U.S. patent application number 10/288103 was filed with the patent office on 2003-05-15 for novel compounds and compositions as protease inhibitors.
This patent application is currently assigned to Axys Pharmaceuticals, Inc.. Invention is credited to Buysse, Ann M., Mendonca, Rohan V., Palmer, James T., Tian, Zong-Qiang, Venkatraman, Shankar.
Application Number | 20030092634 10/288103 |
Document ID | / |
Family ID | 22415407 |
Filed Date | 2003-05-15 |
United States Patent
Application |
20030092634 |
Kind Code |
A1 |
Buysse, Ann M. ; et
al. |
May 15, 2003 |
Novel compounds and compositions as protease inhibitors
Abstract
The present invention relates to novel cysteine protease
inhibitors; the pharmaceutically acceptable salts and N-oxides
thereof; their uses as therapeutic agents and the methods of their
making.
Inventors: |
Buysse, Ann M.; (Carmel,
IN) ; Mendonca, Rohan V.; (Millbrae, CA) ;
Palmer, James T.; (Corte Madera, CA) ; Tian,
Zong-Qiang; (Fremont, CA) ; Venkatraman, Shankar;
(Foster City, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Axys Pharmaceuticals, Inc.
So. San Francisco
CA
|
Family ID: |
22415407 |
Appl. No.: |
10/288103 |
Filed: |
November 4, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10288103 |
Nov 4, 2002 |
|
|
|
09526300 |
Mar 15, 2000 |
|
|
|
6506733 |
|
|
|
|
Current U.S.
Class: |
435/7.1 ;
514/1.7; 514/114; 514/16.4; 514/16.6; 514/17.9; 514/20.2; 514/357;
514/562; 514/7.3; 530/330; 530/331; 546/315; 558/166; 562/556 |
Current CPC
Class: |
C07C 275/24 20130101;
C07C 317/28 20130101; C07C 271/22 20130101; C07C 235/78
20130101 |
Class at
Publication: |
514/18 ; 514/19;
514/562; 530/330; 530/331; 514/114; 546/315; 558/166; 562/556;
514/357 |
International
Class: |
A61K 038/05; A61K
038/06; A61K 031/198; A61K 031/661; A61K 031/44; C07K 005/06; C07K
005/04 |
Claims
We claim:
1. A compound of Formula I: 32in which: X.sup.1 is a bond or a
divalent group of Formula (a) or (b): 33wherein: X.sup.2 and
X.sup.3 independently are --C(O)-- or --CH.sub.2S(O).sub.2--;
R.sup.7 and R.sup.8 are independently (i) (C.sub.1-6)alkyl
optionally substituted with cyano, halo, nitro,
--NR.sup.10R.sup.10, --NR.sup.10C(O)OR.sup.10,
--NR.sup.10C(O)NR.sup.10R.sup.10,
--NR.sup.10C(NR.sup.10)NR.sup.10R.sup.1- 0, --OR.sup.10,
--SR.sup.10, --C(O)OR.sup.10, --C(O)NR.sup.10R.sup.10,
--S(O).sub.2NR.sup.10R.sup.10, --P(O)(OR.sup.10)OR.sup.10,
--OP(O)(OR.sup.10)OR.sup.10, --NR.sup.10C(O)R.sup.11,
--S(O)R.sup.11, --S(O).sub.2R.sup.11, --C(O)R.sup.11, --OR.sup.12,
--SR.sup.2, --S(O)R.sup.12, --S(O).sub.2R.sup.12, --C(O)R.sup.12,
--C(O)OR.sup.12, --OC(O)R.sup.12, --NR.sup.12R.sup.13,
--NR.sup.13C(O)R.sup.12, --NR.sup.13C(O)OR.sup.12,
--C(O)NR.sup.12R.sup.13, --S(O).sub.2NR.sup.12R.sup.13,
--NR.sup.13C(O)NR.sup.12R.sup.13 or
--NR.sup.13C(NR.sup.13)NR.sup.12R.sup.13, wherein R.sup.10 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.11 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.12 is
(C.sub.3-12)cycloalkyl(C.s- ub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl or
hetero(C.sub.5-2)aryl(C.sub.0-3)alkyl and R.sup.13 is hydrogen or
(C.sub.1-6)alkyl, and wherein within R.sup.12 said cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, polycycloaryl or
heterpolycycloaryl ring optionally is substituted by a group
selected from --R.sup.14, --X.sup.4OR.sup.4, --X.sup.4SR.sup.14,
--X.sup.4S(O)R.sup.4, --X.sup.4S(O).sub.2R.sup.14,
--X.sup.4C(O)R.sup.14, --X.sup.4C(O)OR.sup.14,
--X.sup.4OC(O)R.sup.14, --X.sup.4NR.sup.15,
--X.sup.4NR.sup.15C(O)R.sup.14, --X.sup.4NR.sup.15C(O)OR.sup.14,
X.sup.4C(O)NR.sup.14R.sup.15, --X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.sup.15 or
--X.sup.4NR.sup.15C(NR.sup.15)- NR.sup.14R.sup.15, wherein X.sup.4
is a bond or (C.sub.1-6)alkylene, R.sup.14 is hydrogen or
(C.sub.1-6)alkyl and R.sup.15 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-2)aryl(C.sub.0-6)alkyl, hetero(C.sub.5-2)aryl(C.sub.-
0-6)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
heterocyclo(C.sub.3-12)alkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl, wherein within
R.sup.15 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
polycycloaryl or heterpolycycloaryl ring optionally is substituted
by a group selected from --R.sup.14, --X.sup.4OR.sup.4,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
X.sup.4C(O)OR.sup.14, --X.sup.4OC(O)R.sup.14,
--X.sup.4NR.sup.14R.sup.15, --X.sup.4NR.sup.15C(O)R.sup.14,
--X.sup.4NR.sup.15C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.su- p.15 or
--X.sup.4NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein X.sup.4,
R.sup.14 and R.sup.15 are as defined above; wherein within R.sup.7
and/or R.sup.8 any alicyclic or aromatic ring system present may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)N.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10 C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4 is a bond or
(C.sub.1-6)alkylene and R.sup.10 and R.sup.11 are as defined above,
or R.sup.7 taken together with R.sup.5 and/or R.sup.8 taken
together with R.sup.6 forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy or
oxo; R.sup.9 at each occurrence is hydrogen or (C.sub.1-6)alkyl;
and R.sup.5 and R.sup.6 are independently hydrogen,
(C.sub.1-6)alkyl or as defined above; and R.sup.1 is
--X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is --C(O)--, --C(O)C(O)--
or --S(O).sub.2--, X.sup.7 is a bond, --O-- or --NR.sup.17 wherein
R.sup.17 is hydrogen or (C.sub.1-6)alkyl, and R.sup.16 is (i)
(C.sub.1-6)alkyl optionally substituted by cyano, halo, nitro,
--NR.sup.10R.sup.10, --NR.sup.10C(O)OR.sup.10,
--NR.sup.10C(O)NR.sup.10R.sup.10,
--NR.sup.10C(NR.sup.10)NR.sup.10R.sup.10, --OR.sup.10, --SR.sup.10,
--C(O)OR.sup.10, --C(O)NR.sup.10R.sup.10,
--S(O).sub.2NR.sup.10R.sup.10, --P(O)(OR.sup.10)OR.sup.10,
--OP(O)(OR.sup.10)OR.sup.10, --NR.sup.10C(O)R.sup.11,
--S(O)R.sup.11, --S(O).sub.2R.sup.11, --C(O)R.sup.11, --OR.sup.18,
--SR.sup.18, --S(O)R.sup.18, --S(O).sub.2R.sup.18, --C(O)R.sup.18,
--C(O)OR.sup.18, --C(O)NR.sup.18R.sup.19, --NR.sup.18R.sup.19,
--NR.sup.19C(O)R.sup.18, --NR.sup.19C(O)OR.sup.18,
--NR.sup.19C(O)NR.sup.18R.sup.19 or
--NR.sup.19C(NR.sup.19)NR.sup.18R.sup.19, wherein R.sup.10 and
R.sup.11 are as defined above, R.sup.18 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-2)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-2)aryl(C.sub.0-6)al- kyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.19 at
each occurrence independently is hydrogen or (C.sub.1-6)alkyl, and
wherein within R.sup.18 said cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is
substituted by a group selected from --R.sup.14,
--X.sup.4OR.sup.14, --X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
--X.sup.4C(O)OR.sup.14, --X.sup.4OC(O)R.sup.14,
--X.sup.4NR.sup.14R.sup.1- 5, --X.sup.4NR.sup.15C(O)R.sup.14,
--X.sup.4NR.sup.15C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.sup.15 or
--X.sup.4NR.sup.15C(NR.sup.15)- NR.sup.14R.sup.15, wherein X.sup.4,
R.sup.14 and R.sup.15 are as defined above, or (ii)
(C.sub.3-14)cycloalky](C.sub.0-6)alkyl,
hetero(C.sub.3-14)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-14)aryl(C.sub.0-6)- alkyl, diphenyl(C.sub.0-6)alkyl,
hetero(C.sub.5-14)aryl(C.sub.0-6)alkyl,
heterodi(C.sub.5-6)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.sub.- 0-6)alkyl or
hetero(C.sub.9-14)polycyclo(C.sub.8-14)aryl(C.sub.0-6)alkyl,
wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
polycycloaryl or heterpolycycloaryl ring optionally is substituted
by a group selected from --R.sup.14, --X.sup.4OR.sup.14,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
--X.sup.4C(O)OR.sup.14, --X.sup.4OC(O)R.sup.14,
--X.sup.4NR.sup.14R.sup.15, --X.sup.4NR.sup.15C(O)R.sup.14,
--X.sup.4NR.sup.15C(O)OR.sup.4, --X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.su- p.15 or
--X.sup.4NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein X.sup.4,
R.sup.14 and R.sup.15 are as defined above; wherein within R.sup.1
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.1, wherein X.sup.4, R.sup.10 and R.sup.11 are as
defined above; or when X.sup.1 is a divalent group of formula (a)
or (b) then R.sup.1 may also represent hydrogen; R.sup.2 is
hydrogen or (C.sub.1-6)alkyl; R.sup.3 is hydrogen or
(C.sub.1-6)alkyl wherein said alkyl optionally is substituted with
--OR.sup.20, NR.sup.21C(O)OR.sup.20, --C(O)NR.sup.20R.sup.21,
--S(O).sub.2R.sup.20, wherein R.sup.20 is (C.sub.0-6)alkyl or
(C.sub.6-10)aryl(C.sub.0-6)alkyl and R.sup.21 is hydrogen or
(C.sub.1-6)alkyl, or (ii) (C.sub.6-10)aryl(C.sub.1-6)alkyl or
(C.sub.5-10)heteroaryl(C.sub.1-6)alkyl or R.sup.3 taken together
with R.sup.2 forms trimethylene, tetramethylene or phenylene
-1,2-dimethylene, optionally substituted with hydroxy or oxo;
wherein within R.sup.3 any alicyclic or aromatic ring system
present may be substituted further by 1 to 5 radicals independently
selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; and R.sup.4 is nitromethyl,
1-hydroxy-1-methylethyl or --CH.sub.2OR.sup.22, wherein R.sup.22 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.6)alkyl,
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6- )alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl wherein within
R.sup.22 any alicyclic or aromatic ring system present may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR.sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.1- 0,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers;
and the pharmaceutically acceptable salts thereof.
2. The compound of claim 1 in which: X.sup.1 is a bond or a
divalent group of Formula (a) wherein within Formula (a): R.sup.5
is hydrogen or together with R.sup.7 forms
phenylene-1,2-dimethylene; and R.sup.7 is (i) (C.sub.1-6)alkyl
optionally substituted with --OR.sup.10, --C(O)OR.sup.10,
--C(O)NR.sup.10R.sup.10, wherein R.sup.10 at each occurrence
independently is hydrogen or (C.sub.1-6)alkyl or (ii)
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
cyclo(C.sub.3-12)alkyl(C.sub.0-3)alkyl or
(C.sub.6-12)aryl(C.sub.0-3)alkyl or (iii) together with R.sup.5 is
phenylenedimethylene; wherein within R.sup.7 any alicyclic or
aromatic ring system present may be substituted further by 1 to 5
radicals independently selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4 is a bond or
(C.sub.1-6)alkylene, R.sup.10 at each occurrence independently is
hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and
R.sup.11 is (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl;
R.sup.1 is --X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is --C(O)-- or
--S(O).sub.2--, X.sup.7 is a bond, --O-- or --NR.sup.17--, wherein
R.sup.17 is hydrogen or (C.sub.1-6)alkyl, and R.sup.16 is (i)
(C.sub.1-6)alkyl optionally substituted with --C(O)OR.sup.10,
--NR.sup.10R.sup.10 or --NR.sup.10C(O)OR.sup.10, wherein R.sup.10
at each occurrence independently is hydrogen or (C.sub.1-6)alkyl or
(ii) hetero(C.sub.3-14)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-14)aryl(C.sub.0-6)alkyl, diphenyl(C.sub.0-6)alkyl, or
hetero(C.sub.5-14)aryl(C.sub.0-6)alkyl; wherein within R.sup.7 any
alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; R.sup.2 is hydrogen; R.sup.3 is (i) hydrogen or
(C.sub.1-6)alkyl optionally substituted with --OR.sup.20,
--NR.sup.21C(O)OR.sup.20, --C(O)(O)NR.sup.20R.sup.20,
--S(O).sub.2R.sup.20, wherein R.sup.20 is (C.sub.0-6)alkyl or
(C.sub.0-10)aryl(C.sub.0-6)alkyl and R.sup.21 is hydrogen or
(C.sub.1-6)alkyl, or (ii) (C.sub.6-10)aryl(C.sub.1-6)alkyl or
(C.sub.5-10)heteroaryl(C.sub.1-6)alkyl or (ii) together with
R.sup.2 forms trimethylene or phenylene -1,2-dimethylene; wherein
within R.sup.7 any alicyclic or aromatic ring system present may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; and R.sup.4 is nitromethyl,
1-hydroxy-1-methylethyl or --CH.sub.2OR.sup.22, wherein R.sup.22 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.6-2)aryl(C.sub.0-6)alkyl,
heteropolycyclo(C.sub.8-2)aryl(C.sub.0-6- )alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, wherein
within R.sup.4 any aromatic ring present may be substituted further
by 1 to 3 radicals independently selected from halo, --OR.sup.10,
--C(O)NR.sup.10R.sup.10, --S(O).sub.2NR.sup.10R.sup.10 or
--X.sup.4NR.sup.10R.sup.10, wherein X.sup.4, R.sup.10 and R.sup.11
are as defined above; and the N-oxide derivatives, prodrug
derivatives, protected derivatives, individual isomers and mixtures
of isomers; and the pharmaceutically acceptable salts thereof.
3. The compound of claim 2 in which: within Formula (a): R.sup.5 is
hydrogen or as defined below; and R.sup.7 is (i) butyl, ethyl,
methyl, 1-methylethyl, 1-methylpropyl or 2-methylpropyl optionally
substituted with --OR.sup.10, --C(O)OR.sup.10, --NR.sup.10,
--NR.sup.10C(O)OR.sup.10 or --C(O)NR.sup.10R.sup.10, wherein
R.sup.10 is hydrogen or (C.sub.1-6)alkyl, or (ii) benzyl,
benzyoxycarbonylmethyl, biphenyl-4-ylmethyl, cyclohexyl,
cyclohexylmethyl, naphth-2-ylmethyl, phenylcarbamoylmethyl or
phenylethyl or (iii) together with R.sup.5 is phenylenedimethylene;
wherein within R.sup.7 any alicyclic or aromatic ring system
present may be substituted further by 1 to 3 radicals independently
selected from nitro and amino; R.sup.1 is hydrogen, acetyl,
3-aminobenzoyl, 4-aminobutyryl, 3-aminopropionyl, 6-aminohexanoyl,
3-aminomethylbenzoyl, 4-aminomethylbenzoyl, benzoyl,
benzylcarbamoyl, 4-benzyloxybenzoyl, benzyloxycarbonyl,
tert-butoxycarbonyl, 3-tert-butoxycarbonylaminobenzoyl,
4-tert-butoxycarbonylaminobutyryl,
6-tert-butoxycarbonylaminohexanoyl,
3-tert-butoxycarbonylaminomethylbenzo- yl,
4-tert-butoxycarbonylaminomethylbenzoyl,
1-tert-butoxycarbonylpiperidi- n-4-ylcarbonyl,
1-tert-butoxycarbonylpyrrolidin-2-ylcarbonyl, 3-carbamoylbenzoyl,
3-cyanobenzoyl, dibenzofur-2-ylsulfonyl,
3-[N',N"-di(tert-butoxycarbonyl)guanidino]benzoyl,
4-dimethylaminobenzoyl, 2,2-dimethylpropionyl, 3-diphenylpropionyl,
3-fluorobenzoyl, 3-guanidinobenzoyl, 3-hydroxybenzoyl,
1H-indol-3-ylacetyl, 3-methoxycarbonylbenzoyl,
3-methoxycarbonylpropionyl- , 3-methoxyphenylcarbamoyl
4-methylpiperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl,
naphth-1-ylcarbonyl, naphth-2-ylcarbonyl naphth-2-ylsulfonyl,
3-nitrophenylacetyl, phenoxyacetyl, phenylcarbamoyl,
3-phenylpropionyl, piperidin-4-ylcarbonyl,
1-piperidin-1-ylpiperidin-1-yl- carbonyl, pyrid-3-ylacetyl,
pyrid-4-ylacetyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl,
pyrrolidin-2-ylcarbonyl, pyrazinylcarbonyl or 3-ureidobenzoyl;
R.sup.2 is hydrogen or as defined below; R.sup.3 is hydrogen,
benzyl, 2-benzyloxyethyl, 4-benzyloxycarbonylaminobutyl,
benzyloxymethyl, butyl, 2-(4-hydroxyphenyl)ethyl,
1H-indol-3-ylmethyl, 4-methoxybenzyl, methyl,
2-methylsulfonylethyl, 2-methylpropyl, phenethyl,
2-phenylcarbamoylethyl or together with R.sup.2 forms
tetramethylene or phenylenedimethylene; and R.sup.4 is
acetoxymethyl, benzo[1,3]dioxol-5-yloxy, benzyloxymethyl,
4-carbamoylphenoxymethyl, 4-chlorophenoxymethyl,
2,5-dichlorobenzoyloxymethyl, 2,6-dichlorobenzoyloxymethyl,
3-dimethylaminophenoxymethyl, ethoxymethyl, hydroxymethyl,
1-hydroxy-1-methylethyl, 4-(1H-imidazol-1-yl)phenoxymethyl- ,
methoxymethyl, 3-methoxyphenoxymethyl, 4-methoxyphenoxymethyl,
4-sulfamoylphenoxymethyl or phenoxymethyl; and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers; and the pharmaceutically
acceptable salts thereof.
4. The compound of claim 3 in which R.sup.5 is hydrogen and R.sup.7
is butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or
naphth-2-ylmethyl; R.sup.1 is 3-aminobenzoyl, 3-aminomethylbenzoyl,
4-aminomethylbenzoyl, benzoyl, benzylcarbamoyl, benzyloxycarbonyl,
tert-butoxycarbonyl, 3-tert-butoxycarbonylaminobenzoyl,
4-tert-butoxycarbonylaminomethylbenzoyl,
3-[N',N"-di(tert-butoxycarbonyl)- guanidino]benzoyl,
4-dimethylaminobenzoyl, 3-guanidinobenzoyl
4-methylpiperazin-1-ylcarbonyl, naphth-1-ylcarbonyl,
naphth-2-ylcarbonyl or piperidin-4-ylcarbonyl; R.sup.2 is hydrogen;
R.sup.3 is hydrogen, 4-benzyloxycarbonylaminobutyl, butyl or
phenethyl; and R.sup.4 is benzyloxymethyl, hydroxymethyl,
2,5-dichlorobenzoyloxymethyl, ethoxymethyl, 1-hydroxy-1-methylethyl
or phenoxymethyl; and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers;
and the pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 in combination with one
or more pharmaceutically acceptable excipient(s).
6. The composition of claim 5 which further comprises one or more
active ingredient(s) selected from the group consisting of (i) a
therapeutically effective amount of a bisphosphonic acid or acid
ester thereof or a pharmaceutically acceptable salt thereof and
(ii) a therapeutically effective amount of an estrogen receptor
agonist or a pharmaceutically acceptable salt thereof.
7. The composition of claim 6 wherein the bisphosphonic acid is
selected from the group consisting of
1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy
-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid,
1-hydroxyethylidene-1,1-diphosphonic acid,
1-hydroxy-3-(N-methyl-N-pentyl- amino)propylidene-1,1-bisphosphonic
acid, 6-amino-1-hydroxyhexylidene-1,1-- bisphosphonic acid,
3-(dimethylamino)-1-hydroxypropylidene -1,1-bisphosphonic acid,
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,
2-pyrid-2-ylethylidene-1,1-bisphosphonic acid,
1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid,
4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy
-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid
ester thereof or a pharmaceutically acceptable salt thereof.
8. The composition of claim 7 wherein the bisphosphonic acid is
1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically
acceptable salt thereof.
9. The composition of claim 8 which comprises 1,1-dichloromethylene
-1,1-diphosphonate monosodium trihydrate.
10. A method of treating a disease in an animal in which cysteine
protease activity contributes to the pathology and/or
symptomatology of the disease, which method comprises administering
to the animal a therapeutically effective amount of compound of
claim 1; or a N-oxide derivatives, prodrug derivative, protected
derivative, individual isomer and mixtures of isomers; or
pharmaceutically acceptable salt thereof.
11. The method of claim 10 wherein the disease is osteoporosis.
12. The method of claim 11 wherein the animal is a human.
13. The method of claim 12 wherein the human is a post-menopausal
woman.
14. The method of claim 13 wherein the cysteine protease is
cathepsin K.
15. The method of claim 10 in which the cysteine protease is
cathepsin S.
16. The method of claim 15 in which the disease is an autoimmune
disorder, allergic disorder, allogeneic immune response, a disorder
involving excessive elastolysis, cardiovascular disorders or a
disorder involving fibril formation.
17. The method of claim 16 in which the disorder is selected from
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
rheumatoid arthritis, Hashimoto's thyroiditis, asthma, organ
transplant or tissue graft rejections, chronic obstructive
pulmonary disease, bronchiolitis, excessive airway elastolysis in
asthma and bronchitis, pneumonities, plaque rupture, atheroma and
systemic amyloidosis.
18. A process for preparing a compound of Formula I: 34in which:
X.sup.1 is a bond or a divalent group of Formula (a) or (b):
35wherein: X.sup.2 and X.sup.4 independently are --C(O)-- or
--S(O).sub.2--, X.sup.3 is --CHR.sup.7--, --CH.sub.2CHR.sup.7-- or
--CHR.sup.7CH.sub.2-- and X.sup.5 is --CHR.sup.8--,
--CH.sub.2CHR.sup.8-- or --CHR.sup.8CH.sub.2--, wherein: R.sup.7
and R.sup.8 are independently (i) (C.sub.1-6)alkyl or
halo-substituted(C.sub.1-6)alkyl optionally substituted with
--OR.sup.9, --SR.sup.9, --S(O)R.sup.9, --S(O).sub.2R.sup.9,
--C(O)R.sup.9, --C(O)OR.sup.9, --NR.sup.9R.sup.10,
--NR.sup.10C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--S(O).sub.2NR.sup.9R.sup.10, --NR.sup.10C(O)NR.sup.9R.sup.10 or
--NR.sup.10C(NR.sup.10)NR.sup.9R.sup.1- 0, wherein R.sup.9 is
hydrogen, (C.sub.1-6)alkyl, cyclo(C.sub.3-12)alkyl(C-
.sub.0-3)alkyl, heterocyclo(C.sub.3-2)alkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-3)alky- l and R.sup.10 is hydrogen
or (C.sub.1-6)alkyl, or (ii)
cyclo(C.sub.3-12)alkyl(C.sub.0-3)alkyl,
heterocyclo(C.sub.3-12)alkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alkyl, polycyclo(C.sub.9-12)aryl(C.sub.0-3)alkyl or
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-3)alkyl optionally
substituted with --R.sup.11, --X.sup.6OR.sup.11,
--X.sup.6SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --X.sup.6NR.sup.11R.sup.12,
--X.sup.6NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup- .12, wherein X.sup.6 is a
bond or methylene, R.sup.11 is
cyclo(C.sub.3-12)alkyl(C.sub.0-3)alkyl,
heterocyclo(C.sub.3-12)alkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alky), polycyclo(C.sub.9-12)aryl(C.sub.0-3)alkyl or
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-3)alkyl and R.sup.12 is
hydrogen or (C.sub.1-6)alkyl, or (iii) together with R.sup.5 or
R.sup.6, respectively, when X.sup.3 is --CHR.sup.7-- and/or X.sup.5
is --CHR.sup.8--, forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy or
oxo; wherein any 1 to 3 annular atoms of any aromatic ring with
available valences comprising R.sup.7 and/or R.sup.8 are optionally
independently substituted with halo, nitro, cyano,
(C.sub.1-6)alkyl, halo-substituted(C.sub.1-6)alkyl, --OR.sup.13,
--C(O)R.sup.13, --C(O)OR.sup.13, --C(O)NR.sup.13R.sup.13,
S(O)NR.sup.3R.sup.13, --X.sup.6NR.sup.13R.sup.13,
X.sup.6NR.sup.13C(O)OR.sup.13,
--X.sup.6NR.sup.13C(O)NR.sup.13R.sup.13 or
--X.sup.6NR.sup.13C(NR.sup.13N- R.sup.13R.sup.13, wherein X.sup.6
is as defined above and each R.sup.13 independently is hydrogen or
(C.sub.1-6)alkyl; and R.sup.5 and R.sup.6 are independently
hydrogen, (C.sub.1-6)alkyl or as defined above; and R.sup.1 is
hydrogen or --X.sup.7X.sup.8R.sup.14, wherein X.sup.7 is --C(O)--
or --S(O).sub.2--, X.sup.8 is a bond, --O-- or --NR.sup.15--,
wherein R.sup.15 is hydrogen or (C.sub.1-6)alkyl, and R.sup.14 is
(C.sub.1-6)alkyl or halo-substituted(C.sub.1-6)alkyl optionally
substituted with --OR.sup.9, --SR.sup.9, --S(O)R.sup.9,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--NR.sup.9R.sup.10, --NR.sup.10C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, --S(O).sub.2NR.sup.9R.su- p.10,
--NR.sup.10C(O)NR.sup.9R.sup.10 or
--NR.sup.10C(NR.sup.10)NR.sup.9R.- sup.10, wherein R.sup.9 and
R.sup.10 are as defined above, or (ii)
(C.sub.3-14)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-14)cycloalkyl(C.su- b.0-6)alkyl,
(C.sub.6-14)aryl(C.sub.0-6)alkyl, diphenyl(C.sub.0-6)alkyl,
hetero(C.sub.5-14)aryl(C.sub.0-6)alkyl,
heterodi(C.sub.5-6)aryl(C.sub.0-6- )alkyl,
polycyclo(C.sub.9-14)aryl(C.sub.0-6)alkyl or
heteropolycyclo(C.sub.8-14)aryl(C.sub.0-6)alkyl optionally
substituted with --R.sup.11, --X.sup.6OR.sup.11,
--X.sup.6SR.sup.11, --S(O)R.sup.11, --S(O).sub.2R.sup.11,
--C(O)R.sup.11, --C(O)OR.sup.11, --X.sup.6NR.sup.11R.sup.12,
--X.sup.6NR.sup.12C(O)OR.sup.11, --C(O)NR.sup.11R.sup.12,
--S(O).sub.2NR.sup.11R.sup.12, --NR.sup.12C(O)NR.sup.11R.sup.12 or
--NR.sup.12C(NR.sup.12)NR.sup.11R.sup- .12, wherein X.sup.6,
R.sup.11 and R.sup.12 are as defined above; wherein any 1 to 3
annular atoms of any aromatic ring with available valences
comprising R.sup.1 optionally independently are substituted with
halo, nitro, cyano, (C.sub.1-6)alkyl,
halo-substituted(C.sub.1-6)alkyl, --OR.sup.13, --C(O)R.sup.13,
--C(O)OR.sup.13, --C(O)NR.sup.13R.sup.13,
--S(O).sub.2NR.sup.13R.sup.13, --X.sup.6NR.sup.3R.sup.13,
--X.sup.6NR.sup.13C(O)OR.sup.13,
--X.sup.6NR.sup.13C(O)NR.sup.13R.sup.13 or
--X.sup.6NR.sup.13C(NR.sup.13NR.sup.13R.sup.13, wherein X.sup.6 and
R.sup.13 are as defined above; R.sup.2 is hydrogen or
(C.sub.1-6)alkyl; R.sup.3 is (i) hydrogen or (C.sub.1-6)alkyl
optionally substituted with --OR.sup.16, --NR.sup.17C(O)OR.sup.16,
--C(O)NR.sup.16R.sup.17, --S(O).sub.2R.sup.16, wherein R.sup.16 is
(C.sub.0-6)alkyl or (C.sub.6-10)aryl(C.sub.0-6)alkyl and R.sup.17
is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.6-10)aryl(C.sub.1-6)alkyl or
(C.sub.5-10)heteroaryl(C.sub.1-6)alkyl or (iii) together with
R.sup.2 forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy or
oxo; wherein any 1 to 3 annular atoms of any aromatic ring with
available valences comprising R.sup.3 optionally independently are
substituted with halo, nitro, cyano, optionally
halo-substituted(C.sub.1-6)alkyl, --OR.sup.13, --C(O)OR.sup.13,
--C(O)NR.sup.13R.sup.13, --X.sup.6NR.sup.13R.sup.13,
--X.sup.6NR.sup.13C(O)NR.sup.13R.sup.13 and
--X.sup.6NR.sup.13C(NR.sup.13- )NR.sup.13R.sup.13, wherein X.sup.6
and R.sup.13 are as defined above; and R.sup.4 is nitromethyl,
1-hydroxy-1-methylethyl or --CH.sub.2OR.sup.8, wherein R.sup.18 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-- 6)alkyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, wherein any 1
to 3 annular atoms of any aromatic ring with available valences
comprising R.sup.4 optionally independently are substituted with
halo, nitro, cyano, (C.sub.1-6)alkyl,
halo-substituted(C.sub.1-6)alkyl, --OR.sup.13, --C(O)R.sup.13,
--C(O)O.sup.R.sup.13, --C(O)NR.sup.13R.sup.13,
--S(O).sub.2NR.sup.13R.sup.13, --X.sup.6NR.sup.13R.sup.13,
--X.sup.6NR.sup.13C(O)OR.sub.13,
--X.sup.6NR.sup.13C(O)NR.sup.13R.sup.13 or
--X.sup.6NR.sup.13C(NR.sup.13Nk.sup.13R.sup.13, wherein X.sup.6 and
R.sup.3 are as defined above; and the N-oxide derivatives, prodrug
derivatives, protected derivatives, individual isomers and mixtures
of isomers; and the pharmaceutically acceptable salts thereof;
which process comprises: (A) reacting a compound of Formula 2:
36with a compound of the formula LX.sup.1R.sup.21, in which L is a
leaving group, R.sup.20 is --NO.sub.2 or --OR.sup.22, wherein
R.sup.22 is a hydroxy protecting group or optionally substituted
(C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)al- kyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, R.sup.21 is
R.sup.1 or a protecting group and each X.sup.1, R.sup.1, R.sup.2
and R.sup.3 are as defined above, and then removing one or more
protective groups if necessary to provide a compound of Formula I
in which R.sup.4 is nitromethyl or --CH.sub.2OR.sup.17; (B)
reacting a compound of Formula 3: 37with a compound of the formula
LCH.sub.2OR.sup.22, in which L is a leaving group, R.sup.22 is a
hydroxy protecting group or optionally substituted
(C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, R.sup.20 is
R.sup.1 or a protecting group and each X.sup.1, R.sup.1, R.sup.2,
R.sup.3 and R.sup.17 are as defined above, and then removing one or
more protective groups if necessary to provide a compound of
Formula I in which R.sup.4 is --CH.sub.2OR.sup.17; (C) oxidizing a
compound of Formula 4: 38in which R.sup.2 is R.sup.1 or a
protecting group and each X.sup.1, R.sup.1, R.sup.2 and R.sup.3 are
as defined above, and then deprotecting if necessary to provide a
compound of Formula I in which R.sup.4 is 1-hydroxy -1-methylethyl;
(D) reacting a compound of Formula 5: 39with nitromethane, in which
R.sup.21 is R.sup.1 or a protecting group and each X.sup.1,
R.sup.1, R.sup.2 and R.sup.3 are as defined above, and then
deprotecting if necessary to provide a compound of Formula I in
which R.sup.4 is nitromethyl; (E) optionally dealkylating a
compound of Formula I in which R.sup.4 is --CH.sub.2OR.sup.18,
wherein R.sup.18 is (C.sub.1-6)alkyl or
(C.sub.6-12)aryl(C.sub.1-6)alkyl to provide a compound of Formula I
in which R.sup.18 is hydrogen; (F) optionally converting a compound
of Formula I into a pharmaceutically acceptable salt; (G)
optionally converting a salt form of a compound of Formula I to
non-salt form; (H) optionally converting an unoxidized form of a
compound of Formula I into a pharmaceutically acceptable N-oxide;
(I) optionally converting an N-oxide form of a compound of Formula
I its unoxidized form; (K) optionally converting a non-derivatized
compound of Formula I into a pharmaceutically prodrug derivative;
and (L) optionally converting a prodrug derivative of a compound of
Formula I to its non-derivatized form.
