U.S. patent application number 11/625369 was filed with the patent office on 2007-06-14 for novel compounds and compositions as cathepsin inhibitors.
This patent application is currently assigned to Aventis Pharmaceuticals Inc.. Invention is credited to David John Aldous, Michael Graupe, James T. Palmer, Sukanthini Thurairatnam.
Application Number | 20070135386 11/625369 |
Document ID | / |
Family ID | 23254351 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135386 |
Kind Code |
A1 |
Graupe; Michael ; et
al. |
June 14, 2007 |
Novel Compounds and Compositions as Cathepsin Inhibitors
Abstract
The present invention relates to novel cathepsin S inhibitors,
the pharmaceutically acceptable salts and N-oxides thereof, their
uses as therapeutic agents and the methods of their making.
Inventors: |
Graupe; Michael; (Pacifica,
CA) ; Palmer; James T.; (Corte Madera, CA) ;
Aldous; David John; (Gillette, NJ) ; Thurairatnam;
Sukanthini; (Bedminster, NJ) |
Correspondence
Address: |
SYNNESTVEDT & LECHNER LLP
2600 ARAMARK TOWER
1101 MARKET STREET
PHILADELPHIA
PA
19107-2950
US
|
Assignee: |
Aventis Pharmaceuticals
Inc.
Bridgewater
NJ
Axys Pharmaceuticals Inc.
South San Francisco
CA
|
Family ID: |
23254351 |
Appl. No.: |
11/625369 |
Filed: |
January 22, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10787367 |
Feb 26, 2004 |
7196099 |
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11625369 |
Jan 22, 2007 |
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PCT/US02/29323 |
Sep 16, 2002 |
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10787367 |
Feb 26, 2004 |
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60322318 |
Sep 14, 2001 |
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Current U.S.
Class: |
514/80 ; 514/247;
514/255.06; 514/350; 514/416; 514/443; 514/447; 514/89; 544/224;
544/232; 544/406; 546/22; 546/300; 549/467; 549/57; 549/76 |
Current CPC
Class: |
A61P 1/02 20180101; C07D
207/48 20130101; A61P 29/00 20180101; C07D 223/12 20130101; C07D
207/24 20130101; C07K 5/06078 20130101; C07D 307/32 20130101; A61P
19/02 20180101; A61P 35/00 20180101; C07D 295/215 20130101; A61P
21/04 20180101; A61K 38/00 20130101; C07C 317/48 20130101; C07K
5/0606 20130101; Y02A 50/30 20180101; A61P 33/06 20180101; C07D
205/085 20130101; C07C 317/50 20130101; A61P 13/12 20180101 |
Class at
Publication: |
514/080 ;
514/089; 514/247; 514/255.06; 514/350; 514/443; 514/447; 544/224;
544/406; 546/300; 546/022; 544/232; 549/076; 549/467; 549/057;
514/416 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/4965 20060101 A61K031/4965; A61K 31/50
20060101 A61K031/50; A61K 31/4415 20060101 A61K031/4415; A61K
31/381 20060101 A61K031/381; A61K 31/4035 20060101
A61K031/4035 |
Claims
1. A compound of Formula I: ##STR215## in which: X.sup.1 and
X.sup.2 are both methylene or X.sup.1 is ethylene and X.sup.2 is a
bond; R.sup.3 is --CR.sup.5.dbd.CHR.sup.6,
--CR.sup.5(CR.sup.6.sub.3).sub.2 or --CR.sup.7.dbd.NR.sup.8,
wherein R.sup.5 is hydrogen and R.sup.6 is hydrogen or
(C.sub.1-4)alkyl or R.sup.5 and R.sup.6 together with the atoms to
which R.sup.5 and R.sup.6 are attached form
(C.sub.3-12)cycloalkenyl, hetero(C.sub.5-12)cycloalkenyl,
(C.sub.6-12)aryl, hetero(C.sub.6-12)aryl, (C.sub.9-12)bicycloaryl
or hetero(C.sub.8-12)bicycloaryl and R.sup.7 and R.sup.8 together
with the atoms to which R.sup.7 and R.sup.8 are attached form
hetero(C.sub.5-12)cycloalkenyl, hetero(C.sub.6-12)aryl or
hetero(C.sub.8-12)bicycloaryl, wherein R.sup.3 optionally is
substituted by 1 to 5 radicals independently selected from a group
consisting of (C.sub.1-4)alkyl, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.9R.sup.9,
--X.sup.4OR.sup.9, --X.sup.4SR.sup.9, --X.sup.4C(O)NR.sup.9R.sup.9,
--X.sup.4C(O)OR.sup.9, --X.sup.4S(O)R.sup.10,
--X.sup.4S(O).sub.2R.sup.10 and --X.sup.4C(O)R.sup.10, wherein
X.sup.4 is a bond or (C.sub.1-2)alkylene, R.sup.9 at each
occurrence independently is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.10 is (C.sub.1-3)alkyl
or halo-substituted (C.sub.1-3)alkyl; and R.sup.4 is
--C(O)X.sup.5R.sup.11 or --S(O).sub.2X.sup.5R.sup.11, wherein
X.sup.5 is a bond, --O-- or --NR.sup.12--, wherein R.sup.12 is
hydrogen or (C.sub.1-6)alkyl, and R.sup.11 is (i) (C.sub.1-6)alkyl
optionally substituted by --OR.sup.13, --SR.sup.13, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --C(O)R.sup.13, --C(O)OR.sup.13,
--C(O)NR.sup.13R.sup.14, --NR.sup.13R.sup.14,
--NR.sup.14C(O)R.sup.13, --NR.sup.14C(O)OR.sup.13,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl and R.sup.14 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl substituted by
--X.sup.6OR.sup.15, --X.sup.6SR.sup.15, --X.sup.6S(O)R.sup.15,
--X.sup.6S(O).sub.2R.sup.15, --X.sup.6C(O)R.sup.15,
--X.sup.6C(O)OR.sup.15, --X.sup.6C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.15R.sup.16, --X.sup.6NR.sup.16C(O)R.sup.15,
--X.sup.6NR.sup.16C(O)OR.sup.15,
--X.sup.6NR.sup.16C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.16C(O)OR.sup.16,
--X.sup.6NR.sup.16C(NR.sup.16)NR.sup.15R.sup.16, wherein X.sup.6 is
a bond or methylene, R.sup.15 is
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl and R.sup.16 is hydrogen
or (C.sub.1-6)alkyl; wherein R.sup.4 optionally further contains 1
to 5 substituents which when occurring within an alicyclic or
aromatic ring system are radicals independently selected from a
group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano,
halo, nitro, halo-substituted (C.sub.1-3)alkyl,
--X.sup.6NR.sup.17R.sup.17, --X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6SR.sup.17, --.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.18)OR.sup.17,
--X.sup.6OP(O)(OR.sup.18)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NRC.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
X.sup.6 is a bond or (C.sub.1-6)alkylene, R.sup.17 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.18 is (C.sub.1-6)alkyl
or halo-substituted (C.sub.1-3)alkyl; X.sup.3 is a group of Formula
(b) or (c): ##STR216## n is 0, 1 or 2; R.sup.20 is selected from
the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl and
hetero(C.sub.5-12)aryl(C.sub.0-6)alcyl; R.sup.23 is selected from
(C.sub.1-6)alkyl, (C.sub.4-6)alkenyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl optionally substituted with
amino, --NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as
described above; R.sup.25 is selected from hydrogen,
(C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-13)aryl(C.sub.0-6)alkyl, --X.sup.4NHR.sup.15,
--X.sup.4S(O).sub.2R.sup.26 or
--X.sup.4C(O)R.sup.17NR.sup.17C(O)R.sup.17 wherein R.sup.15,
R.sup.17 and X.sup.4 are as described above; R.sup.26 is selected
from the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)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)allyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)-bicycloaryl(C.sub.0-3)alkyl; R.sup.27 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl; wherein X.sup.3 optionally
further contains 1 to 5 substituents which when occurring within an
alicyclic or aromatic ring system are radicals independently
selected from a group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, nitro, halo-substituted
(C.sub.1-3)alkyl, --X.sup.6NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6C(O)R.sup.17, --X.sup.6OR.sup.15,
--X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.8)OR.sup.17,
--X.sup.6OP(O)(OR.sup.8)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
R.sup.15, R.sup.17, R.sup.18 and X.sup.6 are as described above;
and the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers thereof;
and the pharmaceutically acceptable salts and solvates of such
compounds and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers
thereof.
2. The compound of claim 1 in which X.sup.1 and X.sup.2 are both
methylene or X.sup.1 is ethylene and X.sup.2 is a bond; R.sup.3 is
--CR.sup.5.dbd.CHR.sup.6, --CR.sup.5(CR.sup.6.sub.3).sub.2 or
--CR.sup.7.dbd.NR.sup.8, wherein R.sup.5 is hydrogen and R.sup.6 is
hydrogen or (C.sub.1-4)alkyl or R.sup.5 and R.sup.6 together with
the atoms to which R.sup.5 and R.sup.6 are attached form
(C.sub.3-12)cycloalkenyl, (C.sub.6-12)aryl, hetero(C.sub.6-12)aryl
or (C.sub.9-12)bicycloaryl and R.sup.7 and R.sup.8 together with
the atoms to which R.sup.7 and R.sup.8 are attached form
hetero(C.sub.5-12)cycloalkenyl or hetero(C.sub.6-12)aryl, wherein
R.sup.3 optionally is substituted by 1 to 5 radicals independently
selected from a group consisting of (C.sub.1-4)alkyl, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, --X.sup.4R.sup.9 and
--X.sup.4C(O)OR.sup.9, wherein X.sup.4 is a bond or
(C.sub.1-2)alkylene, R.sup.9 at each occurrence independently is
(C.sub.1-3)alkyl or halo-substituted (C.sub.1-3)alkyl; and the
N-oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and mixtures of isomers thereof, and the
pharmaceutically acceptable salts and solvates of such compounds
and the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers
thereof.
3. The compound of claim 2 in which R.sup.4 is
--C(O)X.sup.5R.sup.11 or --S(O).sub.2X.sup.5R.sup.11, wherein
X.sup.5 is a bond, --O-- or --NR.sup.12--, wherein R.sup.12 is
hydrogen or (C.sub.1-6)alkyl, and R.sup.11 is (i) (C.sub.1-6)alkyl
or (ii) hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl or (iii)
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl or
phenyl(C.sub.0-3)alkyl substituted by --X.sup.6OR.sup.15,
--X.sup.6C(O)R.sup.15 or --X.sup.6NR.sup.16C(O)OR.sup.16, wherein
X.sup.6 is a bond or methylene, R.sup.15 is phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl and R.sup.16 is hydrogen
or (C.sub.1-6)alkyl; wherein R.sup.4 optionally further contains 1
to 5 substituents which when occurring within an alicyclic or
aromatic ring system are radicals independently selected from a
group consisting of (C.sub.1-6)alkyl, halo,
--X.sup.6NR.sup.17R.sup.17, --X.sup.6OR.sup.17,
--X.sup.6C(O)OR.sup.17, --X.sup.6NC(O)R.sup.16 and
--X.sup.6C(O)R.sup.18, R.sup.17 at each occurrence independently is
hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and
R.sup.18 is (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl;
and the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers thereof;
and the pharmaceutically acceptable salts and solvates of such
compounds and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers
thereof.
4. The compound of claim 3 in which X.sup.3 is a group of Formula
(b) or (c): ##STR217## n is 0, 1 or 2; R.sup.20 is selected from
the group consisting of hydrogen and (C.sub.1-6)alkyl; R.sup.23 is
selected from (C.sub.1-6)alkyl optionally substituted with amino,
--NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as described
above; R.sup.25 is selected from (C.sub.1-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, --X.sup.4S(O).sub.2R.sup.26 or
--X.sup.4C(O)R.sup.17NR.sup.17C(O)R.sup.17 wherein R.sup.17 and
X.sup.4 are as described above and R.sup.26 is as described below;
R.sup.26 is selected from the group consisting of (C.sub.1-6)alkyl,
hetero(C.sub.5-12)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 and
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl; R.sup.27 is
(C.sub.1-6)alkyl; wherein X.sup.3 optionally further contains 1 to
5 substituents which when occurring within an alicyclic or aromatic
ring system are radicals independently selected from a group
consisting of (C.sub.1-6)alkyl, cyano, halo, --X.sup.6OR.sup.17,
--X.sup.6C(O)R.sup.17 and --X.sup.6OR.sup.15; and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers thereof; and the pharmaceutically
acceptable salts and solvates of such compounds and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers thereof.
