg Trp Lys
Gln Tyr Arg Pro Pro1 5 10514PRTArtificial sequenceantimicrobial
cyclic peptide sequence based on Protegrin 1 peptide 5Arg Trp Leu
Val Lys Arg Arg Trp Lys Tyr Tyr Arg Pro Pro1 5 10614PRTArtificial
sequenceantimicrobial cyclic peptide sequence based on Protegrin 1
peptide 6Arg Trp Leu Lys Lys Arg Arg Trp Val Tyr Tyr Arg Pro Pro1 5
10714PRTArtificial sequenceantimicrobial cyclic peptide sequence
based on Protegrin 1 peptide 7Arg Trp Leu Lys Lys Arg Arg Trp Lys
Tyr Gln Arg Pro Pro1 5 10814PRTArtificial sequenceantimicrobial
cyclic peptide sequence based on Protegrin 1 peptide 8Arg Trp Leu
Lys Lys Arg Arg Trp Lys Tyr Leu Arg Pro Pro1 5 10
* * * * *