19. A process for preparing a compound of Formula UI: 40which
process comprises hydrogenating a compound of Formula 9: 41in which
R.sup.1 is peptidyl, R.sup.2 is hydrogen or (C.sub.1-6)alkyl,
R.sup.3 is an amino acid side chain and R.sup.4 is (C.sub.1-6)alkyl
or (C.sub.6-12)aryl(C.sub.1-6)alkyl, in the presence of a catalytic
amount of 20% palladium hydroxide on carbon.
20. The process of claim 19 in which the hydrogenation is effected
with an excess amount of cyclohexene and in a 1:2 mixture of
cyclohexene:ethanol.
21. The process of claim 20 for preparing an individual (R)- or
(S)-isomer of the compound of Formula II.
Description
[0001] This application claims the benefit under 35 U.S.C. Sec. 119
(e)(1) of prior filed U.S. Provisional Application No. 60/124,529
filed Mar. 15, 1999.
THE INVENTION
[0002] This application relates to compounds and compositions for
treating diseases associated with cysteine protease activity,
particularly diseases associated with activity of cathepsins B, K,
L or S.
DESCRIPTION OF THE FIELD
[0003] Cysteine proteases represent a class of peptidases
characterized by the presence of a cysteine residue in the
catalytic site of the enzyme. Cysteine proteases are associated
with the normal degradation and processing of proteins. The
aberrant activity of cysteine proteases, e.g., as a result of
increase expression or enhanced activation, however, may have
pathological consequences. In this regard, certain cysteine
proteases are associated with a number of disease states, including
arthritis, muscular dystrophy, inflammation, tumor invasion,
glomerulonephritis, malaria, periodontal disease, metachromatic
leukodystrophy and others. For example, increased cathepsin B
levels and redistribution of the enzyme are found in tumors; thus,
suggesting a role for the enzyme in tumor invasion and metastasis.
In addition, aberrant cathepsin B activity is implicated in such
disease states as rheumatoid arthritis, osteo arthritis,
pneumocystis carinii, acute pancreatitis, inflammatory airway
disease and bone and joint disorders.
[0004] The prominent expression of cathepsin K in osteoclasts and
osteoclast-related multinucleated cells and its high collagenolytic
activity suggest that the enzyme is involved in
ososteoclast-mediated bone resorption and, hence, in bone
abnormalities such as occurs in osteoporosis. In addition,
cathepsin K expression in the lung and its elastinolytic activity
suggest that the enzyme plays a role in pulmonary disorders as
well.
[0005] Cathepsin L is implicated in normal lysosomal proteolysis as
well as several disease states, including, but not limited to,
metastasis of melanomas. Cathepsin S is implicated in Alzheimer's
disease and certain autoimmune disorders, including, but not
limited to juvenile onset diabetes, multiple sclerosis, pemphigus
vulgaris, Graves' disease, myasthenia gravis, systemic lupus
erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis;
allergic disorders, including, but not limited to asthma; and
allogeneic immune responses, including, but not limited to,
rejection of organ transplants or tissue grafts.
[0006] In view of the number of diseases wherein it is recognized
that an increase in cysteine protease activity contributes to the
pathology and/or symptomatology of the disease, molecules which are
shown to inhibit the activity of this class of enzymes, in
particular molecules which are inhibitors of cathepsins B, K, L
and/or S, will be useful as therapeutic agents.
[0007] SUMMARY OF THE INVENTION
[0008] This application relates to protease inhibitors of Formula
I: 1
[0009] in which:
[0010] X.sup.1 is a bond or a divalent group of Formula (a) or (b):
2
[0011] wherein:
[0012] X.sup.2 and X.sup.3 independently are --C(O)-- or
--CH.sub.2S(O).sub.2--;
[0013] R.sup.7 and R.sup.8 are independently (i) (C.sub.1-6)alkyl
optionally substituted with cyano, halo, nitro,
--NR.sup.10R.sup.10, --NR.sup.10C(O)OR.sup.10,
--NR.sup.10C(O)NR.sup.10R.sup.10,
--NR.sup.10C(NR.sup.10)NR.sup.10R.sup.10, --OR.sup.10, --SR.sup.10,
--C(O)OR.sup.10, --C(O)NR.sup.10R.sup.10,
--S(O).sub.2NR.sup.10R.sup.10, --P(O)(OR.sup.10)OR.sup.10,
--OP(O)(OR.sup.10)OR.sup.10, --NR.sup.10C(O)R.sup.11,
--S(O)R.sup.11, --S(O).sub.2R.sup.11, --C(O)R.sup.11, --OR.sup.12,
--SR.sup.12, --S(O)R.sup.12, --S(O).sub.2R.sup.12, --C(O)R.sup.12,
--C(O)OR.sup.12, --OC(O)R.sup.12, --NR.sup.12R.sup.13,
--NR.sup.13C(O)R.sup.12, --NR.sup.13C(O)OR.sup.12,
--C(O)NR.sup.12R.sup.13, --S(O).sub.2NR.sup.12R.sup.13,
--NR.sup.13C(O)NR.sup.12R.sup.13 or
--NR.sup.13C(NR.sup.13)NR.sup.12R.sup- .13, wherein R.sup.10 at
each occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.11 is (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl, R.sup.12 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl or hetero(C.sub.5-12)aryl(C.-
sub.0-3)alkyl and R.sup.13 is hydrogen or (C.sub.1-6)alkyl, and
wherein within R.sup.12 said cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is
substituted by a group selected from --R.sup.14, --X.sup.4OR.sup.4,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
--X.sup.4C(O)OR.sup.14, --X.sup.4OC(O)R.sup.14,
--X.sup.4NR.sup.14R.sup.15, --X.sup.4NR.sup.15C(O)R.sup.14,
--X.sup.4NR.sup.15C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.su- p.15 or
--X.sup.4NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein X.sup.4 is
a bond or (C.sub.1-6)alkylene, R.sup.14 is hydrogen or
(C.sub.1-6)alkyl and R.sup.15 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)- alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C- .sub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
heterocyclo(C.sub.3-12)alkyl(C.su- b.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl, hetero(C.sub.5-12)aryl(C.su-
b.0-3)alkyl, (C.sub.9-12)polycycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-3)alkyl, wherein within
R.sup.15 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
polycycloaryl or heterpolycycloaryl ring optionally is substituted
by a group selected from --R.sup.14, --X.sup.4OR.sup.14,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
--X.sup.4C(O)R.sup.14, --X.sup.4OC(O)R.sup.14,X.su- p.4NR.sup.15,
--X.sup.4NR.sup.15C(O)R.sup.14, --X.sup.4NR.sup.15C(O)OR.sup- .14,
--X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.sup.15 or
--X.sup.4NR.sup.15C(NR.sup.5)N- R.sup.14R.sup.15, wherein X.sup.4,
R.sup.14 and R.sup.15 are as defined above; wherein within R.sup.7
and/or R.sup.8 any alicyclic or aromatic ring system present may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10OR.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)N- R.sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10OR.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4 is a bond or
(C.sub.1-6)alkylene and R.sup.10 and R.sup.11 are as defined above,
or
[0014] R.sup.7 taken together with R.sup.5 and/or R.sup.8 taken
together with R.sup.6 forms trimethylene, tetramethylene or
phenylene-1,2-dimethylene, optionally substituted with hydroxy or
oxo;
[0015] R.sup.9 at each occurrence is hydrogen or (C.sub.1-6)alkyl;
and
[0016] R.sup.5 and R.sup.6 are independently hydrogen,
(C.sub.1-6)alkyl or as defined above; and
[0017] R.sup.1 is --X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is
--C(O)--, --C(O)C(O)-- or --S(O).sub.2--, X.sup.7 is a bond, --O--
or --NR.sup.17--, wherein R.sup.17 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.16 is (i) (C.sub.1-6)alkyl optionally substituted by
cyano, halo, nitro, --NR.sup.10R.sup.10, --NR.sup.10C(O)OR.sup.10,
--NR.sup.10C(O)NR.sup.10R.sup.10,
--NR.sup.10C(NR.sup.10)NR.sup.10R.sup.1- 0, --OR.sup.10,
--SR.sup.10, --C(O)OR.sup.10, --C(O)NR.sup.10R.sup.10,
--S(O).sub.2NR.sup.1OR.sup.10, --P(O)(OR.sup.10)OR.sup.10,
--OP(O)(OR.sup.10)OR.sup.10, --NR.sup.10C(O)R.sup.11,
--S(O)R.sup.11, --S(O).sub.2R.sup.11, --C(O)R.sup.11, --OR.sup.18,
--SR.sup.18, --S(O)R.sup.18, --S(O).sub.2R.sup.18, --C(O)R.sup.18,
--C(O)OR.sup.18, --C(O)NR.sup.18R.sup.19, --NR.sup.18R.sup.19,
--NR.sup.19C(O)R.sup.18, --NR.sup.19C(O)OR.sup.18,
--NR.sup.19C(O)NR.sup.18R.sup.19 or
--NR.sup.19C(NR.sup.19)NR.sup.18R.sup.19, wherein R.sup.10 and
R.sup.11 are as defined above, R.sup.18 is
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-2)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-2)aryl(C.sub.0-6)al- kyl,
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycycloaryl(C.s- ub.0-6)alkyl or
hetero(C.sub.8-12)polycycloaryl(C.sub.0-6)alkyl and R.sup.19 at
each occurrence independently is hydrogen or (C.sub.1-6)alkyl, and
wherein within R.sup.18 said cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is
substituted by a group selected from --R.sup.14,
--X.sup.4OR.sup.14, --X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
--X.sup.4C(O)OR.sup.14, --X.sup.4OC(O)R.sup.14,
--X.sup.4NR.sup.14R.sup.1- 5, --X.sup.4NR.sup.15C(O)R.sup.14,
--X.sup.4NR.sup.15C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.sup.15 or
--X.sup.4NR.sup.15C(NR.sup.15)- NR.sup.14R.sup.15, wherein X.sup.4,
R.sup.14 and R.sup.15 are as defined above, or (ii)
(C.sub.3-14)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.3-14)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-4)aryl(C.sub.0-6)a- lkyl, diphenyl(C.sub.0-6)alkyl,
hetero(C.sub.5-14)aryl(C.sub.0-6)alkyl,
heterodi(C.sub.5-6)aryl(C.sub.0-6)alkyl,
(C.sub.9-12)polycyloaryl(C.sub.0- -6)alkyl or
hetero(C.sub.9-14)polycyclo(C.sub.8-14)aryl(C.sub.0-6)alkyl,
wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
polycycloaryl or heterpolycycloaryl ring optionally is substituted
by a group selected from --R.sup.14, --X.sup.4OR.sup.14,
--X.sup.4SR.sup.14, --X.sup.4S(O)R.sup.14,
--X.sup.4S(O).sub.2R.sup.14, --X.sup.4C(O)R.sup.14,
--X.sup.4C(O)OR.sup.14, --X.sup.4OC(O)R.sup.14,
--X.sup.4NR.sup.14R.sup.15, --X.sup.4NR.sup.15C(O)R.sup.14,
--X.sup.4NR.sup.15C(O)OR.sup.14, --X.sup.4C(O)NR.sup.14R.sup.15,
--X.sup.4S(O).sub.2NR.sup.14R.sup.15,
--X.sup.4NR.sup.15C(O)NR.sup.14R.su- p.15 or
--X.sup.4NR.sup.15C(NR.sup.15)NR.sup.14R.sup.15, wherein X.sup.4,
R.sup.14 and R.sup.15 are as defined above; wherein within R.sup.1
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; or when X.sup.1 is a divalent group of Formula
(a) or (b) then R.sup.1 may also represent hydrogen;
[0018] R.sup.2 is hydrogen or (C.sub.1-6)alkyl;
[0019] R.sup.3 is hydrogen or (C.sub.1-6)alkyl wherein said alkyl
optionally is substituted with --OR.sup.20,
--NR.sup.21C(O)OR.sup.20, --C(O)NR.sup.2OR.sup.21,
--S(O).sub.2R.sup.20, wherein R.sup.20 is (C.sub.0-6)alkyl or
(C.sub.6-10)aryl(C.sub.0-6)alkyl and R.sup.21 is hydrogen or
(C.sub.1-6)alkyl, or (ii) (C.sub.6-10)aryl(C.sub.1-6)alkyl or
(C.sub.5-10)heteroaryl(C.sub.1-6)alkyl or
[0020] R.sup.3 taken together with R.sup.2 forms trimethylene,
tetramethylene or phenylene-1,2-dimethylene, optionally substituted
with hydroxy or oxo; wherein within R.sup.3 any alicyclic or
aromatic ring system present may be substituted further by 1 to 5
radicals independently selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10NR.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; and
[0021] R.sup.4 is nitromethyl, 1-hydroxy-1-methylethyl or
--CH.sub.2OR.sup.22, wherein R.sup.22 is hydrogen,
(C.sub.1-6)alkyl, (C.sub.6-2)aryl(C.sub.0-6)alkyl,
hetero(C.sub.8-12)polycycloaryl(C.sub.0-- 6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl wherein within
R.sup.22 any alicyclic or aromatic ring system present may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR.sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.1- 0,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers;
and the pharmaceutically acceptable salts thereof.
[0022] A second aspect of this invention is a pharmaceutical
composition which contains a compound of Formula I or a N-oxide
derivative, prodrug derivative, individual isomer or mixture of
isomers or a pharmaceutically acceptable salt thereof in admixture
with one or more suitable excipients.
[0023] A third aspect of this invention is a method of treating a
disease in an animal in which inhibition of a cysteine protease can
prevent, inhibit or ameliorate the pathology and/or symptomatology
of the disease, which method comprises administering to the animal
a therapeutically effective amount of compound of Formula I or a
N-oxide derivative, prodrug derivative, individual isomer or
mixture of isomers or a pharmaceutically acceptable salt
thereof.
[0024] A fourth aspect of this invention is the processes for
preparing compounds of Formula I and the N-oxide derivatives,
prodrug derivative, protected derivatives, individual isomers and
mixtures of isomers, and the pharmaceutically acceptable salts
thereof as set forth in "Detailed Description of the
Invention".
[0025] A fifth aspect of this invention is a process for preparing
a compound of Formula II: 3
[0026] in which R.sup.1 is peptidyl, R.sup.2 is hydrogen or
(C.sub.1-6)alkyl, R.sup.3 is an amino acid side and R.sup.4 is
(C.sub.1-6)alkyl or (C.sub.6-12)aryl(C.sub.1-6)alkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Definitions:
[0028] Unless otherwise stated, the following terms used in the
specification and claims are defined for the purposes of this
Application and have the meanings given this Section:
[0029] "Alicyclic" means a moiety characterized by arrangement of
the carbon atoms in closed non-aromatic ring structures having
properties resembling those of aliphatics and may be saturated or
partially unsaturated with two or more double or triple bonds.
[0030] "Aliphatic" means a moiety characterized by straight or
branched chain arrangement of the constituent carbon atoms and may
be saturated or partially unsaturated with two or more double or
triple bonds.
[0031] "Alkenyl" means alkyl, as defined in this Application,
provided that the radical is comprised of at least one double bond.
Hence, optionally substituted (C.sub.2-6)alkenyl as used in this
Application to define R.sup.3 includes 2-bromovinyl
(--CH.dbd.CHBr), buta-1,3-dienyl (--CH.dbd.CH--CH.dbd.CH.sub.2),
2-chloro-1-methylpropenyl (--C(CH.sub.3).dbd.CC.sub.1-CH.sub.3),
2-chlorovinyl (--CH.dbd.CHCl), 4-isopropenyl
(--C(CH.sub.3).dbd.CH.sub.2), 1-methylpropenyl
(--C(CH.sub.3).dbd.CH--CH.sub.3), 2-methylpropenyl
(--CH.dbd.C(CH.sub.3).sub.2), 2-nitrovinyl (--CH.dbd.CHNO.sub.2),
propenyl (--CH.dbd.CH--CH.sub.3), 2-trifluoromethylvinyl
(--CH.dbd.CH--CF.sub.3), trifluorovinyl (--CF.dbd.CF.sub.2), vinyl
(--CH.dbd.CH.sub.2), and the like).
[0032] "Alkoxy" means the radical --OR, wherein R is alkyl as
defined in this Application, having the number of carbon atoms
indicated (e.g., (C.sub.1-4)alkoxy includes the radicals methoxy,
ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy,
tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy,
1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy,
ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
[0033] "Alkyl" represented by itself means a straight or branched,
saturated or unsaturated, aliphatic radical having the number of
carbon atoms indicated (e.g. (C.sub.1-6)alkyl includes methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,
vinyl, alkyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-methylalkyl, ethynyl, 1-propynyl, 2-propynyl, and the
like). Alkyl represented along with another radical (e.g. as in
arylalkyl) means a straight or branched, saturated or unsaturated
aliphatic divalent radical having the number of atoms indicated or
when no atoms are indicated means a bond (e.g.
(C.sub.6-12)aryl(C.sub.0-6)alkyl includes phenyl, benzyl,
phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
[0034] "Alkylene", unless indicated otherwise, means a straight or
branched, saturated or unsaturated, aliphatic, divalent radical
having the number of carbon atoms indicated (e.g.
(C.sub.1-6)alkylene includes methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), trimethylene
(--CH.sub.2CH.sub.2CH.sub.2--), 2-methyltrimethylene
(--CH.sub.2CH(CH.sub.3)CH.sub.2--), tetramethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), 2-butenylene
(--CH.sub.2CH.dbd.CHCH.sub.2--), 2-methyltetramethylene
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.2--), pentamethylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the like). For
example, a group of Formula (a), wherein R.sup.11 is hydrogen and
R.sup.12 taken together with R.sup.9 forms optionally substituted
trimethylene is depicted by the following illustration: 4
[0035] in which R is an optional hydroxy or oxo group and X.sup.3
and R.sup.1 are as defined in the Summary of the Invention for
Formula I. Straight, saturated (C.sub.2-5)alkylene includes
ethylene, trimethylene, tetramethylene and pentamethylene. For
example, instances wherein R.sup.3 and R.sup.4 taken together form
straight, saturated (C.sub.2-5)alkylene, wherein within said
alkylene any one to two carbon atoms optionally is replaced by a
heteroatom selected from --O--, --S-- or _NR.sup.28-- wherein
R.sup.28 is hydrogen or (C.sub.1-6)alkyl, may be represented by,
but are not limited to, the following illustrations: 5
[0036] wherein R.sup.2, R.sup.5, R.sup.6 and R.sup.28 are as
defined in the Summary of the Invention for Formulae I and II.
[0037] "Alkylidene" means a straight or branched saturated or
unsaturated, aliphatic, divalent radical having the number of
carbon atoms indicated (e.g. (C.sub.1-6)alkylidene includes
methylene (.dbd.CH.sub.2), ethylidene (.dbd.CHCH.sub.3),
isopropylidene (.dbd.C(CH.sub.3).sub.2), propylidene
(.dbd.CHCH.sub.2CH.sub.3), allylidene (.dbd.CHCH.dbd.CH.sub.2- ),
and the like).
[0038] "Amino" means the radical --NH.sub.2. Unless indicated
otherwise, the compounds of the invention containing amino moieties
include protected derivatives thereof. Suitable protecting groups
for amino moieties include acetyl, tert-butoxycarbonyl,
benzyloxycarbonyl, and the like.
[0039] "Animal" includes humans, non-human mammals (e.g. dogs,
cats, rabbits, cattle, horses, sheep, goats, swine, deer, or the
like) and non-mammals (e.g. birds, or the like).
[0040] "Aryl" means a monocyclic or bicyclic ring assembly (fused
or linked by a single bond) containing the total number of ring
carbon atoms indicated, wherein each ring is comprised of 6 ring
carbon atoms and is aromatic or when fused with a second ring forms
an aromatic ring assembly. For example, (C.sub.6-12)aryl as used in
this Application to define R.sup.1 includes phenyl, naphthyl and
biphenylyl.
[0041] "Aromatic" means a moiety wherein the constituent atoms make
up an unsaturated ring system, all atoms in the ring system are sp2
hybridized and the total number of pi electrons is equal to
4n+2.
[0042] "Carbamoyl" means the radical --C(O)NH.sub.2. Unless
indicated otherwise, the compounds of the invention containing
carbamoyl moieties include protected derivatives thereof. Suitable
protecting groups for carbamoyl moieties include acetyl,
tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the
unprotected and protected derivatives fall within the scope of the
invention.
[0043] "Carboxy" means the radical --C(O)OH. Unless indicated
otherwise, the compounds of the invention containing carboxy
moieties include protected derivatives thereof. Suitable protecting
groups for carboxy moieties include benzyl, tert-butyl, and the
like. For example, a compound of Formula I wherein R.sup.7 contains
a carboxy moiety may exist as either the unprotected or a protected
derivative, e.g. wherein R.sup.7 is methoxycarbonyl, and both the
unprotected and protected derivatives fall within the scope of the
invention.
[0044] "Cycloalkyl" means a saturated or partially unsaturated,
monocyclic ring, bicyclic ring assembly (directly linked by a
single bond or fused) or bridged polycyclic ring assembly
containing the number of ring member carbon atoms indicated, and
any carbocyclic ketone, thioketone or iminoketone derivative
thereof (e.g. (C.sub.3-12)cycloalkyl includes cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl,
bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl,
oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
2-oxobicyclo[2.2.1]hept-1- -yl, and the like).
[0045] "Disease" specifically includes any unhealthy condition of
an animal or part thereof and includes an unhealthy condition which
may be caused by, or incident to, medical or veterinary therapy
applied to that animal, i.e., the "side effects" of such
therapy.
[0046] "Guanidino" means the radical --NHC(NH)NH.sub.2. Unless
indicated otherwise, the compounds of the invention containing
guanidino moieties include protected derivatives thereof. Suitable
protecting groups for amino moieties include acetyl,
tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the
unprotected and protected derivatives fall within the scope of the
invention.
[0047] "Halo" means fluoro, chloro, bromo or iodo.
[0048] "Halo-substituted alkyl", as a group or part of a group,
means "alkyl" substituted by one or more "halo" atoms, as such
terms are defined in this Application. Halo-substituted alkyl
includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the
like (e.g. halo-substituted (C.sub.1-3)alkyl includes chloromethyl,
dicloromethyl, difluoromethyl, trifluromethyl,
2,2,2-trifluoroethyl, perfluoroethyl,
2,2,2-trifluoro-1,1-dichloroethyl, and the like).
[0049] "Heteroaryl" means aryl, as defined herein, provided that
one or more of the ring member carbon atoms indicated, is replaced
by heteroatom moiety selected from --N.dbd., --NR--, --O-- or
--S--, wherein R is hydrogen, (C.sub.1-6)alkyl or a protecting
group, and each ring contained therein is comprised of 5 to 6 ring
member atoms. For example, hetero(C.sub.5-12)aryl as used in this
Application includes benzofuryl, benzooxazolyl, benzothiazolyl,
[2,4']bipyridinylyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl,
furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl,
isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl,
isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl,
2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl,
pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl,
pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl,
quinolyl, quinoxalinyl, tetrazolyl, thiazolyl,
4-thiazol-4-ylphenyl, thienyl, xanthenyl, and the like.
[0050] "Heteroatom moiety" includes --N.dbd., --NR--, --O-- or
--S--, wherein R is hydrogen, (C.sub.1-6)alkyl or a protecting
group.
[0051] "Heterocycloalkyl" means cycloalkyl, as defined herein,
provided that one or more of the ring member carbon atoms indicated
is replaced by heteroatom moiety selected from --N.dbd., --NR--,
--O-- or --S--, wherein R is hydrogen, (C.sub.1-6)alkyl or a
protecting group, and any carbocyclic ketone, thioketone or
iminoketone derivative thereof (e.g. the term
heterocyclo(C.sub.5-12)alkyl includes [1,4']bipiperidinylyl,
dihydrooxazolyl, morpholinyl, 1-morpholin4-ylpiperidinyl,
piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl,
pyrrolidinyl, quinuclidinyl, and the like). Suitable protecting
groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a
compound of Formula I wherein R.sup.1 is piperidin-4-ylcarbonyl may
exist as either the unprotected or a protected derivative, e.g.
wherein R.sup.1 is 1-tert-butoxycarbonylpipe- ridin-4-ylcarbonyl,
and both the unprotected and protected derivatives fall within the
scope of the invention.
[0052] "Heteropolycycloaryl" means polycycloaryl, as defined
herein, except one or more of the ring member carbon atoms
indicated are replaced by a heteroatom moiety selected from
--N.dbd., --NR--, --O-- or --S--, wherein R is hydrogen,
(C.sub.1-6)alkyl or a protecting group, and any carbocyclic ketone,
thioketone or iminoketone derivative thereof. For example,
hetero(C.sub.8-12)polycycloaryl includes 1',2'-dihydro-2H-[1,4']-
bipyridinylyl, chromanyl, imidazolinyl, indolinyl, isochromanyl,
isoindolinyl, and the like.
[0053] "Hydroxy" means the radical --OH. Unless indicated
otherwise, the compounds of the invention containing hydroxy
radicals include protected derivatives thereof. Suitable protecting
groups for hydroxy moieties include benzyl and the like and both
the unprotected and protected derivatives fall within the scope of
the invention.
[0054] "Ininoketone derivative" means a derivative containing the
moiety --C(NR)--, wherein R is hydrogen or (C.sub.1-6)alkyl.
[0055] "Isomers" mean compounds of Formula I having identical
molecular formulae but differ in the nature or sequence of bonding
of their atoms or in the arrangement of their atoms in space.
Isomers that differ in the arrangement of their atoms in space are
termed "stereoisomers". Stereoisomers that are not mirror images of
one another are termed "diastereomers" and stereoisomers that are
nonsuperimposable mirror images are termed "enantiomers" or
sometimes "optical isomers". A carbon atom bonded to four
nonidentical substituents is termed a "chiral center". A compound
with one chiral center has two enantiomeric forms of opposite
chirality is termed a "racemic mixture". A compound that has more
than one chiral center has 2.sup.n-1 enantiomeric pairs, where n is
the number of chiral centers. Compounds with more than one chiral
center may exist as ether an individual diastereomer or as a
mixture of diastereomers, termed a "diastereomeric mixture". When
one chiral center is present a stereoisomer may be characterized by
the absolute configuration of that chiral center. Absolute
configuration refers to the arrangement in space of the
substituents attached to the chiral center. Enantiomers are
characterized by the absolute configuration of their chiral centers
and described by the R- and S-sequencing rules of Cahn, Ingold and
Prelog. Conventions for stereochemical nomenclature, methods for
the determination of stereochemistry and the separation of
stereoisomers are well known in the art (e.g. see "Advanced Organic
Chemistry", 3rd edition, March, Jerry, John Wiley & Sons, New
York, 1985). It is understood that the names and illustration used
in this Application to describe compounds of Formula I are meant to
be encompassed all possible stereoisomers and any mixture, racemic
or otherwise, thereof.
[0056] "Ketone derivative" means a derivative containing the moiety
--C(O)--.
[0057] "Nitro" means the radical --NO.sub.2.
[0058] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where the event or circumstance
occurs and instances in which it does not. For example, the phrase
"(C.sub.1-6)alkyl optionally substituted with cyano, halo, nitro,"
means that the alkyl group referred to may or may not be
substituted in order to fall within the scope of the invention.
[0059] "Oxalo" means the radical --C(O)C(O)OH.
[0060] "N-oxide derivatives" means a derivatives of compound of
Formula I in which nitrogens are in an oxidized state (i.e.,
O.rarw.N) and which possess the desired pharmacological
activity.
[0061] "Oxo" means the radical .dbd.O.
[0062] "Pathology" of a disease means the essential nature, causes
and development of the disease as well as the structural and
functional changes that result from the disease processes.
[0063] "Peptidyl" means a peptide residue, for example, of the
general formula: 6
[0064] in which n is 1 or greater and each X.sup.2, X.sup.3,
R.sup.1and R.sup.5 are as defined in the Summary of the Invention
for Formula I or any other peptide residue comprised of 1 or more
contiguous natural or non-natural occurring amino acid
moieties.
[0065] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary use as well as
human pharmaceutical use.
[0066] "Pharmaceutically acceptable salts" means salts of compounds
of Formula I which are pharmaceutically acceptable, as defined
above, and which possess the desired pharmacological activity. Such
salts include acid addition salts formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or with organic acids such as acetic
acid, propionic acid, hexanoic acid, heptanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartatic acid, citric acid, benzoic acid,
o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]oct-2- -ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis(3-hydroxy-2-- ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid
and the like.
[0067] Pharmaceutically acceptable salts also include base addition
salts which may be formed when acidic protons present are capable
of reacting with inorganic or organic bases. Acceptable inorganic
bases include sodium hydroxide, sodium carbonate, potassium
hydroxide, ammonium hydroxide, aluminum hydroxide and calcium
hydroxide. Acceptable organic bases include ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine
and the like.
[0068] "Phenylene-1,2-dimethylene" means the divalent radical
--CH.sub.2C.sub.6H.sub.4CH.sub.2--, wherein the methylene moieties
are attached at the 1- and 2-positions of the phenylene moiety. For
example, a group of Formula (a), wherein X.sup.4 is --CHR.sup.12--
in which R.sup.12 together with R.sup.9 forms optionally
substituted phenylene-1,2-dimethylene is illustrated by the
following formula: 7
[0069] in which R is an optional hydroxy group and X.sup.3 and
R.sup.1 are as defined in the Summary of the Invention for Formulae
I and II.
[0070] "Polycycloaryl" means a bicyclic ring assembly (directly
linked by a single bond or fused) containing the number of ring
member carbon atoms indicated, wherein at least one, but not all,
of the fused rings comprising the radical is aromatic, and any
carbocyclic ketone, thioketone or iminoketone derivative thereof
(e.g. (C.sub.9-12)polycycloaryl includes indanyl, indenyl,
1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl,
cyclohexylphenyl, phenylcyclohexyl,
2,4-dioxo-1,2,3,4-tetrahydronaphthale- nyl, and the like).
[0071] "Prodrug" means a compound which is convertible in vivo by
metabolic means (e.g. by hydrolysis) to a compound of Formula (1).
For example an ester of a compound of Formula (1) containing a
hydroxy group may be convertible by hydrolysis in vivo to the
parent molecule. Alternatively an ester of a compound of Formula
(1) containing a carboxy group may be convertible by hydrolysis in
vivo to the parent molecule. Suitable esters of compounds of
Formula (I) containing a hydroxy group, are for example acetates,
citrates, lactates, tartrates, malonates, oxalates, salicylates,
propionates, succinates, fumarates, maleates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,
benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and
quinates. Suitable esters of compounds of Formula (I) containing a
carboxy group, are for example those described by F. J. Leinweber,
Drug Metab. Res., 1987, 18, page 379. An especially useful class of
esters of compounds of Formula (I) containing a hydroxy group, may
be formed from acid moieties selected from those described by
Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and
include substituted (aminomethyl)-benzoates, for example,
dialkylamino-methylbenzoates in which the two alkyl groups may be
joined together and/or interrupted by an oxygen atom or by an
optionally substituted nitrogen atom, e.g. an alkylated nitrogen
atom, more especially (morpholino-methyl)benzoates, e.g. 3- or
4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)ben-
zoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
[0072] "Protected derivatives" means derivatives of compounds of
Formula I in which a reactive site or sites are blocked with
protective groups. Protected derivatives of compounds of Formula I
are useful in the preparation of compounds of Formula I or in
themselves may be active cysteine protease inhibitors. A
comprehensive list of suitable protective groups can be found in T.
W. Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981.
[0073] "Sulfamoyl" means the radical --S(O).sub.2N.sub.2. Unless
indicated otherwise, the compounds of the invention containing
sulfamoyl radicals include protected derivatives thereof. Suitable
protecting groups for sulfamoyl radicals include acetyl,
tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the
unprotected and protected derivatives fall within the scope of the
invention.
[0074] "Therapeutically effective amount" means that amount which,
when administered to an animal for treating a disease, is
sufficient to effect such treatment for the disease.
[0075] "Thioketone derivative" means a derivative containing the
moiety --C(S)--.
[0076] "Treatmenf" or "treating" means any administration of a
compound of the present invention and includes:
[0077] (1) preventing the disease from occurring in an animal which
may be predisposed to the disease but does not yet experience or
display the pathology or symptomatology of the disease,
[0078] (2) inhibiting the disease in an animal that is experiencing
or displaying the pathology or symptomatology of the diseased
(i.e., arresting further development of the pathology and/or
symptomatology), or
[0079] (3) ameliorating the disease in an animal that is
experiencing or displaying the pathology or symptomatology of the
diseased (i.e., reversing the pathology and/or symptomatology).
[0080] "Trimethylene" means the divalent radical
--CH.sub.2CH.sub.2CH.sub.- 2--. For example, a group of Formula
(a), wherein X.sup.3 is --CHR.sup.7-- in which R.sup.7 together
with R.sup.5 forms optionally substituted trimethylene is
illustrated by the following formula: 8
[0081] in which R.sup.19 is an optional hydroxy or oxo group and
X.sup.2 and R.sup.1 are as defined in the Summary of the Invention
for Formula I.
[0082] "Ureido" means the radical --NHC(O)NH.sub.2. Unless
indicated otherwise, the compounds of the invention containing
ureido moieties include protected derivatives thereof. Suitable
protective groups for ureido moieties include acetyl,
tert-butoxycarbonyl, benzyloxycarbonyl, and the like. For example,
a compound of Formula I wherein the R.sup.1 contains an ureido
radical may exist as either the unprotected or a protected
derivative and both the unprotected and protected derivatives fall
within the scope of the invention.