5. The compound of claim 4 in which R.sup.3 is selected from the
group consisting of phenyl, pyridin-2-yl, pyridin-3-yl,
pyridin-4-yl, vinyl, 2-difluoromethoxyphenyl, 1-oxy-pyridin-2-yl,
4-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl,
3,5-dimethylphenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl, 2-bromophenyl, naphthalen-2-yl,
3,4-dichlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl,
3-trifluoromethoxyphenyl, 2,3,4,5,6-pentafluoro-phenyl,
2-fluorophenyl, 2-chlorophenyl, 2-cyano-phenyl,
2-trifluoromethylphenyl, 4-tert-butyl-phenyl, 3-chlorophenyl,
4-bromophenyl, 2-fluoro-3-chloro-phenyl, 2-fluoro-3-methyl-phenyl,
3-fluorophenyl, 2,5-difluorophenyl, 3-bromophenyl,
2,5-dichlorophenyl, 2,6-difluorophenyl, 3-cyano-phenyl,
4-cyano-phenyl, 2-trifluoromethoxyphenyl, 2,3-difluorophenyl,
biphenyl, 2-bromo-5-fluoro-phenyl, 4-fluorophenyl,
3,4-difluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl,
2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl,
2-chloro-5-trifluoromethylphenyl, 2,4-bis-trifluoromethylphenyl,
2,5,6-trifluorophenyl, 2-fluoro-3-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl,
2,3,5-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl,
5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl,
2-methoxyphenyl, 3,5-bis-trifluoromethylphenyl,
4-difluoromethoxyphenyl, 3-difluoromethoxyphenyl,
2,6-dichlorophenyl, 4-carboxyphenyl, cyclohexyl, cyclopropyl,
isopropyl, thiophen-2-yl, 5-chloro-thiophen-2-yl and
3,5-dimethyl-isoxazol-4-yl.
6. The compound of claim 5 in which R.sup.4 is benzoyl,
morpholine-4-carbonyl, acetyl, furan-3-carbonyl, 2-methoxy-benzoyl,
3-methoxy-benzoyl, naphthalene-2-carbonyl,
benzo[1,3]dioxole-5-carbonyl, 3-pyridin-3-yl-acryloyl,
benzofuran-2-carbonyl, furan-2-carbonyl, tert-butoxy-carbonyl,
biphenyl-4-carbonyl, quinoline-2-carbonyl, quinoline-3-carbonyl,
3-acetyl-benzoyl, 4-phenoxy-benzoyl, 3-hydroxy-benzoyl,
4-hydroxy-benzoyl, pyridine-3-carbonyl,
3-(tert-butoxycarbonylamino-methyl)-benzoyl,
4-carbonyl-piperazine-1-carboxylic acid tert-butyl ester,
4-carbonyl-piperazine-1-carboxylic acid ethyl ester,
4-(furan-2-carbonyl)-piperazine-1-carbonyl, pyridine-4-carbonyl,
1-oxy-pyridine-4-carbonyl, 1-oxy-pyridine-3-carbonyl,
thiophene-2-carbonyl, thiophene-3-carbonyl, 4-benzoyl-benzoyl,
5-methyl-thiophene-2-carbonyl, 3-chloro-thiophene-2-carbonyl,
3-bromo-thiophene-2-carbonyl, 4-chloro-benzoyl,
3-flouro-4-methoxy-benzoyl, 4-methoxy-benzoyl,
4-triflouromethoxy-benzoyl, 3,4-diflouro-benzoyl, 4-fluoro-benzoyl,
3,4-dimethoxy-benzoyl, 3-methyl-benzoyl, 4-bromo-benzoyl,
4-triflouromethyl-benzoyl, 3-benzoyl-benzoyl,
cyclopentane-carbonyl, benzo[b]thiophene-2-carbonyl,
3-chloro-benzo[b]thiophene-2-carbonyl, benzenesulfonyl,
naphthalene-2-sulfonyl, 5-methyl-thiophene-2-sulfonyl,
thiophene-2-sulfonyl, formamyl-methyl ester, 4-methyl-pentanoyl,
formamyl-isobutyl ester, formamyl-monoallyl ester,
formamyl-isopropyl ester, N,N-dimethyl-formamyl,
N-isopropyl-formamyl, N-pyridin-4-yl-formamyl,
N-pyridin-3-yl-formamyl, 3-phenyl-acryloyl, 1H-indole-5-carbonyl,
pyridine-2-carbonyl, pyrazine-2-carbonyl,
3-hydroxy-pyridine-2-carbonyl, 2-amino-pyridine-3-carbonyl,
2-hydroxy-pyridine-3-carbonyl, 6-amino-pyridine-3-carbonyl,
6-hydroxy-pyridine-3-carbonyl, pyridazine-4-carbonyl,
3-phenoxy-benzoyl and 1-oxo-1,3-dihydro-isoindole-2-carbonyl.
7. The compound of claim 6 in which X.sup.3 is selected from a
group consisting of
1-ethyl-2-oxo-3-(toluene-4-sulfonylamino)-butylamino,
1-ethyl-2-oxo-3-(4-phenoxy-benzenesulfonylamino)-propylamino,
1-ethyl-2-oxo-3-[4-(pyridin-3-yloxy)-benzenesulfonylamino]-propylamino,
3-(dibenzofuran-2-sulfonylamino)-1-ethyl-2-oxo-butylamino,
1-ethyl-3-[4-methyl-2-(4-methyl-pentanoylamino)-pentanoylamino]-2-oxo-pro-
pylamino,
5-amino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylamino,
5-benzyloxycarbonylamino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylami-
no, 1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino,
1-{[4-(1-hydroxy-ethyl)-phenylsulfamoyl]-methyl}-3-phenyl-propylamino,
1-[(4-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylamino,
1-[(4-hydroxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino and
3-phenyl-1-[(2-phenylamino-ethylsulfamoyl)-methyl]-propylamino.
8. The compound of claim 7 selected from the group consisting of
morpholine-4-carboxylic acid
(1-{5-amino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylcarbamoyl}-2-phe-
nylmethanesulfonyl-ethyl)-amide,
(6-(4-methoxy-phenylsulfamoyl)-5-{2-[(morpholine-4-carbonyl)-amino]-3-phe-
nylmethane-sulfonyl-propionylamino}-hexyl)-carbamic acid benzyl
ester, morpholine-4-carboxylic acid
(1-{1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-2-ph-
enylmethanesulfonyl-ethyl)-amide and morpholine-4-carboxylic acid
[1-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2-phenyhethanesulfonyl--
ethyl]-amide.
9. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 in combination with a
pharmaceutically acceptable excipient.
10. A method for treating a disease in an animal in which
inhibition of Cathepsin S can prevent, inhibit or ameliorate the
pathology and/or symptomology of the disease, which method
comprises administering to the animal a therapeutically effective
amount of compound of claim 1 or a N-oxide derivative or individual
isomer or mixture of isomers thereof; or a pharmaceutically
acceptable salt or solvate of such compounds and the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixtures of isomers thereof.
11. A process for preparing a compound of Formula I: ##STR218## in
which: X.sup.1 and X.sup.2 are both methylene or X.sup.1 is
ethylene and X.sup.2 is a bond; R.sup.3 is
--CR.sup.5.dbd.CHR.sup.6, --CR.sup.5(CR.sup.6.sub.3).sub.2 or
--CR.sup.7.dbd.NR.sup.8, wherein R.sup.5 is hydrogen and R.sup.6 is
hydrogen or (C.sub.1-4)alkyl or R.sup.5 and R.sup.6 together with
the atoms to which R.sup.5 and R.sup.6 are attached form
(C.sub.3-12)cycloalkenyl, hetero(C.sub.5-12)cycloalkenyl,
(C.sub.6-12)aryl, hetero(C.sub.6-12)aryl, (C.sub.9-12)bicycloaryl
or hetero(C.sub.8-12)bicycloaryl and R.sup.7 and R.sup.8 together
with the atoms to which R.sup.7 and R.sup.8 are attached form
hetero(C.sub.5-12)cycloalkenyl, hetero(C.sub.6-12)aryl or
hetero(C.sub.8-12)bicycloaryl, wherein R.sup.3 optionally is
substituted by 1 to 5 radicals independently selected from a group
consisting of (C.sub.1-4)alkyl, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.9R.sup.9,
--X.sup.4OR.sup.9, --X.sup.4SR.sup.9, --X.sup.4C(O)NR.sup.9R.sup.9,
--X.sup.4C(O)OR.sup.9, --X.sup.4S(O)R.sup.10,
--X.sup.4S(O).sub.2R.sup.10 and --X.sup.4C(O)R.sup.10, wherein
X.sup.4 is a bond or (C.sub.1-2)alkylene, R.sup.9 at each
occurrence independently is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.10 is (C.sub.1-3)alkyl
or halo-substituted (C.sub.1-3)alkyl; and R.sup.4 is --C(O)X.sup.5
R.sup.11 or --S(O).sub.2X.sup.5R.sup.11, wherein X.sup.5 is a bond,
--O-- or --NR.sup.12--, wherein R.sup.12 is hydrogen or
(C.sub.1-6)alkyl, and R.sup.11 is (i) (C.sub.1-6)alkyl optionally
substituted by --OR.sup.17, --SR.sup.13, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --C(O)R.sup.13, --C(O)OR.sup.13,
--C(O)NR.sup.13R.sup.14, --NR.sup.13R.sup.14,
--NR.sup.14C(O)R.sup.13, --NR.sup.14C(O)OR.sup.13,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alklyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl and R.sup.14 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl substituted by
--X.sup.6OR.sup.15, --X.sup.6SR.sup.15, --X.sup.6S(O)R.sup.15,
--X.sup.6S(O).sub.2R.sup.15, --X.sup.6C(O)R.sup.15,
--X.sup.6C(O)OR.sup.15, --X.sup.6C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.15R.sup.16, --X.sup.6NR.sup.16C(O)R.sup.15,
--X.sup.6NR.sup.16C(O)OR.sup.15,
--X.sup.6NR.sup.16C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.16C(O)OR.sup.16,
--X.sup.6NR.sup.16C(NR.sup.16)NR.sup.15R.sup.17, wherein X.sup.6 is
a bond or methylene, R.sup.15 is
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl and R.sup.16 is hydrogen
or (C.sub.1-6)alkyl; wherein R.sup.4 optionally further contains 1
to 5 substituents which when occurring within an alicyclic or
aromatic ring system are radicals independently selected from a
group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano,
halo, nitro, halo-substituted (C.sub.1-3)alkyl,
--X.sup.6NR.sup.17R.sup.17, --X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.18)OR.sup.17,
--X.sup.6OP(O)(OR.sup.18)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
X.sup.6 is a bond or (C.sub.1-6)alkylene, R.sup.17 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.18 is (C.sub.1-6)alkyl
or halo-substituted (C.sub.1-3)alkyl; X.sup.3 is a group of Formula
(b) or (c): ##STR219## n is 0, 1 or 2; R.sup.20 is selected from
the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alklyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl and
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl; R.sup.23 is selected from
(C.sub.1-6)alkyl, (C.sub.4-6)alkenyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl optionally substituted with
amino, --NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as
described above; R.sup.25 is selected from hydrogen,
(C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-13)aryl(C.sub.0-6)alkyl, --X.sup.4NHR.sup.15,
--X.sup.4S(O).sub.2R.sup.26 or
--X.sup.4C(O)R.sup.17NR.sup.17C(O)R.sup.17 wherein R.sup.15,
R.sup.17 and X.sup.4 are as described above; R.sup.26 is selected
from the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)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)bicycloaryl(C.sub.0-3)alkyl and
hetero(C.sub.8-12)-bicycloaryl(C.sub.0-3)alkyl; R.sup.27 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl; wherein X.sup.3 optionally
further contains 1 to 5 substituents which when occurring within an
alicyclic or aromatic ring system are radicals independently
selected from a group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, nitro, halo-substituted
(C.sub.1-3)alkyl, --X.sup.6NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6C(O)R.sup.17, --X.sup.6OR.sup.15,
--X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.8)OR.sup.17,
--X.sup.6OP(O)(OR.sup.8)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
R.sup.15, R.sup.17, R.sup.18 and X.sup.6 are as described above;
said process comprising: (A) reacting a compound of Formula 2 with
a compound of the formula (b): ##STR220## in which R.sup.20,
R.sup.23 and R.sup.25 are the same as defined above for Formula I;
or (B) reacting a compound of Formula 2 with a compound of the
formula (c): ##STR221## in which R.sup.20, R.sup.23 and R.sup.25
are the same as defined above for Formula I; and (C) optionally
converting a compound of Formula I into a pharmaceutically
acceptable salt; or (D) optionally converting a salt form of a
compound of Formula I to non-salt form; or (E) optionally
converting an unoxidized form of a compound of Formula I into a
pharmaceutically acceptable N-oxide; or (F) optionally converting
an N-oxide form of a compound of Formula I into an unoxidized form;
or (G) optionally resolving an individual isomer of a compound of
Formula I from a mixture of isomers; or (H) optionally converting a
non-derivatized compound of Formula I into a pharmaceutically
prodrug derivative; or (I) optionally converting a prodrug
derivative of a compound of Formula 1 to its non-derivatized
form.