[0083] Specific Embodiments:
[0084] While the broadest definition of this invention is set forth
in the Summary of the Invention, certain aspects of the invention
are preferred. Preferred are compounds of Formula I in which:
[0085] X.sup.1 is a bond or a divalent group of Formula (a)
wherein:
[0086] R.sup.5 is hydrogen or together with R.sup.7 forms
phenylene-1,2-dimethylene; and
[0087] R.sup.7 is (i) (C.sub.1-6)alkyl optionally substituted with
--OR.sup.10, --C(O)OR.sup.10, --C(O)NR.sup.10R.sup.10, wherein
R.sup.10 at each occurrence independently is hydrogen or
(C.sub.1-6)alkyl or (ii) (C.sub.6-12)aryl(C.sub.0-3)alkyl,
cyclo(C.sub.3-12)alkyl(C.sub.0-3)alkyl or
(C.sub.6-12)aryl(C.sub.0-3)alkyl or (iii) together with R.sup.5 is
phenylenedimethylene; wherein within R.sup.7 any alicyclic or
aromatic ring system present may be substituted further by 1 to 5
radicals independently selected from (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.10,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4 is a bond or
(C.sub.1-6)alkylene, R.sup.10 at each occurrence independently is
hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and
R.sup.11 is (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl;
[0088] R.sup.1 is --X.sup.6X.sup.7R.sup.16, wherein X.sup.6 is
--C(O)-- or --S(O).sub.2--, X.sup.7 is a bond, --O-- or
--NR.sup.17--, wherein R.sup.17 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.16 is (i) (C.sub.1-6)alkyl optionally substituted with
--C(O)OR.sup.10, --NR.sup.10R.sup.10 or --NR.sup.10C(O)OR.sup.10,
wherein R.sup.10 at each occurrence independently is hydrogen or
(C.sub.1-6)alkyl or (ii)
hetero(C.sub.3-14)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-14)aryl(C.sub.0-6)- alkyl, diphenyl(C.sub.0-6)alkyl, or
hetero(C.sub.5-14)aryl(C.sub.0-6)alkyl- ; wherein within R.sup.7
any alicyclic or aromatic ring system present may be substituted
further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.11)NR.sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.1- 0,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above;
[0089] R.sup.2 is hydrogen;
[0090] R.sup.3 is (i) hydrogen or (C.sub.1-6)alkyl optionally
substituted with --OR.sup.20, --NR.sup.21C(O)OR.sup.20,
--C(O)NR.sup.20R.sup.21, --S(O).sub.2R.sup.20, wherein R.sup.20 is
(C.sub.0-6)alkyl or (C.sub.0-10)aryl(C.sub.0-6)alkyl and R.sup.21
is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.6-10)aryl(C.sub.1-6)alkyl or
(C.sub.5-10)heteroaryl(C.sub.1-6)alkyl or (ii) together with
R.sup.2 forms trimethylene or phenylene-1,2-dimethylene; wherein
within R.sup.7 any alicyclic or aromatic ring system present may be
substituted further by 1 to 5 radicals independently selected from
(C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, nitro,
--X.sup.4NR.sup.10R.sup.10, --X.sup.4NR.sup.10C(O)OR.sup.10,
--X.sup.4NR.sup.10C(O)NR.sup.10R.sup.10,
--X.sup.4NR.sup.10C(NR.sup.10)NR- .sup.10R.sup.10,
--X.sup.4OR.sup.10, --X.sup.4SR.sup.10, --X.sup.4C(O)OR.sup.10,
--X.sup.4C(O)NR.sup.10R.sup.10,
--X.sup.4S(O).sub.2NR.sup.10R.sup.10,
--X.sup.4P(O)(OR.sup.4)OR.sup.10,
--X.sup.4OP(O)(OR.sup.4)OR.sup.10, --X.sup.4NR.sup.10C(O)R.sup.11,
--X.sup.4S(O)R.sup.11, --X.sup.4S(O).sub.2R.sup.11 and
--X.sup.4C(O)R.sup.11, wherein X.sup.4, R.sup.10 and R.sup.11 are
as defined above; and
[0091] R.sup.4 is nitromethyl, 1-hydroxy-1-methylethyl or
--CH.sub.2OR.sup.22, wherein R.sup.22 is hydrogen,
(C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0- -6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, wherein
within R.sup.4 any aromatic ring present may be substituted further
by 1 to 3 radicals independently selected from halo, --OR.sup.10,
--C(O)NR.sup.10R.sup.10, --S(O).sub.2NR.sup.10R.sup.10 or
--X.sup.4NR.sup.10R.sup.10, wherein X.sup.4, R.sup.10 and R.sup.11
are as defined above; and the N-oxide derivatives, prodrug
derivatives, protected derivatives, individual isomers and mixtures
of isomers; and the pharmaceutically acceptable salts thereof.
[0092] Preferred are compounds of Formula I in which within Formula
(a):
[0093] R.sup.5 is hydrogen or as defined below; and
[0094] R.sup.7 is (i) butyl, ethyl, methyl, 1-methylethyl,
1-methylpropyl or 2-methylpropyl optionally substituted with
--OR.sup.10, --C(O)OR.sup.10, --NR.sup.10R.sup.10,
--NR.sup.10C(O)OR.sup.10 or --C(O)NR.sup.10R.sup.10, wherein
R.sup.10 is hydrogen or (C.sub.1-6)alkyl, or (ii) benzyl,
benzyoxycarbonylmethyl, biphenyl4-ylmethyl, cyclohexyl,
cyclohexylmethyl, naphth-2-ylmethyl, phenylcarbamoylmethyl or
phenylethyl or (iii) together with R.sup.5 is phenylenedimethylene;
wherein within R.sup.7 any alicyclic or aromatic ring system
present may be substituted further by 1 to 3 radicals independently
selected from nitro and amino;
[0095] R.sup.1 is hydrogen, acetyl, 3-aminobenzoyl, 4-aminobutyryl,
3-aminopropionyl, 6-aminohexanoyl, 3-aminomethylbenzoyl,
4-aminomethylbenzoyl, benzoyl, benzylcarbamoyl, 4-benzyloxybenzoyl,
benzyloxycarbonyl, tert-butoxycarbonyl,
3-tert-butoxycarbonylaminobenzoyl- ,
4-tert-butoxycarbonylaminobutyryl,
6-tert-butoxycarbonylaminohexanoyl,
3-tert-butoxycarbonylaminomethylbenzoyl,
4-tert-butoxycarbonylaminomethyl- benzoyl,
1-tert-butoxycarbonylpiperidin-4-ylcarbonyl,
1-tert-butoxycarbonylpyrrolidin-2-ylcarbonyl, 3-carbamoylbenzoyl,
3-cyanobenzoyl, dibenzofur-2-ylsulfonyl,
3-[N',N"-di(tert-butoxycarbonyl)- guanidino]benzoyl,
4-dimethylaminobenzoyl, 2,2-dimethylpropionyl, 3-diphenylpropionyl,
3-fluorobenzoyl, 3-guanidinobenzoyl, 3-hydroxybenzoyl,
1H-indol-3-ylacetyl, 3-methoxycarbonylbenzoyl,
3-methoxycarbonylpropionyl, 3-methoxyphenylcarbamoyl
4-methylpiperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl,
naphth-1-ylcarbonyl, naphth-2-ylcarbonyl naphth-2-ylsulfonyl,
3-nitrophenylacetyl, phenoxyacetyl, phenylcarbamoyl,
3-phenylpropionyl, piperidin-4-ylcarbonyl,
1-piperidin-1-ylpiperidin-1-ylcarbonyl, pyrid-3-ylacetyl,
pyrid-4-ylacetyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl,
pyrrolidin-2-ylcarbonyl, pyrazinylcarbonyl or 3-ureidobenzoyl;
[0096] R.sup.2 is hydrogen or as defined below;
[0097] R.sup.3 is hydrogen, benzyl, 2-benzyloxyethyl,
4-benzyloxycarbonylaminobutyl, benzyloxymethyl, butyl,
2-(4-hydroxyphenyl)ethyl, 1H-indol-3-ylmethyl, 4-methoxybenzyl,
methyl, 2-methylsulfonylethyl, 2-methylpropyl, phenethyl,
2-phenylcarbamoylethyl or together with R.sup.2 forms
tetramethylene or phenylenedimethylene; and
[0098] R.sup.4 is acetoxymethyl, benzo[1,3]dioxol-5-yloxy,
benzyloxymethyl, 4-carbamoylphenoxymethyl, 4-chlorophenoxymethyl,
2,5-dichlorobenzoyloxymethyl, 2,6-dichlorobenzoyloxymethyl,
3-dimethylaminophenoxymethyl, ethoxymethyl, hydroxymethyl,
1-hydroxy-1-methylethyl, 4-(1H-imidazol-1-yl)phenoxymethyl,
methoxymethyl, 3-methoxyphenoxymethyl, 4-methoxyphenoxymethyl,
4-sulfamoylphenoxymethyl or phenoxymethyl; and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers; and the pharmaceutically
acceptable salts thereof.
[0099] Preferred are compounds of Formula I in which within Formula
(a), R.sup.5 is hydrogen and R.sup.7 is butyl, 1-methylethyl,
1-methylpropyl, 2-methylpropyl or naphth-2-ylmethyl; R.sup.1 is
3-aminobenzoyl, 3-aminomethylbenzoyl, 4-aminomethylbenzoyl,
benzoyl, benzylcarbamoyl, benzyloxycarbonyl, tert-butoxycarbonyl,
3-tert-butoxycarbonylaminobenzoyl- ,
4-tert-butoxycarbonylaminomethylbenzoyl,
3-[N',N"-di(tert-butoxycarbonyl- )guanidino]benzoyl,
4-dimethylaminobenzoyl, 3-guanidinobenzoyl
4-methylpiperazin-1-ylcarbonyl, naphth-1-ylcarbonyl,
naphth-2-ylcarbonyl or piperidin-4-ylcarbonyl; R.sup.2 is hydrogen;
R.sup.3 is hydrogen, 4-benzyloxycarbonylaminobutyl, butyl or
phenethyl; and R.sup.4 is benzyloxymethyl, hydroxymethyl,
2,5-dichlorobenzoyloxymethyl, ethoxymethyl, 1-hydroxy-1-methylethyl
or phenoxymethyl; and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers;
and the pharmaceutically acceptable salts thereof.
[0100] Pharmacology and Utility:
[0101] The compounds of the invention are cysteine protease
inhibitors, in particular the compounds of the invention inhibit
the activity of cathepsins B, L, K and/or S and, as such, are
useful for treating diseases in which cathepsin B, L, K and/or S
activity contributes to the pathology and/or symptomatology of the
disease. For example, the compounds of the invention are useful in
treating tumor invasion and metastasis, in particular as
anti-angiogenic agents, rheumatoid arthritis, osteo arthritis,
pneumocystis carinii, acute pancreatitis, inflammatory airway
disease and bone and joint disorders. Furthermore, the compounds of
the invention are useful in treating bone resorption disorders,
e.g., osteoporosis. The compounds of the invention also are useful
in treating autoimmune disorders, including, but not limited to
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
rheumatoid arthritis and Hashimoto's thyroiditis, allergic
disorders, including, but not limited to asthma, and allogeneic
immune reponses, including, but not limited to, organ transplants
or tissue grafts.
[0102] The cysteine protease inhibitory activities of the compounds
of the invention can be determined by methods known to those of
ordinary skill in the art. Suitable in vitro assays for measuring
protease activity and the inhibition thereof by test compounds are
known. Typically, the assay measures protease induced hydrolysis of
a peptide based substrate. Details of assays for measuring protease
inhibitory activity are set forth in Examples 7, 8, 9 and 10,
infra.
[0103] Nomenclature:
[0104] The compounds of Formula I and the intermediates and
starting materials used in their preparation are named in
accordance with JUPAC rules of nomenclature in which the
characteristic groups have decreasing priority for citation as the
principle group as follows: acids, esters, amides, etc. For
example, a compound of Formula I in which X.sup.1 is a divalent
group of Formula (a), wherein X.sup.2 is --C(O)--, R.sup.7 is
isobutyl and R.sup.5 and R.sup.9 both are hydrogen; R.sup.1 is
benzyloxycarbonyl; R.sup.2 is hydrogen; R.sup.3 is phenethyl; and
R.sup.4 is methoxymethyl; that is, a compound having the following
structure: 9
[0105] is named benzyl
1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3--
methylbutylcarbamate; and a compound of Formula I in which X.sup.1
is a divalent group of Formula (a), wherein X.sup.2 is --C(O)--,
R.sup.7 is isobutyl and R.sup.5 and R.sup.9 both are hydrogen;
R.sup.1 is benzyloxycarbonyl; R.sup.2 is hydrogen; R.sup.3 is
phenethyl; and R.sup.4 is 2,5-dichlorobenzoyl; that is, a compound
having the following structure: 10
[0106] is named
3S-(2S-benzyloxycarbonylamino4-methylpentanoylamino)-2-oxo-
-5-phenylpentyl 2,5-dichlorobenzoate; and a compound of Formula I
in which Xi is a divalent group of Formula (a), wherein X.sup.2 is
--C(O)--, R.sup.7 is 1-methylpropyl and R.sup.5 and R.sup.9 both
are hydrogen; R.sup.1 is 3-aminomethylbenzoyl; R.sup.2 is hydrogen;
R.sup.3 is phenethyl; and R.sup.4 is hydroxymethyl; that is, a
compound having the following structure: 11
[0107] is named
3-aminomethyl-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcar-
bamoyl)-2-methylbutyl]benzamide.
[0108] Administration and Pharmaceutical Compositions:
[0109] In general, compounds of Formula I will be administered in
therapeutically effective amounts via any of the usual and
acceptable modes known in the art, either singly or in combination
with another therapeutic agent. A therapeutically effective amount
may vary widely depending on the severity of the disease, the age
and relative health of the subject, the potency of the compound
used and other factors. For example, therapeutically effective
amounts of a compound of Formula I may range from 0.1 micrograms
per kilogram body weight (.mu.g/kg) per day to 10 milligram per
kilogram body weight (mg/kg) per day, typically 1 .mu.g/kg/day to 1
mg/kg/day. Therefore, a therapeutically effective amount for a 80
kg human patient may range from 10 .mu.g/day to 100 mg/day,
typically 0.1 mg/day to 10 mg/day. In general, one of ordinary
skill in the art, acting in reliance upon personal knowledge and
the disclosure of this Application, will be able to ascertain a
therapeutically effective amount of a compound of Formula I for
treating a given disease.
[0110] The compounds of Formula I can be administered as
pharmaceutical compositions by one of the following routes: oral,
systemic (e.g., transdermal, intranasal or by suppository) or
parenteral (e.g., intramuscular, intravenous or subcutaneous).
Compositions can take the form of tablets, pills, capsules,
semisolids, powders, sustained release formulations, solutions,
suspensions, elixirs, aerosols, or any other appropriate
composition and are comprised of, in general, a compound of Formula
I in combination with at least one pharmaceutically acceptable
excipient. Acceptable excipients are non-toxic, aid administration,
and do not adversely affect the therapeutic benefit of the active
ingredient. Such excipient may be any solid, liquid, semisolid or,
in the case of an aerosol composition, gaseous excipient that is
generally available to one of skill in the art.
[0111] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk, and the like.
Liquid and semisolid excipients may be selected from water,
ethanol, glycerol, propylene glycol and various oils, including
those of petroleum, animal, vegetable or synthetic origin (e.g.,
peanut oil, soybean oil, mineral oil, sesame oil, or the like).
Preferred liquid carriers, particularly for injectable solutions,
include water, saline, aqueous dextrose and glycols.
[0112] The amount of a compound of Formula I in the composition may
vary widely depending upon the type of formulation, size of a unit
dosage, kind of excipients and other factors known to those of
skill in the art of pharmaceutical sciences. In general, a
composition of a compound of Formula I for treating a given disease
will comprise from 0.01% w to 10% w, preferably 0.3% w to 1% w, of
active ingredient with the remainder being the excipient or
excipients. Preferably the pharmaceutical composition is
administered in a single unit dosage form for continuous treatment
or in a single unit dosage form ad libitum when relief of symptoms
is specifically required. Representative pharmaceutical
formulations containing a compound of Formula I are described in
Example 11.
[0113] The compounds of Formula I can be administered alone or in
combination with other compounds of Formula I or in combination
with one or more other active ingredient(s). For example, the
compounds of Formula I can be administered in combination with a
therapeutically active amount of a bisphosphonic acid or acid ester
derivative or any pharmaceutically acceptable salt thereof.
Suitable bisphosphonic acids and acid ester derivatives include
compounds corresponding to the following formula: 12
[0114] wherein X.sup.11 is a bond or (C.sub.1-7)alkylene, each
R.sup.43 independently is hydrogen or (C.sub.1-30)alkyl, R.sup.44
and R.sup.45 are selected independently from a group consisting of
hydrogen, halo, optionally substituted (C.sub.1-30)alkyl,
(C.sub.3-30)cycloalkyl, hetero(C.sub.5-30)cycloalkyl, optionally
substituted (C.sub.6-10)aryl, hetero(C.sub.6-10)aryl,
--NR.sup.46R.sup.46, --OR.sup.46, --SR.sup.46, wherein each
R.sup.46 independently is hydrogen, (C.sub.1-10)alkyl,
(C.sub.3-10)cycloalkyl, optionally substituted (C.sub.6-10)aryl,
provided that both R.sup.44 and R.sup.45 are not selected from
hydrogen or hydroxy when X.sup.11 is a bond; or R.sup.44 and
R.sup.45 taken together form (C.sub.2-9)alkylene; wherein
(C.sub.3-10)cycloalkyl includes adamantyl and the like,
hetero(C.sub.5-10)cycloalkyl includes pyrrolidinyl and the like,
(C.sub.6-10)aryl includes phenyl and naphthyl, and
hetero(C.sub.6-10)aryl includes quinolyl, isoquinolyl, pyridyl,
furyl, imidazolyl, imidazopyridyl and the like.
[0115] Instances wherein R.sup.44 and/or R.sup.45 are substituted
(C.sub.1-30)alkyl may include, but are not limited to,
(C.sub.1-30)alkyl substituted by hetero(C.sub.5-10)cycloalkyl,
(C.sub.6-10)aryl, hetero(C.sub.6-10)aryl, --NR.sup.47R.sup.47,
--OR.sup.47 and --SR.sup.47, wherein each R.sup.47 is independently
hydrogen or (C.sub.1-10)alkyl; wherein hetero(C.sub.5-10)cycloalkyl
includes pyrrolidinyl and the like, (C.sub.6-10)aryl includes
phenyl and naphthyl, and hetero(C.sub.6-10)aryl includes quinolyl,
isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the
like. Suitable optionally substituted aryl groups include, but are
not limited to, halo-substituted phenyl.
[0116] A non-limiting class of bisphosphonic acids and acid ester
derivatives thereof suitable for administration in combination with
compounds of Formula I include those in which R.sup.44 is selected
from the group consisting of hydrogen, hydroxy or halo, and
R.sup.45 is selected from the group consisting of optionally
substituted (C.sub.1-30)alkyl, halo and --SR.sup.46, wherein
R.sup.46 is (C.sub.1-10)alkyl or phenyl.
[0117] A non-limiting subclass of bisphosphonic acids and acid
ester derivatives thereof suitable for administration in
combination with compounds of Formula I include those in which
R.sup.44 is selected from the group consisting of hydrogen, hydroxy
and chloro and R.sup.45 is selected from the group consisting of
optionally substituted (C.sub.1-30)alkyl, chloro and
chlorophenylthio.
[0118] A non-limiting example of a bisphosphonic acid suitable for
administration in combination with compounds of Formula I include
that in which X.sup.11 is a bond, each R.sup.43 is hydrogen,
R.sup.44 is hydroxy and R.sup.45 is 3-aminopropyl, namely
4-amino-1-hydroxybutylidene-1,1-bis- phosphonic acid (aka
alendronic acid), or the monosodium trihydrate salt thereof, namely
4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium
trihydrate (aka alendronate monosodium trihydrate), described in
U.S. Pat. Nos. 4,922,007, to Kieczykowski et al., issued May 1,
1990; 5,019,651, to Kieczykowski et al., issued May 28, 1991;
5,510,517, to Dauer et al., issued Apr. 23, 1996; 5,648,491, to
Dauer et al., issued Jul. 15, 1997, all of which patents are
incorporated by reference herein in their entirety.
[0119] Further non-limiting examples of bisphosphonic acids
suitable for administration in combination with compounds of
Formula I include the following:
[0120] cycloheptylaminomethylene-1,1-bisphosphonic acid (aka
cimadronic acid), described in U.S. Pat. No. 4,970,335, to Isomura
et al., issued Nov. 13, 1990;
[0121] 1,1-dichloromethylene-1,1-diphosphonic acid (aka clodronic
acid) and the disodium salt thereof, namely clodronate disodium,
described in Belgium Patent 672,205 (1966) and J. Org. Chem 32,
4111 (1967);
[0122] 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic
acid (aka EB-1053);
[0123] 1-hydroxyethylidene-1,1-diphosphonic acid (aka etidronic
acid);
[0124]
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic
acid (aka ibandronic acid), described in U.S. Pat. No. 4,927,814,
issued May 22, 1990;
[0125] 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (aka
neridronic acid);
[0126] 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic
acid (aka olpadronic acid);
[0127] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (aka
pamidronic acid);
[0128] 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid (aka
piridronic acid), described in U.S. Pat. No. 4,761,406;
[0129] 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid (aka
risedronic acid);
[0130] 4-chlorophenylthiomethylenebisphosphonic acid (aka
tiludronic acid), described in U.S. Pat. No. 4,876,248, to Breliere
et al., Oct. 24, 1989; and
[0131] 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic
acid (aka zoledronic acid); all of which patents and other
documents referred to above are incorporated by reference herein in
their entirety.
[0132] A non-limiting subclass of bisphosphonic acids suitable for
administration in combination with compounds of Formula I include
those selected from the group consisting of alendronic acid,
cimadronic acid, clodronic acid, tiludronic acid, etidronic acid,
ibandronic acid, risedronic acid, piridronic acid, pamidronic acid,
zolendronic acid, pharmaceutically acceptable salts thereof, and
mixtures thereof. A further example of a bisphosphonic acid
suitable for administration in combination with compounds of
Formula I is alendronic acid or a pharmaceutically acceptable salt
thereof, and mixtures thereof. A further non-limiting example is
alendronate monosodium trihydrate.
[0133] Compounds of Formula I can be administered in combination
with a therapeutically active amount of an estrogen receptor
agonist. Non-limiting examples of estrogen receptor agonists
suitable for administration in combination with the compounds of
Formula I include naturally occurring estrogens such as estradiol,
estrone and estroil, or synthetic estrogen receptor agonists such
as [6-hydroxy-2-(4-hydroxypheny-
l)benzo[b]thien-3-yl][4-(2-piperidin-1-ylethoxy)phenyl]methanone
(aka raloxifene) and
{2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine (aka
tamoxifen). A non-limiting subclass of estrogen receptor agonists
suitable for administration in combination with the compounds of
Formula I include estrogen receptor partial agonists (i.e.,
estrogen receptor agonists with mixed agonist/antagonist
properties), sometimes referred to as estrogen receptor modulators.
Estrogen receptor partial agonists can exert tissue-selective
estrogen agonist effects. Tamoxifen, for example, selectively
exerts an estrogen agonist effect on the bone, in humans.
Additional suitable estrogen receptor partial agonists are
described in Tissue-Selective Actions Of Estrogen Analogs, Bone
Vol. 17, No. 4, October 1995, 181S-190S. Certain
3-[4-(2-phenylindol-1-ylmethyl)phenyl]ac- rylamides, described in
U.S. Pat. No. 5,985,910 to Miller et al., Nov. 16, 1999;
benzothiphene compounds, described in U.S. Pat. No. 5,985,897 to
Meuhl et al., Nov. 16, 1999; naphthyl compounds, described in U.S.
Pat. No. 5,952,350 to Cullinan et al., Sep. 14, 1999; substituted
benzothiophene compounds, described in U.S. Pat. No. 5,962,475 to
Schmid et al., Oct. 4, 1999, are suitable estrogen receptor partial
agonists for administration with the compounds of Formula I; all of
which patents and other documents referred to above are
incorporated by reference herein in their entirety.
[0134] More particularly a pharmaceutical composition of this
invention may comprise a therapeutically effect amount of a
compound of Formula I in combination with one or more active
ingredient(s) selected from the group consisting of (i) a
therapeutically effect amount of a bisphosphonic acid or acid ester
thereof or a pharmaceutically acceptable salt thereof and (ii) a
therapeutically effect amount of an estrogen receptor agonist or a
pharmaceutically acceptable salt thereof; and one or more
pharmaceutically acceptable excipient(s). Non-limiting examples of
such bisphosphonic acids include
1,1-dichloromethylene-1,1-diphosphoni- c acid,
1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid,
[0135] 1-hydroxyethylidene-1,1-diphosphonic acid,
1-hydroxy-3-(N-methyl-N-- pentylamino)propylidene-1,1-bisphosphonic
acid, 6-amino-1-hydroxyhexyliden- e-1,1-bisphosphonic acid,
3-(dimethylamino)-1-hydroxypropylidene-1,1-bisph- osphonic acid,
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,
2-pyrid-2-ylethylidene-1,1-bisphosphonic acid,
1-hydroxy-2-pyrid-3-ylethy- lidene-1,1-bisphosphonic acid,
4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy
-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid
ester thereof or a pharmaceutically acceptable salt thereof;
particularly 1,1-dichloromethylene-1,1-diphosphonic acid or a
pharmaceutically acceptable salt thereof and preferably
1,1-dichloromethylene -1,1-diphosphonate monosodium trihydrate.
[0136] Chemistry:
[0137] Processes for Making Compounds of Formula I:
[0138] Compounds of Formula I in which R.sup.4 is nitromethyl or
--CH.sub.2OR.sup.18 can be prepared by proceeding as in the
following Scheme 1: 13
[0139] in which L is a leaving group, R.sup.20 is --OR.sup.22,
wherein R.sup.22 is a hydroxy protecting group or optionally
substituted (C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, R.sup.21 is
R.sup.1 or a protecting group and each X.sup.1, R.sup.1, R.sup.2
and R.sup.3 are as defined in the Summary of the Invention for
Formula I.
[0140] Compounds of Formula I in which R.sup.4 is nitromethyl or
--CH.sub.2OR.sup.18 (Formula I(a)) can be prepared by condensing a
compound of Formula 2 with a compound of the formula
LX.sup.1R.sup.21, and then removing one or more protecting groups
if necessary. The compound of Formula 2 may be in a free base or an
acid addition salt form, preferably an acid addition salt form
(e.g., p-toluenesulfonic acid salt, or the like). Typically the
condensation reaction is carried out under nitrogen in the presence
of a suitable condensing agent (e.g., isobutyl chloroformate, or
the like), a base (e.g., 4-methylmorpholine, triethylamine, or the
like) and a suitable solvent (e.g., tetrahydrofuran (THF), or the
like), at -20 to 0.degree. C., preferably at about -10.degree. C.,
and requires 45 minutes to 4 hours to complete. A detailed
description of the condensation reaction is found in Example 2,
infra. Deprotection can be effected by any means which removes the
protective group and gives the desired product in reasonable yield.
A detailed description of a deprotection procedure is found in
Example 3, infra.
[0141] Compounds of Formula I in which R.sup.4 is
--CH.sub.2OR.sup.18 can be prepared by proceeding as in the
following reaction Scheme 2: 14
[0142] in which L is a leaving group, R.sup.22 is a hydroxy
protecting group or optionally substituted (C.sub.1-6)alkyl,
(C.sub.6-12)aryl(C.sub.- 0-6)alkyl,
beteropolycyclo(C.sub.8-12)aryl(C.sub.0-6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, R.sup.20 is
R.sup.1 or a protecting group and each X.sup.1, R.sup.1, R.sup.2,
R.sup.3 and R.sup.17 are as defined in the Summary of the Invention
for Formula I.
[0143] Compounds of Formula I in which R.sup.4 is
--CH.sub.2OR.sup.18 (Formula I(b)) can be prepared by condensing a
compound of Formula 3 with a compound of the formula
LCH.sub.2OR.sup.22 and then removing one or more protecting groups
if necessary. Typically the condensation reaction is carried out
under nitrogen in a suitable solvent (e.g., THF) at -60 to
25.degree. C. and requires 10 to 20 hours to complete. A detailed
description of the preparation of a compound of Formula I(c) is
found in Example 1, infra.
[0144] Compounds of Formula I in which R.sup.4 is
1-hydroxy-1-methylethyl can be prepared by proceeding as in the
following reaction Scheme 3: 15
[0145] in which R.sup.21 is R.sup.1 or a protecting group and each
X.sup.1, R.sup.1, R.sup.2 and R.sup.3 are as defined in the Summary
of the Invention for Formula I.
[0146] Compounds of Formula I in which R.sup.4 is
1-hydroxy-1-methylethyl (Formula I(c)) can be prepared by oxidizing
a compound of Formula 4 and then deprotecting if necessary.
Typically the oxidation is carried out with a suitable oxidizing
agent (e.g., Dess-Martin periodinate, or the like) in a suitable
solvent (e.g., methylene chloride, or the like) at 15 to 25.degree.
C. and requires 10 to 20 hours to complete. A detailed description
of the preparation of a compound of Formula I(c) is found in
Example 4, infra.
[0147] Compounds of Formula I in which R.sup.4 is nitromethyl can
be prepared by proceeding as in the following Scheme 4: 16
[0148] in which R.sup.21 is R.sup.1 or a protecting group and each
X.sup.1, R.sup.1, R.sup.2 and R.sup.3 are as defined in the Summary
of the Invention for Formula I.
[0149] Compounds of Formula I in which R.sup.4 is nitromethyl
(Formula I(d)) can be prepared by reacting a compound of Formula 5
with nitromethane and then deprotecting if necessary. Typically the
reaction with the nitromethane is carried out under nitrogen in the
presence of a coupling agent (e.g., 1,1'-carbonyldiimidazole, or
the like) and in a suitable solvent (e.g., THF) at -10 to
25.degree. C. and requires 10 to 20 hours to complete.
[0150] Additional Processes for Preparing Compounds of Formula
I:
[0151] A compound of Formula I can be prepared as a
pharmaceutically acceptable acid addition salt by reacting the free
base form of the compound with a pharmaceutically acceptable
inorganic or organic acid. Alternatively, a pharmaceutically
acceptable base addition salt of a compound of Formula I can be
prepared by reacting the free acid form of the compound with a
pharmaceutically acceptable inorganic or organic base. Inorganic
and organic acids and bases suitable for the preparation of the
pharmaceutically acceptable salts of compounds of Formula I are set
forth in the definitions section of this application.
Alternatively, the salt forms of the compounds of Formula I can be
prepared using salts of the starting materials or
intermediates.
[0152] The free acid or free base forms of the compounds of Formula
I can be prepared from the corresponding base addition salt or acid
addition salt form. For example, a compound of Formula I in an acid
addition salt form can be converted to the corresponding free base
by treating with a suitable base (e.g., ammonium hydroxide
solution, sodium hydroxide, or the like). A compound of Formula I
in a base addition salt form can be converted to the corresponding
free acid by treating with a suitable acid (e.g., hydrochloric
acid, etc).
[0153] The N-oxides of compounds of Formula I can be prepared by
methods known to those of ordinary skill in the art. For example,
N-oxides can be prepared by treating an unoxidized form of the
compound of Formula I with an oxidizing agent (e.g.,
trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic
acid, meta-chloroperoxybenzoic acid, or the like) in a suitable
inert organic solvent (e.g., a halogenated hydrocarbon such as
methylene chloride) at approximately 0.degree. C. Alternatively,
the N-oxides of the compounds of Formula I can be prepared from the
N-oxide of an appropriate starting material.
[0154] Compounds of Formula I in unoxidized form can be prepared
from N-oxides of compounds of Formula I by treating with a reducing
agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium
borohydride, sodium borohydride, phosphorus trichloride,
tribromide, or the like) in an suitable inert organic solvent
(e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to
80.degree. C.
[0155] Prodrug derivatives of the compounds of Formula I can be
prepared by methods known to those of ordinary skill in the art
(e.g., for further details see Saulnier et al.(1994), Bioorganic
and Medicinal Chemistry Letters. 4:1985). For example, appropriate
prodrugs can be prepared by reacting a non-derivatized compound of
Formula I with a suitable carbamylating agent (e.g.,
1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or
the like).
[0156] Protected derivatives of the compounds of Formula I can be
made by means known to those of ordinary skill in the art. A
detailed description of the techniques applicable to the creation
of protective groups and their removal can be found in T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, Inc. 1981.
[0157] Compounds of Formula I can be prepared as their individual
stereoisomers by reacting a racemic mixture of the compound with an
optically active resolving agent to form a pair of
diastereoisomeric compounds, separating the diastereomers and
recovering the i5 optically pure enantiomer. While resolution of
enantiomers can be carried out using covalent diasteromeric
derivatives of compounds of Formula I, dissociable complexes are
preferred (e.g., crystalline diastereoisomeric salts).
Diastereomers have distinct physical properties (e.g., melting
points, boiling points, solubilities, reactivity, and the like) and
can be readily separated by taking advantage of these
dissimilarities. The diastereomers can be separated by
chromatography or, preferably, by separation/resolution techniques
based upon differences in solubility. The optically pure enantiomer
is then recovered, along with the resolving agent, by any practical
means that would not result in racemization. A more detailed
description of the techniques applicable to the resolution of
stereoisomers of compounds from their racemic mixture can be found
in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers,
Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981).
[0158] In summary, an aspect of this invention is a process for
preparing a compound of Formula I, which process comprises:
[0159] (A) reacting a compound of Formula 2: 17
[0160] with a compound of the formula LX.sup.1R.sup.2, in which L
is a leaving group, R.sup.20 is --NO.sub.2 or --OR.sup.22, wherein
R.sup.22 is a hydroxy protecting group or optionally substituted
(C.sub.1-6)alkyl, (C.sub.6-12)aryl(C.sub.0-6)alkyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0- -6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, R.sup.21 is
R.sup.1 or a protecting group and each X.sup.1, R.sup.1, R.sup.2
and R.sup.3 are as defined in the Summary of the Invention for
Formula I, and then removing one or more protective groups if
necessary to provide a compound of Formula I in which R.sup.4 is
nitromethyl or --CH.sub.2OR.sup.17;
[0161] (B) reacting a compound of Formula 3: 18
[0162] with a compound of the formula LCH.sub.2OR.sup.22, in which
L is a leaving group, R.sup.22 is a hydroxy protecting group or
optionally substituted (C.sub.1-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
heteropolycyclo(C.sub.8-12)aryl(C.sub.0-6)alkyl,
(C.sub.1-6)alkylcarbonyl or (C.sub.6-12)arylcarbonyl, R.sup.20 is
R.sup.1 or a protecting group and each X.sup.1, R.sup.1, R.sup.2,
R.sup.3 and R.sup.17 are as defined in the Summary of the Invention
for Formula I, and then removing one or more protective groups if
necessary to provide a compound of Formula I in which R.sup.4 is
--CH.sub.2OR.sup.17;
[0163] (C) oxidizing a compound of Formula 4: 19
[0164] in which R.sup.21 is R.sup.1 or a protecting group and each
X.sup.1, R.sup.1, R.sup.2 and R.sup.3 are as defined in the Summary
of the Invention for Formula I, and then deprotecting if necessary
to provide a compound of Formula I in which R.sup.4 is
l-hydroxy-1-methylethyl;
[0165] (D) reacting a compound of Formula 5: 20
[0166] with nitromethane, in which R.sup.21 is R.sup.1 or a
protecting group and each X.sup.1, R.sup.1, R.sup.2 and R.sup.3 are
as defined in the Summary of the Invention for Formula I, and then
deprotecting if necessary to provide a compound of Formula I in
which R.sup.4 is nitromethyl;
[0167] (E) optionally dealkylating a compound of Formula I in which
R.sup.4 is --CH.sub.2OR.sup.18, wherein R.sup.18 is
(C.sub.1-6)alkyl or (C.sub.6-2)aryl(C.sub.1-6)alkyl to provide a
compound of Formula I in which R.sup.18 is hydrogen;
[0168] (F) optionally converting a compound of Formula I into a
pharmaceutically acceptable salt;
[0169] (G) optionally converting a salt form of a compound of
Formula I to non-salt form;
[0170] (H) optionally converting an unoxidized form of a compound
of Formula I into a pharmaceutically acceptable N-oxide;
[0171] (I) optionally converting an N-oxide form of a compound of
Formula I its unoxidized form;
[0172] (K) optionally converting a non-derivatized compound of
Formula I into a pharmaceutically prodrug derivative; and
[0173] (L) optionally converting a prodrug derivative of a compound
of Formula I to its non-derivatized form.
[0174] Processes for Making the Intermediates Used in Making
Compounds of Formula I:
[0175] Compounds of Formula 2 in which R.sup.20 is --OR.sup.22 can
be prepared by condensing an a-aminoketone of Formula 6: 21
[0176] in which L is a leaving group and R.sup.23 is an amino
protective group, with a compound of the formula HOR.sup.22 and
then selectively removing the amino protective group. The
condensation reaction is carried out in the presence of potassium
fluoride and a suitable solvent (N,N-dimethylformamide (DMF), or
the like) at 20 to 30.degree. C., preferably at about -25.degree.
C., and requires 1 to 3 hours to complete. The a-aminoketone of
Formula 3 is prepared from a corresponding
.alpha.-amino-.alpha.'-diazoketone derivative. For example, a
compound of Formula 3 in which L is bromo is prepared by treating a
corresponding .alpha.-amino-.alpha.'-diazoketone derivative with
hydrogen bromide in a suitable solvent (e.g., ether, or the like)
at -20 to 0.degree. C., typically at about -10.degree. C., and
requires approximately 30 minutes to 1 hour to complete. The
.alpha.-amino-.alpha.'-diazoketone derivative is prepared by
treating a corresponding .alpha.-aminocarboxylic acid with
diazomethane in the presence of a suitable condensing agent (e.g.,
isobutyl chloroformate, or the like) and base (e.g.,
4-methylmorpholine, triethylamine, or the like) and in a suitable
solvent (e.g., tetrahydrofuran (THF), or the like) at -10 to
0.degree. C., preferably at about -10.degree. C., and requires
approximately 30 minutes to complete. Deprotection is conveniently
effected by treating the protected intermediate with acid (e.g.,
p-toluenesulfonic acid) to provide the compound of Formula 2 in an
acid addition salt form.
[0177] Compounds of Formula 2 in which R.sup.20 is --OR.sup.22 can
be prepared by condensing a
.alpha.-amino-N-methoxy-N-methylcarboxamide of Formula 7: 22
[0178] in which R.sup.23 is an amino protective group, with a
compound of the formula LCH.sub.2OR.sup.22 and then selectively
removing the amino protective group. Typically the reaction is
carried out under nitrogen in a suitable solvent (e.g., TF) at -60
to 25.degree. C. and requires 10 to 20 hours to complete. Compounds
of Formula 7 are prepared by reacting a corresponding
.alpha.-aminocarboxylic acid with N,O-dimethylhydroxylamine
hydrochloride.
[0179] Compounds of Formula 2 in which R.sup.20 is --NO.sub.2 can
be prepared by reacting a a-aminocarboxylic acid of Formula 8:
23
[0180] in which R.sup.23 is an amino protective group, with
nitromethane and then selectively removing the amino protecting
group. Typically the reaction with the nitromethane is carried out
under nitrogen in the presence of a coupling agent (e.g.,
1,1'-carbonyldiimidazole, or the like) and in a suitable solvent
(e.g., THF) at -10 to 25.degree. C. and requires 10 to 20 hours to
complete. Detailed descriptions for the preparation of compounds of
Formula 2 are found in References 1, 2 and 3, supra.
[0181] Compounds of Formula 3 are prepared by reacting a
corresponding carboxylic acid with N,O-dimethylhydroxylamine
hydrochloride. Compounds of Formula 4 can be prepared by oxidizing
a corresponding N-(3-methylbut-2-enyl) derivative. Typically the
oxidation of the N-(3-methylbut-2-enyl) derivative is carried out
with a suitable oxidizing agent (e.g., osmium tetroxide, or the
like) in a suitable solvent (e.g., acetonitrile, or the like) at
approximately 0.degree. C. and requires 10 to 20 hours to complete.
The N-(3-methylbut-2-enyl) derivative is prepared from a
corresponding N-(2-oxoethyl) derivative via a Wittig reaction.
[0182] Process for Making Compounds of Formula II:
[0183] A process for preparing a compound of Formula II: 24
[0184] which process comprises hydrogenating a compound of Formula
9: 25
[0185] in which R.sup.1 is peptidyl, R.sup.2 is hydrogen or
(C.sub.1-6)alkyl, R.sup.3 is an amino acid side chain and R.sup.4
is (C.sub.1-6)alkyl or (C.sub.6-2)aryl(C.sub.1-6)alkyl, in the
presence of a catalytic amount of 20% palladium hydroxide on
carbon. The hydrogenation can be effected with hydrogen gas or an
effective amount of cyclohexene. The hydrogenation may be carried
out in cyclohexene alone or along with a suitable solvent (e.g.,
ethanol, or the like) at 80 to 90.degree. C. and requires 1 to 2
hours to complete. Preferably, the process is carried out in an
excess amount of cyclohexene, typically 100 times the molar amount
of the compound of Formula II, in a 1:2 mixture of
cyclohexene:ethanol. The process is particularly useful in
preparing the individual (R)- or (S)-isomers of the compounds of
Formula II. Thus, by proceeding as set forth above, the individual
isomers of the compounds of Formula I in which R.sup.4 is
hydroxymethyl can be prepared by dealkylating a compound of Formula
I in which R.sup.1 is --CH.sub.2OR.sup.18, wherein R.sup.18 is
(C.sub.1-6)alkyl or (C.sub.6-12)aryl(C.sub.1-6)alkyl. A detailed
description of this process is found in Example 5, infra.
EXAMPLES
Reference 1
(S)-3-Amino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate
toluenesulfonic acid salt
[0186] (a) A solution comprised of
(S)-2-tert-butoxycarbonylamino-4-phenyl- butyric acid (7.82 g, 28
mmol) in THF (35 mL) was cooled to -10.degree. C. and
4-methylmorpholine (3.08 mL, 28 mmol) and isobutyl chloroformate
(3.63 mL, 28 mmol) were added. The mixture was stirred for 5
minutes and filtered. The solids were washed with THF (15 mL) and
the combined filtrates were transferred to the receiving flask of a
Diazald(D kit (Aldrich). Diazomethane, prepared by ethanolic
potassium hydroxide cleavage of an ethereal solution of
Diazald.COPYRGT. (10 g, 46 mmol/100 mL diethyl ether), was
distilled into the mixed anhydride over 30 minutes and then acetic
acid was added to quench the reaction. Ethyl acetate (100 mL) was
added and the mixture was washed with saturated aqueous sodium
bicarbonate, dried (MgSO.sub.4), filtered, and concentrated to
provide tert-butyl (S)-3-diazo-2-oxo-1-phenethylpropylcarbamate
(8.44 g, 27.7 mmol).
[0187] (b) A solution comprised of tert-butyl
(S)-3-diazo-2-oxo-1-phenethy- lpropylcarbamate (7.09 g, 23.4 mmol)
in ether (100 mL) was cooled to -10.degree. C. and a solution
comprised of hydrogen bromide/acetic acid (4.66 mL, 30% by weight)
in ether (30 mL) was added dropwise. The mixture was stirred for 30
minutes and then ether (200 mL) was added. The mixture was washed
with brine (50 mL), saturated aqueous sodium bicarbonate (150 mL),
brine (50 mL), dried (MgSO.sub.4), filtered, and concentrated.
Product was crystallized from hexane, to provide tert-butyl
(S)-3-bromo-2-oxo-1-phenethylpropylcarbamate (5.29 g, 14.7 mmol).
.sup.1H NMR (CDCl.sub.3): .delta. 1.44 (9H, s, t-Bu), .delta. 1.86
(1H, m, one CH.sub.2CH.sub.2C.sub.6H.sub.5), .delta. 2.18 (1H, m,
other CH.sub.2CH.sub.2C.sub.6H.sub.5), .delta. 2.67 (2H, t, J=7.7
Hz, CH.sub.2CH.sub.2C.sub.6H.sub.5), .delta. 3.99 (2H, 2.times.d,
J=13 Hz, CH.sub.2Br), .delta. 4.53 (1H, m, CHNH), .delta. 5.08 (1H,
br. D, 5 Hz, NH), .delta. 7.17-7.29 (5H, m, aromatic H).
[0188] (c) Potassium fluoride (0.326 g, 5.61 mmol) was added to a
mixture of the tert-butyl
(S)-3-bromo-2-oxo-1-phenethylpropylcarbamate (1.00 g, 2.81 mmol)
and 2,5-dichlorobenzoic acid (1.07 g, 5.61 mmol) in DMF (10 mL).
The mixture was stirred for 2 hours at room temperature and then
ethyl acetate (75 mL) was added. The solution was washed with 1M
hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20
mL), dried (MgSO.sub.4), filtered, and evaporated to dryness to
provide crude (S)-3-tert-butoxycarbonylamino-2-oxo-5-phenylpentyl
2,5-dichlorobenzoate.
[0189] (d) The crude
(S)-3-tert-butoxycarbonylamino-2-oxo-5-phenylpentyl
2,5-dichlorobenzoate was dissolved in ether (5 mL) and a solution
of azeotropically dried p-toluenesulfonic acid (1.31 g, 7.7 mmol)
in ether (5 mL) was added. The mixture was stirred at room
temperature for approximately 12 hours and then ether (200 mL) was
added to provide a solid material. The solid material was broken
up, filtered, washed with ether (2.times.50 mL) and dried in vacuo
to provide (S)-3-amino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate
toluenesulfonic acid salt (1.24 g, 2.3 mmol).
Reference 2
3-Amino-1-benzyloxy-5-phenylpentan-2-one p-toluenesulfonic Acid
Salt
[0190] (a) Magnesium turnings (7.3 g, 300.29 mmol), previously
dried in an oven at 100.degree. C. for approximately 12 hours, and
mercuric chloride (1.2 g, 4.42 mmol) were weighed into a dry flask.
The flask was purged with nitrogen for 10-15 minutes and then
anhydrous THF (200 mL) was added under nitrogen. The mixture was
cooled to 40.degree. C. and stirred while
chloromethoxymethylbenzene (42.9 g, 273.93 mmol) was added via
syringe. The mixture was stirred under nitrogen for 6 hours while
the temperature was allowed to warm to 3 to 5.degree. C.
[0191] (b) The mixture was cooled to -60.degree. C. and stirred
under nitrogen while a solution comprised of tert-butyl
1-(N-methoxy-N-methylca- rbamoyl)-3-phenylpropylcarbamate (17 g,
52.73 mmol) in anhydrous THF was added via syringe and the mixture
was stirred until the reaction was complete. The reaction was
quenched slowly with ammonium chloride solution and the mixture was
stirred for 15-30 minutes. The mixture was extracted with ethyl
acetate (3.times.7 mL) and the combined extract was dried
(Mg.sub.2SO.sub.4), filtered and concentrated. Product was purified
from the residue by flash column chromatography using silica gel 60
to provide tert-butyl 3-benzyloxy-2-oxo-1-phenethylpropylcarbamate
(17.15 g, 44.72 mmol). .sup.1H NMR (CDCl.sub.3): .delta. 1.43 (s,
9H), .delta. 1.74-1.82 (m. 1H), .delta. 2.14-2.16 (m, 1H), .delta.
2.60-2.67 (m, 2H), .delta. 4.13-4.14 (d, 2H), .delta. 4.49-4.61 (m,
3H), .delta. 5.14-5.17 (d, 1H), .delta. 7.1-7.4 (m, 10H).
[0192] (c) p-Toluenesulfonic acid hydrate (17.15 g, 90.16 mmol) was
azeotroped with an isopropyl alcohol/toluene mixture (1:1) to
provide anhydrous p-toluene sulfonic acid. The sulfonic acid was
dried under high vacuum and dissolved in a minimum of anhydrous
ether. The solution of sulfonic acid was added to a solution of
tert-butyl 3-benzyloxy-2-oxo -1-phenethylpropylcarbamate (17.15 g,
44.72 mmol) in a minimum of anhydrous ether under nitrogen to
provide a precipitate. The mixture was stirred under nitrogen until
the reaction was complete and then filtered. The precipitate was
dried under vacuum to provide 3-amino-1-benzyloxy-5-p-
henylpentan-2-one p-toluenesulfonic acid salt (17.78 g, 38.9 mmol).
.sup.1H NMR (DMSO-d.sub.6): .delta. 1.84-2.01 (m, M1), .delta.
2.12-2.22 (m, 1H), .delta. 2.28 (s, 3H), .delta. 2.59-2.70 (m, 2H),
.delta. 4.24-4.35 (m, 1H), .delta. 4.4 (d, 2H), .delta. 4.5-4.6 (m,
2H), 67.09-7.50 (m, 14H), .delta. 8.15-8.35 (s, 3 11).
[0193] Proceeding as in Reference 2(a)-(b) or 2(a)-(c), provided
the following compounds:
[0194] tert-butyl 1-benzyloxyacetylpentylcarbamate; .sup.1H N
(CDCl.sub.3): .delta. 0.82-0.87 (m, 3H), .delta. 1.21-1.20 (m, 3H),
.delta. 1.41 (s, 9H), .delta. 1.7-1.9 (m, 1H), .delta. 1.41 (d,
2H), .delta. 4.5-4.7 (m, 3H), .delta. 5.06-5.09 (d, 1H), .delta.
7.3-7.4 (m, 5H);
[0195] tert-butyl 3-benzyloxy-2-oxopropylcarbamate; .sup.1H NMR
(CDCl.sub.3): .delta. 1.42 (s, 9H), .delta. 4.08-4.15 (m, 2H),
.delta. 4.17-4.22 (d, 2H), .delta. 4.57 (s, 2H), .delta. 5.19 (m,
1H), .delta. 7.24-7.40 (m, 5H); and
[0196] 3-amino-1-benzyloxyheptan-2-one p-toluenesulfonic acid salt;
.sup.1H NMR (DMSO-d.sub.6): .delta. 0.8-0.9 (m, 3H), .delta.
1.15-1.40 (m, 4H), .delta. 1.6-1.72 (m,1H), .delta. 1.72-1.9 (m,
1H), .delta. 2.28 (s, 3H), .delta. 4.15-4.3 (m, 1H), .delta.
4.35-4.45 (d, 2H), .delta. 4.5-4.6 (m, 2H), .delta. 7.09-7.12 (d,
2H), .delta. 7.25-7.5 (m, 7H), .delta. 8.0-8.2 (s, 3H);
[0197] 1-amino-3-benzyloxypropan-2-one p-toluenesulfonic acid salt;
.sup.1H NMR (DMSO-d.sub.6): .delta. 2.28 (s, 3H), .delta. 3.9-4.1
(m, 2H), .delta. 4.3 (s, 2H), .delta. 4.55 (s, 2H), .delta.
7.05-7.15 (d, 2H), .delta. 7.25-7.50 (m, 7H), .delta. 7.9-8.15 (s,
3H);
[0198] 3-amino-1-benzyloxy-5-(4-hydroxyphenyl)pentan-2-one
p-toluenesulfonic acid salt;
[0199] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.80-1.95 (m, 1H),
.delta. 2.0-2.2 (m, 1H), .delta. 2.28 (s, 3H), .delta. 4.2-4.3 (m,
1H), .delta. 4.37 (d, 2H), .delta. 4.48-4.58 (m, 2H), .delta.
6.66-6.69 (d, 2H), .delta. 6.95-6.98 (d, 2H), .delta. 7.09-7.12 (d,
2H), .delta. 7.28-7.41 (m, 4H), .delta. 7.45-7.48 (d, 2H), 68.1-8.3
(m, 3H);
[0200]
2-amino-N-(3-benzyloxy-2-oxo-1-phenethylpropyl)-3-methylpentanamide
p-toluenesulfonic acid salt; .sup.1H NMR (CDCl.sub.3): .delta.
0.87-0.95 (d, 6H), .delta. 1.16 (m, 1H), .delta. 1.48 (m, 1H),
.delta. 1.79-1.84 (m, 1H), .delta. 2.08 (m, 1H), .delta. 2.28 (s,
3H), .delta. 2.56-2.60 (m, 2H), .delta. 3.75 (t, 1H), .delta. 4.29
(d, 1H), .delta. 4.33 (d, 1H), .delta. 4.50-4.54 (m, 3H), .delta.
7.12-7.33 (m, 12H), .delta. 7.48 (s, 2H), .delta. 8.10 (s, 3H),
.delta. 8.78 (d, 1H); and
[0201] 2-amino-N-(1-benzyloxyacetylpentyl)-3-methylpentanamide
p-toluenesulfonic acid salt; .sup.1H NMR (CDCl.sub.3): .delta.
0.82-0.89 (m, 9H), .delta. 0.92-1.47 (in, 7H), .delta. 1.77-1.78
(m, 2H), .delta. 2.28 (s, 3H), .delta. 3.49 (s, 1H), .delta. 3.70
(t, 1H), .delta. 4.29 (d, 1H), .delta. 4.33 (d, 1H), .delta.
4.51-4.52 (m, 2H), .delta. 7.10-7.13 (d, 2H), .delta. 7.34-7.38 (m,
5H), .delta. 7.49 (d, 2H), .delta. 8.07 (s, 3H), .delta. 8.65 ppm
(d, 1H).
Reference 3
(S)-3-amino-1-nitro-5-phenylpentan-2-one p-toluenesulfonic Acid
Salt
[0202] (a) A suspension comprised of sodium hydride (5.6 g of 60%
dispersion in mineral oil, washed twice with hexane, 140 mmol) in
TIHF (50 nL) was cooled under nitrogen to 0.degree. C. and a
solution comprised of nitromethane (10 mL, 180 mmol) in THF (50 mL)
was added dropwise. The mixture was stirred at 0 to 20.degree. C.
for 2 hours and then cooled to -10.degree. C. A solution comprised
of (S)-2-tert-butoxycarbonylamino-4-phenylbutyric acid (12.5 g, 45
mmol) in THF (50 mL) was cooled to 0.degree. C. and then
1,1'-carbonyldiimidazole (7.5 g, 46 mmol) was added. The butyric
acid mixture was stirred for 30 minutes, while allowing it to warm
to room temperature, and then added dropwise to the nitromethane
mixture. The combined mixture was allowed to warm to room
temperature and stirred under nitrogen for 14 hours. The reaction
was quenched with a small amount of water added slowly and then the
mixture was diluted with 1M aqueous hydrochloric acid (200 mL) and
ethyl acetate (500 mL). The organic layer was separated, washed
with saturated aqueous sodium chloride (2.times.250 mL), dried over
anhydrous magnesium sulfate, filtered and concentrated in vacuo to
provide a yellow solid (14 g). The residue was recrystallized from
ethyl acetate-hexane to provide tert-butyl
(S)-3-nitro-2-oxo-1-phenethylpropylcarbamate (9.2 g, 28.4 mmol) as
a pale yellow solid. .sup.1H NMR (270 MHz, CDCl.sub.3): .delta.
1.44 (s, 9H), .delta. 1.85-1.98 (m, 1H), .delta. 2.15-2.25 (m, 1H),
.delta. 2.61-2.74 (m, 2H), .delta. 4.16-4.23 (m, 1H), 64.94 (d,
J=4.9 Hz, 1 NH), .delta. 5.30 (d, J=15.1 Hz, 1H), .delta. 5.44 (d
J=15.1 Hz, 1H), .delta. 7.15-7.32 (m, 5H); .sup.13C NMR
(CDCl.sub.3): .delta. 28.29, 31.61, 31.89, 58.09, 81.33, 126.69,
128.45, 128.85, 139.86, 155.6, 196.24.
[0203] (b) A solution comprised of anhydrous p-toluenesulfonic acid
(26 mmol) in ethyl ether (10 mL) was added to a suspension
comprised of tert-butyl
(S)-3-nitro-2-oxo-1-phenethylpropylcarbamate (4.5 g, 14 mmol) in
dichloromethane (20 mL) and ethyl ether (150 mL). The mixture was
stirred for 70 hours at room temperature and the filtered. The
solid collected was washed thoroughly with ethyl ether and dried in
vacuo to provide
(S)-3-amino-1-nitro-5-phenylpentan-2-onep-toluenesulfonic acid salt
(5.4 g, 13.7 mmol) as a white solid. .sup.1H NMR (270 MHz,
DMSO-d.sub.6): .delta. 1.92-2.05 (m, 1H), .delta. 2.15-2.28 (m,
1H), .delta. 2.29 (s, 3H), .delta. 2.56-2.76 (m, 2H), .delta. 4.44
(br. s, 1H), 66.97 (d, J=16.1 Hz, 1H), .delta. 6.29 (d J=16.1 Hz,
1H), 67.12 (d, J=8.4 Hz, 2H), .delta. 7.20-7.35 (m, 5H), .delta.
7.49 (d, J=8.2 Hz, 11H), .delta. 8.46 (br. s, 3 NH).
Example 1
Benzyl
1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbutylcarba-
mate
[0204] 26
[0205] A mixture comprised of magnesium turnings (235 mg, 9.58
mmol) and mercuric chloride (35 mg, 0.13 mmol) in dry THF under
nitrogen was cooled to between -10 and -20.degree. C. and
chloromethoxymethane (0.75 mL, 9.58 mmol) was added. The mixture
was stirred for 6 hours while the temperature was allowed to warm
to between -8 and 0.degree. C. The mixture was then cooled to
-78.degree. C. and stirred while a solution comprised of benzyl
1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarb-
amoyl]-3-methylbutylcarbamate (500 mg, 1.08 mmol) in anhydrous THF
(6 mL) was added. The mixture was allowed to warm slowly over
approximately 12 hours and then the reaction was quenched with
ammonium chloride solution and then extracted with ethyl acetate.
The ethyl acetate was dried (MgSO.sub.4), filtered and
concentrated. Product was purified from the residue by flash column
chromatography eluting with 33:1 ethyl acetate/hexanes to provide
benzyl 1S-(3-hydroxy-2-oxo-1S-phenethylpropylc-
arbamoyl)-3-methylbutylcarbamate (374.8 mg, 0.824 mmol); .sup.1H
NMR (CDCl.sub.3): .delta. 0.91-93 ppm (d, 6H), .delta. 1.55 ppm (s,
3H), .delta. 1.55-1.63 ppm (m, 1H), .delta. 1.8-1.95 ppm (m, 1H),
.delta. 2.2-2.3 ppm (m, 1H), .delta. 2.57-2.63 ppm (t, 2H), .delta.
3.37 ppm (s, 3H), .delta. 4.06-4.15 ppm (m, 2H), .delta. 4.78-4.84
ppm (m, 1H), .delta. 5.1 ppm (s, 2 H), .delta. 6.49-6.52 ppm (d,
1H), .delta. 7.12-7.31 ppm (m, 10H); LC/MS (455 M+H.sup.+);
[0206] Proceeding as in Example 1 provided the following compounds
of Formula I:
[0207]
N-{1-[3-benzyloxy-2-oxo-1-(2-phenylcarbamoylethyl)propylcarbamoy]L--
2-methylbutyl}naphthalene-2-carboxamide (Compound 2);
[0208] benzyl
3S-acetylamino-N-(3-benzyloxy-2-oxo-1-phenethylpropyl)succin- amate
(Compound 3);
[0209] 2S-acetyl
amino-N.sup.1-(3-benzyloxy-2-oxo-1-phenethylpropyl)-N.sup-
.4-phenylsuccinamide (Compound 4);
[0210] tert-butyl
1-(3-benzyloxy-2-oxo-1-phenethylpropylcarbamoyl)-3-pheny-
lpropylcarbamate (Compound 5); and
[0211] 4-benzyloxy-N-(3-benzyloxy-2-oxo-1-phenethylpropyl)benzamide
(Compound 6).
Example 2
3S-(2S-Benzyloxycarbonylamino-4-methylpentanoylamino)-2-oxo-5-phenylpentyl
2,5-dichlorobenzoate (Compound 7),
[0212] 27
[0213] A solution comprised of
(S)-2-benzyloxycarbonylamino-4-methylpentan- oic acid (0.20 g, 0.76
mmol) in THF (5 mL) was cooled to -10.degree. C. and then
4-methylmorpholine (84 .mu.L, 0.76 mmol) and isobutyl chloroformate
(99 .mu.L, 0.76 mmol) were added. The mixture was stirred for 5
minutes and then (S)-3-amino-2-oxo-5-phenylpentyl
2,5-dichlorobenzoate toluenesulfonic acid salt (0.41 g, 0.76 mmol)
and 4-methylmorpholine (84 .mu.L, 0.76 mmol) were added
sequentially. The mixture was stirred for 45 minutes and then ethyl
acetate (30 mL) was added. The mixture was washed with 1M
hydrochloric acid (5 mL), saturated aqueous sodium bicarbonate (5
mL) and brine (5 mL), dried (MgSO.sub.4), filtered and
concentrated. The residue was crystallized from
CH.sub.2Cl.sub.2/ether to provide
3S-(2S-benzyloxycarbonylamno-4-methylpe-
ntanoylamino)-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate (0.32 g,
0.52 mmol). .sup.1H NMR (CDCl.sub.3): .delta. 0.92 (6H, 2.times.d*,
2.times.CH.sub.3, .delta. 1.46-1.78 (3H, m*,
CH.sub.2CH(CH.sub.3).sub.2, .delta. 1.96 (1H, m, one
CH.sub.2CH.sub.2C.sub.6H, .delta. 2.25 (1H, m, other
CH.sub.2CH.sub.2C.sub.6H.sub.5, .delta. 2.65 (2H, t, J=7.7 Hz,
CH.sub.2CH.sub.2C.sub.6H.sub.5, .delta. 4.18 (1H, m, CHNH (Leu),
.delta. 4.65 (1H, m, CHCH.sub.2CH.sub.2C.sub.6H.sub.5, .delta. 4.99
(2H, 2.times.d*, CH.sub.2OOCC.sub.6H.sub.3Cl.sub.2, .delta. 5.06
(2H, s*, C.sub.6H.sub.5CH.sub.2O, .delta. 5.08 (1H, m*, CHNH(CBZ),
.delta. 6.7 (1H, br., CHNH (amide), .delta. 7.14-7.48 (12H, m*,
aromatic, 6 7.92 (1H, s, 6-CH(C.sub.6H.sub.3Cl.sub.2).
[0214] Proceeding as in Example 5 provided the following compounds
of Formula I:
[0215] tert-butyl
1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-met-
hylbutylcarbamate (Compound 8); .sup.1H NMR (CDCl.sub.3): .delta.
0.91-0.93 (d, 6H), .delta. 1.21-1.24 (t, 1H), .delta. 1.42-1.53 (m,
1H), .delta. 1.60-1.68 (m, 1H), .delta. 1.78-1.93 (m, 1H), .delta.
2.13-2.30 (m, 1H), .delta. 2.54-2.62 (m, 2H), .delta. 4.09-4.14 (m,
2H), .delta. 4.48-4.60 (q, 2H), .delta. 5.09 (s, 1), .delta.
6.52-6.55 (d, 1H), .delta. 7.07-7.37 (m, 15H);
[0216] N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutyl]pyrrolidine-2-carboxamide (Compound 9); .sup.1H NMR
(CD.sub.3OD): .delta. 0.88-1.0 (m, 6H), .delta. 1.15-1.19 (t, 1H),
.delta. 2.5-2.8 (m, 4H), .delta. 1.9-2.25 (m, 4H), .delta.
2.40-2.80 (m, 3H), .delta. 3.45-3.70 (m, 1H), .delta. 4.20-4.40 (m,
2H), .delta. 4.50-4.70 (m, 2H), .delta. 7.16-7.40 (m, 10H);
M+H.sup.+ (494.4);
[0217]
N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-2S-(2-1H-indol-3-ylacetyla-
mino) -3-methylpentanamide (Compound 10); .sup.1H NMR (CDCl.sub.3):
.delta. 0.93 (m, 6H), .delta. 1.21 (m, 1H), .delta. 1.66 (m, 2H),
.delta. 2.01 (m, 1H), .delta. 2.54 (m, 3H), .delta. 4.06 (q, J=14
Hz, 7.2 Hz, 2H), .delta. 4.23 (m, 1H), .delta. 4.45 (m, 2H),
.delta. 4.58 (m, 1H), .delta. 6.29 (d, J=8.8 Hz, 1H), .delta. 7.13
(m, 14), .delta. 7.61 (m, 1H), .delta. 9.24 (br.s. 1H). LC-MS:
554.3 (M+H.sup.+, 100%);
[0218] tert-Butyl
1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylcarbamate (Compound 11), .sup.1H NMR (CDCl.sub.3):
.delta. 0.87-0.92 (m, 6H), .delta. 1.02-1.22 (m, 1H), .delta.
1.4-1.5 (s, m, 10H), .delta. 1.75-1.95 (m, 2H), .delta. 2.15-2.30
(m, 1H), .delta. 2.5-2.7 (m, 2H), .delta. 2.89-3.95 (t, 1H),
.delta. 4.12 (s, 2H), .delta. 4.48-4.62 (q, 2H), .delta. 4.85-5.0
(m, 2H), .delta. 6.49-6.52 (d, 1H), .delta. 7.07-7.4 (m, 10H);
M+H.sup.+ (497.2);
[0219]
N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-2S-(3,3-diphenylpropionyla-
mino) -3-methylpentanamide (Compound 12); .sup.1H NMR (CDCl.sub.3):
.delta. 0.72 (m, 6H), .delta. 1.12 (m, 1H), .delta. 1.45-1.56 (m,
4H), .delta. 1.77-1.86 (m, 1H), .delta. 2.12 (m, 11H), .delta.
2.49-2.56 (m, 2H), .delta. 2.93 (t, J=7.1 Hz, 2H), .delta. 4.09 (s,
2H), 64.12-4.18 (m, 1H), .delta. 4.51-4.56 (m, 3H), .delta. 4.80
(m, 1H), .delta. 5.85 (br.d., 1H), .delta. 6.24 (d, J=8.6 Hz),
.delta. 7.08-7.40 (m, 20H). LC-MS: 605.3 (M+H.sup.+, 100%);
[0220] N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]naphthalene-2-carboxamide (Compound 13); LC-MS:
551.3 (M+H.sup.+, 100%);
[0221]
N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-2S-[3-(3-methoxyphenyl)ure-
idol -3-methylpentanamide (Compound 14); .sup.1H NMR (CDCl.sub.3):
.delta. 0.88 (m, 6H), .delta. 1.04 (m, 1H), .delta. 1.50 (m, 1H),
.delta. 1.74-1.83 (m, 2H), .delta. 2.04 (m, 1H), .delta. 2.41-2.60
(m, 2H), .delta. 3.59 (s, 3), .delta. 4.19-4.32 (m, 4H), .delta.