12. A compound of Formula Ix: ##STR222## in which: X.sup.1 and
X.sup.2 are both methylene or X.sup.1 is ethylene and X.sup.2 is a
bond; R.sup.3 is --CR.sup.5.dbd.CHR.sup.6,
--CR.sup.5(CR.sup.6.sub.3).sub.2 or --CR.sup.7.dbd.NR.sup.8,
wherein R.sup.5 is hydrogen and R.sup.6 is hydrogen or
(C.sub.1-4)alkyl or R.sup.5 and R.sup.6 together with the atoms to
which R.sup.5 and R.sup.6 are attached form
(C.sub.3-12)cycloalkenyl, hetero(C.sub.5-12)cycloalkenyl,
(C.sub.6-12)aryl, hetero(C.sub.6-12)aryl, (C.sub.9-12)bicycloaryl
or hetero(C.sub.8-12)bicycloaryl and R.sup.7 and R.sup.8 together
with the atoms to which R.sup.7 and R.sup.8 are attached form
hetero(C.sub.5-12)cycloalkenyl, hetero(C.sub.6-12)aryl or
hetero(C.sub.8-12)bicycloaryl, wherein R.sup.3 optionally is
substituted by 1 to 5 radicals independently selected from a group
consisting of (C.sub.1-4)alkyl, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.9R.sup.9,
--X.sup.4OR.sup.9, --X.sup.4SR.sup.9, --X.sup.4C(O)NR.sup.9R.sup.9,
--X.sup.4C(O)OR.sup.9, --X.sup.4S(O)R.sup.10,
--X.sup.4S(O).sub.2R.sup.10 and --X.sup.4C(O)R.sup.10, wherein
X.sup.4 is a bond or (C.sub.1-2)alkylene, R.sup.9 at each
occurrence independently is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.10 is (C.sub.1-3)alkyl
or halo-substituted (C.sub.1-3)alkyl; and R.sup.4 is
--C(O)X.sup.5R.sup.11 or --S(O).sub.2X.sup.5R.sup.11, wherein
X.sup.5 is a bond, --O-- or --NR.sup.12, wherein R.sup.12 is
hydrogen or (C.sub.1-6)alkyl, and R.sup.11 is (i) (C.sub.1-6)alkyl
optionally substituted by --OR.sup.13, --SR.sup.13, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --C(O)R.sup.13, --C(O)OR.sup.13,
--C(O)NR.sup.13R.sup.14, --NR.sup.13R.sup.14,
--NR.sup.14C(O)R.sup.13, --NR.sup.14C(O)OR.sup.13,
--NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl and R.sup.14 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl substituted by
--X.sup.6OR.sup.15, --X.sup.6SR.sup.15, --X.sup.6S(O)R.sup.15,
--X.sup.6S(O).sub.2R.sup.15, --X.sup.6C(O)R.sup.15,
--X.sup.6C(O)OR.sup.15, --X.sup.6C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.15R.sup.16, --X.sup.6NR.sup.16C(O)R.sup.15,
--X.sup.6NR.sup.16C(O)OR.sup.15,
--X.sup.6NR.sup.16C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.16C(O)OR.sup.16,
--X.sup.6NR.sup.16C(NR.sup.16)NR.sup.15R.sup.16, wherein X.sup.6 is
a bond or methylene, R.sup.15 is
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl and R.sup.16 is hydrogen
or (C.sub.1-6)alkyl; wherein R.sup.4 optionally further contains 1
to 5 substituents which when occurring within an alicyclic or
aromatic ring system are radicals independently selected from a
group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano,
halo, nitro, halo-substituted (C.sub.1-3)alkyl,
--X.sup.6NR.sup.17R.sup.17, --X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.18)OR.sup.17,
--X.sup.6OP(O)(OR.sup.18)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring with aliphatic moiety are
radicals independently selected from a group consisting of cyano,
halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
X.sup.6 is a bond or (C.sub.1-6)alkylene, R.sup.17 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.18 is (C.sub.1-6)alkyl
or halo-substituted (C.sub.1-3)alkyl; X.sup.3 is a group of Formula
(b), (c), (d), (e), (f), (g) or (h): ##STR223## represents a single
bond, or a double bond; X.sup.7 represents aryl, heteroaryl or
NR.sup.20R.sup.25; n is 0, 1 or 2; R.sup.20 is selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl and
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl; R.sup.23 is selected from
--H, (C.sub.1-6)alkyl, (C.sub.4-6)alkenyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl optionally substituted with
amino, --NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as
described above; R.sup.25 is selected from hydrogen,
(C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-13)aryl(C.sub.0-6)alkyl, --X.sup.4NHR.sup.15,
--X.sup.4S(O).sub.2R.sup.26 or
--X.sup.4C(O)R.sup.17NR.sup.17C(O)R.sup.17 wherein R.sup.15,
R.sup.17 and X.sup.4 are as described above; R.sup.26 is selected
from the group consisting of hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)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)bicycloaryl(C.sub.0-3)alkyl and
hetero(C.sub.8-12)-bicycloaryl(C.sub.0-3)alkyl; R.sup.27 is
hydrogen, (C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl; R.sup.28 is R.sup.20 or
--O--C(.dbd.O)--R.sup.29; R.sup.29 is (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl; wherein X.sup.3
optionally further contains 1 to 5 substituents which when
occurring within an alicyclic or aromatic ring system are radicals
independently selected from a group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, nitro, halo-substituted
(C.sub.1-3)alkyl, --X.sup.6NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6C(O)R.sup.17, --X.sup.6OR.sup.15,
--X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.8)OR.sup.17,
--X.sup.6OP(O)(OR.sup.8)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein R.sup.15,
R.sup.17, R.sup.18 and X.sup.6 are as described above; or one of
N-oxide derivatives, prodrug derivatives, protected derivatives,
individual isomers and mixtures of isomers of compounds of formula
Ix; or one of pharmaceutically acceptable salts and solvates of
such compounds and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers
formula Ix.
13. A compound of claim 13, wherein R.sup.13 is selected from
(C.sub.1-6)alkyl, (C.sub.4-6)alkenyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl optionally substituted with
amino, --NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as
described above.
14. A compound of claim 13, selected from the group consisting of:
Morpholine-4-carboxylic acid
[1-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2-phenylmethanesulfonyl-
-ethyl]-amide; or
N-{1S-[1S-(4-Methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]2-benz-
ylsulfonylethyl}-morpholine-4-carboxamide.
15. A compound of claim 13, selected from the group consisting of:
Morpholine-4-carboxylic acid
[(R)-1-(6-oxo-cyclohex-1-enylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide; Morpholine-4-carboxylic acid
[(R)-2-cyclopropylmethanesulfonyl-1-(6-oxo-cyclohex-1-enylcarbamoyl)-ethy-
l]-amide; Morpholine-4-carboxylic acid
[(R)-1-(3,4-dioxo-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide; Morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclohexylcarba-moy-
l)-ethyl]-amide; Morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phen-ylmethanesulfonyl)-1-(2-oxo-cyclopentylcarbamo-
yl)-ethyl]-amide; Morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclobutylcarbamoyl-
)-ethyl]-amide; (Morpholine-4-carboxylic
acid[1-(2-benzylcarbamoyl-2-oxo-ethylcarbamoyl)-2-phenylmethanesulfonyl-e-
thyl]-amide); Acetic acid
3-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylami-
no}-4-oxo-azetidin-2-yl ester; Morpholine-4-carboxylic acid
[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethan-
esulfonyl-ethyl]-amide; Morpholine-4-carboxylic acid
[1-(4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]--
amide; or Morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(1,1-dimethyl-2,3-diox-o-3-
-phenyl-propylcarbamoyl)-ethyl]-amide.
Description
[0001] This application is a divisional of Non-Provisional
application Ser. No. 10/787,367, filed on Feb. 2, 2004, which is a
continuation of International Application No. PCT/US02/29323, filed
Sep. 16, 2002, which claims the benefit of Provisional Application
No. 60/322,318, filed on Sep. 14, 2001.
[0002] This Application relates to compounds and compositions for
treating diseases associated with cysteine protease activity,
particularly diseases associated with activity of cathepsin 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. An increase in cathepsin S activity
contributes to the pathology and/or symptomatology of a number of
diseases. Accordingly, molecules that inhibit the activity of
cathepsin S protease are useful as therapeutic agents in the
treatment of such diseases.
SUMMARY OF THE INVENTION
[0004] This Application relates to compounds of Formula I: ##STR1##
in which:
[0005] X.sup.1 and X.sup.2 are both methylene or X.sup.1 is
ethylene and X.sup.2 is a bond;
[0006] R.sup.3 is --CR.sup.5.dbd.CHR.sup.6,
--CR.sup.5(CR.sup.6.sub.3).sub.2 or --CR.sup.7.dbd.NR.sup.8,
wherein R.sup.5 is hydrogen and R.sup.6 is hydrogen or
(C.sub.1-4)alkyl or R.sup.5 and R.sup.6 together with the atoms to
which R.sup.5 and R.sup.6 are attached form
(C.sub.3-12)cycloalkenyl, hetero(C.sub.5-12)cycloalkenyl,
(C.sub.6-12)aryl, hetero(C.sub.6-12)aryl, (C.sub.9-12)bicycloaryl
or hetero(C.sub.8-12)bicycloaryl and R.sup.7 and R.sup.8 together
with the atoms to which R.sup.7 and R.sup.8 are attached form
hetero(C.sub.5-12)cycloalkenyl, hetero(C.sub.6-12)aryl or
hetero(C.sub.8-12)bicycloaryl, wherein R.sup.3 optionally is
substituted by 1 to 5 radicals independently selected from a group
consisting of (C.sub.1-4)alkyl, cyano, halo, halo-substituted
(C.sub.1-4)alkyl, nitro, --X.sup.4NR.sup.9R.sup.9,
--X.sup.4OR.sup.9, --X.sup.4SR.sup.9, --X.sup.4C(O)NR.sup.9R.sup.9,
--X.sup.4C(O)OR.sup.9, --X.sup.4S(O)R.sup.10,
--X.sup.4S(O).sub.2R.sup.10 and --X.sup.4C(O)R.sup.10, wherein
X.sup.4 is a bond or (C.sub.1-2)alkylene, R.sup.9 at each
occurrence independently is hydrogen, (C.sub.1-3)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.10 is (C.sub.1-3)alkyl
or halo-substituted (C.sub.1-3)alkyl; and
[0007] R.sup.4 is --C(O)X.sup.5R.sup.11 or
--S(O).sub.2X.sup.5R.sup.11, wherein X.sup.5 is a bond, --O-- or
--NR.sup.12--, wherein R.sup.12 is hydrogen or (C.sub.1-6)alkyl,
and R.sup.11 is (i) (C.sub.1-6)alkyl optionally substituted by
--OR.sup.13, --SR.sup.13, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--C(O)R.sup.13, --C(O)OR.sup.13, --C(O)NR.sup.13R.sup.14,
--NR.sup.13R.sup.14, --NR.sup.14C(O)R.sup.13,
--NR.sup.14C(O)OR.sup.13, --NR.sup.14C(O)NR.sup.13R.sup.14 or
--NR.sup.14C(NR.sup.14)NR.sup.13R.sup.14, wherein R.sup.13 is
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl and R.sup.14 at each
occurrence independently is hydrogen or (C.sub.1-6)alkyl, or (ii)
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl or (iii)
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl substituted by
--X.sup.6OR.sup.15, --X.sup.6SR.sup.15, --X.sup.6S(O)R.sup.15,
--X.sup.6S(O).sub.2R.sup.15, --X.sup.6C(O)R.sup.15,
--X.sup.6C(O)OR.sup.15, --X.sup.6C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.15R.sup.16, --X.sup.6NR.sup.16C(O)R.sup.15,
--X.sup.6NR.sup.16C(O)OR.sup.15,
--X.sup.6NR.sup.16C(O)NR.sup.15R.sup.16,
--X.sup.6NR.sup.16C(O)OR.sup.16,
--X.sup.6NR.sup.16C(NR.sup.16)NR.sup.15R.sup.16, wherein X.sup.6 is
a bond or methylene, R.sup.15 is
(C.sub.3-6)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl, phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl and R.sup.16 is hydrogen
or (C.sub.1-6)alkyl; wherein R.sup.4 optionally further contains 1
to 5 substituents which when occurring within an alicyclic or
aromatic ring system are radicals independently selected from a
group consisting of (C.sub.1-6)alkyl, (C.sub.1-6)alkylidene, cyano,
halo, nitro, halo-substituted (C.sub.1-3)alkyl,
--X.sup.6NR.sup.17R.sup.17, --X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.18)OR.sup.17,
--X.sup.6OP(O)(OR.sup.18)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
X.sup.6 is a bond or (C.sub.1-6)alkylene, R.sup.17 at each
occurrence independently is hydrogen, (C.sub.1-6)alkyl or
halo-substituted (C.sub.1-3)alkyl and R.sup.18 is (C.sub.1-6)alkyl
or halo-substituted (C.sub.1-3)alkyl;
[0008] X.sup.3 is a group of Formula (a), (b), (c), (d), (e), (f),
(g) or (h): ##STR2##
[0009] represents a single bond, or a double bond;
[0010] X.sup.7 represents aryl, heteroaryl or
NR.sup.20R.sup.25;
[0011] n is 0, 1 or 2;
[0012] R.sup.20 is selected from tie group consisting of hydrogen,
(C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl and
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl;
[0013] R.sup.21 is selected from the group consisting of hydrogen,
(C.sub.1-9)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)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)bicycloaryl(C.sub.0-3)alkyl,
hetero(C.sub.8-12)-bicycloaryl(C.sub.0-3)alkyl, --C(O)R.sup.26,
--C(S)R.sup.26, --S(O).sub.2R.sup.26, --C(O)OR.sup.26,
--C(O)N(R.sup.26)R.sup.27, --C(S)N(R.sup.26)R.sup.27 and
--S(O).sub.2N(R.sup.27)R.sup.26;
[0014] R.sup.23 is selected from --H, (C.sub.1-6)alkyl,
(C.sub.4-6)alkenyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl optionally substituted with
amino, --NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as
described above;
[0015] R.sup.25 is selected from hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl,
hetero(C.sub.5-13)aryl(C.sub.0-6)alkyl, --X.sup.4NHR.sup.15,
--X.sup.4S(O).sub.2R.sup.26 or
--X.sup.4C(O)R.sup.17NR.sup.17C(O)R.sup.17 wherein R.sup.15,
R.sup.17 and X.sup.4 are as described above;
[0016] R.sup.26 is selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, (C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)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)bicycloaryl(C.sub.0-3)alkyl and
hetero(C.sub.8-12)-bicycloaryl(C.sub.0-3)alkyl;
[0017] R.sup.27 is hydrogen, (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl or
hetero(C.sub.5-12)aryl(C.sub.0-6)alkyl;
[0018] R.sup.28 is R.sup.20 or --O--C(.dbd.O)--R.sup.29;
[0019] R.sup.29 is (C.sub.1-6)alkyl,
(C.sub.3-12)cycloalkyl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl; [0020] wherein
X.sup.3 optionally further contains 1 to 5 substituents which when
occurring within an alicyclic or aromatic ring system are radicals
independently selected from a group consisting of (C.sub.1-6)alkyl,
(C.sub.1-6)alkylidene, cyano, halo, nitro, halo-substituted
(C.sub.1-3)alkyl, --X.sup.6NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(O)OR.sup.17,
--X.sup.6NR.sup.17C(O)NR.sup.17R.sup.17,
--X.sup.6NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17,
--X.sup.6OR.sup.17, --X.sup.6C(O)R.sup.17, --X.sup.6OR.sup.15,
--X.sup.6SR.sup.17, --X.sup.6C(O)OR.sup.17,
--X.sup.6C(O)NR.sup.17R.sup.17,
--X.sup.6S(O).sub.2NR.sup.17R.sup.17,
--X.sup.6P(O)(OR.sup.8)OR.sup.17,
--X.sup.6OP(O)(OR.sup.8)OR.sup.17, --X.sup.6NR.sup.17C(O)R.sup.18,
--X.sup.6S(O)R.sup.18, --X.sup.6S(O).sub.2R.sup.18 and
--X.sup.6C(O)R.sup.18 and when occurring within an aliphatic moiety
are radicals independently selected from a group consisting of
cyano, halo, nitro, --NR.sup.17R.sup.17, --NR.sup.17C(O)OR.sup.17,
--NR.sup.17C(O)NR.sup.17R.sup.17,
--NR.sup.17C(NR.sup.17)NR.sup.17R.sup.17, --OR.sup.17, --SR.sup.17,
--C(O)OR.sup.17, --C(O)NR.sup.17R.sup.17,
--S(O).sub.2NR.sup.17R.sup.17, --P(O)(OR.sup.17)OR.sup.17,
--OP(O)(OR.sup.17)OR.sup.17, --NR.sup.17C(O)R.sup.18,
--S(O)R.sup.18, --S(O).sub.2R.sup.18 and --C(O)R.sup.18, wherein
R.sup.15, R.sup.17, R.sup.18 and X.sup.6 are as described
above.