4.53 (s, 2H), .delta. 6.48 (d, J=7.6 Hz, 1H), .delta. 6.84 (d,
J=7.1 Hz, 1H), .delta. 7.19-7.51 (m, 14H). LC-MS: 546.3 (M+H.sup.+,
100%);
[0222] N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-[2-(3-nitrophenyl)acetylamino]pentanamide (Compound 15);
.sup.1H NMR (CDCl.sub.3): .delta. 0.87 (m, 6H), .delta. 1.12 (m,
1H), .delta. 1.45-1.83 (m, 5H), 62.20 (m, 1H), 62.56 (m, 2H), 63.65
(m, 2H), .delta. 4.23 (m, 2H), .delta. 4.27 (t, J=8.3 Hz), .delta.
4.55 (q, J=14 Hz, 8.6 Hz), .delta. 4.89 (m, 1H), 66.22 (d, J=8.7
Hz, 11H), .delta. 6.33 (d, J=7.6 Hz, 1H), .delta. 7.05 (m, 11H),
.delta. 7.19-7.41 (m, 10H), .delta. 7.62 (d, J=8.3 Hz, 1H), .delta.
8.07-8.15 (m, 2H). LC-MS: 560.3 (M+H.sup.+, 100%);
[0223] N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(2-naphthalen-1-ylacetylamino)pentanamide (Compound 16);
.sup.1H NMR (CDCl.sub.3): .delta. 0.99 (m, 6H), .delta. 1.06 (m,
1H), .delta. 1.55-1.65 (m, 2H), .delta. 1.72-2.02 (m, 2H), .delta.
2.22-2.30 (m, 1H), .delta. 2.60-2.72 (m, 1H), .delta. 4.08 (s, 2H),
.delta. 4.49-4.65 (m, 3H), .delta. 4.93-5.01 (m, 1H), .delta. 6.53
(d, J=7.2 Hz, 1H), .delta. 6.64 (s, 1H), .delta. 7.08-7.61 (m,
13H), .delta. 7.72 (d, J=8.5 Hz, 1H), .delta. 7.80-8.01 (m, 2H),
.delta. 8.29-8.32 (m, 1H). LC-MS: 551.1 (M+H.sup.+, 100%);
[0224] N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(2-pyridin-4-ylacetylamino)pentanamide (Compound 17); .sup.1H
NMR (DMSO-d.sub.6, mixture of diastereomers): .delta. 0.79 (m, 7H),
.delta. 1.42 (m, 1H), .delta. 1.73-1.78 (m, 2H), .delta. 2.11 (m,
1H), .delta. 2.40-2.53 (m, 3H), .delta. 3.44 (m, 2H), .delta.
4.03-4.10 (m, 2H), .delta. 4.34-4.51 (m, 3H), .delta. 4.79 (m, 1H),
.delta. 6.79 (d, 1H), .delta. 7.00-7.29 (m, 13H), .delta. 8.48,
8.49 (d, 1H). LC-MS: M+1(516.2);
[0225] tert-butyl
4-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutylcarbamoyl]benzyl}carbamate (Compound 18); .sup.1H NMR
(DMSO-d): .delta. 0.95 (d, J=6 Hz, 6H), .delta. 1.42 (s, 9H),
.delta. 1.53-1.86 (m, 4H), .delta. 2.21 (m, 1H), .delta. 2.57 (t,
J=8.2 Hz, 2H), 64.13 (s, 2H), 64.35 (s, 2H), 64.53-4.68 (m, 3H),
64.84-4.92 (m, 1H), .delta. 6.47 (d, J=6.9 Hz; 1H), 66.68 (d, J=7.1
Hz, 1H), .delta. 7.16 (d, J=8.1 Hz, 1H), .delta. 7.16-7.40 (m,
11H), .delta. 7.71 (d, J=9.0 Hz, 2H). LC-MS: 630.2 (M+H.sup.+,
100%);
[0226]
4-aminomethyl-N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutyl]benzamide hydrochloride (Compound 19);
[0227] N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(2-pyridin-3-ylacetylamino)pentanamide (Compound 20); .sup.1H
NMR (DMSO-d.sub.6,): .delta. 0.81-0.90 (m, 6H), .delta. 1.05 (m,
1H), .delta. 1.43 (m, 1H), .delta. 1.76-1.82 (m, 2H), .delta. 2.02
(m, 1H), .delta. 2.49-2.52 (m, 2H), .delta. 3.53 (s, 2H), .delta.
4.07-4.10 (m, 2H), .delta. 4.12-4.53 (m, 3H), .delta. 4.82 (m, 1H),
.delta. 6.45 (t, 1H), .delta. 6.71 (d, 1H), .delta. 7.19-7.31 (m,
11H), .delta. 7.60 (d, 1H), .delta. 8.49 (m, 2H).
LC-MS:M+1(516.2);
[0228]
2S-amino-N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-4-phenylbutyramid-
e hydrochloride (Compound 21); .sup.1H NMR (CDCl.sub.3): .delta.
1.81-1.92 (m, 2H), .delta. 2.13-1.21 (m, 2H), .delta. 2.51-2.72 (m,
4H), 64.11 (s, 2H), 64.15-4.22 (m, 1H), 64.55 (q, J=14 Hz, 7.2 Hz,
2H), .delta. 4.86-4.92 (m, 2H), .delta. 6.69 (br. s; 1H), .delta.
7.02-7.40 (m, 15H). LC-MS: 445.3 (M+H.sup.+, 100%);
[0229] N-1[S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]nicotinamide (Compound 22); .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.93-0.97 (m, 6H), .delta. 1.23 (m, 1H),
.delta. 1.57-1.63 (m, 2H), .delta. 1.85-1.93 (m, 1H), .delta. 2.25
(m, 1H), .delta. 2.56-2.61 (m, 2H), .delta. 3.84-3.85 (m, 2H),
.delta. 4.51-4.57 (m, 3H), .delta. 4.91-4.94 (m, 1H), .delta. 6.52
(d, 1H), .delta. 7.18-7.36 (m, 12H), .delta. 8.09 (d, 1H), .delta.
8.72-8.73 (m, 1H), .delta. 9.03 (s, 1H). LC-MS: M+1(502.3);
[0230] N-[1-(3-benzyloxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutyl]pyrazine-2-carboxamide (Compound 23); .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.90-0.98 (m, 6H), .delta. 1.22 (m, 1H0;
1.86-1.89 (m, 2H), .delta. 2.02 (m, 1H), .delta. 2.19 (m, 1H0;
2.53-2.61 (m, 2H), .delta. 4.13-4.21 (m, 2H), .delta. 4.55-4.56 (m,
3H), .delta. 4.90-4.92 (M, 1H), .delta. 6.52 (D, 1H), .delta.
7.17-7.32 (M, 10H), .delta. 8.29 (D, 1H), .delta. 8.55 (S, 1H),
.delta. 8.75 (d, 1H), .delta. 9.37 (s, 1H). LC-MS: M+1(503.3);
[0231]
N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamovl)-2-methylbutyl-
]-3-cyanobenzamide (Compound 24); .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.91-0.96 (m, 6H), .delta. 1.21 (m, 1H), .delta. 1.57 (m,
2H), .delta. 1.89 (m, 1), .delta. 2.24 (m, 1), .delta. 2.56-2.75
(m, 2), .delta. 4.13 (s, 2H), .delta. 4.49-4.57 (m, 2H), .delta.
4.93-4.99 (m, 1H), .delta. 7.05 (d, 1H), .delta. 7.19-7.59 (m,
11H), .delta. 7.56-7.59 (d, 1H), .delta. 7.77-7.80 (m, 1H), .delta.
8.41 (m, 1H). LC-MS: M+1 (526.3);
[0232]
N-{1S-[1-(3-benzyloxy-2-oxopropyl)pentylcarbamoyl]-2-methylbutyl}be-
nzamide (Compound 25);
[0233] tert-butyl 4-[1S-(1S-benzyloxyacetylpentylcarbamoyl)
-2-methylbutylcarbamoyl]benzylcarbamate (Compound 26); LC-MS: 582.3
(M+H.sup.+, 100%);
[0234] N-1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]isophthalamide (Compound 27); .sup.1H NMR
(CDCl.sub.3): .delta. 0.80-1.05 (m, 6H), .delta. 1.20-1.35 (m, 1H),
.delta. 1.6-1.7 (m, 1H), .delta. 1.80-1.95 (m, 1H), .delta.
2.00-2.30 (m, 2H), .delta. 2.52-2.60 (t, 2H), .delta. 4.08-4.25 (m,
2H), .delta. 4.48-4.65 (m, 2H), .delta. 4.80-4.90 (m, 1H), .delta.
6.50-6.60 (m, 11H), .delta. 6.80-6.90 (m, 11H), .delta. 7.0-7.4 (m,
9H), .delta. 7.48-7.51 (t, 1H), .delta. 7.87-7.90 (d, 1H), .delta.
8.04-8.20 (m, 2H), .delta. 8.59 (s, 1H), 6 M+H.sup.+ (544.3);
[0235]
N-[1S-(1S-benzyloxyacetylpentylcarbamoyl)-2-methylbutyl]isophthalam-
ide (Compound 28); .sup.1H NMR (CDCl.sub.3): .delta. 0.70-0.80 (m,
3H), .delta. 0.80-1.0 (m, 6H), .delta. 1.1-1.3 (m, 4H), .delta.
1.50-1.70 (m, 2H), .delta. 1.80-2.10 (m, 3H), .delta. 4.12-4.30 (q,
2H), .delta. 4.50-4.65 (m, 3H), .delta. 4.78-4.90 (m, 11H), .delta.
6.50-6.60 (m, 11H), .delta. 6.70-6.80 (m, 1H), .delta. 6.91-6.94
(d, 1H), .delta. 7.3-7.4 (m, 4H), .delta. 7.45-7.55 (t, 1H),
.delta. 7.88-7.93 (t, 2H), .delta. 8.02-8.05 (d, 1H), .delta. 8.52
(s, 1H), .delta. M+H.sup.+ (496.2);
[0236] 4-aminomethyl-N-[1S-(1S-benzyloxyacetylpentylcarbamoyl)
-2-naphthalen-2-ylethyl]benzamide hydrochloride (Compound 29);
.sup.1H NMR (DMSO-d.sub.6): .delta. 0.76 (t, J=8.9 Hz, 3H), .delta.
1.06-1.27 (m, 4H), .delta. 1.54-1.77 (m, 2H), .delta. 3.23-3.41 (m,
2H), .delta. 4.04-4.19 (m, 4H), 64.75-4.82 (m, 2H), 67.21-7.86 (m,
13H), .delta. 8.39 (br.s, 4H), .delta. 8.72-8.85 (m, 2H). LC-MS:
566.2 (M+H.sup.+, 100%);
[0237] 3-aminomethyl-N-[1S-(1S-benzyloxyacetylpentylcarbamoyl)
-2-naphthalen-2-ylethyl]benzamide hydrochoride (Compound 30);
.sup.1H NMR (DMSO-d.sub.6): .delta. 0.83 (m, 3H), .delta. 1.10 (m,
1H), .delta. 1.26 (m, 3H), .delta. 1.54 (m, 1H), .delta. 1.75 (m,
1H), .delta. 3.26 (m, 2H), .delta. 4.03 (s, 2H), .delta. 4.36 (m,
2H), .delta. 4.36 (s, 2H), .delta. 4.90 (m, 1H), .delta. 7.45 (m,
4H), .delta. 7.83 (m, 5H), .delta. 8.21 (s, 2H), .delta. 8.61 (d,
J=8.1 Hz, 1H), .delta. 8.74 (d, J=8.1 Hz, 1H). LC-MS: 476.2
(M+H.sup.+, 100%);
[0238]
2S-(dibenzofur-2-ylsulfonylamino)-N-(3-benzyloxy-2-oxo-1S-phenethyl-
propyl) -3-methylpentanamide (Compound 31); .sup.1H NMR
(CDCl.sub.3): .delta. 0.79-0.88 (m, 6H), .delta. 1.0-1.14 (m, 1H),
.delta. 1.51-1.71 (m, 1H), .delta. 1.68-1.80 (m, 1H), .delta.
2.0-2.20 (m, 1H), .delta. 2.35-2.50 (m, 2H), .delta. 3.59-3.65 (m,
2H), .delta. 3.76 (s, 1H), .delta. 4.26-4.40 (q, 2H), .delta.
4.44-4.47 (d, 1H), .delta. 4.52-4.60 (m, 1H), .delta. 5.20-5.23 (d,
1H), .delta. 6.49-6.51 (d, 1H), .delta. 6.79-6.81 (m, 1H), .delta.
6.95-6.98 (d, 2H), .delta. 7.10-7.18 (m, 2H), .delta. 7.20-7.45 (m,
4H), .delta. 7.50-7.65 (m, 4H), .delta. 7.90-8.0 (m, 3H), .delta.
8.44 (d, 1H), 6 M+H.sup.+ (627.3);
[0239]
N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl-
]-3-ureidobenzamide (Compound 32); .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.93 (m, 6H), .delta. 1.12 (m, 1H), .delta. 1.50 (m, 1H),
.delta. 1.81-2.2 (m, 5H), .delta. 2.51-2.58 (m, 2H), .delta.
4.25-4.61 (m, 6H), .delta. 5.89 (m, 1H), .delta. 7.15-7.62 (m,
10H), .delta. 7.71 (d, J=8.1 Hz, 1H), .delta. 7.80 (s, 1H), .delta.
8.28 (d, J=7.9 Hz, 1H), .delta. 8.51 (d, J=8.1 Hz, 1H), .delta.
8.67 (s, 2H). LC-MS: 559.2 (M+H.sup.+, 100%);
[0240]
N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl-
]-3-fluorobenzamide (Compound 33); .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.85-0.93 (m, 6H), .delta. 1.10-1.31 (m, 1H), .delta. 1.54
(m, 1H), .delta. 1.80-2.00 (m, 3H), .delta. 2.56-2.66 (m, 2H),
.delta. 4.26-4.44 (m, 6H), .delta. 7.15-7.33 (m, 14H), .delta.
8.55-8.58 (d, 2H) LC-MS: M+1(429.1);
[0241] tert-butyl
3-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]phenylcarbamate (Compound 34);
[0242]
3-amino-N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]benzamide (Compound 35);
[0243] N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]-3-hydroxybenzamide (Compound 36);
[0244] tert-butyl 1-(3-benzyloxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutylcarbamate (Compound 37); .sup.1H NMR (CDCl.sub.3):
.delta. 0.87-0.92 (m, 6H), .delta. 1.02-1.22 (m, 1H), .delta.
1.4-1.5 (s, m, 10H), .delta. 1.75-1.95 (m, 2H), .delta. 2.15-2.30
(m, 1H), .delta. 2.5-2.7 (m, 2H), .delta. 2.89-3.95 (t, 1H),
.delta. 4.12 (s, 2H), .delta. 4.48-4.62 (q, 2H), .delta. 4.85-5.0
(m, 2H), .delta. 6.49-6.52 (d, 1H), .delta. 7.07-7.4 (m, 10H),
[0245] tert-butyl
1-(1-benzyloxyacetylpentylcarbamoyl)-2-methylbutylcarbam- ate
(Compound 38); .sup.1H NMR (CDCl.sub.3): .delta. 0.77-1.0 (m, 9H),
.delta. 1.1-1.35 (m, 3H), .delta. 1.38-1.6 (s, m, 10H), .delta.
1.78-1.95 (m, 2H), .delta. 3.89-3.99 (t, 1H), .delta. 4.14.23 (m,
2H), .delta. 4.50-4.63 (q, 2H), .delta. 4.77-4.90 (m, 1H), .delta.
4.95-5.10 (d, 1H), .delta. 6.46-6.48 (d, 1H), .delta. 7.25-7.40 (m,
5H),
[0246] tert-butyl
1-(3-benzyloxy-2-oxopropylcarbamoyl)-2-methylbutylcarbam- ate
(Compound 39); .sup.1H NMR (CDCl.sub.3): .delta. 0.80-1.0 (m, 6H),
.delta. 1.02-1.22 (m, 1H), .delta. 1.4-1.5 (s, m, 10H), .delta.
1.80-2.0 (m, 1H), .delta. 3.90-4.10 (m, 1H), .delta. 4.11 (s, 2H),
.delta. 4.30-4.32 (d, 2H), .delta. 4.58 (s, 2H), .delta. 4.90-5.10
(m, 1H), .delta. 6.50-6.70 (m, 1H), .delta. 7.24-7.50 (m, 5H),
[0247] benzyl 2-naphthalen-2-yl-1S-(3-nitro-2-oxo
-1S-phenethylpropylcarba- moyl)ethylcarbamate (Compound 40);
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 1.72-1.86 (m, 1H),
.delta. 1.98-2.10 (m, 1H), .delta. 2.39-2.62 (m, 2H), .delta. 3.00
(dd, 1H), .delta. 3.19 (dd, 1H), .delta. 4.21-4.32 (m, 1H), .delta.
4.38-4.48 (m, 1H), .delta. 4.90 (d, J=12.3 Hz, 1H), .delta. 4.95
(d, J=12.3 Hz, 1H), .delta. 5.50 (d, J=15.9 Hz, 1H), .delta. 5.57
(d, J=15.9 Hz, 1H), .delta. 7.12-7.26 (m, 10H), .delta. 7.41-7.46
(m, 3H), .delta. 7.78-7.84 (m, 5H), .delta. 8.74 (d, J=7.2 Hz, 1
NH); MS (ESI, m/z) 554.5 [M+H].sup.+.
[0248] benzyl
3-methyl-1S-(3-nitro-2-oxo-1S-phenethylpropylcarbamoyl)butyl-
carbamate (Compound 41); .sup.1H NMR (270 MHz, CDCl.sub.3) .delta.
0.91 (d, J=8.2 Hz, 3H), .delta. 0.93 (d, J=6.4 Hz, 3H), .delta.
1.40-1.50 (m, 1H), .delta. 1.56-1.66 (m, 2H), .delta. 1.90-2.00 (m,
1H), .delta. 2.16-2.29 (m, 1H), .delta. 2.55-2.70 (m, 2H),
64.06-4.14 (m, 1H), 64.43 (ddd, J=4.7, 7.1, 8.6 Hz, 1H), .delta.
4.96 (d, J=6.9 Hz, 1NH), .delta. 5.06 (d, J=12.1 Hz, 1H), .delta.
5.11 (d, J=12.1 Hz, 1H), .delta. 5.21 (d, J=15.3 Hz, 1H), .delta.
5.37 (d, J=15.1 Hz, 1H), .delta. 6.59 (d, J=7.2 Hz, 1 NH), .delta.
7.10-7.32 (m, 10H); .sup.13C NMR (CDCl.sub.3, 6) 21.78, 22.96,
24.82, 31.34, 31.63, 40.31, 53.70, 56.99, 67.64, 81.25, 126.70,
128.32, 128.47, 128.60, 128.74, 128.95, 135.82, 139.98, 156.50,
172.93, 195.31; MS (ESI, m/z) 470.2 [M+H].sup.+;
[0249] benzyl
2-naphthalen-2-yl-1-(1-nitroacetylpentylcarbamoyl)ethylcarba- mate
(Compound 42); .sup.1HNMR (DMSO-d.sub.6): .delta. 0.81 (t, 3H),
.delta. 1.19 (m, 4H), .delta. 1.53 (m, 1H), .delta. 1.73 (m, 1H),
.delta. 2.97 (m, 1H), .delta. 3.13 (m, 1H), 64.34 (m, 2H), .delta.
4.93 (s, 2H), .delta. 5.56 (q, J=6.5 Hz, J=14 Hz, 2H), .delta. 7.23
(m, 5), .delta. 7.47 (m, 3), .delta. 7.82 (m, 5H), .delta. 8.63 (d,
J=5.4 Hz, 1H); MS-CI 506.0 (M+H.sup.+, 80%); 401.2 (100%);
[0250] benzyl
2-methyl-1-(1-nitroacetylpentylcarbamoyl)butylcarbamate (Compound
43); .sup.1HNMR (DMSO-d.sub.6): .delta. 0.88 (m, 9H), .delta. 1.16
(m,, 3H), .delta. 1.59 (m, 4H), .delta. 1.97 (m, 2H), .delta. 3.99
(t, 1H), .delta. 4.47 (m, 1H), .delta. 5.09 (s, 2H), .delta. 5.14
(br. s. 1H), .delta. 5.56 (q, J=7.1 Hz, J=14 Hz, 2H), .delta. 6.43
(d, J=5.1 Hz, 1H), .delta. 7.34 (m, 5H); MS-CI 422.0 (M+H.sup.+,
100%);
[0251] 2S-(3-benzylureido)-3-naphthalen-2-yl-N-(3-nitro-2-oxo
-1S-phenethylpropyl)propionamide (Compound 44); .sup.1H NMR (270
MHz, DMSO-d.sub.6): .delta. 1.77-1.88 (m, 1H), .delta. 1.98-2.10
(m, 1H), .delta. 2.39-2.62 (m, 2H), .delta. 3.00 (dd, J=8.9, 13.6
Hz, 1H), .delta. 3.18 (dd, J=5.7, 13.6 Hz, 1H), .delta. 4.16 (br.
d, J=4.7 Hz, 2H), .delta. 4.22-4.30 (m, 1H), .delta. 4.56-4.64 (m,
1H), .delta. 5.48 (d, J=16.6 Hz, 1H), .delta. 5.57 (d, J=15.6 Hz,
1H), .delta. 6.39 (d, J=8.2 Hz, 1NH), .delta. 6.53 (t, J=6.1 Hz,
1NH), .delta. 7.11-7.28 (m, 10H), .delta. 7.43-7.51 (m, 3H),
.delta. 7.76 (br. s, 1H), .delta. 7.79-7.88 (m, 4H), .delta. 8.76
(d, J=7.2 Hz, 1NH); MS (ESI, m/z) 553.5 [M+H].sup.+;
[0252] benzyl
2-methyl-1S-(3-nitro-2-oxo-1S-phenethylpropylcarbamoyl)butyl-
carbamate (Compound 45); .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 0.77-0.88 (m, 6H), .delta. 1.06-1.22 (m, 1H), .delta.
1.36-1.48 (m, 1H), .delta. 1.69-1.86 (m, 2H), .delta. 1.98-2.12 (m,
1H), .delta. 2.4-2.7 (m, 2H), .delta. 3.87-3.93 (m, 1H), .delta.
4.22-4.30 (m, 11), .delta. 5.00 (br. s, 2H), .delta. 5.71 (d,
J=15.6 Hz, 1H), .delta. 5.81 (d, J=15.6 Hz, 1H), .delta. 7.14-7.30
(m, 10H), .delta. 7.50 (d, J=7.8 Hz, 1NH), .delta. 8.66 (d, J=3.0
Hz, 1NH); MS (ESI, m/z) 470.2 [M+H].sup.+;
[0253] benzyl 1-nitroacetylpentylcarbamoyl)phenylmethylcarbamate
(Compound 46); .sup.1HNMR (CDCl.sub.3): .delta. 0.88 (m, 3H),
.delta. 1.25 (m, 4H), .delta. 1.54 (m, 1H), .delta. 1.86 (m, 1),
.delta. 4.47 (m, 1H), 65.07 (q, J=5.7 Hz, J=13.5 Hz, 2H),
65.13-5.20 (m, 3H), .delta. 5.83 (d, J=6 Hz, 1H), .delta. 6.31 (br.
d, 1H), .delta. 7.34 (m, 10H); MS-Cl 442.0 (M+H.sup.+, 100%);
[0254] benzyl
5S-(2S-benzyloxycarbonylamino-3-naphthalen-2-ylpropionylamin-
o)-7-nitro -6-oxoheptylcarbamate (Compound 47); .sup.1H NMR (DMSO):
.delta. 1.21 (m, 5H), .delta. 1.76 (m, 1H), .delta. 2.97 (m, 3H),
.delta. 3.17 (dd, 1H), .delta. 4.364.41 (m, 2H), .delta. 4.92 (s,
2H), .delta. 4.99 (s, 2H), .delta. 5.56 (d, 11), .delta. 5.63 (d,
1H), .delta. 7.21-7.48 (14H), .delta. 7.78-7.88 (m, 5H), .delta.
8.66 (d, 1H); MS M+1 (655.3);
[0255]
N-[3-methyl-1S-(3-nitro-2-oxo-1S-phenethylpropylcarbamoyl)butyl]-[1-
.4']bipiperidinyl-1'-carboxamide (Compound 48); .sup.1H NMR (270
MHz, DMSO-d.sub.6): .delta. 0.88 (d, J=6.4 Hz, 3H), .delta. 0.92
(d, J=6.4 Hz, 3H), .delta. 1.35-2.12 (m, 15H), .delta. 2.47-2.72
(m, 4H), .delta. 2.83-2.96 (m, 2), .delta. 3.25-3.52 (m, 3H),
.delta. 4.08-4.22 (m, 4H), .delta. 5.74 (d, J=15.8 Hz, 1H), .delta.
5.83 (d, J=15.6 Hz, 1H), .delta. 6.67 (d, J=7.4 Hz, 1NH), .delta.
7.15-7.31 (m, 5H), .delta. 8.63 (d, J=7.2 Hz, 1 NH), .delta. 8.99
(br. s, 1 NH); MS (ESI, m/z) 530.3 [M+H].sup.+;
[0256]
N-[3-methyl-1S-(3-nitro-2-oxo-1S-phenethylpropylcarbamoyl)butyl]-4--
hydroxypipenidine-1-carboxamide (Compound 49); .sup.1H NMR (270
MLz, DMSO-d.sub.6): .delta. 0.87 (d, J=6.4 Hz, 3H), 60.92 (d, J=6.4
Hz, 3H), .delta. 1.14-1.32 (m, 2H), .delta. 1.38-1.48 (m, 1H),
.delta. 1.52-1.71 (m, 4H), .delta. 1.79-1.93 (m, 1H), .delta.
2.00-2.13 (m, 1H), .delta. 2.46-2.69 (m, 2H), .delta. 2.84-2.96 (m,
2H), .delta. 3.54-3.77 (m, 3H), .delta. 4.06-4.23 (m, 2H), .delta.
5.71 (d, J=15.6 Hz, 1H), .delta. 5.82 (d, J=15.8 Hz, 1H), .delta.
6.51 (d, J=7.4 Hz, 1 NH), .delta. 7.16-7.31 (m, 5H), .delta. 8.52
(d, J=6.9 Hz, 1 NH); MS (ESI, m/z) 463.2 [M+H].sup.+;
[0257] benzyl
3-methyl-1S-(3-methyl-1S-nitroacetylbutylcarbamoyl)butylcarb- amate
(Compound 50); .sup.1H NMR (270 MHz, CDCl.sub.3): .delta. 0.85-0.98
(m, 12H), .delta. 1.46-1.71 (m, 6H), .delta. 4.12-4.20 (m, 1H),
.delta. 4.46-4.54 (m, 1H), .delta. 5.08 (br. s, 2H), .delta.
5.24-5.33 (m, 1H and 1NH), .delta. 5.46 (d, J=15.3 Hz, 1H), .delta.
6.73 (d, J=6.2 Hz, 1NH), .delta. 7.29-7.39 (m, 5H), .delta.
.sup.13C NMR (CDCl.sub.3, 6) 21.48, 21.87, 22.93, 23.08, 24.79,
24.79, 38.58, 40.45, 53.69, 55.78, 67.56, 81.45, 128.20, 128.57,
128.74, 135.85, 156.54, 173.17, 196.00; MS (ESI, m/z) 470.2
[M+H].sup.+;
[0258] benzyl
5S-[4-methyl-2S-(3-phenylpropionylamino)pentanoylamino]-7-ni- tro
-6-oxoheptylcarbamate (Compound 51); .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.811 (d, 3H), .delta. 0.86 (d, 3H), .delta. 1.23-1.79 (m,
7H), .delta. 2.49-2.50 (m, 4H), .delta. 2.76-2.79 (m, 2H), .delta.
2.96-2.98 (m, 2H), .delta. 4.21-4.26 (m, 2H), .delta. 4.99 (s, 1H),
.delta. 5.78 (d, 1), .delta. 5.73 (d, 1), .delta. 7.19-7.33 (m,
11H), .delta. 8.06 (d, 1H), .delta. 8.48 (d, 1H); MS M+1
(569.3);
[0259] benzyl 2-methyl-1S-(3-nitro-2-oxo
-1S-phenethylpropylsulfamoylmethy- l)butylcarbamate (Compound 52);
.sup.1H NMR (DMSO-d.sup.6): .delta. 0.75 (3H, d, J=7 Hz); 0.85 (3H,
t, J=7 Hz); 1.00 (1H, m); 1.28 (1H, m); 1.5 (1H, m); 1.65 (1H, m);
1.95 (1H, m); 2.4-2.7 (3H, m*); 2.94 (2H, m); 396 (1H, m); 5.01
(2H, s); 6.49 (1H, s); 6.87 (1H, s, J=8 Hz); 7.15-7.35 (11H, m*).
MS (M+1): 520;
[0260] benzyl 1S-(1S-nitroacetylpentylcarbamoyl)butylcarbamate
(Compound 53);
[0261] benzyl 3-methyl-1R-(3-nitro-2-oxo
-1S-phenethylpropylsulfamoylmethy- l)butylcarbamate (Compound 54);
.sup.1H NMR (DMSO-d.sup.6): .delta. 0.83 (6H, d, J=6 Hz); 1.38 (2H,
m); 1.57 (1H, m*); 1.69 (1H, m*); 1.91 (1H, m); 2.63 (2H, m);
2.88-3.1 (2H, m); 3.99 (1H, m); 5.02 (2H, s); 5.99 and 6.56 (1H
total, 2.times.s, keto and enol form protons); 7.00 (1H, d, J=8 Hz)
7.16-1.34 (11H, m). MS (M+1): 520;
[0262] benzyl
3-methyl-1R-(1S-nitroacetylpentylsulfamoylmethyl)butylcarbam- ate
(Compound 55); .sup.1HNMR (DMSO-d.sup.6): .delta. 0.75-0.87 (9H,
m*); 1.2-1.65 (9H, m*); 2.83-3.3 (2H total, m, from keto and enol
forms); 3.98 and 4.12 (1H, total, m, from keto and enol forms);
5.01 (2H, s); 5.94, 6.49 (1H, total, 2.times.s, from keto and enol
forms); 1H, br. d); 7.32 (5H, m); 7.31, 7.83 (1H, total,
2.times.d). MS (M+1): 456;
[0263] tert-butyl 3-[2-methyl
-1S-(1S-nitroacetylpentylcarbamoyl)butylcarb- amoyl]benzylcarbamate
(Compound 56);
[0264]
3-aminomethyl-N-[2-methyl-1S-(1S-nitroacetylpentylcarbamoyl)butyl]b-
enzaniide (Compound 57); .sup.1H NMR (DMSO, d ppm) 0.85-0.92 (m,
9H), .delta. 1.26-1.95 (m, 9H), .delta. 4.06-4.07 (m 2H), .delta.
4.31-4.37 (m, 2H), .delta. 5.78 (d, 1H), .delta. 5.85 (d, 1H),
.delta. 7.50-7.53 (m, 1H), .delta. 7.65 (d, 1H), .delta. 7.90 (d,
1H), .delta. 8.04 (s, 1H), .delta. 8.44-8.56 (m, 3H), .delta. 8.78
(d, 1H); MS M+1 (421.1);
[0265] benzyl
4S-(4-methyl-2S-piperidin-4-ylcarbonylaminopentanoylamino)-6-
-nitro -5-oxohexylcarbamate (Compound 58); .sup.1H NMR (DMSO):
.delta. 0.81-0.86 (m, 7H), .delta. 1.43-1.80 (m, 10H), .delta.
2.84-2.99 (m, 2H), .delta. 3.21-3.54 (m, 10H), .delta. 5.00 (d,
2H), .delta. 7.27-7.66 (m, 6H), .delta. 8.63 (m, 1H), .delta. 9.07
(m, 1H); MS M+1 (534.3);
[0266] N-[2-naphthalen-2-yl-1S-(3-nitro-2-oxo
-1S-phenethylpropylcarbamoyl- )ethyl]piperidine4-carboxyamide
(Compound 59); .sup.1H NMR (DMSO-d.sub.6): .delta. 1.63-2.05 (m,
7H), .delta. 2.49-2.50 (m, 2H), .delta. 2.7502.78 (m, 2H), .delta.