[0021] A second aspect of the invention is a pharmaceutical
composition that contains a compound of Formula I or their N-oxide
derivatives, individual isomers or mixture of isomers thereof, or
pharmaceutically acceptable salts thereof, in admixture with one or
more suitable excipients.
[0022] A third aspect of the invention is a method for treating a
disease in an animal in which inhibition of cathepsin S 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, individual isomer or mixture of isomers
thereof; or a pharmaceutically acceptable salt thereof.
[0023] A fourth aspect of the invention is the processes for
preparing compounds of Formula I and the N-oxide derivatives,
prodrug derivatives, protected derivatives, individual isomers and
mixtures of isomers thereof; and the pharmaceutically acceptable
salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
[0024] Unless otherwise stated, the following terms used in the
specification and claims are defined for the purposes of this
Application and have the following meanings.
[0025] "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.
[0026] "Aliphatic" means a moiety characterized by a 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.
[0027] "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, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-methylallyl, 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.6-10)aryl(C.sub.0-3)alkyl includes phenyl, benzyl,
phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
[0028] "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--), 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).
[0029] "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.CH--CH.dbd.CH.sub.2),
and the like).
[0030] "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.
[0031] "Animal" includes humans, non-human mammals (e.g., dogs,
cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the
like) and non-mammals (e.g., birds, and the like).
[0032] "Aromatic" means a moiety wherein the constituent atoms make
up an unsaturated ring system, all atoms in the ring system are
Sp.sup.2 hybridized and the total number of pi electrons is equal
to 4n+2.
[0033] "Aryl" means a monocyclic or fused bicyclic ring assembly
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, optionally substituted (C.sub.6-10)aryl as used in this
Application includes, but is not limited to, biphenyl-2-yl,
2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo-5-fluorophenyl,
4-tert-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl,
2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl,
4-chlorocarbonylphenyl, 2-chloro-4-fluorophenyl,
2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl,
6-chloro-2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl,
2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-difluoromethoxyphenyl,
3,5-dimethylphenyl, 2-ethoxycarbonylphenyl, 2-fluorophenyl,
2-iodophenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4-methoxyphenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl,
5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-yl,
2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl,
2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifluoromethoxyphenyl,
3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,
2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl,
4-trifluoromethylsulfanylphenyl, and the like. Optionally
substituted (C.sub.6-10)aryl as used in this Application includes
3-acetylphenyl, 3-tert-butoxycarbonylaminomethylphenyl,
biphenyl-4-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl,
naphth-2-yl, 3-phenoxyphenyl, phenyl, and the like.
[0034] "Bicycloaryl" means a bicyclic ring assembly containing the
number of ring carbon atoms indicated, wherein the rings are linked
by a single bond or fused and at least one of the rings comprising
the assembly is aromatic, and any carbocyclic ketone, thioketone or
iminoketone derivative thereof (e.g., (C.sub.9-10)bicycloaryl
includes cyclohexylphenyl, 1,2-dihydronaphthyl,
2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl,
1,2,3,4-tetrahydronaphthyl, and the like).
[0035] "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.
[0036] "Carbocyclic ketone derivative" means a derivative
containing the moiety --C(O)--.
[0037] "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.
[0038] "Cycloalkyl" means a saturated or partially unsaturated,
monocyclic, fused bicyclic or bridged polycyclic ring assembly
containing the number of ring carbon atoms indicated, and any
carbocyclic ketone, thioketone or iminoketone derivative thereof
(e.g., (C.sub.3-10)cycloalkyl includes cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl,
bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl,
oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,
2-oxobicyclo[2.2.1]hept-1-yl, and the like).
[0039] "Cycloalkylene" means a divalent saturated or partially
unsaturated, monocyclic ring or bridged polycyclic ring assembly
containing the number of ring carbon atoms indicated, and any
carbocyclic ketone, thioketone or iminoketone derivative thereof.
For example, the instance wherein "R.sup.1 and R.sup.2 together
with the carbon atom to which both R.sup.1 and R.sup.2 are attached
form (C.sub.3-8)cycloalkylene" includes, but is not limited to, the
following: ##STR3##
[0040] "Disease" specifically includes any unhealthy condition of
an animal orpart thereof and includes an unhealthy condition that
may be caused by, or incident to, medical or veterinary therapy
applied to that animal, i.e., the "side effects" of such
therapy.
[0041] "Halo" means fluoro, chloro, bromo or iodo.
[0042] "Halo-substituted alkyl", as an isolated group or part of a
larger 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, dichloromethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the
like).
[0043] "Heteroatom moiety" includes --N.dbd., --NR--,
--N.sup.+(O.sup.-).dbd., --O--; --S-- or --S(O).sub.2--, wherein R
is hydrogen, (C.sub.1-6)alkyl or a protecting group.
[0044] "Heterocycloalkylene" means cycloalkylene, as defined in
this Application, provided that one or more of the ring member
carbon atoms indicated, is replaced by heteroatom moiety selected
from --N.dbd., --NR--, --O--, --S-- or --S(O).sub.2--, wherein R is
hydrogen or (C.sub.1-6)alkyl. For example, the instance wherein
R.sup.1 and R.sup.2 together with the carbon atom to which both
R.sup.1 and R.sup.2 are attached form
hetero(C.sub.3-8)cycloalkylene" includes, but is not limited to,
the following: ##STR4## in which R is hydrogen, (C.sub.1-6)alkyl,
or a protecting group.
[0045] "Heteroaryl" means aryl, as defined in this Application,
provided that one or more of the ring carbon atoms indicated are
replaced by a heteroatom moiety selected from --N.dbd., --NR--,
--N.sup.+(O.sup.-).dbd., --O-- or --S--, wherein R is hydrogen,
(C.sub.1-6)alkyl, a protecting group or represents the free valence
which serves as the point of attachment to a ring nitrogen, and
each ring is comprised of 5 or 6 ring atoms. For example,
optionally substituted hetero(C.sub.5-13)aryl as used in this
Application includes, but is not limited to,
4-amino-2-hydroxypyrimidin-5-yl, dibenzofuranyl, benzothiazol-2-yl,
1H-benzoimidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl,
4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl,
5-carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl,
5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydroxypyrimidin-4-yl,
fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl,
8-hydroxy-5,7-dimethylquinolin-2-yl, 5-hydroxymethylisoxazol-3-yl,
3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl,
1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-indol-3-yl, isothiazol-4-yl,
isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl,
1-methyl-1H-imidazol-2-yl, 5-methyl-3H-imidazol-4-yl,
5-methylisoxazol-3-yl, 5-methyl-2H-pyrazol-3-yl,
3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl,
6-methylpyrid-2-yl, 2-methylpyrid-3-yl, 2-methylthiazol-4-yl,
5-nitropyrid-2-yl, 2H-pyrazol-3-yl, 3H-pyrazolyl, pyridazin-3-yl,
pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,
5-pyrid-3-yl-2H-[1,2,4]triazol-3-yl, pyrimidin-4-yl,
pyrimidin-5-yl, 1H-pyrrol-3-yl, quinolin-2-yl, 1H-tetrazol-5-yl,
thiazol-2-yl, thiazol-5-yl, thien-2-yl, thien-3-yl,
2H-[1,2,4]triazol-3-yl, 3H-[1,2,3]triazol-4-yl,
5-trifluoromethylpyrid-2-yl, and the like. Suitable protecting
groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
4-methoxybenzyl, 2-nitrobenzyl, and the like. Optionally
substituted hetero(C.sub.5-10)aryl as used in this Application to
define R.sup.4 includes benzofur-2-yl, fur-2-yl, fur-3-yl,
pyrid-3-yl, pyrid-4-yl, quinol-2-yl, quinol-3-yl, thien-2-yl,
thien-3-yl, and the like.
[0046] "Heterobicycloaryl" means bicycloaryl, as defined in this
Application, provided that one or more of the ring 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, a protecting group or represents the free valence
which serves as the point of attachment to a ring nitrogen, and any
carbocyclic ketone, thioketone or iminoketone derivative thereof.
For example, optionally substituted hetero(C.sub.8-10)bicycloaryl
as used in this Application includes, but is not limited to,
2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like. In general,
the term heterobicycloaryl as used in this Application includes,
for example, benzo[1,3]dioxol-5-yl,
3,4-dihydro-2H-[1,8]naphthyridinyl, 3,4-dihydro-2H-quinolinyl,
2,4-dioxo-3,4-dihydro-2H-quinazolinyl,
1,2,3,4,5,6-hexahydro[2,2']bipyridinylyl,
3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl,
and the like.
[0047] "Heterocycloalkyl" means cycloalkyl, as defined in this
Application, provided that one or more of the ring 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, a protecting group or represents the free valence
which serves as the point of attachment to a ring nitrogen, and any
carbocyclic ketone, thioketone or iminoketone derivative thereof
(e.g., the term hetero(C.sub.5-10)cycloalkyl includes
imidazolidinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl,
pyrrolinyl, quinuclidinyl, and the like). Suitable protecting
groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl,
4-methoxybenzyl, 2-nitrobenzyl, and the like. Both the unprotected
and protected derivatives fall within the scope of the
invention.
[0048] "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.
[0049] "Iminoketone derivative" means a derivative containing the
moiety --C(NR)--, wherein R is hydrogen or (C.sub.1-6)alkyl.
[0050] "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 "opfical 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, whereAn is
the number of chiral centers. Compounds with more than one chiral
center may exist as -ether an individual diastereomers 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. Enanfiomers 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", 4th edition, March, Jerry, John Wiley &
Sons, New York, 1992). 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.
Thus, for example, the name morpholine-4-carboxylic acid
[1(1-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethy-
l]-amide is meant to include morpholine-4-carboxylic acid
[S-1-(1-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-e-
thyl]-amide and morpholine-4-carboxylic acid
[R-1-(1-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-e-
thyl]-amide and any mixture, racemic or otherwise, thereof.
[0051] "Ketone derivative" means a derivative containing the moiety
--C(O)--. For example, for 2-acetoxy-azetidin-3-yl, the
"carbocyclic ketone derivative" would be
2-acetoxy-4-oxo-azetidin-3-yl.
[0052] "Nitro" means the radical --NO.sub.2.
[0053] "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
"wherein within R.sup.3 and R.sup.4 any alicyclic or aromatic ring
system may be subsfituted further by 1-5 radicals . . . " means
that R.sup.3 and R.sup.4 may or may not be substituted in order to
fall within the scope of the invention.
[0054] "Oxoalkyl" means alkyl, as defined above, wherein one of the
number of carbon atoms indicated is replaced by an oxygen group
(--O--), e.g., oxo(C.sub.2-6)alkyl includes methoxymethyl, etc.
[0055] "N-oxide derivatives" means derivatives of compounds of
Formula I in which nitrogens are in an oxidized state (i.e., O--N)
and which possess the desired pharmacological activity.
[0056] "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.
[0057] "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.
[0058] "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.
[0059] 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, aluminum hydroxide and calcium hydroxide. Acceptable
organic bases include ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine and the like.
[0060] "Prodrug" means a compound which is convertible in vivo by
metabolic means (e.g. by hydrolysis) to a compound of Formula I.
For example an ester of a compound of Formula I containing a
hydroxy group may be convertible by hydrolysis in vivo to the
parent molecule. Alternatively an ester of a compound of Formula I
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)benzoates, e.g. 3- or
4-(4-alkylpiperazin-1-yl)benzoates.
[0061] "Protected derivatives" means derivatives of compounds of
Formula I in which a reactive site or sites are blocked with
protecting groups. Protected derivatives of compounds of Formula I
are useful in the preparation of compounds of Formula I or in
themselves may be active cathepsin S inhibitors. A comprehensive
list of suitable protecting groups can be found in T. W. Greene,
Protecting Groups in Organic Synthesis, 3rd edition, John Wiley
& Sons, Inc. 1999.
[0062] "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.
[0063] "Thioketone derivative" means a derivative containing the
moiety --C(S)--.
[0064] "Treatment" or "treating" means any administration of a
compound of the present invention and includes: [0065] (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, [0066] (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 [0067] (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). Nomenclature:
[0068] The compounds of Formula I and the intermediates and
starting materials used in their preparation are named in
accordance with IUPAC rules of nomenclature in which the
characteristic groups have decreasing priority for citation as the
principle group as follows: acids, esters, amides, etc.
Alternatively, the compounds are named by AutoNom 4.0 (Beilstein
Information Systems, Inc.). For example, a compound of Formula I in
which R.sup.3 is phenyl, R.sup.4 is morpholine-4-carbonyl and
X.sup.3 is 1-benzoyl-4-oxo-pyrrolidin-3-ylamino; that is, a
compound having the following structure: ##STR5## is named
morpholine-4-carboxylic acid
[1-(1-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-eth-
yl]-amide.
Presently Preferred Embodiments
[0069] While the broadest definition of the invention is set forth
in the Summary of the Invention, certain aspects of the invention
are preferred. For example, for a compound of Formula I, in which
X.sup.1 and X.sup.2 are both methylene or X.sup.1 is ethylene and
X.sup.2 is a bond; R.sup.3 is --CR.sup.5.dbd.CHR.sup.6,
--CR.sup.5(CR.sup.6.sub.3).sub.2 or --CR.sup.7.dbd.NR.sup.8,
wherein R.sup.5 is hydrogen and R.sup.6 is hydrogen or
(C.sub.1-4)alkyl or R.sup.5 and R.sup.6 together with the atoms to
which R.sup.5 and R.sup.6 are attached form
(C.sub.3-12)cycloalkenyl, (C.sub.6-12)aryl, hetero(C.sub.6-12)aryl
or (C.sub.9-12)bicycloaryl and R.sup.7 and R.sup.8 together with
the atoms to which R.sup.7 and R.sup.8 are attached form
hetero(C.sub.5-12)cycloalkenyl or hetero(C.sub.6-12)aryl, wherein
R.sup.3 optionally is substituted by 1 to 5 radicals independently
selected from a group consisting of (C.sub.1-4)alkyl, cyano, halo,
halo-substituted (C.sub.1-4)alkyl, --X.sup.4OR.sup.9 and
--X.sup.4C(O)OR.sup.9, wherein X.sup.4 is a bond or
(C.sub.1-2)alkylene, R.sup.9 at each occurrence independently is
(C.sub.1-3)alkyl or halo-substituted (C.sub.1-3)alkyl; R.sup.4 is
--C(O)X.sup.5R.sup.11 or --S(O).sub.2X.sup.5R.sup.11, wherein
X.sup.5 is a bond, --O-- or --NR.sup.12--, wherein R.sup.12 is
hydrogen or (C.sub.1-6)alkyl, and R.sup.11 is (i) (C.sub.1-6)alkyl
or (ii) hetero(C.sub.5-12)cycloalkyl(C.sub.0-3)alkyl,
(C.sub.6-12)aryl(C.sub.0-3)alkyl,
hetero(C.sub.5-12)aryl(C.sub.0-3)alkyl,
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl or
hetero(C.sub.8-12)bicycloaryl(C.sub.0-3)alkyl or (iii)
hetero(C.sub.5-6)cycloalkyl(C.sub.0-3)alkyl or
phenyl(C.sub.0-3)alkyl substituted by --X.sup.6OR.sup.15,
--X.sup.6C(O)R.sup.15 or --X.sup.6NR.sup.16C(O)OR.sup.16, wherein
X.sup.6 is a bond or methylene, R.sup.15 is phenyl(C.sub.0-3)alkyl
or hetero(C.sub.5-6)aryl(C.sub.0-3)alkyl and R.sup.16 is hydrogen
or (C.sub.1-6)alkyl; wherein R.sup.4 optionally further contains 1
to 5 substituents which when occurring within an alicyclic or
aromatic ring system are radicals independently selected from a
group consisting of (C.sub.1-6)alkyl, halo,
--X.sup.6NR.sup.17R.sup.17, --X.sup.6OR.sup.17,
--X.sup.6C(O)OR.sup.17, --X.sup.6NC(O)R.sup.16 and
--X.sup.6C(O)R.sup.18, R.sup.17 at each occurrence independently is
hydrogen, (C.sub.1-6)alkyl or halo-substituted (C.sub.1-3)alkyl and
R.sup.18 is (C.sub.1-6)alkyl or halo-substituted
(C.sub.1-3)alkyl.
[0070] In particular, X.sup.3 is a group of Formula (a), (b) or (c)
in which: n is 0, 1 or 2; R.sup.20 is selected from the group
consisting of hydrogen and (C.sub.1-6)alkyl; R.sup.21 is selected
from the group consisting of (C.sub.1-9)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, --C(O)R.sup.26,
--S(O).sub.2R.sup.26, --C(O)OR.sup.26 and
--C(O)N(R.sup.26)R.sup.27; R.sup.23 is selected from
(C.sub.1-6)alkyl optionally substituted with amino,
--NHC(O)R.sup.15 or --R.sup.15 wherein R.sup.15 is as described
above; R.sup.25 is selected from (C.sub.1-6)alkyl,
(C.sub.6-12)aryl(C.sub.0-6)alkyl, --X.sup.4S(O).sub.2R.sup.26 or
--X.sup.4C(O)R.sup.17NR.sup.17C(O)R.sup.17 wherein R.sup.17 and
X.sup.4 are as described above and R.sup.26 is as described below;
R.sup.26 is selected from the group consisting of (C.sub.1-6)alkyl,
hetero(C.sub.5-12)cycloalkyl(Q.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 and
(C.sub.9-12)bicycloaryl(C.sub.0-3)alkyl; R.sup.27 is
(C.sub.1-6)alkyl; herein X.sup.3 optionally further contains 1 to 5
substituents which when occurring within an alicyclic or aromatic
ring system are radicals independently selected from a group
consisting of (C.sub.1-6)alkyl, cyano, halo, --X.sup.6OR.sup.17,
--X.sup.6C(O)R.sup.17 and --X.sup.6OR.sup.15.
[0071] R.sup.3 more preferably is selected from the group
consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,
vinyl, 2-difluoromethoxyphenyl, 1-oxy-pyridin-2-yl,
4-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl,
3,5-dimethylphenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl, 2-bromophenyl, naphthalen-2-yl,
3,4-dichlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl,
3-trifluoromethoxyphenyl, 2,3,4,5,6-pentafluoro-phenyl,
2-fluorophenyl, 2-chlorophenyl, 2-cyano-phenyl,
2-trifluoromethylphenyl, 4-tert-butyl-phenyl, 3-chlorophenyl,
4-bromophenyl, 2-fluoro-3-chloro-phenyl, 2-fluoro-3-methyl-phenyl,
3-fluorophenyl, 2,5-difluorophenyl, 3-bromophenyl,
2,5-dichlorophenyl, 2,6-difluorophenyl, 3-cyano-phenyl,
4-cyano-phenyl, 2-trifluoromethoxyphenyl, 2,3-difluorophenyl,
biphenyl, 2-bromo-5-fluoro-phenyl, 4-fluorophenyl,
3,4-difluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl,
2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl,
2-chloro-5-trifluoromethylphenyl, 2,4-bis-trifluoromethylphenyl,
2,5,6-trifluorophenyl, 2-fluoro-3-trifluoromethylphenyl,
2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl,
2,3,5-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl,
5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl,
2-methoxyphenyl, 3,5-bis-trifluoromethylphenyl,
4-difluoromethoxyphenyl, 3-difluoromethoxyphenyl,
2,6-dichlorophenyl, 4-carboxyphenyl, cyclohexyl, cyclopropyl,
isopropyl, thiophen-2-yl, 5-chloro-thiophen-2-yl and
3,5-dimethyl-isoxazol-4-yl.
[0072] R.sup.4 more preferably is selected from the group
consisting of benzoyl, morpholine-4-carbonyl, acetyl,
furan-3-carbonyl, 2-methoxy-benzoyl, 3-methoxy-benzoyl,
naphthalene-2-carbonyl, benzo[1,3]dioxole-5-carbonyl,
3-pyridin-3-yl-acryloyl, benzofuran-2-carbonyl, furan-2-carbonyl,
tert-butoxy-carbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl,
quinoline-3-carbonyl, 3-acetyl-benzoyl, 4-phenoxy-benzoyl,
3-hydroxy-benzoyl, 4-hydroxy-benzoyl, pyridine-3-carbonyl,
3-(tert-butoxycarbonylamino-methyl)-benzoyl,
4-carbonyl-piperazine-1-carboxylic acid tert-butyl ester,
4-carbonyl-piperazine-1-carboxylic acid ethyl ester,
4-(furan-2-carbonyl)-piperazine-1-carbonyl, pyridine-4-carbonyl,
1-oxy-pyridine-4-carbonyl, 1-oxy-pyridine-3-carbonyl,
thiophene-2-carbonyl, thiophene-3-carbonyl, 4-benzoyl-benzoyl,
5-methyl-thiophene-2-carbonyl, 3-chloro-thiophene-2-carbonyl,
3-bromo-thiophene-2-carbonyl, 4-chloro-benzoyl,
3-flouro-4-methoxy-benzoyl, 4-methoxy-benzoyl,
4-triflouromethoxy-benzoyl, 3,4-diflouro-benzoyl, 4-fluoro-benzoyl,
3,4-dimethoxy-benzoyl, 3-methyl-benzoyl, 4-bromo-benzoyl,
4-triflouromethyl-benzoyl, 3-benzoyl-benzoyl,
cyclopentane-carbonyl, benzo[b]thiophene-2-carbonyl,
3-chloro-benzo[b]thiophene-2-carbonyl, benzenesulfonyl,
naphthalene-2-sulfonyl, 5-methyl-thiophene-2-sulfonyl,
thiophene-2-sulfonyl, formamyl-methyl ester, 4-methyl-pentanoyl,
formamyl-isobutyl ester, formamyl-monoallyl ester,
formamyl-isopropyl ester, N,N-dimethyl-formamyl,
N-isopropyl-formamyl, N-pyridin-4-yl-formamyl,
N-pyridin-3-yl-formamyl, 3-phenyl-acryloyl, 1H-indole-5-carbonyl,
pyridine-2-carbonyl, pyrazine-2-carbonyl,
3-hydroxy-pyridine-2-carbonyl, 2-amino-pyridine-3-carbonyl,
2-hydroxy-pyridine-3-carbonyl,
6-amino-pyridine-3-carbonyl,-6-hydroxy-pyridine-3-carbonyl,
pyridazine-4-carbonyl, 3-phenoxy-benzoyl and
1-oxo-1,3-dihydro-isoindole-2-carbonyl.