3.04-3.23 (m, 5H), .delta. 4.52 (m, 1H), .delta. 5.57 (m, 1H),
.delta. 7.10-7.49 (m, 7H), .delta. 7.72-7.83 (m, 6), .delta. 8.35
(d, 1H), .delta. 8.66 (m, 1H), .delta. 9.08 (m, 1H); MS M+1
(531.2);
[0267]
N-[3-methyl-1S-(3-nitro-2-oxo-1S-phenethylpropylcarbamoyl)butyl]pip-
eridine -4-carboxamide (Compound 60);
[0268] benzyl
3-methyl-1S-(3-nitro-2-oxo-1S-benzylpropylcarbamoyl)butylcar-
bamate (Compound 61);
[0269] benzyl
1S-[1S-(1H-indol-3-ylmethyl)-3-nitro-2-oxopropylcarbamoyl]-3-
-methylbutylcarbamate (Compound 62);
[0270] benzyl 1S-(1S-benzyl-3-nitro-2-oxopropylcarbamoyl)
-2-naphthalen-2-ylethylcarbamate (Compound 63);
[0271] benzyl ester N-[3-methyl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamoyl)butyl]carbamate (Compound 64);
[0272]
N-[3-methyl-1S-(2-oxo-1S-phenethyl-3-phenoxypropylcarbamoyl)butyl]--
4-methylpiperazine-1-carboxamide (Compound 65);
[0273] tert-butyl 4-{1S-[3-(2,5-dichlorobenzoyloxy)-2-oxo
-1S-phenethylpropylcarbamoyl]-3-methylbutylcarbamoyl}piperidine
-1-carboxylate (Compound 66)
[0274] 7-benzyloxycarbonylamino-3S-(2S-benzyloxycarbonylamino
-4-methylpentanoylamino)-2-oxoheptyl 2,5-dichlorobenzoic acid
(Compound 67);
[0275] benzyl
4-methyl-2-(2-oxo-1-phenethyl-3-phenoxypropylsulfamoyl)penty-
lcarbamate (Compound 68);
[0276] benzyl
1-(3-benzyloxy-2-oxopropylcarbamoyl)-2-methylbutylcarbamate
(Compound 69);
[0277] benzyl
3-methyl-1-(2-oxo-3-phenoxypropylcarbamovl)butylcarbamate (Compound
70);
[0278]
N-[2-methyl-1-(2-oxo-3-phenoxypropylcarbamoyl)butyl]nicotinamide
(Compound 71);
[0279]
2-acetylamino-3-cyclohexyl-N-(2-oxo-3-phenoxypropyl)propionamide
(Compound 72); and
[0280] benzyl
1-(2-oxo-3-phenoxypropylcarbamoyl)-2-phenylethylcarbamate (Compound
73).
Example 3
Benzyl
1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamovl)-3-methylbutylcarba-
mate
[0281] 28
[0282] Potassium carbonate (31 mg, 0.225 mmol) was added to a
solution comprised of the 3S--
(2S-benzyloxycarbonylamino-4-methylpentanoylamino)--
2-oxo-5-phenylpentyl 2,5-dichlorobenzoate (0.92 g, 1.5 mmol),
provided as in Example 2, in 1:1 methanol/THF (40 mL). The mixture
was stirred for 60 minutes and then 1M hydrochloric acid (2 mL) was
added. The mixture was concentrated in vacuo at room temperature
and the residue was dissolved in ethyl acetate (40 mL). The
solution was washed with 1M hydrochloric acid (5 mL) and saturated
aqueous sodium bicarbonate (5 mL), dried (MgSO.sub.4), filtered and
concentrated. Product was purified from the residue by flash
chromatography (50% CH.sub.2Cl.sub.2/ethyl acetate) to provide
benzyl 1S-(3-hydroxy-2-oxo -1S-phenethylpropylcarbamoyl)-3-methyl-
butylcarbamate (0.37 g, 0.84 mmol) in approximately a 3:1 mixture
of (S,S)- to (S,R)-diastereomers. .sup.1H NMR (CDCl.sub.3): 0.89
(2.times.d*, 6H, 2.times.CH.sub.3), 1.43-1.6 (3H, m*,
(CH.sub.3).sub.2CHCH.sub.2, .delta. 1.86 (1H, m, one
CH.sub.2CH.sub.2C.sub.6H.sub.5, .delta. 2.12 (1H, m, other
CH.sub.2CH.sub.2C.sub.6H.sub.5, .delta. 2.58 (2H, t, J=7.7 Hz,
CH.sub.2CH.sub.2C.sub.6H.sub.5, .delta. 3.0 (1H, m*, OH), .delta.
4.2 (1H, CHNH (Leu)), .delta. 4.29 (2H, m*, CH.sub.2OH), .delta.
4.61 (1H, m*, NHCHCOCH.sub.2OH), .delta. 5.07 (2H, s*,
C.sub.6HsCH.sub.2O), .delta. 5.29-4.58 (1H, 2.times.d, approx. 3:1
ratio (S,S:S,) diastereomers), CBZ-NH), .delta. 6.9 (1H, d,
NHCHCOCH.sub.2OH), .delta. 7.03-7.31 (10H, m*, aromatic CH). MS:
441 (M+1).
[0283] Proceeding as in Example 3 provided the following compounds
of Formula I:
[0284] benzyl
5S-(2S-benzyloxycarbonylamino-4-methylpentanoylamino)-7-hydr- oxy
-6-oxoheptylcarbamate as an approximately 2:1 diastereomeric
mixture for L,L:L,D (Compound 75); MS (M+) 541: .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.87 (6H, 2.times.d, J=5 Hz); 1.15-1.57
(9H, m*); 3.1 (2H, m); 3.5-3.65 (1H, 2.times.m, 2:1 ratio); 4.3
(3H, m, CH.sub.2OH and CHNH (Leu)); 4.55 (1H, m); 5.03 (4H,
2.times.AB, 2.times.C.sub.6H.sub.5CH.sub.- 2O); 5.51 (1H, br. d);
5.68-5.76 (1H, 2.times.br. d, .about.2:1 ratio); 7.2-7.25 (11H,
aromatic CH, amide NH);
[0285]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbutyl]--
4-methylpiperazine-1-carboxamide as an approximately 9:1
diasteromeric mixture for L,L:L,D (Compound 76); .sup.1H NMR
(CDCl.sub.3): .delta. 0.93 (3H, 2.times.d (appears as t), J=6 Hz);
1.51 (1H, m); 1.67 (2H, m); 1.91 (1H, m); 2.16 (1H, m); 2.31 (3H,
s); 2.33 (4H, dd, appears as t, J=5.7 Hz); 2.62 (2H, m); 3.37 (4H,
dd, appears as t, J=5.2 Hz); 4.30 (2H, 2.times.d (AB)); 4.36 (1H,
m); 4.51 (1H, m); 4.89 (1H, d, J=8 Hz); 7.12-7.24 (6H, m); MS: 433
(M+1);
[0286]
N-[1S-(3-hydroxy-2-oxo-1R-phenethylpropylcarbamoyl)-3-methylbutyl]--
4-methylpiperazine-1-carboxamide as an approximately 3:1
diasteromeric mixture for L,L:L,D (Compound 77); MS: 433 (M+1);
.sup.1H NMR (CDCl.sub.3): .delta. 0.93 (3H, 2.times.d (appears as
t), J=6 Hz); 1.62 (1H, m); 1.67 (2H, m); 1.91 (1H, m); 2.16 (1H,
m); 2.28 (3H, s); 2.33 (4H, dd, appears as t, J=5.7 Hz); 2.62 (2H,
m); 3.37 (4H, dd, appears as t, J=5.2 Hz); 4.30 (2H, 2.times.d
(AB)); 4.36 (1H, m); 4.51 (1H, m); 5.11 (1H, d, J=8 Hz); 7.12-7.24
(5H, m); 7.44 (1H, m, J=8 Hz);
[0287] tert-butyl
4-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutylcarbamoyl]piperazine-1-carboxylate (Compound 78);
[0288] N-[1S-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-3-methylbutyl]piperazine-1-carboxamide (Compound 79);
[0289] benzyl 1S-(1-benzyloxymethyl-3-hydroxy-2-oxopropylcarbamoyl)
-3-methylbutylcarbamate (Compound 80); .sup.1H NMR (CDCl.sub.3):
.delta. 0.91 (6H, 2.times.d, J=6 Hz); 1.52 (1H, m); 1.64 (2H, m);
3.12 (1H, m); 3.57 (1H, m); 3.84 (1H, m); 4.22 (1H, m); 4.30 (2H,
br. s); 4.43 (2H, 2.times.d (AB)); 4.74 (1H, m); 5.08 (2H,
2.times.d (AB)); 5.32-5.43 (1H, 2.times.d, J=8 Hz, 1:1 ratio, L,L;
L,D isomers); 7.04-7.17 (H, 2.times.d 1:1 ratio, L,L; L,D isomers);
7.24-7.37 (10H, m); MS (M+1): 457;
[0290] benzyl
1S-[3-hydroxy-1S-(1H-indol-3-ylmethyl)-2-oxopropylcarbamoyl]-
-3-methylbutylcarbamate (Compound 81); .sup.1H NMR (CDCl.sub.3):
.delta. 0.84 (6H, m); 1.25-1.65 (3H, m); 3.13 (2H, m); 4.09 (2H,
2.times.d (AB), J=19 Hz); 4.25 (1H, m); 4.84 (1H, m); 5.00 (2H,
2.times.d (AB), J=11 Hz); 5.49-5.69 (1H, 2.times.d, J=8 Hz, approx,
4:1 ratio, L,L to L,D isomers); 6.81 (1H, d, J=2 Hz); 7.04-7.29
(9H, m); 7.5 (1H, d, J=7.6 Hz); 8.48 (1H, s); MS (M+1): 466;
[0291] benzyl 1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylpropylcarbamate as an approximately 2.5:1 diastereomeric
mixture of L,L: L,D (Compound 82); .sup.1H (CDCl.sub.3): .delta.
(6H, 2.times.d, J=6.7 Hz); 1.89 (1H, m); 2.12 (2H, m); 2.60 (2H, t,
J=7.5 Hz); 3.98 (1H, m); 4.30 (2H, 2.times.s, 2.5:1 ratio); 4.65
(1H, m); 5.09 (2H, s); 5.30 (1H, 2.times.d, .about.2.5:1 ratio);
6.6 (1H, 2.times.br. d, 2.5:1 ratio); 7.08-7.3 (10H, m); MS (M+1)
427;
[0292]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbutyl]m-
orpholine -4-carboxamide (Compound 83); .sup.1H NMR (CDCl.sub.3):
.delta. 0.87 (6H, 2.times.d, J=7 Hz); 1.49-1.69 (3H, m); 1.82 (1H,
m); 2.08 (1H, m); 2.55 (1H, m); 3.30 (4H, m); 3.56 (4H, m); 4.30
(2H, 2.times.d (AB), J=19 Hz); 4.37-4.5 (2H, m); 5.35 (1H, d, J=8
Hz); 7.04-7.27 (5H, m); 7.73 (1H, d, J=7 Hz); MS (M+1): 420;
[0293] benzyl 1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-naphthalen-2-ylethylcarbamate (Compound 84); .sup.1H NMR
(CDCl.sub.3): .delta. 1.63 (m, 1H), .delta. 2.01 (m, 1H), .delta.
2.41 (m, 2H), .delta. 3.17 (m, 2H), .delta. 4.21 (q, J=13.1 Hz,
J=6.3 Hz, 2H), .delta. 4.52 (m, 2H), .delta. 5.06 (s, 2H), .delta.
5.19 (m, 1), .delta. 6.27 (br. s., 1H), .delta. 6.81 (d, J=7.1 Hz,
1H), .delta. 6.98 (d, J=7.3 Hz, 1H), .delta. 7.28 (m, 10H), .delta.
7.44 (m. 2H), 67.60 (m, 1H), .delta. 7.78 (m, 2H). LC-MS: 525.1
(M+H.sup.+, 33%), 349 (40%), 305 (100%);
[0294] benzyl 1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylcarbamate (Compound 85); .sup.1H NMR (CDCl.sub.3):
.delta. 0.89 (3H, t, J=7 Hz); 0.91 (3H, d, J=7 Hz); 1.1 (1H, m);
1.47 (1H, m); 1.84 (2H, m); 2.13 (1H, m); 2.60 (2H, dd, J=7, 8 Hz);
4.01 (1H, m); 4.30 (2H, 2.times.s, .about.5:1 ratio, L,L: L,D
isomers); 4.63 (1H, m); 5.09 (2H, s); 5.25-5.35 (1H, 2.times.d*,
J=8.7 Hz, 5:1 ratio); 6.57 (1H, d, J=7 Hz); 7.05-7.31 (10H, m); MS
(M+1): 441;
[0295] benzyl 1S-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutylcarbamoyl]-3-methylbutylcarbamate (Compound 86);
.sup.1H NMR (CDCl.sub.3): .delta. 0.85 (12H, m); 1.44-1.75 (6H, m);
1.82 (1H, m); 2.10 (1H, m); 2.57 (1H, m); 4.2-4.38 (2H, m);
4.45-4.61 (2H, m); 4.9 (1H, m); 5.05 (2H, 2.times.d (AB); 7.05-7.35
(10H); MS (M+1): 554;
[0296]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbutyl]--
1-methylpiperidine-4-carboxamide (Compound 87);
[0297] benzyl 2-hydroxy-1-(3-hydroxy-2-oxo
-1-phenethylpropylcarbamoyl)pro- pylcarbamate (Compound 88);
.sup.1H NMR (CDCl.sub.3): .delta. 1.18 (d, J=8.1 Hz, 3H), .delta.
1.87 (m, 1H), .delta. 2.12 (m, 1H), .delta. 2.58 (m, 3H), .delta.
4.13 (m, 1H), .delta. 4.28 (m, 3H), .delta. 4.52 (m, 1H), .delta.
5.16 (s, 2H), .delta. 5.77 (br. d., 1H), .delta. 7.10 (d, J=7.1 Hz,
2H), .delta. 7.28 (m, 8H). LC-MS: 429.1 (M+H.sup.+, 100%);
[0298] benzyl
1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)pentylcarbamat- e
(Compound 89); .sup.1H NMR (CDCl.sub.3,): .delta. 0.90 (t, J=8.5
Hz, 3H), .delta. 1.30 (m, 4H), .delta. 1.59 (m, 2H), .delta. 1.84
(m, 2H), .delta. 2.15 (m, 1H), .delta. 2.60 (t, J=7.4 Hz, 2H),
64.09 (m, 1H), .delta. 4.29 (s, 2H), .delta. 4.58 (m, 1H), .delta.
5.1 (s, 2H), .delta. 5.18 (br. s., 1H), .delta. 6.51 (br. d., 1H),
.delta. 7.12 (m, 2H), .delta. 7.26 (m, 8 M). LC-MS: 441.2
(M+H.sup.+, 100%);
[0299] benzyl 5-(2-benzyloxycarbonylaminohexanoylamino)-7-hydroxy
-6-oxoheptylcarbamate (Compound 90); .sup.1H NMR (CDCl.sub.3):
.delta. 0.90 (t, J=8.5 Hz, 3H), .delta. 1.26 (m, 6H), .delta. 1.47
(m, 2H), .delta. 1.61 (m, 3H), .delta. 1.80 (m, 2H), .delta. 3.12
(m, 2H), .delta. 4.14 (m, 1H), .delta. 4.31 (s, 2H), .delta. 4.57
(m, 11), .delta. 5.12 (s, 4H), .delta. 5.15 (br. s. 1H), .delta.
5.34 (br. s., 1H), .delta. 6.85 (br. d. 1H), .delta. 7.13 (m, 15H).
LC-MS: 542.1 (M+H.sup.+, 33%), 221 (40%), 157 (100%);
[0300] benzyl 1-[3-hydroxy-2-oxo
-1-(2-phenylcarbamoylethyl)propylcarbamoy- l]pentylcarbamate
(Compound 91); .sup.1H NMR (DMSO-d.sub.6,): 0.90 (m, 3H), .delta.
1.30 (m, 3H), .delta. 1.59 (m, 3H), .delta. 2.15 (m, 2H), .delta.
2.40 (t, J=7.4 Hz, 2H), .delta. 4.09 (m, 2H), .delta. 4.17 (m, 1H),
64.36 (m, 1H), .delta. 4.68 (m, 1H), .delta. 5.1 (s, 2H), .delta.
5.18 (br. s., 11H), .delta. 6.51 (br. d., 1H), .delta. 7.12 (m,
2H), .delta. 7.26 (m, 8H). LC-MS: 484.2 (M+H.sup.+, 100%);
[0301] benzyl
1S-(1S-hydroxyacetylpentylcarbamoyl)-3-methylbutylcarbamate
(Compound 92);
[0302] benzyl
1S-[1S-(1S-hydroxyacetylpentylcarbamoyl)-3-methylbutylcarbam-
oyl]-3-methylbutylcarbamate (Compound 93); .sup.1H N (CDCl.sub.3):
.delta. 0.81-0.9 (15H, m), .delta. 1.24 (4H, m), .delta. 1.4-1.8
(8H, m), .delta. 4.23 (1H, m), .delta. 4.34 (2H, 2.times.d (AB),
J=19 Hz), .delta. 4.57 (2H, m), .delta. 5.04 (2H, 2.times.d (AB),
J=12 Hz), .delta. 5.75 (1H, m), .delta. 7.18 (1H, m), .delta.
7.24-7.29 (6H, m);
[0303] tert-butyl 4-benzyloxycarbonylamino-4S-(3-hydroxy-2-oxo
-1S-phenethylpropylcarbamoyl)butyrate (Compound 94); .sup.1H NMR
(CDCl.sub.3, mixture of diastereomers): .delta. 1.44 (s, 9H),
.delta. 1.83-1.96 (m, 2H), .delta. 1.98-2.25 (m, 2H), .delta.
2.26-2.52 (m, 2H), .delta. 2.58-2.65 (m, 2H), .delta. 4.16-4.23 (q,
1H), .delta. 4.30 and 4.31 (s and s, 2H), .delta. 4.54-4.63 (m,
1H), .delta. 5.62 and 5.74 (d and d, J=6.7 and 7.4 Hz, 1NH),
.delta. 6.93 and 7.01 (d and d, 1NH), .delta. 7.10-7.33 (m, 10H);
MS (ESI, m/z) 513.3 [M+H].sup.+;
[0304] benzyl
1-(1-hydroxyacetylpentylcarbamoyl)-2-naphthalen-2-ylethylcar-
bainate (Compound 95); .sup.1H NMR (CDCl.sub.3): 0.82 (m, 3H),
.delta. 1.18 (m, 3H), .delta. 1.38 (m, 1H), .delta. 1.68 (m, 3H),
.delta. 3.24 (m, 2H), .delta. 4.18 (m, 2H), .delta. 4.54 (m, 2H),
.delta. 5.06 (s, 2H), .delta. 5.37 (br.s., 11H), .delta. 6.30
(br.s., 1H), .delta. 7.29 (m, 7H), .delta. 7.47 (m, 2H), .delta.
7.60 (m, 1H), .delta. 7.77 (m, 2H). LC-MS: 477.2 (M+H.sup.+,
100%);
[0305] benzyl 1-(1-hydroxyacetylpentylcarbamoyl)pentylcarbamate
(Compound 96); .sup.1H NMR (CDCl.sub.3): 0.87 (m, 6H), .delta. 1.28
(m, 8H), .delta. 1.57 (m, 2H), .delta. 1.81 (m, 3H), .delta. 4.12
(m, 1H), .delta. 4.35 (s, 2H), .delta. 4.60 (m, 1H), .delta. 5.09
(s, 2H), .delta. 5.21 (br.d., 1H), .delta. 6.57 (br.d., 1H),
.delta. 7.29 (m, 5H). LC-MS: 393.1 (M+H.sup.+, 100%);
[0306] benzyl
1-[3-hydroxy-1-(4-methoxybenzyl)-2-oxopropylcarbamoyl]-2-nap-
hthalen-2-ylethylcarbamate (Compound 97); .sup.1H NMR (CDCl.sub.3):
.delta. 2.87 (q, J=14 Hz, J=7.1 Hz, 2H), .delta. 3.15 (m, 2H),
.delta. 3.73 (s, 3H), .delta. 4.49 (m, 1H), .delta. 4.68 (s, 2H),
.delta. 4.73 (m, 1H), .delta. 5.04 (s, 2H), .delta. 5.34 (br. d.,
1H), .delta. 6.31 (br. d., 1H), .delta. 6.68 (d, J=7.5 Hz, 2H),
.delta. 6.87 (d, J=8.10 Hz, 2H), .delta. 7.25 (m, 4H), .delta. 7.41
(m, 4H), .delta. 7.61 (s, 1H), .delta. 7.75 (m, 2H), .delta. 7.85
(m, 1H). LC-MS: 541.2 (M+H.sup.+, 100%);
[0307] benzyl
1-[3-hydroxy-1-(4-methoxybenyl)-2-oxopropylcarbamoyl]pentylc-
arbamate (Compound 98); .sup.1H NMR (CDCl.sub.3): 0.87 (m, 3H),
.delta. 1.25 (m, 4H), .delta. 1.59 (m, 1H), .delta. 1.75 (m, 2H),
.delta. 2.97 (m, 2H), .delta. 3.74 (s, 3H), .delta. 4.14 (m, 2H),
.delta. 4.19 (m, 1H), .delta. 4.78 (m, 1H), .delta. 5.08 (s, 2H),
.delta. 5.18 (br. s., 1H), .delta. 6.54 (br. s., 1H), .delta. 6.81
(d, J=8.1 Hz, 2H), .delta. 6.99 (d, J=7.7 Hz, 2H), .delta. 7.33 (m,
5H). LC-MS: 457.2 (M+H.sup.+, 100%);
[0308] benzyl
1-[3-hydroxy-1-(4-methoxybenzyl)-2-oxopropylcarbamoyl]-2-phe-
nylethylcarbamate (Compound 99); .sup.1H NMR (CDCl.sub.3): 2.75 (m,
2H), .delta. 3.01 (m, 2H), .delta. 3.73 (s, 3H), .delta. 3.81 (br.
s, 1H), .delta. 4.07 (m, 2H), .delta. 4.36 (m, 1H), .delta. 4.70
(m, 1H), .delta. 5.05 (s, 2H), .delta. 5.24 (br. s., 1H), .delta.
6.34 (br. d., 1H), .delta. 6.74 (m, 2H), .delta. 6.87 (m, 2H),
.delta. 7.26 (m, 2H), .delta. 7.38 (m, 8H). LC-MS: 491.2
(M+H.sup.+, 100%);
[0309]
1-tert-butoxymethyl-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbam-
oyl) -2-naphthalen-2-ylethyl]-piperidine-4-carboxamide (Compound
100); .sup.1H NMR (CDCl.sub.3): .delta. 1.43 (s, 9H), .delta.
1.5-1.7 (m, 6H), .delta. 1.99-2.11 (m, 1H), .delta. 2.12-2.28 (m,
1H), .delta. 2.43-2.49 (m, 2H), .delta. 2.62-2.75 (m, 2H), .delta.
3.10-3.30 (m, 2H), .delta. 4.02-4.22 (m, 4H), .delta. 4.42-4.52 (m,
1H), .delta. 4.66-4.74 (m, 1H), .delta. 6.09 (d, J=7.2 Hz, 1NH),
.delta. 6.32 (d, J=7.4 Hz, 1NH), .delta. 6.98-7.02 (m, 2H),
67.16-7.26 (m, 3H), .delta. 7.32-7.36 (m, 1H), .delta. 7.42-7.49
(m, 2H), .delta. 7.63 (s, 1H), .delta. 7.73-7.83 (m, 3H); MS (ESI,
m/z) 602.4 [M+H].sup.+;
[0310] N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-naphthalen-2-ylethyl]piperidine4-carboxyamide (Compound 101);
.sup.1H NMR (DMSO-d.sub.6, (mixture of diastereomers): .delta.
1.4-2.1 (m, 6H), .delta. 2.25-2.65 (m, 3H), .delta. 2.70-2.90 (m,
2H), .delta. 2.95-3.30 (m, 4H), .delta. 4.05-4.32 (m, 3H), .delta.
4.65-4.76 (m, 1H), .delta. 6.98-7.30 (m, 5H), .delta. 7.38-7.52 (m,
3H), .delta. 7.70-7.88 (m, 4H), .delta. 8.2-8.5 (m, 2NH), .delta.
8.5-8.8 (m, 2NH); MS (ESI, m/z) 502.3 [M+H].sup.+;
[0311] benzyl
1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)-4-methylpenty-
lcarbamate (Compound 102); .sup.1H NMR (CDCl.sub.3): 0.91-0.93 (d,
6H), .delta. 1.21-1.24 (t, 1H), .delta. 1.42-1.53 (m, 1H), .delta.
1.60-1.68 (m, 1H), .delta. 1.78-1.93 (m, 1H), .delta. 2.13-2.30 (m,
1H), .delta. 2.54-2.62 (m, 2H), .delta. 4.09-4.14 (m, 2H), .delta.
4.48-4.60 (q, 2H), .delta. 5.09 (s, 1H), .delta. 6.52-6.55 (d, 1H),
.delta. 7.07-7.37 (m, 15H), .delta. M+H.sup.+ (531.4);
[0312]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamovl)-2-phenylethyl]p-
yrrolidine -2-carboxamide hydrochoride (Compound 103); .sup.1H NMR
(DMSO-d.sub.6): 1.6-2.1 (m, 4H), .delta. 2.20-2.70 (m, 2H), .delta.
3.0-3.30 (m, 3H), .delta. 3.56 (s, 1H), .delta. 4.04-4.19 (m, 2H),
.delta. 4.20-4.40 (m, 1H), .delta. 4.63-4.70 (m, 1H), .delta.
7.07-7.40 (m, 10H), .delta. 8.66-8.75 (m, 1H), .delta. 8.89-8.92
(d, d, 1H), .delta. M+H.sup.+ (438.2);
[0313] benzyl 3-carbamoyl-1S-(3-hydroxy-2-oxo
-1S-phenethylpropylcarbamoyl- )propylcarbamate (Compound 104);
.sup.1H NMR (CDCl.sub.3, mixture of diastereomers): .delta. 1.8-2.1
(m, 2H), .delta. 2.1-2.2 (m, 2H), .delta. 2.3-2.5 (m, 2H), .delta.
2.6-2.7 (m, 2H), .delta. 4.2-4.4 (m, 3H), .delta. 4.6-4.7 (m, 1H),
.delta. 5.8-6.0 (m, 2NH), 6.1 and 6.2 (br. s and br. s, 1NH),
.delta. 7.1-7.4 (m, 10H), .delta. 7.7 (br. s, 1NH); MS (ESI, m/z)
456.2 [M+H].sup.+;
[0314] benzyl 5-(2-benzyloxycarbonylamino-3-methyl
hexanoylamino)-7-hydrox- y -6-oxoheptylcarbamate (Compound 105);
.sup.1H NMR (CDCl.sub.3): .delta. 0.86 (m, 6H), .delta. 1.10 (m,
1H), .delta. 1.26 (m, 2H), .delta. 1.43 (m, 3H), .delta. 1.61 (m,
3H), .delta. 1.80 (m, 11), .delta. 3.12 (m, 2H), .delta. 4.10 (m,
1H), .delta. 4.34 (s, 2H), .delta. 4.57 (m, 1H), .delta. 5.12 (s,
4H), .delta. 5.15 (m. 1H), .delta. 5.34 (br. s., 1H), .delta. 6.85
(br. d. 1H), .delta. 7.13 (m, 10 1H). LC-MS: 542.3 (M+H.sup.+,
100%);
[0315] benzyl 4-carbamoyl-1S-(3-hydroxy-2-oxo
-1R-phenethylpropylcarbamoyl- )butylcarbamate (Compound 106);
ESI-MS m/z 456.3 (M+H.sup.+);
[0316] tert-butyl
2-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutylcarbamoyl]pyrrolidine-1-carboxylate (Compound 107);
.sup.1H NMR (CDCl.sub.3): 0.80-1.0 (m, 6H), .delta. 1.42 (s, 9H),
.delta. 1.50-1.70 (m, 3H), .delta. 1.80-2.0 (m, 3H), .delta.
2.1-2.3 (m, 2H), .delta. 2.55-2.60 (t, 2H), .delta. 3.32-3.44 (m,
2H), .delta. 4.11-4.24 (m, 3H), .delta. 4.3-4.4 (m, 1H), .delta.
4.48-4.60 (q, 2H), .delta. 4.65-4.70 (m, 1H), .delta. 7.00-7.40 (m,
10H), .delta. M+H.sup.+ (594.4);
[0317] 2S-(3-benzylureido)-N-(3-hydroxy-2-oxo-1S-phenethylpropyl)
-4-methylpentanamide (Compound 108); .sup.1H NMR (DMSO-d.sub.6,
mixture of diastereomers): .delta. 0.89-0.94 (m, 6H), .delta.
1.34-1.49 (m, 2H), .delta. 1.59-1.69 (m, 1H), .delta. 1.71-1.84 (m,
1H), .delta. 1.91-2.08 (m, 1H), .delta. 2.44-2.66 (m, 2H), .delta.
4.10-4.35 (m, 6H), .delta. 5.07 (br. s, 1H), .delta. 6.18 (d, J=8.4
Hz, 1NH), .delta. 6.46 (t, J=5.3 Hz, 1NH), .delta. 7.14-7.30 (m,
10H), .delta. 8.41 and 8.51 (d and d, J=7.6 and 7.9 Hz, 1 NH); MS
(ESI, m/z) 440.2 [M+H].sup.+;
[0318] tert-butyl
4-[1S-(5-benzyloxycarbonylamino-1S-hydroxyacetylpentylca- rbamoyl)
-2-naphthalen-2-yiethylcarbamoyl]piperidine-1-carboxylate (Compound
109); .sup.1H NMR (DMSO-d.sub.6, mixture of diastereomers): .delta.
1.35 (s, 9H), .delta. 1.01-1.80 (m, 10H), .delta. 2.24-2.36 (m,
1H), .delta. 2.52-2.76 (m, 2H), .delta. 2.81-2.98 (m, 3H), .delta.
3.06-3.22 (m, 1H), .delta. 3.64-3.90 (m, 2H), .delta. 4.11-4.20 (m,
2H), .delta. 4.28-4.38 (m, 1H), .delta. 4.60-4.70 (m, 1H), .delta.
4.98 and 5.00 (br. s and br. s, 2H), .delta. 5.02-5.10 (m, 1H),
.delta. 7.17-7.38 (m, 6H), .delta. 7.42-7.50 (m, 3H), .delta.
7.70-7.88 (m, 5H), .delta. 8.12-8.17 (m, 1NH), .delta. 8.31-8.36
(m, 1 NH); MS (ESI, m/z) 703.4 [M+H].sup.+;
[0319] benzyl
1S-(1S-hydroxyacetylpentylcarbamoyl)-2-methylbutylcarbamate
(Compound 110); .sup.1H NMR (DMSO-d.sub.6): .delta. 0.78-0.85 (m,
9H), .delta. 1.1401.24 (m, 7H), .delta. 1.41-1.69 (m, 2H), .delta.
4.15 (t, 1H), .delta. 4.17-4.19 (m, 2H), 64.35 (m, 1H), .delta.
5.02-5.10 (m, 3H), .delta. 7.34-7.68 (m, 5H), .delta. 8.17 (d, 1H);
MS M+1 (393.1);
[0320] tert-butyl 2-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]-ethylcarbamate (Compound 111); .sup.1H NMR
(CDCl.sub.3): 0.92 (m, 6H), .delta. 1.11 (m, 1H), .delta. 1.42 (s,
9H), .delta. 1.84 (m. 4H), .delta. 2.44 (m, 2H), .delta. 2.63 (m,
2H), .delta. 3.39 (t, J=8.6 Hz, 2H), .delta. 4.24 (m, 1H), .delta.
4.31 (s, 2H), .delta. 4.62 (m, 2H), .delta. 6.19 (br. s., 1H),
.delta. 6.50 (br. d., 1H), .delta. 7.24 (m, 5H). LC-MS: 478.1
(M+H.sup.+, 20%); 378 (100%);
[0321]
2-(3-aminopropionylamino)-N-(3-hydroxy-2-oxo-1-phenethylpropyl)
-3-methylpentanamide hydrochloride (Compound 112); .sup.1H NMR
(MeOH-d.sub.4, dppm): 0.92 (m, 6H), .delta. 1.11 (m, 1H), .delta.
1.84 (m. 4H), .delta. 2.44 (m, 2H), .delta. 2.63 (m, 2H), .delta.
3.39 (t, J=8.6 Hz); 4.24 (m, 1H), .delta. 4.31 (s, 2H), .delta.
4.62 (m, 2H), .delta. 6.19 (br. s., 1H), .delta. 6.50 (br. d., 1H),
.delta. 7.24 (m, 5H). LC-MS: 378.1 (M+H.sup.+, 100%);
[0322] tert-butyl 3-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]propylcarbamate (Compound 113); .sup.1H NMR
(CDCl.sub.3): 0.92 (m, 6H), .delta. 1.11 (m, 1H), .delta. 1.42 (s,
9H), .delta. 1.84 (m. 4H), 62.23 (m, 2H), 62.61 (m, 2H), .delta.
3.08 (m, 2H), .delta. 4.39 (m, 3H), .delta. 4.58 (m, 1H), .delta.
4.95 (br.s. 1H), .delta. 7.20 (m, 5H). LC-MS: 492.1 (M+H.sup.+,
20%); 392 (100%);
[0323]
2-(4-aminobutyrylamino)-N-(3-hydroxy-2-oxo-1-phenethylpropyl)
-3-methylpentanamide hydrochloride (Compound 114); .sup.1H NMR
(MeOH-d.sub.4): 0.92 (m, 6H), .delta. 1.11 (m, 1H), .delta. 1.84
(m. 4H), .delta. 2.23 (m, 2H), .delta. 2.61 (m, 2H), .delta. 3.08
(m, 2H), .delta. 4.39 (m, 3H), .delta. 4.58 (m, 1H), .delta. 4.95
(br.s. 1H), .delta. 7.20 (m, 5H). LC-MS: 392.1 (M+H.sup.+,
100%);
[0324] tert-butyl 5-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyllpentylcarbamate (Compound 115); .sup.1H NMR
(CDCl.sub.3): 0.92 (m, 6H), .delta. 1.13 (m, 1H), .delta. 1.34 (m,
1H), .delta. 1.42 (s, 9H), .delta. 1.48-1.53 (m, 5H), .delta. 1.64
(m, 1H), .delta. 1.84-2.00 (m. 4H), .delta. 2.23 (m, 2H), .delta.
2.62 (m, 2H), .delta. 3.08 (m, 2H), .delta. 4.24 (m, 1H), .delta.