[0073] X.sup.3 more preferably is selected from a group consisting
of 4-amino-3-oxo-azepane-1-carboxylic acid benzyl ester,
4-amino-3-oxo-azepane-1-carboxylic acid isobutyl ester,
4-amino-1-benzoyl-azepan-3-one,
4-amino-1-benzenesulfonyl-azepan-3-one,
4-amino-1-(pyridine-2-sulfonyl)-azepan-3-one,
4-amino-1-(1-oxy-pyridine-2-sulfonyl)-azepan-3-one,
4-amino-1-(3,4-dichloro-benzenesulfonyl)-azepan-3-one,
4-amino-1-(2-flouro-benzenesulfonyl)-azepan-3-one,
4-amino-1-(3,4-dimethoxy-benzenesulfonyl)-azepan-3-one,
4-amino-1-(2-cyano-benzenesulfonyl)-azepan-3-one,
4-amino-1-(naphthalene-1-sulfonyl)-azepan-3-one,
4-amino-1-(thiophene-2-sulfonyl)-azepan-3-one,
4-amino-1-(thiazole-2-sulfonyl)-azepan-3-one,
4-amino-1-(pyrrolidine-1-sulfonyl)-azepan-3-one,
4-amino-1-methanesulfonyl-azepan-3-one,
4-amino-1-(pyrrolidine-1-carbonyl)-azepan-3-one,
4-amino-3-oxo-azepane-1-carboxylic-acid-dimethylamide,
4-amino-3-oxo-azepane-1-carboxylic-acid-benzylamide,
4-amino-1-benzyl-azepan-3-one, 4-amino-1-benzyl-piperidin-3-one,
4-amino-1-benzoyl-piperidin-3-one,
4-amino-1-benzoyl-pyrrolidin-3-one,
4-amino-1-benzyl-pyrrolidin-3-one,
4-amino-1-benzenesulfonyl-pyrrolidin-3-one,
4-amino-1-(5-methyl-hexyl)-pyrrolidin-3-one,
1-ethyl-2-oxo-3-(toluene-4-sulfonylamino)-butylamino,
1-ethyl-2-oxo-3-(4-phenoxy-benzenesulfonylamino)-propylamino,
1-ethyl-2-oxo-3-[4-(pyridin-3-yloxy)-benzenesulfonylamino]-propylamino,
3-(dibenzofuran-2-sulfonylamino)-1-ethyl-2-oxo-butylamino,
1-ethyl-3-[4-methyl-2-(4-methyl-pentanoylamino)-pentanoylamino]-2-oxo-pro-
pylamino,
5-amino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylamino,
5-benzyloxycarbonylamino-1-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylami-
no, 1-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino,
1-{[4-(1-hydroxy-ethyl)-phenylsulfamoyl]-methyl)-3-phenyl-propylamino,
1-[(4-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylamino,
1-[(4-hydroxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino and
3-phenyl-1-[(2-phenylamino-ethylsulfamoyl)-methyl]-propylamino; and
the N-oxide derivatives, prodrug derivatives, protected
derivatives, individual isomers and mixtures of isomers thereof;
and the pharmaceutically acceptable salts and solvates of such
compounds and the N-oxide derivatives, prodrug derivatives,
protected derivatives, individual isomers and mixtures of isomers
thereof.
[0074] Reference to the preferred embodiments set forth above is
meant to include all combinations of particular and preferred
groups.
[0075] Particular compounds of the invention may be prepared by
joining C* of one of the fragments (A1 to A72) shown in Table 1 to
the nitrogen atom (*N) of one of the fragments (B1 to B80) shown in
Table 2, and joining the methine carbon atom (CH*) of one of the
fragments (B1 to B80) shown in Table 2 to the acyl carbon atom (C*)
of one of the fragments (C1 to C37) depicted in Table 3.
TABLE-US-00001 TABLE 1 A1 ##STR6## ##STR7## A2 ##STR8## A3 ##STR9##
A4 ##STR10## A5 ##STR11## A6 ##STR12## A7 ##STR13## A8 ##STR14## A9
A10 ##STR15## ##STR16## A11 ##STR17## A12 ##STR18## A13 ##STR19##
A14 ##STR20## A15 ##STR21## A16 ##STR22## A17 ##STR23## A18
##STR24## A19 ##STR25## A20 ##STR26## A21 ##STR27## A22 ##STR28##
A23 ##STR29## A24 ##STR30## A25 ##STR31## A26 ##STR32## A27
##STR33## A28 ##STR34## A29 ##STR35## A30 ##STR36## A31 ##STR37##
A32 ##STR38## A33 ##STR39## A34 ##STR40## A35 ##STR41## A36
##STR42## A37 ##STR43## A38 ##STR44## A39 ##STR45## A40 ##STR46##
A41 ##STR47## A42 ##STR48## A43 ##STR49## A44 ##STR50## A45
##STR51## A46 ##STR52## A47 ##STR53## A48 ##STR54## A49 ##STR55##
A50 ##STR56## A51 ##STR57## A52 ##STR58## A53 ##STR59## A54
##STR60## A55 ##STR61## A56 ##STR62## A57 ##STR63## A58 ##STR64##
A59 ##STR65## A60 ##STR66## A61 ##STR67## A62 ##STR68## A63
##STR69## A64 ##STR70## A65 ##STR71## A66 ##STR72## A67 ##STR73##
A68 ##STR74## A69 ##STR75## A70 ##STR76## A71 ##STR77## A72
[0076] TABLE-US-00002 TABLE 2 B1 ##STR78## ##STR79## B2 ##STR80##
B3 ##STR81## B4 ##STR82## B5 ##STR83## B6 ##STR84## B7 ##STR85## B8
##STR86## B9 B10 ##STR87## ##STR88## B11 ##STR89## B12 ##STR90##
B13 ##STR91## B14 ##STR92## B15 ##STR93## B16 ##STR94## B17
##STR95## B18 ##STR96## B19 ##STR97## B20 ##STR98## B21 ##STR99##
B22 ##STR100## B23 ##STR101## B24 ##STR102## B25 ##STR103## B26
##STR104## B27 ##STR105## B28 ##STR106## B29 ##STR107## B30
##STR108## B31 ##STR109## B32 ##STR110## B33 ##STR111## B34
##STR112## B35 ##STR113## B36 ##STR114## B37 ##STR115## B38
##STR116## B39 ##STR117## B40 ##STR118## B41 ##STR119## B42
##STR120## B43 ##STR121## B44 ##STR122## B45 ##STR123## B46
##STR124## B47 ##STR125## B48 ##STR126## B49 ##STR127## B50
##STR128## B51 ##STR129## B52 ##STR130## B53 ##STR131## B54
##STR132## B55 ##STR133## B56 ##STR134## B57 ##STR135## B58
##STR136## B59 ##STR137## B60 ##STR138## B61 ##STR139## B62
##STR140## B63 ##STR141## B64 ##STR142## B65 ##STR143## B66
##STR144## B67 ##STR145## B68 ##STR146## B69 ##STR147## B70
##STR148## B71 ##STR149## B72 ##STR150## B73 ##STR151## B74
##STR152## B75 ##STR153## B76 ##STR154## B77 ##STR155## B78
##STR156## B79 ##STR157## B80
[0077] TABLE-US-00003 TABLE 3 C1 ##STR158## ##STR159## C2
##STR160## C3 ##STR161## C4 ##STR162## C5 ##STR163## C6 ##STR164##
C7 ##STR165## C8 ##STR166## C9 C10 ##STR167## ##STR168## C11
##STR169## C12 ##STR170## C13 ##STR171## C14 ##STR172## C15
##STR173## C16 ##STR174## C17 ##STR175## C18 ##STR176## C19
##STR177## C20 ##STR178## C21 ##STR179## C22 ##STR180## C23
##STR181## C24 ##STR182## C25 ##STR183## C26 ##STR184## C27
##STR185## C28 ##STR186## C29 ##STR187## C30 ##STR188## C31
##STR189## C32 ##STR190## C33 ##STR191## C34 ##STR192## C35
##STR193## C36 ##STR194## C37
Pharmacology and Utility:
[0078] The compounds of the invention are selective inhibitors of
cathepsin S and, as such, are useful for treating diseases in which
cathepsin S activity contributes to the pathology and/or
symptomatology of the disease. For example, the compounds of the
invention 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 responses, including, but not limited
to, organ transplants or tissue grafts.
[0079] Cathepsin S also is implicated in disorders involving
excessive elastolysis, such as chronic obstructive pulmonary
disease (e.g., emphysema), bronchiolitis, excessive airway
elastolysis in asthma and bronchitis, pneumonities and
cardiovascular disease such as plaque rupture and atheroma.
Cathepsin S is implicated in fibril formation and, therefore,
inhibitors of cathepsins S are of use in treatment of systemic
amyloidosis.
[0080] 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 14-17, infra.
Administration and Pharmaceutical Compositions:
[0081] 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 one or more therapeutic agents. 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 about 1
micrograms per kilogram body weight (.mu.g/kg) per day to about 1
milligram per kilogram body weight (mg/kg) per day, typically from
about 10 .mu.g/kg/day to about 0.1 mg/kg/day. Therefore, a
therapeutically effective amount for a 80 kg human patient may
range from about 100 .mu.g/day to about 100 mg/day, typically from
about 1 .mu.g/day to about 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.
[0082] 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.
[0083] 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, and the like).
Preferred liquid carriers, particularly for injectable solutions,
include water, saline, aqueous dextrose and glycols.
[0084] 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 10, infra.
Chemistry:
Processes for Making Compounds of Formula I:
[0085] Compounds of the invention may be prepared by the
application or adaptation of known methods, by which is meant
methods used heretofore or described in the literature, for example
those described by R. C. Larock in Comprehensive Organic
Transformations, VCH publishers, 1989.
[0086] In the reactions described hereinafter it may be necessary
to protect reactive functional groups, for example hydroxy, amino,
imino, thio or carboxy groups, where these are desired in the final
product, to avoid their unwanted participation in the reactions.
Conventional protecting groups may be used in accordance with
standard practice, for examples see T. W. Greene and P. G. M. Wuts
in "Protective Groups in Organic Chemistry" John Wiley and Sons,
1991.
[0087] Compounds of Formula I, in which X.sup.3 is a compound of
formula (a) (as defined in the Summary of the Invention), can be
prepared by proceeding as in the following Reaction Scheme 1:
##STR195## in which each X.sup.1, X.sup.2, R.sup.3, R.sup.4,
R.sup.20 and R.sup.21 are as defined for Formula I in the Summary
of the Invention.
[0088] Compounds of Formula I can be prepared by condensing an acid
of Formula 2 with an amino compound of formula (a). The
condensation reaction can be effected with an appropriate coupling
agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium
hexafluorophosphate (PyBOP.RTM.),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or
the like) and optionally an appropriate catalyst (e.g.,
1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt),
O-(7-azabenzotrizol-1-yl)-1,1,3,3,
tetra-methyluroniumhexafluorophosphate (HATU), or the like) and
non-nucleophilic base (e.g., triethylamine, N-methylmorpholine, and
the like, or any suitable combination thereof) at ambient
temperature and requires 5 to 10 hours to complete.
[0089] An oxidation step, if required, can be carried out with an
oxidizing agent (e.g., Oxone.RTM., metachloroperbenzoic acid or the
like) in a suitable solvent (e.g., methanol, water, or the like, or
any suitable combination thereof) at ambient temperature and
requires 16 to 24 hours to complete. Detailed descriptions for the
synthesis of a compound of Formula I by the processes in Reaction
Scheme 1 are set forth in the Examples 1 to 11, infra.
[0090] Compounds of Formula I, where X.sup.3 is a compound of
formula (b) (as defined in the Summary of the Invention), can be
prepared by proceeding as in the following Reaction Scheme 2:
##STR196## in which each X.sup.1, X.sup.2, R.sup.3, R.sup.4,
R.sup.20, R.sup.23 and R.sup.25 are as defined for Formula I in the
Summary of the Invention.
[0091] Compounds of Formula I can be prepared by condensing an acid
of Formula 2 with an amino compound of formula (b). The
condensation reaction can be effected with an appropriate coupling
agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium
hexafluorophosphate (PyBOP.RTM.),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or
the like) and optionally an appropriate catalyst (e.g.,
1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt),
O-(7-azabenzotrizol-1-yl)-1,1,3,3,
tetra-methyluroniumhexafluorophosphate (HATU), or the like) and
non-nucleophilic base (e.g., triethylamine, N-methylmorpholine, and
the like, or any suitable combination thereof) at ambient
temperature and requires 5 to 10 hours to complete.
[0092] An oxidation step, if required, can be carried out with an
oxidizing agent (e.g., Oxone.RTM., metachloroperbenzoic acid or the
like) in a suitable solvent (e.g., methanol, water, or the like, or
any suitable combination thereof at ambient temperature and
requires 16 to 24 hours to complete.
[0093] Compounds of Formula 1 in which X.sup.3 is a compound of
formula (c) (as defined in the Summary of the Invention), can be
prepared by reacting a compound of Formula 2 with a compound of
Formula (c) according to the following reaction scheme: ##STR197##
in which each X.sup.1, x.sup.2, R.sup.3, R.sup.4, R.sup.20,
R.sup.23 and R.sup.25 are as defined for Formula I in the Summary
of the Invention. Additional Processes for Preparing Compounds of
Formula I:
[0094] 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.
[0095] 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, and 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).
[0096] 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
dichloromethane) 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.
[0097] 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.
[0098] 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, Vol. 4, p. 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).
[0099] 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 protecting groups and their removal can be found in T. W.
Greene, Protecting Groups in Organic Synthesis, 3.sup.rd edition,
John Wiley & Sons, Inc. 1999. Compounds of the present
invention may be conveniently prepared, or formed during the
process of the invention, as solvates (e.g. hydrates). Hydrates of
compounds of the present invention may be conveniently prepared by
recrystallisation from an aqueous/organic solvent mixture, using
organic solvents such as dioxin, tetrahydrofuran or methanol.