4.33 (m, 2H), .delta. 4.61 (m, 1H), .delta. 6.01 (br.s. 1H),
.delta. 6.60 (br. s. 1H), .delta. 7.24 (m, 5H). LC-MS: 520.1
(M+H.sup.+, 20%); 420.1 (20%); 392 (100%);
[0325] 6-amino-N-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutyl]hexanamide hydrochloride (Compound 116);
[0326]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]--
1,4']bipiperidinyl-1'-carboxamide (Compound 117); .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.80-0.87 (m, 6H), .delta. 1.23-1.64 (m,
15H), .delta. 2.46-2.61 (m, 10H), .delta. 3.99-4.19 (m, 6H),
.delta. 6.37 (d, 11), .delta. 7.16-7.23 (m, 5H), .delta. 8.29 (d,
1H); MS M+1(501.4);
[0327]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]--
4-methylpiperazine-1-carboxamide (Compound 118); .sup.1H NMR
(DMSO-d.sub.6, mixture of diastereomers): .delta. 0.80-0.87 (m,
6H), .delta. 1.15 (m, 1H), .delta. 1.77 (m, 1H), .delta. 1.79-2.22
(m, 10H), .delta. 2.55-2.58 (m, 2H), .delta. 3.31-3.40 (m, 6H),
.delta. 4.00-4.26 (m, 3H), .delta. 6.35 (m, 1H), .delta. 7.15-7.23
(m, 5H), .delta. 8.29, 8.31 (d, 1H); MS M+1 (433.2);
[0328] N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-phenylacetylaminopentanamide (Compound 119); .sup.1H NMR
(CDCl.sub.3). 0.79-0.86 (6H, d, t, J=7 Hz); 1.0 (1H, m); 1.24-1.38
(2H, m); 1.79 (2H, m); 2.07 (1H, m); 2.53 (2H, m); 3.55 (2H, s);
4.28 (2H, s); 4.32 (1H, m); 4.51 (1H, m); 6.16 (1H, d, J=8.6 Hz);
7.05-7.26 (11H, m); MS (M+1): 425.
[0329] tert-butyl
2-benzyloxycarbonylamino-2-(3-hydroxy-2-oxo-1-phenethylp-
ropylcarbamoyl)ethylcarbamate (Compound 120); .sup.1H NMR
(CDCl.sub.3): 1.42 (s, 9H), .delta. 1.87 (m, 1H), .delta. 2.17 (m,
1H), .delta. 2.62 (m, 2H), .delta. 4.28 (m, 3H), .delta. 4.54 (m,
1H), .delta. 5.13 (s, 2H), .delta. 5.17 (m, 1H), .delta. 6.26 (br.
s., 1H), .delta. 6.39 (br. s. 1H), .delta. 2.30 (m, 10H). LC-MS:
514.2 (M+H.sup.+, 100%);
[0330] tert-butyl 1-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]-2-phenylethylcarbamate (Compound 121);
.sup.1H NMR (CDCl.sub.3): 0.92 (m, 6H), .delta. 1.11 (m, 1H),
.delta. 1.24 (m, 2H), .delta. 1.42 (s, 9H), .delta. 1.98 (m. 4H),
.delta. 2.63 (m, 2H), .delta. 3.31 (m, 2H), .delta. 4.21 (m, 1H),
.delta. 4.30 (s, 2H), .delta. 4.56 (m, 1H), .delta. 5.00 (br.s.,
1H), .delta. 6.00 (br. s., 1H), .delta. 6.31 (br. d., 1H), .delta.
7.24 (m, 10H). LC-MS: 554.2 (M+H.sup.+, 20%); 422.9 (30%); 317
(33%); 275.9 (100%);
[0331] tert-butyl 1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoylmethylcarbamate (Compound 122);
[0332] benzyl 2-biphenyl-4-yl-1-(3-hydroxy-2-oxo
-1-phenethylpropylcarbamo- yl)ethylcarbamate (Compound 123);
.sup.1H NMR (CDCl.sub.3): 1.85 (m, 2H), .delta. 2.12 (m, 2H),
.delta. 2.49 (m, 2H), .delta. 3.08 (m, 2H), .delta. 4.21 (m, 2H),
.delta. 4.40 (m, 1H), .delta. 4.56 (m, 1H), .delta. 5.04 (s, 2H),
.delta. 5.14 (br.s, 1H), .delta. 6.32 Bbr.s., 1H), .delta. 7.02 (m,
2H), .delta. 7.24-7.51 (m, 16H). LC-MS: 551.2 (M+H.sup.+,
100%);
[0333] benzyl 1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-(4-nitrophenyl)ethylcarbamate (Compound 124); .sup.1H NMR
(CDCl.sub.3, mix. of diastereomers): 1.85 (m, 21H), .delta. 2.12
(m, 2H), .delta. 2.56 (m, 2H), .delta. 3.06 (m, 1H), .delta. 3.21
(m, 1H), .delta. 4.29 (m, 2H), .delta. 4.37 (m, 1H), .delta. 4.62
(m, 1H), .delta. 5.04 (s, 2H), .delta. 5.14 (br.s. M), .delta.
6.39.6.59 (br. s., 1H), 67.23 (d, J=8.1 Hz, 2H), .delta. 7.28 (m,
10H), .delta. 8.08 (d J=8.3 Hz, 2H). LC-MS: 520.2 (M+H.sup.+,
100%);
[0334] methyl N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]succinamate (Compound 125); .sup.1H NMR
(CDCl.sub.3): 0.94 (6H, d, t, J=7 Hz); 1.12 (1H, m); 1.47 (1H, m);
1.98 (2H, m); 2.20 (1H, m); 2.46 (2H, m); 2.55-2.9 (4H, m); 3.61
(3H, s); 4.30 (2H, s); 4.31 (2H, m); 4.61 (1H, m); 5.97 (1H, d, J=8
Hz); 6.89 (11H, d, J=7 Hz); 7.14-7.27 (5H); MS (M+1): 421;
[0335] 2-(2-aminoacetylamino)-N-(3-hydroxy-2-oxo-1-phenethylpropyl)
-3-methylpentanamide hydrochloride (Compound 126); .sup.1H NMR
(MeOH-d.sub.4): 0.91 (m, 6H), .delta. 1.11 (m, 1H), .delta. 1.96
(m. 5H), .delta. 2.63 (m, 2H), .delta. 3.78 (m, 2H), .delta. 4.21
(m, 1H), .delta. 4.30 (m, 2H), .delta. 4.62 (m, 1H), .delta. 5.10
(br.s. 1H), .delta. 6.39 (br. s., 1H), .delta. 6.50 (br. s., 1H),
.delta. 7.24 (m, 5H). LC-MS: 364.2 (M+H.sup.+, 100%);
[0336]
2-(2-amino-3-phenylpropionylamino)-N-(3-hydroxy-2-oxo-1-phenethylpr-
opyl) -3-methylpentanamide hydrochloride (Compound 127);
[0337] benzyl
2-amino-1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)ethylc-
arbamate hydrochloride (Compound 128); .sup.1H NMR (MeOH-d.sub.4):
1.87 (m, 1H), .delta. 2.17 (m, 1H), .delta. 2.62 (m, 2H), .delta.
4.28 (m, 3H), .delta. 4.54 (m, 1H), .delta. 5.13 (s, 2H), .delta.
5.17 (m, 1H), .delta. 6.26 (br. s., 1H), .delta. 6.39 (br. s. 1H),
.delta. 2.30 (m, 10H). LC-MS: 414.2 (M+H.sup.+, 100%).
[0338] N-(3-hydroxy-2-oxo-1-phenethylpropyl)-3-methyl
-2-(naphthalen-2-ylsulfonylamino)pentanamide (Compound 129);
.sup.1H NMR (CDCl.sub.3): 0.91 (m, 6H), .delta. 1.11 (m, 1H),
.delta. 1.58-1.77 (m, 41), .delta. 2.30 (t, J=7.9 Hz, 2H), .delta.
3.58 (m, 1H), .delta. 4.21 (m, 2H), .delta. 4.42 (m, 1H), .delta.
5.14 (d, J=7.9 Hz, 1H), .delta. 6.28 (d, J=7.3 Hz, 1H), .delta.
6.94 (d, J=8.2 Hz, 2H), .delta. 7.24 (m, 3H), .delta. 7.55 (m, 2H),
.delta. 7.81 (m, 2H), .delta. 7.93 (m, 2H), .delta. 8.41 (m, 1M).
LC-MS: 497.2 (M+H.sup.+, 100%);
[0339]
N-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)-2-methylbutyl]nap-
hthalene -2-carboxamide (Compound 130); .sup.1H NMR (DMSO-d.sub.6):
0.93 (m, 6H), .delta. 1.21 (m, 1H), .delta. 1.64 (m, 1H), .delta.
2.05 (m, 3H), .delta. 2.63 (m, 2H), .delta. 4.30 (m, 2H), .delta.
4.63 (m, 2H), .delta. 6.82-7.37 (m, 6H), .delta. 7.55 (m, 11),
.delta. 7.86 (m, 4H), .delta. 8.37 (m, 1H). LC-MS: 461.2
(M+H.sup.+, 100%);
[0340] 2S-(3-benzylureido)-N-(3-hydroxy-2-oxo-1S-phenethylpropyl)
-3-methylpentanamide (Compound 131); .sup.1H NMR (DMSO-d.sub.6,
mixture of diastereomers): .delta. 0.83-0.89 (m, 6H), .delta.
1.02-1.14 (m, 1H), .delta. 1.40-1.52 (m, 1H), .delta. 1.65-1.84 (m,
2H), .delta. 1.94-2.06 (m, 1H), .delta. 2.48-2.68 (m, 2H), .delta.
4.10-4.36 (m, 6H), .delta. 5.08 (br. s, 1H), .delta. 6.16 (d, J=9.1
Hz, 1NH), .delta. 6.50-6.54 (m, 1NH), .delta. 7.14-7.32 (m, 10H),
.delta. 8.41 and 8.51 (d and d, J=7.4 and 7.4 Hz, 1NH); MS (ESI,
m/z) 440.1 [M+H].sup.+;
[0341] tert-butyl
3-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]benzylcarbamate (Compound 132); .sup.1H NMR
(CDCl.sub.3): 0.89 (3H, t, J=7 Hz); 0.93 (3H, d, 7 Hz); 1.2 (1H,
m); 1.42 (9H, s); 1.62 (1H, m); 1.97 (1H, m); 2.05 (2H, m);
2.48-2.63 (2H, m, 2 isomers, LL, LD at Ile-HpH), .delta. 4.23 (2H,
m); 4.33 (2H, d, J=8 Hz); 4.57 (1H, m); 4.64 (1H, m); 5.10 (1H, m);
7.09 (1H, m); 7.14-7.8 (9H, m). MS: 540 (M+1);
[0342] benzyl 7-hydroxy-5S-[3-naphthalen-1-yl
-2S-(piperidin-4-ylcarbonyla-
mino)propionylamino]-6-oxoheptylcarbamate (Compound 133); .sup.1H
NMR (DMSO-d.sub.6, mixture of diastereomer): .delta. 1.0-1.8 (m,
10H), .delta. 2.35-2.48 (m, 1H), .delta. 2.7-3.5 (m, 8H), .delta.
4.09-4.18 (m, 2H), .delta. 4.18-4.36 (m, 1H), .delta. 4.62-4.71 (m,
1H), .delta. 4.92-5.10 (m, 3H), .delta. 7.16-7.50 (m, 5H), .delta.
7.40-7.50 (m, 3H), .delta. 7.71-7.87 (m, 5H), .delta. 8.1-8.7 (br.
m, 4 NH); MS (ESI, m/z) 603.3 [M+H].sup.+;
[0343] benzyl
3-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)-3,4-dihydro
-1H-isoquinoline-2-carboxyate (Compound 134); .sup.1H NMR
(CDC.sub.3): 1.55 (m, 2), .delta. 1.88 (m, 2H), .delta. 3.10 (m,
1H), .delta. 3.29 (m, 1H), .delta. 4.08 (m, 1H), .delta. 4.17 (m,
1H), .delta. 4.40 (m, 1H), .delta. 4.62 (m, 2H), .delta. 4.88 (m,
1H), .delta. 5.22 (s, 2H), .delta. 6.90 (br.s, 1H), .delta. 7.21
(m, 13H). LC-MS: 487.2 (M+H.sup.+, 100%);
[0344] benzyl
cyclohexyl-(1S-hydroxyacetylpentylcarbamoyl)methylcarbamate
(Compound 135); .sup.1H NMR (CDCl.sub.3): .delta. 1.26 (m, 8H),
.delta. 1.62 (m, 9H), .delta. 4.18 (m, 11H), .delta. 4.35 (s, 2H),
.delta. 4.58 (m, 2H), .delta. 5.03 (br.s., 1H), .delta. 5.10 (s,
2H), .delta. 6.47 (br.s, 1H), .delta. 7.33 (m, 10H). LC-MS: 419.2
(M+H.sup.+, 100%);
[0345] N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2S-methylbutyl]isonicotinamide (Compound 136); .sup.1H NMR
(DMSO-d.sub.6, mixture of diastereomers): .delta. 0.86-1.02 (m,
6H), .delta. 1.17-1.31 (m, 1H), .delta. 1.51-1.66 (m, 1H), .delta.
1.90-2.08 (m, 2H), .delta. 2.08-2.23 (m, 1H), .delta. 2.50-2.67 (m,
2H), .delta. 3.65 and 3.71 (s and s, 2H), .delta. 4.49-4.66 (m,
2H), .delta. 6.68 and 6.84 (d and d, J=7.9 Hz, 1NH), .delta.
7.00-7.30 (m, 6H), .delta. 7.62-7.67 (m, 2H), .delta. 8.68-8.78 (m,
2H); MS (ESI, m/z) 412.2 [M+H].sup.+;
[0346] N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(3-phenylpropionylamino)pentanamide (Compound 137); .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.76-0.84 (m, 6H), .delta. 1.06 (m, 1H),
.delta. 1.36 (m, 1H), .delta. 1.69-1.98 (m, 2H), .delta. 2.45-3.00
(m, 6H), .delta. 4.15-4.25 (m, 4H), .delta. 5.08 (t, 1H), .delta.
7.17-7.26 (m, 10H), .delta. 7.99 (d, 1H), .delta. 8.38 (d, 1H); MS:
M+1(439.2);
[0347] tert-butyl
4-[1S-(1S-benzyloxymethyl-3-hydroxy-2-oxopropylcarbamoyl- )
-2-naphthalen-2-ylethylcarbamoyl]piperidine-1-carboxylate (Compound
138); .sup.1H NMR (DMSO-d.sub.6, mixture of diastereomers): .delta.
1.35 (s, 9H), .delta. 1.23-1.56 (m, 4H), .delta. 2.22-2.34 (m, 1H),
.delta. 2.50-2.75 (m, 2H), .delta. 2.88-3.26 (m, 2H), .delta.
3.62-3.86 (m, 4H), .delta. 4.1-4.3 (m, 2H), .delta. 4.35-4.55 (m,
2H), .delta. 4.62-4.78 (m, 2H), .delta. 5.14-5.20 (m, 1H), .delta.
7.25-7.35 (m, 5H), .delta. 7.40-7.50 (m, 3H), .delta. 7.70-7.87 (m,
4H), .delta. 8.15-8.19 (m, 1NH), .delta. 8.43 and 8.48 (d and d,
J=7.2 Hz, 1 NH); MS (ESI, m/z) 618.3 [M+H].sup.+;
[0348]
N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-2S-(2-1H-indol-3-ylacetylami-
no) -3-methylpentanamide (Compound 139); .sup.1H NMR (CDCl.sub.3):
0.93 (m, 6H), .delta. 1.21 (m, 1H), .delta. 1.34 (m, 1H), .delta.
1.43 (m, 1H), .delta. 1.73 (m, 2H), .delta. 1.96 (m, 1H), .delta.
2.05 (m, 3H), .delta. 2.54 (m, 2H), .delta. 3.58 (m, 2), .delta.
4.15 (m, 2), .delta. 4.28 (m, 2H), .delta. 6.82 (m, 1H), .delta.
6.91 (m, 1H), .delta. 7.37 (m, 5H), .delta. 7.56 (m, 1H), .delta.
7.98 (m, 1H), .delta. 8.50 (m, 1H), .delta. 10.85 (s, 1H). LC-MS:
464.2 (M+H.sup.+, 100%);
[0349]
N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-2S-(3,3-diphenylpropionylami-
no) -3-methylpentanamide (Compound 140); .sup.1H NMR (CDCl.sub.3):
0.65 (m, 6H), .delta. 0.85-1.00 (m, 3H), .delta. 1.57-1.94 (m, 4H),
.delta. 2.58-2.78 (m, 2H), .delta. 3.10 (m, 1H), .delta. 3.19(m,
2H), .delta. 4.13(s, 1H), .delta. 4.22-4.46 (m, 2H), .delta.
6.91-7.41 (m, 15H), .delta. 7.97 (s, 1H), .delta. 8.34 (s, 1H).
LC-MS: 515.2 (M+H.sup.+, 100%);
[0350]
N-1[S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]n-
aphthalene -1-carboxamide (Compound 141); .sup.1H NMR
(DMSO-d.sub.6): 0.93 (m, 6H), .delta. 1.24 (m, 1H), .delta. 1.59
(m, 1H), .delta. 1.81 (m, 1H), .delta. 2.05 (m, 2H), .delta. 2.63
(m, 2H), .delta. 4.15 (m, 2H), .delta. 4.22 (m, 1H), .delta. 4.55
(m, 1H) 5.08 (m, 1H), .delta. 7.19 (m, 5H), .delta. 7.60 (m, 2H),
.delta. 7.98 (m, 4H), .delta. 8.56 (m, 3H). LC-MS: 461.2
(M+H.sup.+, 100%);
[0351] 2S-(3-benzylureido)-N-(3-hydroxy-2-oxo-1S-phenethylpropyl)
-3-naphthalen-2-ylpropionamide (Compound 142); .sup.1H NMR
(DMSO-d.sub.6, mixture of diastereomers): .delta. 1.74-1.88 (m,
1H), .delta. 1.95-2.10 (m, 1H), .delta. 2.48-2.65 (m, 2H), .delta.
2.89-3.28 (m, 2H), .delta. 4.03-4.39 (m, 5H), .delta. 4.61-4.69 (m,
1H), .delta. 6.25-6.33 (m, 1NH), .delta. 6.49-6.54 (m, 1NH),
.delta. 6.94-7.28 (m, 10H), .delta. 7.41-7.50 (m, 3H), .delta. 7.74
(br. s, 1H), .delta. 7.79-7.89 (m, 4H), .delta. 8.53 (d, J=7.7 Hz,
1NH); MS (ESI, m/z) 524.3 [M+H].sup.+;
[0352] N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(2-pyridin-4-ylacetylamino)pentanamide (Compound 143); .sup.1H
NMR (DMSO-d.sub.6, mixture of diastereomers): .delta. 0.67-0.98 (m,
6H), .delta. 1.15-1.57 (m, 2H), .delta. 1.83-2.11 (m, 3H),
62.53-2.66 (m, 2H), .delta. 3.72 (s, 2H), .delta. 4.26-4.30 (m,
4H), .delta. 7.12-7.17 (m, 5H), .delta. 7.45-7.47 (m, 2H), .delta.
8.32,8.41(m, 4H); MS: M+1(426.1);
[0353]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]b-
enzamide (Compound 144);
[0354] tert-butyl
4-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutylcarbamoyl]benzylcarbamate (Compound 145); .sup.1H NMR
(DMSO-d.sub.6): 0.93 (m, 6H), .delta. 1.38 (s, 9H), .delta. 1.56
(m, 1H), .delta. 1.73 (m, 2H), .delta. 1.81 (m, 1H), .delta. 2.63
(m, 2H), .delta. 4.15 (m, 2H), .delta. 4.22 (m, 1H), .delta. 5.08
(m, 1H), .delta. 7.19 (m, 4H), .delta. 7.32 (m, 1H), .delta. 7.88
(m, 2H), .delta. 8.56 (m, 2H). LC-MS: 540.1 (M+H.sup.+, 100%);
[0355]
4-aminomethyl-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-3-methylbutyl]benzamide hydrochoride (Compound 146); .sup.1H NMR
(DMSO-d): 0.93 (m, 6H), .delta. 1.56 (m, 1H), .delta. 1.73 (m, 2H),
.delta. 1.81 (m, 1H), .delta. 2.63 (m, 2H), .delta. 4.15 (m, 2H),
.delta. 4.22 (m, 3H), .delta. 5.08 (m, 1H), .delta. 7.19 (m, 4H),
67.32 (m, 1H), .delta. 7.88 (m, 2H), .delta. 8.56 (m, 2H). LC-MS:
440.1 (M+H.sup.+, 100%);
[0356] N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(2-pyridin-3-ylacetylamino)pentanamide (Compound 147); .sup.1H
NMR (DMSO-d.sub.6): .delta. 0.78-0.86 (m, 6H), .delta. 1.15 (m,
1H), .delta. 1.44 (m, 1H), .delta. 1.72-1.77 (m, 3H), .delta.
2.50-2.59 (m, 2H), .delta. 3.48-3.62 (m, 2H), .delta. 4.14-4.26 (m,
4H), .delta. 5.08 (m, 1H), .delta. 7.14-7.67 (m, 6H), .delta. 7.65
(m, 1H), .delta. 8.35-8.46 (m, 4H); MS: M+1(426.1);
[0357] tert-butyl 4-[1S-(1S-hydroxyacetylpentylcarbamoyl)
-2-methylbutylcarbamoyl]benzylcarbamate (Compound 148); .sup.1H NMR
(DMSO-d.sub.6): 0.88 (m, 9H), .delta. 1.23 (m, 5H), .delta. 1.42
(s, 9H), .delta. 1.56 (m, 1H), .delta. 1.69 (m, 2H), .delta. 1.81
(m, 1H), .delta. 4.19 (m, 5H), .delta. 4.36 (m, 1H), .delta. 5.08
(t, J=8.3 Hz, 1H), .delta. 7.32 (m, 2H), .delta. 7.45 (t, J=8.0 Hz,
1H), .delta. 7.83 (d, J=8.1 Hz, 1H), .delta. 8.30 (d, J=7.5 Hz, 1H)
LC-MS: 492.3 (M+H.sup.+, 100%);
[0358]
4-aminomethyl-N-[1S-(1S-hydroxyacetylpentylcarbamoyl)-2-methylbutyl-
]benzamide hydrochloride (Compound 149);
[0359] N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]isophthalamide (Compound 150); .sup.1H NMR
(DMSO-d.sub.6): 0.80-1.0 (m, 6H), .delta. 1.19-1.3 (m, 1H), .delta.
1.50-1.60 (m, 1H), .delta. 1.70-1.85 (m, 1H), .delta. 1.90-2.10 (m,
1H), .delta. 3.60-3.70 (m, 1H), .delta. 4.17-4.19 (d, 2H), .delta.
4.29-4.35 (m, 1H), .delta. 4.40-4.45 (t, 1H), .delta. 5.0-5.10 (m,
1H), .delta. 7.14-7.30 (m, 4H), .delta. 7.50-7.60 (m, 1H), .delta.
8.0-8.10 (m, 2H), .delta. 8.37 (s, 1H), .delta. 8.50-8.53 (d, 1H),
6 M+H.sup.+ (454.2);
[0360] 4-benzyloxycarbonylamino-4S-(3-hydroxy
-2-oxo-1S-phenethylpropylcar- bamoyl)butyric acid (Compound 151);
.sup.1H NMR (DMSO-d.sub.6) 1.70-2.05 (m, 4H), .delta. 2.31 (t,
J=7.7 Hz, 2H), .delta. 2.5-2.7 (m, 2H), .delta. 4.03-4.36 (m, 4H),
.delta. 5.04 (br. s, 2H), .delta. 7.12-7.35 (m, 10H), .delta. 7.75
(d, J=7 Hz, 1NH), .delta. 8.36 (d, J=7.4 Hz, 1NH), .delta. 12.2
(br. s, 1);
[0361]
N-[1S-(1S-hydroxyacetylpentylcarbamoyl)-2-methylbutyl]isophthalamid-
e (Compound 152); .sup.1H NMR (CD.sub.3OD): 0.80-1.10 (m, 9H),
.delta. 1.30-1.35 (m, 614), .delta. 1.51-1.71 (m, 2H), .delta.
1.80-1.90 (m, 1H), .delta. 1.90-2.10 (m, 1H), .delta. 4.34 (s, 2H),
.delta. 4.44-4.61 (m, 2H), .delta. 7.54-7.60 (t, 1H), .delta.
7.97-8.04 (m, 2H), .delta. 8.33 (s, 1H), 6 M+H.sup.+ (406. 1);
[0362] 4-aminomethyl-N-[1S-(1S-hydroxyacetylpentylcarbamoyl)
-2-naphthalen-2-ylethyl]benzamide hydrochloride (Compound 153);
.sup.1H NMR (DMSO-d.sub.6): 0.72 (s, 3H), .delta. 1.10 (m, 1H),
.delta. 1.25-1.31 (m, 3H), .delta. 1.54 (m, 1H), .delta. 1.75 (m,
1H), .delta. 3.26-3.31 (m, 2H), .delta. 4.04 (s, 2H), .delta.
4.25-4.58 (m, 6H), .delta. 4.90 (br.s., 1H), .delta. 7.31-7.72 (m,
10H), .delta. 7.83-7,92 (m, 5H), .delta. 8.21 (br. s, 2H), .delta.
8.56 (d, J=8.1 Hz, 1H), .delta. 8.74 (d, J=8.1 Hz, 1H) LC-MS: 566.3
(M+H.sup.+, 100%);
[0363] 3-aminomethyl-N-[1S-(1S-hydroxyacetylpentylcarbamoyl)
-2-naphthalen-2-ylethyl]benzamide hydrochloride (Compound 154); MS:
476.2 (M+H.sup.+, 100%);
[0364] tert-butyl 4-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2S-methylbutylcarbamoyl]piperidine-1-carboxylate (Compound 155);
.sup.1H NMR (DMSO-d.sub.6, mixture of two less polar diastereomers)
0.79-0.87 (m, 6H), .delta. 1.02-1.18 (m, 1H), .delta. 1.38 (s, 9H),
.delta. 1.3-1.5 (m, 3), .delta. 1.56-1.78 (m, 3), .delta. 1.85-2.00
(m, 2H), .delta. 2.4-2.8 (m, 5H), .delta. 3.58 and 3.59 (br. s and
br. s, 2H), .delta. 3.92 (br. d, J=12 Hz, 2H), .delta. 4.08-4.30
(m, 2H), .delta. 7.15-7.28 (m, 5H), .delta. 7.83 and 7.92 (d and d,
J=8.9 Hz, 1NH), .delta. 8.44 and 8.47 (d and d, J=7.4 and 7.9 Hz,
1NM); MS (ESI, m/z) 518.3 [M+H].sup.+;
[0365] tert-butyl 4-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)
-2S-methylbutylcarbamoyl]piperidine-1-carboxylate (Compound 156);
.sup.1H NMR (DMSO-d.sub.6, mixture of two more polar
diastereomers): .delta. 0.80-0.87 (m, 6H), .delta. 1.04-1.18 (m,
1H), .delta. 1.38 (s, 9H), .delta. 1.3-1.5 (m, 3H), .delta.
1.556-1.82 (m, 4H), .delta. 1.90-2.05 (m, 1H), .delta. 2.4-2.8 (m,
5H), .delta. 3.58 and 3.59 (br. s and br. s, 2H), .delta. 3.92 (br.
d, J=12 Hz, 2H), .delta. 4.08-4.30 (m, 2H), .delta. 7.15-7.28 (m,
5H), .delta. 7.83 and 7.92 (d and d, J=8.9 Hz, 1NH), .delta. 8.44
and 8.47 (d and d, J=7.4 and 7.9 Hz, 1NH); MS (ESI, m/z) 518.3
[M+H].sup.+;
[0366] 3-fluoro-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]benzaniide (Compound 157); .sup.1H NMR
(DMSO-d.sub.6): .delta. 0.84-0.95 (m, 6H), .delta. 1.20-2.00 (m,
5H), .delta. 2.50-2.60 (m, 2H), .delta. 4.16-4.37 (m, 4H), .delta.
5.06-5.08 (m, 1H), .delta. 7.15-7.75 (m, 9H), .delta. 8.52-8.59 (m,
2H); MS: M+1(429.1);
[0367]
2S-(dibenzofuran-2-sulfonylamino)-N-(3-hydroxy-2-oxo-1S-phenethylpr-
opyl) -3-methylpentanamide (Compound 158); .sup.1H NMR
(CD.sub.3OD): 0.76-0.98 (m, 6H), .delta. 1.0-1.20 (m, 2H), .delta.
1.40-1.60 (m, 1H), .delta. 1.65-1.81 (m, 2H), .delta. 1.95-2.10 (m,
1H), .delta. 2.40-2.60 (m, 1H), .delta. 3.68-3.80 (m, 2H), .delta.
4.02 (s, 2H), .delta. 4.29-4.34 (m, 1H), .delta. 6.81-6.82 (m, 1H),
.delta. 7.08-7.21 (m, 4H), .delta. 7.35-7.75 (m, 4H), .delta.
8.00-8.19 (m, 4H), .delta. 7.95-8.15 (m, 2H), .delta. 8.58 (m, 1H),
6 M+H.sup.+ (537.2);
[0368]
N-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)-2S-methylbutyl]pi-
peridine -4-carboxamide (Compound 159); .sup.1H NMR (DMSO-d.sub.6,
mixture of two less polar diastereomers): .delta. 0.80-0.88 (m,
6H), .delta. 1.06-1.16 (m, 1H), .delta. 1.36-1.52 (m, 1H), .delta.
1.66-2.02 (m, 7H), .delta. 2.5-2.7 (m, 3H), .delta. 2.76-2.92 (m,
2H), .delta. 3.21-3.33 (m, 2H), .delta. 3.58 and 3.59 (br. s and
br. s, 2H), .delta. 4.07-4.32 (m, 2H), .delta. 7.15-7.32 (m, 5H),
.delta. 8.01-8.09 (m, 1NH), .delta. 8.52 and 8.58 (d and d, J=7.4
and 7.2 z, 1NH), .delta. 8.5-8.65 (br, 1 NH), .delta. 8.9-9.0 (br,
1 NH); MS (ESI, m/z) 418.2 [M+H].sup.+;
[0369]
N-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamovl)-2S-methylbutyl]pi-
peridine -4-carboxamide (Compound 160); .sup.1H NMR (DMSO-d.sub.6,
mixture of two less polar diastereomers): .delta. 0.80-0.88 (m,
6H), .delta. 1.06-1.18 (m, 1H), .delta. 1.36-1.50 (m, 1H), .delta.
1.66-2.04 (m, 7H), .delta. 2.5-2.7 (m, 3H), .delta. 2.75-2.91 (m,
2H), .delta. 3.2-3.3 (m, 2H), .delta. 3.56 (s, 2H), .delta.
4.07-4.32 (m, 2H), .delta. 7.14-7.32 (m, 5H), .delta. 8.05-8.16 (m,
1NH), 6,8.47 and 8.57 (d and d, J=7.4 and 7.2 Hz, 1NH), .delta.
8.5-8.65 (br, 1 NH), .delta. 8.9-9.05 (br, 1NH); MS (ESI, m/z)
418.2 [M+H].sup.+;
[0370]
N-[1-(3-hydroxy-2-oxo-1-phenethylpropylcarbamoyl)-2-methylbutyl]-3--
ureido-benzamide (Compound 161); .sup.1H NMR (DMSO-d.sub.6):
.delta. 0.93 (m, 6H), .delta. 1.11 (m, 1H), .delta. 1.56 (m, 2H),
.delta. 1.81 (m, 1H), .delta. 2.00 (m, 2H), .delta. 2.51 (m, 2H),
.delta. 4.17 (m, 2H), .delta. 4.37 (m, 2H), .delta. 5.06 (s, 1),
.delta. 1.68 (s, 2H), .delta. 7.25 (m, 5H), .delta. 7.61 (m, 1H),
.delta. 7.82 (s, 1H), .delta. 8.30 (br. d, 1H), .delta. 8.43 (br.
d, 1H), .delta. 8.70 (s, 1H). LC-MS: 469.1 (M+H.sup.+, 100%);
[0371] tert-butyl
3-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]phenylcarbamate (Compound 162);
[0372] 3-amino-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]benzamide (Compound 163);
[0373]
3-hydroxy-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]benzaminde (Compound 164); and
[0374] benzyl
1S-(3-hydroxyacetyl-3,4-dihydro-1H-isoquinolin-2-ylcarbonyl)
-3-methylbutylcarbamate (Compound 165).
Example 4
Benzyl
1-(3-hydroxy-3-methyl-2-oxo-1-phenethylbutylcarbamoyl)-3-methylbuty-
lcarbamate (Compound 166)
[0375] 29
[0376] (a) A solution comprised of isopropyltriphenylphosphonium
iodide (13.02 g, 30.1 mmol) in THF (80 mL) was cooled to
-78.degree. C. and then n-butyllithium (12.44 mL, 2.5M in hexane)
was added. The mixture was stirred for 5 minutes, heated to room
temperature and stirred for an additional 25 minutes. Benzyl
1-(1-formyl-3-phenylpropylcarbamoyl)-3-meth- ylbutylcarbamate (4.12
g, 10.04 mmol), prepared as in the procedure set forth in
Synthesis, 1983, pp 676-678, was dissolved in THF (40 mL) and the
solution was added dropwise. The mixture was stirred for 18 hours
at room temperature and then diluted with water (5 mL) and ethyl
acetate (250 mL). The organic layer was washed with 1M hydrochloric
acid, saturated aqueous sodium bicarbonate and brine, dried
(MgSO.sub.4) and concentrated to dryness in vacuo. Product was
purified from the residue by column chromatography using 20% ethyl
acetate/hexane to provide benzyl
3-methyl-1-(3-methyl-1-phenethylbut-2-enylcarbamoyl)butylcarbamate
(0.75 g, 1.68 mmol) as a clear oil.