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 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, etc.) 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, John Wiley & Sons, Inc. (1981).
[0100] In summary, the compounds of Formula I are made by a process
which comprises: [0101] (A) reacting a compound of Formula 2:
##STR198## with a compound of the formula (a): ##STR199## [0102] in
which X.sup.1, X.sup.2, R.sup.3, R.sup.4, R.sup.20 and R.sup.21 are
as defined in the Summary of the Invention for Formula I; or [0103]
(B) reacting a compound of Formula 2 with a compound of the formula
(b): ##STR200## in which R.sup.20, R.sup.23 and R.sup.25 are as
defined in the Summary of the Invention for Formula I; or [0104]
(C) reacting a compound of Formula 2 with a compound of the formula
(c): ##STR201## [0105] in which R.sup.20, R.sup.23 and R.sup.25 are
as defined in the Summary of the Invention for Formula I; and
[0106] (D) optionally converting a compound of Formula I into a
pharmaceutically acceptable salt; [0107] (E) optionally converting
a salt form of a compound of Formula I to non-salt form; [0108] (F)
optionally converting an unoxidized form of a compound of Formula I
into a pharmaceutically acceptable N-oxide; [0109] (G) optionally
converting an N-oxide form of a compound of Formula I its
unoxidized form; [0110] (H) optionally resolving an individual
isomer of a compound of Formula I from a mixture of isomers; [0111]
(I) optionally converting a non-derivatized compound of Formula I
into a pharmaceutically prodrug derivative; and [0112] (J)
optionally converting a prodrug derivative of a compound of Formula
I to its non-derivatized form.
EXAMPLES
[0113] The present invention is further exemplified, but not
limited by, the following examples that illustrate the preparation
of compounds of Formula I (Examples) and intermediates (References)
according to the invention.
Reference 1
3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl
ester
[0114] 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid
tert-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8:1
methanol/water mixture (108 mL). Ammonium chloride (15 g) and
sodium azide (21.4 g, 329 mmol) was added and the mixture was
heated at 60.degree. C. overnight. After dilution with ether (500
mL), the mixture was washed with saturated aqueous NaHCO.sub.3 (200
mL) and brine (200 mL), dried with MgSO.sub.4 and evaporated under
vacuum. The crude product was dissolved in methanol (200 mL). 10%
Palladium on activated carbon (1.5 g) was added and the mixture was
stirred at ambient temperature under a hydrogen atmosphere until
TLC analysis showed the disappearance of the starting material. The
mixture was filtered through a pad of Celite and evaporated to
dryness under vacuum. The product was purified by flash
chromatography on silica gel. Eluent: 5% methanol in ethyl acetate
to 20% methanol, 3% triethylamine in ethyl acetate. Yield: 4.3 g
3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as
yellowish solid.
Reference 2
4-Amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester
[0115] Sodium hydride (60% in mineral oil, 10 g, 250 mmol) was
suspended in dry DMF. Allyl-carbamic acid benzyl ester (19.1 g, 100
mmol) was added drop wise at ambient temperature. After stirring
for 5 minutes, 5-bromo-1-pentene (25 g, 168 mmol) was added drop
wise. Stirring was continued at 50.degree. C. for 1 hour. The
reaction was quenched with water and then partitioned between
diethyl ether and water. The ether layer was washed with water and
brine, dried with MgSO.sub.4 and evaporated under vacuum. Flash
chromatography (ethyl acetatelhexane 1:9) gave
allyl-pent-4-enyl-carbamic acid benzyl ester (15.5 g).
[0116] Allyl-pent-4-enyl-carbamic acid benzyl ester (15.5 g, 59.8
mmol) was dissolved in dichloromethane and
bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride
(Ig) was added. The mixture was refluxed under a nitrogen
atmosphere until TLC analysis showed complete reaction. The solvent
was evaporated under vacuum and the residue was purified by flash
chromatography (ethyl acetate/hexane 1:9) to give
2,3,4,7-Tetrahydro-azepine-1-carboxylic acid benzyl ester (7.8
g).
[0117] To a solution of 2,3,4,7-tetrahydro-azepine-1-carboxylic
acid benzyl ester (4.5 g, 19.45 mmol) in dichloromethane (50 mL)
was added m-chloroperbenzoic acid (60 mmol). The mixture was
stirred at ambient temperature for 16 hours. Saturated aqueous
K.sub.2CO.sub.3 solution was added and the mixture was extracted
with dichloromethane. The combined organic layers were washed with
saturated aqueous NaHCO.sub.3 and brine, dried with MgSO.sub.4 and
evaporated under vacuum. The crude epoxide was dissolved in an 8:1
methanol/water mixture (100 mL). Ammonium chloride (3.2 g, 60 mmol)
and sodium azide (3.9 g, 60 mmol) were added and the mixture was
heated at 60.degree. C. for 48 hours. Most of the solvent was
removed under vacuum. The residue was extracted with ethyl acetate.
The combined organic layers were washed with saturated aqueous
NaHCO.sub.3 (200 mL) and brine (200 mL), dried with MgSO.sub.4 and
evaporated under vacuum. Flash chromatography of the residue
(hexane/ethyl acetate 3:1) gave
4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester (3.3
g).
[0118] To a solution of 4-azido-3-hydroxy-azepane-1-carboxylic acid
benzyl ester (3.3 g, 11.37 mmol) in methanol (50 mL) was added
triethylamine (5 mL) and 1,3-propanedithiol (3.42 mL, 35 mmol). The
mixture was stirred at ambient temperature until TLC analysis
showed complete consumption of the starting material. A white
precipitate was removed by filtration and the filtrate was
evaporated to dryness. The residue was triturated with a 1:1
hexane/diethyl ether mixture to remove excess dithiol and dried
under vacuum to yield 4-amino-3-hydroxy-azepane-1-carboxylic acid
benzyl ester.
Reference 3
2S-Amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamide
hydrochloride
[0119] A solution comprised of crude tert-butyl
1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamate (1.92 g,
4.42 mmol), prepared as in Reference Example 2, in DCM (10 mL) was
treated with a 4M solution of hydrogen chloride in dioxane (11 mL).
The mixture was stirred for 16 hours at room temperature and
diluted with diethyl ether. A resulting precipitate was collected
by filtration, washed several times with diethyl ether and hexane
and pumped dry to provide
2S-amino-N-4-methoxyphenyl-4-phenylbutane-1-sulfonamide
hydrochloride with quantitative mass recovery. .sup.1H NMR (DMSO):
2.05 (2H, m); 2.6-2.7 (2H, m); 3.4 (3H, m*); 3.72 (3H, s); 6.9 (2H,
d, J=7 Hz); 7.25 (5H, m); 7.3 (2H, d, J=7 Hz); 8.5 (br. s); 10.0
(1H, s).
Example 1
Morpholine-4-carboxylic acid
[1-(1-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-eth-
yl]-amide
Compound 1
[0120] ##STR202##
[0121]
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propioni-
c acid (1 g, 2.8 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic
acid tert-butyl ester (700 mg, 3.46 mmol) prepared as in Reference
1, EDC (1.5 g, 7.8 mmol), and HOBt (1.5 g, 9.6 mmol) were combined.
Dichloromethane (10 mL) was added and then 4-methylmorpholine (1.5
mL). The mixture was stirred at ambient temperature for 2 hours.
After dilution with ethyl acetate (200 mL) the solution was washed
with saturated aqueous NaHCO.sub.3 (100 mL) and brine (100 mL),
dried with MgSO.sub.4 and evaporated under vacuum.
3-Hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-pr-
opionylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05
g, 1.94 mmol) was obtained as yellowish foam and was dissolved in
dichloromethane (6 mL). Trifluoroacetic acid (6 mL) was added and
the mixture was stirred at ambient temperature for 1 hour.
Evaporation under vacuum gave crude morpholine-4-carboxylic acid
[1-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide as TFA salt, which was used without further purification.
[0122] Morpholine-4-carboxylic acid
[1-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide TFA salt (215 mg, 0.39 mmol) was dissolved in 1,4-dioxane (20
mL). Saturated aqueous NaHCO.sub.3 solution (10 mL) was added
followed by benzoyl chloride (0.2 mL, 1.72 mmol). The mixture was
stirred at ambient temperature for 1 hour and then extracted with
ethyl acetate. The combined organic layers were washed with
saturated aqueous NaHCO.sub.3 and brine, dried with MgSO.sub.4 and
evaporated under vacuum. The residue was purified by flash
chromatography on silica gel (Eluent: 5% methanol in ethyl acetate
to 20% methanol in ethyl acetate) to yield morpholine-4-carboxylic
acid
[1-(1-benzoyl-4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-
-ethyl]-amide (92 mg).
[0123] Morpholine-4-carboxylic acid
[1-(1-benzoyl-4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-
-ethyl]-amide (92 mg, 0.169 mmol) was dissolved in DMSO (5 mL).
Triethylamine (0.5 mL) and then SO.sub.3 pyridine complex (150 mg)
were added and the mixture was stirred at ambient temperature for 3
hours. After dilution with ethyl acetate (100 mL), the solution was
washed with water (50 mL) and brine, dried with MgSO.sub.4 and
evaporated under vacuum. The residue was purified by flash
chromatography on silica gel (Eluent: 5% methanol in ethyl acetate)
to yield morpholine-4-carboxylic acid
[1-(1-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfony-
l-ethyl]-amide as a mixture of diastereomers (Yellowish solid; 38
mg); .sup.1H NMR: (DMSO) 8.50-8.35 (m, 1H), 7.55-7.34 (m, 10H),
7.16-6.95 (m, 1H), 4.80-4.65 (m, 1H), 4.54-4.22 (m, 3H), 3.98-3.25
(m, 14H); MS: (M+H).sup.+ 543.
Example 2
Morpholine-4-carboxylic acid
[1-(1-benzenesulfonyl-4-oxo-pyrrolidin-3-ylcarbamoyl)
2-phenylmethanesulfonyl-ethyl]-amide
Compound 2
[0124] ##STR203##
[0125] Morpholine-4-carboxylic acid
[1-(1-benzenesulfonyl-4-oxo-pyrrolidin-3-ylcarbamoyl)
2-phenylmethanesulfonyl-ethyl]-amide was prepared following the
procedure detailed in Example 1, substituting benzenesulfonyl
chloride for benzoyl chloride; .sup.1H NMR: (DMSO) [8.35 (d, J=7.4
Hz), 8.28 (d, J=7.6 Hz), 1H], 7.87-7.62 (m, 5H), 7.41-7.32 (m, 5H),
7.06-6.98 (m, 1H), 4.72-4.60 (m, 1H), 4.45 (s, 2H), 4.42-4.23 (m,
1H), 3.92-3.79 (m, 2H), 3.55-3.20 (m, 11H), 3.06-2.97 (m, 1H). MS:
(M+H).sup.+ 579.
Example 3
4-2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino-
}-3-oxo-azepane-1-carboxylic acid benzyl ester
Compound 3
[0126] ##STR204##
[0127] Crude 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl
ester (150 mg, 0.57 mmol) prepared as in Reference 2,
2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic
acid (400 mg, 1.12 mmol), EDC (400 mg, 2.1 mmol), and HOBt (400 mg,
2.5 mmol) were combined. Dichloromethane (10 mL) was added followed
by 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient
temperature for 2 hours. After dilution with ethyl acetate (100 mL)
the solution was washed with 1N HCl, saturated aqueous NaHCO.sub.3
and brine, dried with MgSO.sub.4 and evaporated under vacuum. The
residue was purified by flash chromatography (ethyl
acetate/methanol 9:1) to yield
3-hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-pr-
opionyl-amino}-azepane-1-carboxylic acid benzyl ester (320 mg).
[0128]
3-Hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulf-
onyl-propionylamino}-azepane-1-carboxylic acid benzyl ester (100
mg, 0.167 mmol) was dissolved in DMSO (5 mL). Triethylamine (0.3
mL) and then SO.sub.3 pyridine complex (150 mg) were added and the
mixture was stirred at ambient temperature for 3 hours. After
dilution with ethyl acetate (100 mL), the solution was washed with
water (50 mL) and brine, dried with MgSO.sub.4 and evaporated under
vacuum. The residue was purified by flash chromatography on silica
gel (Eluent: 5% methanol in ethyl acetate) to yield
4-{2-[(morpholine-4-carbonyl)-amino]-3-Dhenylmethanesulfonyl-pro-
pionylamino}-3-oxo-azepane-1-carboxylic acid benzyl ester (75 mg);
.sup.1H NMR: (DMSO) 8.23-8.08 (m, 1H), 7.40-7.29 (m, 10H),
7.06-6.98 (m, 1H), 5.20-5.09 (m, 2H), 4.79-4.65 (m, 1H), 4.52-4.31
(m, 3H), 4.02-3.80 (m, 2H), 3.62-3.23 (m, 11H), 3.00-2.78 (m, 1H),
1.88-1.55 (m, 4H); MS: (M+H).sup.+ 601.