[0377] (b) A solution comprised of benzyl 3-methyl-1-(3-methyl
-1-phenethylbut-2-enylcarbamoyl)butylcarbamate (0.750 g, 1.72 mmol)
in acetonitrile (10 mL) was cooled in an ice bath and then
4-methylmorpholine N-oxide (0.403 g, 3.44 mmol) and osmium
tetroxide (2.0 mL, 4% by weight solution in water) were added. The
mixture was stirred, while continually cooled in the ice bath, for
18 hours and then diluted with 1M hydrochloric acid and ethyl
acetate. The mixture was washed with saturated aqueous sodium
bicarbonate, dried (MgSO.sub.4) and concentrated to dryness in
vacuo. Product was purified from the residue by column
chromatography in 20% ethyl acetate/methylene chloride to provide
benzyl 1-(2,3-dihydroxy-3-methyl-1-phenethylbutylcarbamoyl)
-3-methylbutylcarbamate (0.25 g, 0.53 mmol) as a white solid.
[0378] (c) A solution comprised of benzyl 1-(2,3-dihydroxy-3-methyl
-1-phenethylbutylcarbamoyl)-3-methylbutylcarbamate (0.250 g, 0.532
mmol) and Dess-Martin Periodate (0.451 g, 1.06 mmol) in dry
methylene chloride (27 mL) was stirred vigorously and then a
mixture of wet methylene chloride (20 mL, 95 mL of dry methylene
chloride and 95 .mu.L of water) was added by a separatory funnel.
The mixture was stirred 18 hours at room temperature and
concentrated to dryness in vacuo. The residue was dissolved in
ethyl acetate and the solution was washed with saturated aqueous
sodium bicarbonate and brine, dried (MgSO.sub.4) and concentrated
to dryness in vacuo. Product was purified from the residue by prep
HPLC using 100% water to 20% water/acetonitrile over a 60 minute
period. The desired fractions were collected and lyophilized to
dryness to provide benzyl
1-(3-hydroxy-3-methyl-2-oxo-1-phenethylbutylcarbamoyl)-3-methylbut-
ylcarbamate (0.05 g, 0. 1 1 mmol) as a white solid. .sup.1H NMR
(CDCl.sub.3):0.89-0.91 (m, 6H), .delta. 1.23-1.32 (2.times.s, 6H),
.delta. 1.42-4.65 (m, 2H), .delta. 1.86-1.89 (m, 1H), .delta.
2.05-2.15 (m, 1H), .delta. 2.58-2.63 (m, 2H), .delta. 4.12 (m, 1H),
.delta. 5.09-5.21 (m, 4H), .delta. 6.52 (d, 1H), .delta. 7.12-7.31
(m, 10H).
Example 5
tert-Butyl
1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-1-methylbutylc-
arbamate
[0379] 30
[0380] A mixture comprised of tert-butyl 1S-(3-benzyloxy-2-oxo
-1S-phenethylpropylcarbamoyl)-1-methylbutylcarbamate (200 mg, 0.4
mmol), provided as in Example 1, cyclohexene (4.2 mL, 41.46 mmol)
and a catalytic amount of 20% palladium hydroxide on carbon (44 mg)
in 6 mL ethanol was heated at reflux until the reaction was
complete. The mixture then was cooled to room temperature and
filtered through celite. The filtrate was concentrated to provide
tert-butyl 1S-(3-hydroxy-2-oxo
-1S-phenethylpropylcarbamoyl)-2-methylbutylcarbamate (161 mg, 0.4
mmol); .sup.1H NMR (CDCl.sub.3): 0.80-0.95 (m, 6H), .delta.
1.0-1.32 (m, 2H), .delta. 1.42 (s, 9H), .delta. 1.75-2.05 (m, 2H),
.delta. 2.10-2.35 (m, 1), .delta. 2.59-2.65 (m, 2H), .delta.
3.88-3.94 (t, 1H), .delta. 4.32 (s, 2H), .delta. 4.55-4.75 (m, 1H),
.delta. 5.02-5.05 (m, 1H), .delta. 6.72-6.75 (d, 1H), .delta.
7.10-7.4 (m, 5H).
[0381] Proceeding as in Example 8 provided the following compounds
of Formula I:
[0382]
N-[1S-(1S-hydroxyacetylpentylcarbamoyl)-2-methylbutyl]benzamide
(Compound 168); .sup.1H NMR (CDCl.sub.3): 0.78 (3H, t, J=6 Hz);
0.92 (3H, t, J=7 Hz); 0.98 (3H, d, J=7 Hz); 1.1-1.35 (5H, br. in);
1.45-1.7 (2H, m); 1.81 (1H, m); 1.99 (1H, m); 3.15 (<1H, br. m*,
CH.sub.2OH), .delta. 4.39 (2H, s, CH.sub.2OH), .delta. 4.6 (2H, m,
2.times.CHNH), .delta. 6.87 (1H, d, J=8 Hz); 7.02 (1H, d, J=7 Hz);
7.41-5.51 (3H, m); 7.76 (2H, in); MS (M+1): 363;
[0383] tert-butyl
4-(1S-{3-hydroxy-1-[2S-(4-hydroxyphenyl)ethyl]-2-oxoprop-
ylcarbamoyl}-2-methylbutylcarbamoyl)piperidine-1-carboxylate
(Compound 169); .sup.1H NMR (CDCl.sub.3): 0.87-0.91 (6H, 2.times.d,
J=7 Hz); 1.42 (9H, s); 1.5-1.8 (7H, m*); 2.01 (1H, m); 2.22 (1H,
m); 2.4-2.67 (6H, m*); 4.00-4.1 (2H, m*); 4.29 (2H, s); 4.51 (2H,
m*); 6.47 (1H, d, J=9 Hz); 6.68 (2H, d, J=8 Hz); 6.84 (2H, d, J=8
Hz); 7.37 (1H, d, J=7 Hz); MS (M+1): 534;
[0384] N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-3-methyl
-2S-(2-phenoxyacetylamino)pentanamide (Compound 170); .sup.1H NMR
(CDCl.sub.3): 0.88 (3H, t, J=7 Hz); 0.92 (3H, d, J=7 Hz); 1.09 (1H,
m); 1.44 (1H, m); 1.63 (1H, m); 1.91 (2H, m); 2.18 (1H, m); 2.60
(2H, dd, J=7, 8 Hz); 4.31 (1H, m*); 4.34 (2H, s); 4.53 (2H,
2.times.d (AB), J=15 Hz); 4.59 (1H, m); 6.51 (1H, m); 6.9-7.3 (1H,
m); MS (M+1): 441;
[0385]
N-{1-[3-hydroxy-2-oxo-1-(2-phenylcarbamoylethyl)propylcarbamoyl]-2--
methylbutyl}naphthalene-2-carboxamide (Compound 171);
[0386]
N-[1-(2-hydroxyacetylpyrrolidin-1-ylcarbonyl)-2-methylbutyl]naphtha-
lene -2-carboxamide (Compound 172);
[0387] N-(1-hydroxyacetylpentyl)-2,2-dimethyl-propionainide
(Compound 173); and
[0388] benzyl
1-[3-hydroxy-1-(2-methanesulfonylethyl)-2-oxopropylcarbamoyl-
]-2-naphthalen-2-ylethylcarbamate (Compound 174); .sup.1H NMR
(CDCl.sub.3): .delta. 0.05 ppm (s, 1H), .delta. 0.85-0.9 ppm (t,
4H), .delta. 1.20 ppm (s, 10H), .delta. 1.1-1.2 ppm (m, 1H),
.delta. 1.5-1.75 ppm (m, 4H), .delta. 1.75-1.8 ppm (m, 1H), .delta.
4.36 ppm (s, 2H), 64.58-4.65 (m, 1H), .delta. 6.07 (m, 1H); LC/MS
(229.8 M+H.sup.+).
Example 6
3-Aminomethyl-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutyl]benzamide Hydrochloride
[0389] 31
[0390] A solution comprised of tert-butyl 3-[1S-(3-hydroxy-2-oxo
-1S-phenethylpropylcarbamoyl)-2-methylbutylcarbamoyl]benzylcarbamate
(0.135 g, 0.25 mmol) in methylene chloride (2 mL) was combined with
a solution of hydrogen chloride in dioxane (0.625 mL, 4.0 M). The
mixture was stirred at room temperature for 3 hours and then ether
(100 mL) was added to provide a precipitate. The precipitate was
collected by filtering and washed with ether (2.times.30 mL) and
hexane (2.times.30 mL) and dried in vacuo to provide
3-aminomethyl-N-[1S-(3-hydroxy-2-oxo-1S- -phenethylpropylcarbamoyl)
-2-methylbutyl]benzamide hydrochloride (95 mg, 0.2 mmol). .sup.1H
NMR (DMSO-d.sup.6): .delta. 0.86 (3H, t, J=7 Hz); 0.94 (3H, d, J=7
Hz); 1.24 (1H, m); 1.57 (1H, m); 1.8 (1H, m); 1.98 (2H, m);
2.6-2.75 (2H, m); 4.07 (2H, br. q, J=6 Hz); 4.17 (2H,
2.times.d(AB)); 4.3 (1H, m); 4.42 (1H, m); 7.12-7.31 (5H, m); 7.52
(1H, t, J=8 Hz); 7.65 (1H, d, J=8 Hz); 7.95 (1H, d, J=8 Hz); 8.07
(1H, s); 8.42 (3H, br. s); 8.48 (1H, d); 8.65 (0.7H, d) 8.7 (0.3H,
d). LC/MS indicated an approximately 3:1 ratio of diastereomers
(L,L:L,D) regardless of synthetic route. MS: (M+1,440).
[0391] Proceeding in a fashion analogous to the procedures
exemplified above provided the following compounds of Formula
I:
[0392]
N-(1S-{3-hydroxy-1-[2S-(4-hydroxyphenyl)ethyl]-2-oxopropylcarbamoyl-
}-2-methylbutyl)piperidine-4-carboxylainide (Compound 176); MS
(M+1): 434. .sup.1H NMR (DMSO-d.sup.6): 0.99 (6H, 2.times.d, J=6
Hz); 1.4-2 (9H, m*); 2.3-2.5 (5H, m, incl. DMSO); 2.84 (2H, m);
3.2-3.7 (3H, m*); 3.6 (1H, s); 4.1-4.3 (2H, 2.times.d* (AB)); 4.2
(1H, m*); 4.33 (1H, m*); 6.65 (2H, d, J=8 Hz); 6.95 (2H, d, J=8
Hz); 8.19 (1H, d, J=8 Hz); 8.37 (1H, d, J=7 Hz); 8.64 (1H, br.);
9.05 (1H, br.); 9.22 (1H, br.); MS (M+1): 434;
[0393]
N-[3-methyl-1S-(2-oxo-1S-phenethyl-3-phenoxypropylcarbamoyl)butyl]--
piperidine -4-carboxamide (Compound 177);
[0394]
35-(4-methyl-25-piperidin-4-ylcarbonylaminopentanoylamino)-2-oxo-5--
phenylpentyl 2,5-dichlorobenzoate (Compound 178);
[0395] benzyl
3-methyl-1S-(3-methyl-1S-phenoxyacetylbutylcarbamoyl)butylca-
rbamate (Compound 179);
[0396] N-[2-naphthalen-2-yl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamo- yl)ethyl]piperidine-4-carboxamide
(Compound 180);
[0397] benzyl
1S-(3-ethoxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbuty-
lcarbamate (Compound 181); .sup.1H NMR (CDCl.sub.3): .delta.
0.91-93 ppm (d, 6H), .delta. 1.17-1.22 ppm (t, 3H), .delta.
1.40-1.7 ppm (m, 4 11), .delta. 1.75-1.9 ppm (m, 2H), .delta.
2.2-2.3 ppm (m, 1H), .delta. 2.55-2.65 ppm (t, 2H), .delta.
3.45-3.6 ppm (q, m, 3H), .delta. 4.09-4.11 ppm (m, 2 1), .delta.
4.8-4.9 ppm (m, 1H), .delta. 5.1 ppm (s, 2 1), .delta. 6.48-6.52
ppm (d, 1H), .delta. 7.11-7.32 ppm (m, 10H); LC/MS (469.2
M+H.sup.+);
[0398]
N-[3-methyl-1S-(2-oxo-1S-phenethyl-3-phenoxypropylcarbamoyl)butyl]p-
iperidine -4-carboxamide (Compound 182);
[0399] benzyl 1
S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)ethylcarbam- ate
(Compound 183);
[0400] tert-butyl
2-[1S-(3-hydroxy-2-oxo-1S-phenethylpropyelcarbamoyl)
-3-methylbutylcarbamoylpyrrolidine-1-carboxylate (Compound
184);
[0401] N-1
[-(2-benzyloxyacetylpyrrolidin-1-ylcarbonyl)-3-methylbutyl]naph-
thalene -2-carboxamide (Compound 185);
[0402]
N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl-
]benzamide (Compound 186);
[0403] 4-aminomethyl-N-[1S-(1S-benzyloxyacetylpentylcarbamoyl)
-2-methylbutyl]benzamide (Compound 187);
[0404]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]p-
yrazine -2-carboxamide (Compound 188);
[0405] tert-butyl 3-[1S(3-methoxy-2-oxo-1Sphenethylpropylcarbamoyl)
-2-methylbutylcarbamoyl]benzylcarbamate (Compound 189); .sup.1H NMR
(CDCl.sub.3): .delta. 0.85-1.01 ppm (m, 6H), .delta. 1.23 ppm (m.
1H), .delta. 1.44 ppm (s, 9H), .delta. 1.8-2.0 ppm (m, 2H), .delta.
2.15-2.3 ppm (m, 1H), .delta. 2.58-2.63 ppm (t, 2H), .delta. 3.34
ppm (s, 1H), .delta. 3.38 ppm (s, 2H), .delta. 404-4.11 ppm (m,
2H); .delta. 4.32-4.34 ppm (m, 2H), .delta. 4.5-4.65 ppm (m, 1H),
.delta. 4.8-5.0 ppm (m, 2H), .delta. 6.49-6.51 ppm (d, 1H), .delta.
6.70-6.73 ppm (d, 1H), .delta. 7.1-7.5 ppm (m, 7H), .delta.
7.65-7.69 ppm (m, 2H); LC/MS (554.3 M+H.sup.+);
[0406]
3-aminomethyl-N-[1-(3-methoxy-2-oxo-1-phenethylpropylcarbamoyl)
-2-methylbutyl]benzamide (Compound 190); .sup.1H NMR (CDCl.sub.3):
.delta. 0.85-1.0 ppm (m, 6H), .delta. 1.1-1.3 ppm (m. 1H), .delta.
1.52-1.58 ppm (m, 1H), .delta. 1.8-2.0 ppm (m, 2H), .delta. 2.1-2.2
ppm (m, 1H), .delta. 3.19 ppm (m, 3H), .delta. 3.67 ppm (s, 2H),
64.18-4.20 ppm (m, 2H), 64.3-4.4 ppm (m, 3H), .delta. 7.1-7.35 ppm
(m, 5H), .delta. 7.5-7.65 ppm (m, 2H), 67.75-7.8 ppm (m, 2H); LC/MS
(454.1 M+H.sup.+);
[0407] tert-butyl 3-[2-methyl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamoyl)butylcarbamoyl]benzylcarbamate (Compound
191);
[0408] tert-butyl 2-naphthalen-2-yl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamoyl)ethylcarbamate (Compound 192);
[0409] 3-anunomethyl-N-[2-naphthalen-2-yl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamoyl)ethylbenzamide (Compound 193);
[0410] 3-aminomethyl-N-[2-methyl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamoyl)butylbenzamide (Compound 194);
[0411] tert-butyl 3-[2-naphthalen-2-yl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylcarbamoyl)ethylcarbamoyl]benzylcarbamate (Compound
195);
[0412] N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-3-met by
-2S-(2-phenoxyacetylamino)pentanamide (Compound 196);
[0413]
2S-acetylamino-N-(3-benzyloxy-2-oxo-1S-phenethylpropyl)-3-methylpen-
tanamide (Compound 197);
[0414] benzyl
1S-(3-benzyloxy-2-oxo-1S-phenethylpropylsulfamoylmethyl)
-2-methylbutylcarbamate (Compound 198);
[0415] benzyl
1S-(1S-benzyloxyacetylpentylsulfamoylmethyl)-2-methylbutylca-
rbamate (Compound 199);
[0416]
2S-acetylamino-N-(3-hydroxy-2-oxo-1S-phenethylpropyl)-3-methylpenta-
namide (Compound 200);
[0417] methyl N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylisophthalamate (Compound 201); .sup.1H NMR
(CDCl.sub.3): .delta. 0.9-0.97 ppm (m, 6H) .delta. 1.2-1.3 ppm (m,
2H), .delta. 1.8-2 ppm (m, 2H), .delta. 2.2-2.3 ppm (m, 1H),
.delta. 2.55-2.62 ppm (t, 2H), .delta. 3.9 ppm (s, 3H), 64.13 ppm
(m, 2H), 64.45-4.65 ppm (m, 3H), .delta. 4.87-4.93 ppm (m, 1H),
.delta. 6.43-6.46 ppm (d, 1H), .delta. 6.78-6.82 ppm (d, 1H),
.delta. 7.04-7.06 ppm (d, 2H), .delta. 7.15-7.4 ppm (m, 13H),
.delta. 7.5-7.6 ppm (t, 1H), .delta. 8.00-8.03 ppm (d, 1H), .delta.
8.15-8.18 ppm (d, 1H), .delta. 8.40 ppm (m, 1H); LC/MS (559.3
M+H.sup.+);
[0418] benzyl 2-methyl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylsulfamoylmet- hyl)butylcarbamate (Compound
202);
[0419]
2S-acetylamino-N.sup.4-(3-aminomethylphenyl)-N'-(3-benzyloxy-2-oxo
-1-phenethy]propyl)succinamide (Compound 203);
[0420] methyl N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)
-2-methylbutylisophthalamate (Compound 204); .sup.1H NMR
(CDCl.sub.3): .delta. 0.91-1.04 ppm (m, 6H), .delta. 1.5-1.7 ppm
(m, 2H), .delta. 1.85-2.05 ppm (m, 2H), .delta. 2.1-2.25 ppm (m,
1H), .delta. 2.58-2.64 ppm (t, 2H), .delta. 3.92 ppm (s, 3H),
.delta. 4.35 ppm (s, 2H), .delta. 4.46-4.52 ppm (t, 1H), .delta.
4.6-4.7 ppm (m, 1H), .delta. 6.65-6.68 ppm (d, 1H), .delta.
6.82-6.85 ppm (d, 1H), .delta. 7.06-7.08 ppm (d,1H), .delta.
7.1-7.24 ppm (m, 8H), .delta. 7.48-7.54 ppm (t, 1H), .delta.
8.00-8.03 ppm (d, 1H), .delta. 8.15-8.18 ppm (d, 1H), .delta. 8.40
ppm (m, 1H); LC/MS (469.2 M+H.sup.+);
[0421]
N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl-
]-3-[N',N"-di(tert-butoxycarbonyl)guanidino]benzamide (Compound
205);
[0422]
N-[1S-(3-benzyloxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl-
]-3-guanidinobenzamide (Compound 206);
[0423] benzyl 1S-(3-benzyloxy-2-oxo-1S-phenethylpropylsul
famoylmethyl)pentylcarbamate (Compound 207);
[0424] benzyl
1S-(1S-benzyloxyacetylpentylsulfamoylmethyl)-3-phenylpropylc-
arbamate (Compound 208);
[0425] tert-butyl
1S-(3-benzyloxy-2-oxo-1S-phenethylpropylsulfamoylmethyl)
-3-phenylpropylcarbamate (Compound 209);
[0426]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]--
3-[N',N"-di(tert-butoxycarbonyl)guanidino]benzamide (Compound
210);
[0427]
N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamovl)-2-methylbutyl]--
3-guanidinobenzamide (Compound 211);
[0428] tert-butyl
3-[1S-(3-benzyloxy-1S-methyl-2-oxopropylcarbamoyl)
-2-methylbutylcarbamoyl]benzylcarbamate (Compound 212); .sup.1H NMR
(CDCl.sub.3): .delta. 0.92-0.97 ppm (m, 6H), .delta. 1.34-1.36 ppm
(d. 3H), .delta. 1.44 ppm (s, 9H), 64.19-4.2 ppm (d, 2H), .delta.
4.33-4.35 ppm (d, 2H), .delta. 4.58-4.61 ppm (d, 2H), .delta. 4.8-5
ppm (m, 1H), .delta. 6.47-6.49 ppm (d,1H), .delta. 6.75-6.8 ppm (d,
1H), .delta. 7.3-7.42 ppm (m, 6H), .delta. 7.64-7.69 ppm (m, 2H);
LC/MS (540.2 M+H.sup.+);
[0429] tert-butyl 3-[1S-(3-hydroxy-1S-methyl-2-oxopropylcarbamoyl)
-2-methylbutylcarbamoyl]benzylcarbamate (Compound 213); .sup.1H NMR
(CDCl.sub.3): .delta. 0.88-1.00 ppm (m, 6H), .delta. 1.23 ppm (m.
2H), .delta. 1.36-1.38 ppm (d, 2H), .delta. 1.48 ppm (s, 9H), 63.47
ppm (s, 1H), .delta. 4.33-4.35 ppm (d, 2H), .delta. 4.4-4.41 ppm
(m, 1H), .delta. 4.45-4.5 ppm (t, 1H), .delta. 4.57-4.64 ppm (m,
1H), .delta. 4.9 ppm (m, 1H), .delta. 6.57 ppm (m, 1H), .delta.
6.69-6.72 ppm (d, 1H), .delta. 7.37-7.5 ppm (m, 2H), .delta.
7.64-7.69 ppm (m, 2H); LC/MS (450.1 M+H.sup.+);
[0430]
3-aminomethyl-N-[1S-(3-benzyloxy-1S-methyl-2-oxopropylcarbamoyl)
-2-methylbutyl]benzamide (Compound 214); .sup.1H NMR (DMSO):
.delta. 0.82-0.91 ppm (m, 6H), .delta. 1.19-1.21 ppm (d.m 2H),
.delta. 1.4-1.6 ppm (m, 1H), .delta. 1.8-2.0 ppm (m, 1H), .delta.
4.01-4.1 ppm (m, 2H), .delta. 4.3-4.4 ppm (m, 2H), .delta.
4.46-4.47 ppm (m, 2H), .delta. 7.26-7.37 ppm (m, 5H), .delta.
7.5-7.59 ppm (m, 1H), .delta. 7.6-7.63 ppm (m, 1H), .delta.
7.88-7.95 ppm (m, 1H), .delta. 7.99 ppm (s, 1H), .delta. 8.2-8.4
ppm (m, 3H), .delta. 8.55-8.59 ppm (t, 1H); LC/MS (440.1
M+H.sup.+);
[0431]
3-aminomethyl-N-[1S-(3-hydroxy-1S-methyl-2-oxopropylcarbamoyl)
-2-methylbutyl]benzamide (Compound 215); .sup.1H NMR (DMSO):
.delta. 0.82-0.90 ppm (m, 6H), .delta. 1.19-1.21 ppm (d. 2H),
.delta. 1.4-1.6 ppm (m, 1H), .delta. 1.95-2.0 ppm (m, 1H), .delta.
4.01-4.1 ppm (m, 2H), .delta. 4.19 ppm (s, 1H), .delta. 4.3-4.4 ppm
(m, 1H), .delta. 7.5-7.55 ppm (t, 1H), .delta. 7.59-7.61 ppm (m,
1H), .delta. 7.89-7.91 ppm (m, 1H), .delta. 7.98 ppm (s, 1H),
.delta. 8.1-8.4 ppm (m, 3H); LC/MS (350 M+H.sup.+);
[0432] benzyl
1S-(3-benzyloxy-1S-methyl-2-oxopropylcarbamoyl)-2-methylbuty-
lcarbamate (Compound 216); .sup.1H NMR (CDCl.sub.3): .delta.
0.90-0.92 ppm (d, 6H), .delta. 1.30-1.33 ppm (d. 3H), .delta.
4.10-4.2 ppm (m, 3H), .delta. 4.57-4.59 ppm (d, 2H), .delta.
4.75-4.85 ppm (m, 1H), .delta. 5.09-5.12 ppm (s, 3H), .delta.
6.54-6.57 ppm (d, 1H), .delta. 7.32-7.38 ppm (m, 10H); LC/MS (441
M+H.sup.+);
[0433] benzyl 3-methyl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylsulfamoylmet- hyl)butylcarbamate (Compound
217);
[0434] benzyl 3-methyl-1R-(2-oxo-1S-phenethyl
-3-phenoxypropylsulfamoylmet- hyl)butylcarbamate (Compound
218);
[0435] tert-butyl
1S-(2-oxo-1S-phenethyl-3-phenoxypropylsulfamoylmethyl)
-3-phenylpropylcarbamate (Compound 219);
[0436] benzyl 2-methyl-1S-(2-oxo-1R-phenethyl
-3-phenoxypropylsulfamoylmet- hyl)butylcarbamate (Compound
220);
[0437] benzyl
5-(2S-benzyloxycarbonylamIno-3-methylpentane-1-sulfonylamino-
)-6-oxo -7-phenoxyheptylcarbamate (Compound 221);
[0438] benzyl 5S-(2S-benzyloxycarbonylamino
-3-methylpentan-1-ylsulfonylam-
ino)-7-(4-methoxyphenoxy)-6-oxoheptylcarbamate (Compound 222);
[0439] tert-butyl 2-methyl-1S-(2-oxo-1S-phenethyl
-3-phenoxypropylsulfamoy- lmethyl)butylcarbamate (Compound
223);
[0440]
2S-amino-3-methylpentane-N-(2-oxo-1S-phenethyl-3-phenoxypropyl)
-1-sulfonamide (Compound 224);
[0441] N-[3-methyl-1-(2-oxo-1-phenethyl
-3-phenoxypropyjsulfamoylmethyl)bu- tyllnicotinamide (Compound
225);
[0442] benzyl
1S-[3-(3-methoxyphenoxy)-2-oxo-1S-phenethylpropylsulfamoylme-
thyl]-2-methylbutylcarbamate (Compound 226);
[0443] benzyl 1S-(3-benzo[1,3]dioxol-5-yloxy-2-oxo
-1S-phenethylpropylsulf- amoylmethyl]-2-methylbutylcarbamate
(Compound 227);
[0444] tert-butyl 1S-(3-benzo[1,3]dioxol-5-yloxy-2-oxo
-1S-phenethylpropylsulfamoylmethyl)-2-methylbutylcarbamate
(Compound 228);
[0445] tert-butyl
1S-[3-(3-methoxyphenoxy)-2-oxo-1S-phenethylpropylsulfamo-
ylmethyl]-2-methylbutylcarbamate (Compound 229);
[0446] benzyl
1S-[3-(3-dimethylaminophenoxy)-2-oxo-1S-phenethylpropylsulfa-
moylmethyl]-2-methylbutylcarbamate (Compound 230);
[0447]
3S-(2S-benzyloxycarbonylamino-3-hydroxybutyrylamino)-5-methanesulfo-
nyl -2-oxopentyl 2,5-dichlorobenzoate (Compound 231);
[0448] benzyl
1S-[3-(4-methoxyphenoxy)-2-oxo-1S-phenethylpropylsulfamoylme-
thyl]-2-methylbutylcarbamate (Compound 232);
[0449] benzyl 1S-(3-benzyloxy-1S-methyl-2-oxo-propylcarbamoyl)
-2-hydroxypropylcarbamate (Compound 233); .sup.1H NMR (CDCl.sub.3):
.delta. 1.14-1.17 ppm (d, 3H), .delta. 1.30-1.32 ppm (d, 2H),
.delta. 4.17-4.18 ppm (d, 2H), .delta. 4.57-4.60 ppm (d, 2H),
.delta. 4.76-4.82 ppm (m, 1H), .delta. 5.11-5.14 ppm (m, 2H),
.delta. 5.66-5.69 ppm (d, 1H), .delta. 6.94-6.97 ppm (d, 1H),
.delta. 7.28-7.4 ppm (m, 10H);
[0450] benzyl
1S-[3-(4-chlorophenoxy)-2-oxo-1S-phenethylpropylsulfamoylmet-
hyl]-2-methylbutylcarbamate (Compound 234);
[0451] benzyl 2-methyl-1S-[2-oxo-1S-phenethyl
-3-(4-sulfamoylphenoxy)propy- lsulfamoylmethyl]butylcarbamate
(Compound 235);
[0452] benzyl 2-methyl-1S-12-oxo-1S-phenethyl
-3-(4-carbamoylphenoxy)propy- lsulfamoylmethyl]butylcarbamate
(Compound 236);
[0453] 4-dimethylamino-N-[3-methyl-1-(2-oxo
-3-phenoxypropylcarbamoyl)buty- l]benzamide (Compound 237);
[0454] benzyl
2-methyl-1-{3-methyl-1-[1-(2-oxo-3-phenoxypropylcarbamoyl)
-2-phenylethylcarbamoyl]butylcarbamoyl}propyl)carbamate (Compound
238);
[0455] 2-(3-aminomethylphenyl)oxazole-N-(3-hydroxy-2-oxo
-1-phenethylpropyl)-4-carboxamide (Compound 239);
[0456] benzyl
1-[3-(4-imidazol-1-ylphenoxy)-2-oxo-1-phenethylpropylsulfamo-
ylmethyl]-2-methylbutylcarbamate (Compound 240);
[0457] 2-(3-aminomethylphenyl)-N-(3-hydroxy-2-oxo
-1-phenethylpropyl)oxazo- le-4-carboxamide (Compound 241);
[0458]
2-amino-N-(3-benzyloxy-2-oxo-1-phenethylpropyl)-4-phenylbutyramide
(Compound 242);
[0459]
N-(2-oxo-1-phenethyl-3-phenoxypropyl)dibenzofuran-2-sulfonamide
(Compound 243); ESI-MS m/z 500.2 (M+H.sup.+);
[0460] tert-butyl
4-[1-(3-hydroxy-2-oxo-1-phenethylpropylsulfamoylmethyl)
-3-methylbutylcarbamoyl]piperidine-1-carboxylate (Compound
244);
[0461] tert-butyl
1-(3-benzyloxy-1-methyl-2-oxopropylsulfamoylmethyl)
-3-methylbutylcarbamate (Compound 245); and
[0462] N-(1-benzyloxyacetylpentyl)-2,2-dimethylpropionamide
(Compound 246); .sup.1H NMR (CDCl.sub.3): .delta. 0.82-0.87 ppm (m,
3H), .delta. 1.21-1.20 ppm (m, 3H), .delta. 1.41 ppm (s, 9H),
61.7-1.9 ppm (m,1H), .delta. 4.1 ppm (d, 2H), .delta. 4.5-4.7 (m,
3H), .delta. 5.06-5.09 (d, 1H), .delta. 7.3-7.4 ppm (m, 5H); LC/MS
(320 M+H.sup.+).
Example 7
Cathepsin B Assay
[0463] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising:
N,N-bis(2-hydroxyethyl)-2-aminoethanesulfon- ic acid (BES), 50 MM
(pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and
dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in
25 .mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-FR-AMC (20
nMoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda. 460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0464] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin B
inhibitory activity.
Example 8
Cathepsin K Assay
[0465] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising: MES, 50 mM (pH 5.5); EDTA,
2.5 mM; and DTT, 2.5 mM). Human catliepsin K (0.0906 pmoles in 25
.mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (4
mmoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda. 460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0466] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin K
inhibitory activity.
Example 9
Cathepsin L Assay
[0467] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising: MES, is 50 mM (pH 5.5);
EDTA, 2.5 mM; and DTTI, 2.5 mM). Human cathepsin L (0.05 pmoles in
25 .mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (1
nmoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda. 460 nm) for 5 minutes. Apparent inhibition constants (K,)
were calculated from the enzyme progress curves using standard
mathematical models.
[0468] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin L
inhibitory activity.
Example 10
Cathepsin S Assay
[0469] Solutions of test compounds in varying concentrations were
prepared in 10 .mu.L of dimethyl sulfoxide (DMSO) and then diluted
into assay buffer (40 .mu.L, comprising: MES, 50 mM (pH 6.5); EDTA,
2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25
.mu.L of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered
and incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC
(9 nMoles in 25 mL of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lambda. 460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0470] Compounds of the invention were tested by the
above-described assay and observed to exhibit cathepsin S
inhibitory activity.
Example 11
[0471] Representative Pharmaceutical Formulations Containing a
Compound of Formula I
1 ORAL FORMULATION Compound of Formula I 10-100 mg Citric Acid
Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to
100 mL INTRAVENOUS FORMULATION Compound of Formula I 0.1-10 mg
Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate
1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL
TABLET FORMULATION Compound of Formula I 1% Microcrystalline
Cellulose 73% Stearic Acid 25% Colloidal Silica 1%
[0472] The resulting tablets are useful for administration in
accordance with the methods of this invention for treating or
preventing a cathepsin mediated disease state, such as
osteoporosis, juvenile onset diabetes, multiple sclerosis,
pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic
lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis,
asthma, organ transplant or tissue graft rejections, chronic
obstructive pulmonary disease, bronchiolitis, excessive airway
elastolysis in asthma and bronchitis, pneumonities, plaque rupture,
atheroma and systemic amyloidosis.
* * * * *