Example 4
Morpholine-4-carboxylic acid
[1-(3-benzenesulfonylamino-2-oxo-prolylcarbamoyl)-2-phenylmethanesulfonyl-
-ethyl]-amide
Compound 4
[0129] ##STR205##
[0130] N-(3-Amino-2-hydroxy-propyl)-benzenesulfonamide TFA salt was
prepared as outlined in Renee L. DesJarlais et al. J. Am. Chem.
Soc. 1998, 120, 9114-9115.
[0131]
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propioni-
c acid (50 mg, 0.14 mmol),
N-(3-amino-2-hydroxy-propyl)-benzenesulfonamide TFA salt (60 mg,
0.17 mmol), EDC (100 mg, 0.52 mmol), and HOBt (100 mg, 0.64 mmol)
were combined. DMF (3 mL) was added and then 4-methylmorpholine
(0.3 mL). The mixture was stirred at ambient temperature for 3
hours. After dilution with ethyl acetate (100 mL) the solution was
washed with 1N HCl, saturated aqueous NaHCO.sub.3 and brine, dried
with MgSO.sub.4 and evaporated under vacuum. The residue was
dissolved in acetone (5 mL). Jones reagent was added until the
orange color persisted. The mixture was stirred for 2 hours,
quenched with isopropanol, and diluted with ethyl acetate (100 mL).
The solution was washed with water, saturated aqueous NaHCO.sub.3
and brine, dried with MgSO.sub.4 and evaporated under vacuum. The
crude product was recrystallized from ethyl acetate/diethyl ether
to give morpholine-4-carboxylic acid
[1-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2-phenylmethanesulfonyl-
-ethyl]-amide as white solid (19 mg); .sup.1H NMR: (DMSO) 8.17 (t,
J=5.7 Hz, 1H), 7.93 (t, J=5.9 Hz, 1H), 7.76-7.48 (m, 5H), 7.36-7.29
(m, 5H), 7.05 (d, J=8.1 Hz, 1H), 4.68-4.59 (m, 1H), 4.45 (s, 2H),
3.89 (d, J=5.7 Hz, 2H), 3.79-3.75 (m, 2H), 3.56-3.22 (m, 10H); MS:
(M+H).sup.+ 567.
Example 5
N-{1S-[1S-(4-Methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]2-benzy-
lsulfonylethyl}-morpholine-4-carboxamide
Compound 7
[0132] ##STR206##
[0133] A mixture comprised of
2S-morpholin-4-ylcarbonylamino-3-benzylsulfonyl-propionic acid
(0.194 g, 0.599 mmol),
2S-amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamide
hydrochloride (0.222 g, 0.599 mmol), prepared as in Reference 3,
and HATU (0.228 g, 0.599 mmol) in DMF (5 mL) was treated with
4-methylmorpholine (0.198 g, 1.80 mmol). The mixture was stirred at
room temperature for approximately 12 hours and then partitioned
among a 4:1:2:3 mixture (100 mL total) of ethyl acetate, THF,
water, and brine, respectively. The organic phase was separated and
washed with saturated aqueous sodium bicarbonate (30 mL), brine (30
mL), dried (MgSO.sub.4), filtered and concentrated. The residue was
triturated with of 5:1 ether/ethyl acetate (100 mL), collected by
filtration, washed with ether (30 mL), hexane (30 mL), and pumped
dry to provide
N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-ben-
zylsulfonylethyl}-morpholine-4-carboxamide. TLC R.sub.f (ethyl
acetate): 0.65; .sup.1H NMR (DMSO): 1.74 (1H, m); 1.92 (1H, m);
2.39-2.61 (2H, m); 3.1-3.35 (2H, 2.times.dd*); 3.34 (4H, m);
3.42-3.65 (6H, m*); 3.72 (3H, s); 4.24 (1H, m); 4.51 (2H, s); 4.61
(1H, m); 6.88 (2H, d, J=9 Hz); 7.1-7.34 (8H, m); 7.4 (5H, s); 8.12
(1H, d, J=8.7 Hz); MS (M+1): 673.
Proceeding as in Example 5 the following compounds of Formula I
were prepared:
[0134]
N-{1S-[5-amino-1S-(4-methoxyphenylsulfamoyl-methyl)pentylcarbamoyl-
}-2-benzylsulfonylethyl-morpholine-4-carboxamide hydrobromide
(Compound 5); .sup.1H NMR (DMSO): 1.15-1.73 (6H, m*); 2.71 (2H, m);
3.05-3.25 (2H, 2.times.dd); 3.37 (4H, m); 3.45-3.6 (6H, m*); 3.72
(3H, s); 4.21 (1H, m); 4.49 (2H, dd); 4.5 (1H, m*); 6.89 (2H, d,
J=8.9 Hz); 7.09 (1H, m*); 7.15 (2H, d, J=8.9 Hz); 7.39 (5H, s);
7.73 (3H, br. s); 8.03 (1H, d, J=8.6 Hz); 9.47 (1H, s); MS (M+1):
640, free base); and
[0135] Benzyl
6-(4-methoxyphenylsulfamoyl)-5S-(2S-morpholin-4-ylcarbonylamino-3-benzyls-
ulfonyl-propionylamino)hexylcarbamate (Compound 6); TLC R.sub.f
(ethyl acetate): 0.3; .sup.1H NMR (DMSO): 1.1-1.65 (6H, m); 2.94
(2H, q, J=6 Hz); 3.05-3.22 (2H, 2.times.dd); 3.34 (4H, m*);
3.35-3.59 (2H, m*); 3.53 (4H, br s); 3.71 (3H, s); 4.19 (1H, m*);
4.53 (2H, dd, J=15 Hz); 4.57 (1H, m*); 5.00 (2H, s); 6.89 (2H, d,
J=8.4 Hz); 7.05 (1H, d, J=8 Hz); 7.15 (2H, d, J=8.4 Hz); 7.24 (1H,
t); 7.3-7.45 (10H, 2.times.s); 7.99 (1H, J=8 Hz); MS (M+): 774.
Example 6
Morpholine-4-carboxylic acid
[(R)-1-(6-oxo-cyclohex-1-enylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide
Compound 8
[0136] ##STR207##
[0137] A solution of 2-amino-cyclohexane-1,3-diol (0.55 g) in
dimethylformamide (30 ml) was treated with diisopropylethylamine
(1.6 ml, 9.2 mmol). After stirring at room temperature for 5
minutes the mixture was treated with
(R)-2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic
acid (1.73 g, 4.86 mmol) followed by HATU (1.68 g, 4.42 mmol). This
mixture was stirred at room temperature overnight and then
evaporated. The residue was subjected to flash chromatography on
silica eluting with ethyl acetate and then a mixture of ethyl
acetate and methanol to give morpholine-4-carboxylic acid
[(R)-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-
-amide as a white solid (210 mg). MS: 470 (MH.sup.+).
[0138] A solution of morpholine-4-carboxylic acid
[(R)-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-
-amide (90 mg, 0.19 mmol) in methylene chloride (6 ml) was treated
with Dess-Martin periodinane (162 mg, 0.38 mmol). After stirring at
room temperature for 2 hours the reaction mixture was washed with a
solution of Na.sub.2S.sub.2O.sub.3 in water (0.26M), then with
saturated aqueous bicarbonate solution then with water, then dried
over Na.sub.2SO.sub.4 and then evaporated under reduced pressure.
The residue was subjected to flash chromatography on silica eluting
with a mixture of ethyl acetate and heptane to give
morpholine-4-carboxylic acid
[(R)-1-(6-oxo-cyclohex-1-enylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide (8 mg). .sup.1H NMR (CDCl.sub.3): 9.00 (s, 1H), 7.82 (t, J=5
Hz, 1H), 7.53-7.38 (m, 5H), 6.06 (d, J=6 Hz, 1H), 5.00 (m, 1H),
4.47-4.27 (m, 2H), 3.85 (m, 1H), 3.77-3.62 (m, 4H), 3.48-3.36 (m,
4H), 3.27 (m, 1H), 2.58-2.46 (m, 4H), 2.08-1.97 (m, 2H). MS: 450
(MH.sup.+).
Example 7
Morpholine-4-carboxylic acid
[(R)-2-cyclopropylmethanesulfonyl-1-(6-oxo-cyclohex-1-enylcarbamoyl)-ethy-
l]-amide
Compound 9
[0139] ##STR208##
[0140] A mixture of
(R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-amino]-propio-
nic acid (0.352 g, 1.1 mmol) and N-cyclohexylcarbodiimide
N'-methylpolystyrene (1.93 mmol/g, 1.03 g) in DCM (10 mL) was
treated with hydroxybenzotriazole (0.27 g, 2 mmol). After stirring
at room temperature for 5 minutes the mixture was treated with
2-amino-cyclohexane-1,3-diol (0.0.131 g, 1 mmol) and stirring was
continued for a further 2 days. The reaction mixture was treated
with PS Trisamine (3.75 mmol/g, 1.3 g) and after stirring at room
temperature for 2 hours the resin was filtered off and washed with
DCM. The combined filtrate plus washings were evaporated under
reduced pressure to give morpholine-4-carboxylic acid
[(R)-2-cyclopropylmethanesulfonyl-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-e-
thyl]-amide (0.32 g) as pale yellow thick oil. MS: 434
(MH.sup.+).
[0141] Dess Martin Periodinane (0.688 g, 1.62 mmol) was added to a
solution of the
[(R)-2-cyclopropylmethanesulfonyl-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-e-
thyl]-amide (0.32 g) in DCM (10 mL) and the mixture was stirred at
room temperature for 3 hours then treated with resin bound
Na.sub.2S.sub.2O.sub.3 (1.5 mmol/g, 1.9 g) and stirred at room
temperature for a further 24 hours. The reaction mixture was
diluted with DCM (20 mL), then filtered. The filtrate was washed
with a solution of 0.25 M Na.sub.2S.sub.2O.sub.3, then with
saturated NaHCO.sub.3, then dried (MgSO.sub.4), and then evaporated
under reduced pressure. The residue was subjected to column
chromatography elufing with a mixture of ethyl acetate and heptane
to give morpholine-4-carboxylic acid
[(R)-2-cyclopropylmethanesulfonyl-1-(6-oxo-cyclohex-1-enylcarbamoyl)-ethy-
l]-amide. .sup.1H NMR (CDCl.sub.3): 9.00 (s, 1H), 7.78 (t, 1H),
6.18 (d, 1H), 4.9 (m, 1H), 3.85 (m, 1H), 3.77-3.62 (m, 4H),
3.58-3.45 (dd, 1H), 3.48-3.36 (m, 4H), 3.0 (d, 2H), 2.55-2.42 (m,
4H), 2.08-1.97 (m, 2H), 1.2 (m, 1H), 0.8-0.7 (m, 2H), 0.6-0.4 (m,
2H). MS: 414 (MH.sup.+).
Example 8
Morpholine-4-carboxylic acid
[(R)-1-(3,4-dioxo-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide
Compound 10
[0142] ##STR209##
[0143] A solution of 4-amino-cyclopentane-1,2-diol; compound with
trifluoroacetic acid (745 mg, 3.23 mmol) in DMF (15 ml) was treated
with DIPEA (1.12 ml, 6.4 mmol) and the mixture was stirred for 5
minutes at room temperature. Then
(R)-2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic
acid (1.15 g, 3.23 mmol) was added followed by HATU (1.23 g, 3.24
mmol). This mixture was stirred at room temperature overnight and
then evaporated. The residue was subjected to flash chromatography
on silica eluting with ethyl acetate and then with a mixture of
ethyl acetate and methanol to give morpholine-4-carboxylic acid
[(R)-1-(3,4-dihydroxy-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl-
]-amide as a brown solid (680 mg). LC/MS: RT=2.64 min. (215 and 254
nM), MH.sup.+=456.
[0144] A solution of morpholine-4-carboxylic acid
[(R)-1-(3,4-dihydroxy-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl-
]-amide (670 mg, 1.47 mmol) in methylene chloride (40 ml) was
treated with Dess-Martin periodinane (624 mg, 1.47 mmol) and the
reaction stirred at room temperature overnight. More Dess-Martin
periodinane (642 mg, 1.51 mmol) was added and the reaction stirred
at room temperature for 6 hours and then overnight. The reaction
mixture was washed with a solution of Na.sub.2S.sub.2O.sub.3 in
water (0.26M), then with saturated aqueous bicarbonate solution,
then with water, then dried over Na.sub.2SO.sub.4 and then
evaporated under reduced pressure. The residue was subjected to
flash chromatography on silica eluting with a mixture of ethyl
acetate and heptane, then with ethyl acetate to give
morpholine-4-carboxylic acid
[(R)-1-(3,4-dioxo-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-am-
ide as an off white solid (45 mg). .sup.1H NMR (CDCl.sub.3):
7.50-7.38 (m, 5H), 6.62 (m, 1H), 5.91 (d, J=5 Hz, 1H), 4.81 (m,
1H), 4.58-4.35 (m, 3H), 3.73-3.61 (m, 5H), 3.44-3.32 (m, 4H), 3.22
(m, 1H), 2.72-2.12 (m, 4H). MS: 452 (MH.sup.+).
Example 9
Morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclohexylcarbamoyl-
)-ethyl]-amide
Compound 11
[0145] ##STR210##
[0146]
3-(2-Difluoromethoxy-phenylmethanesulfonyl)-2-[(morpholine-4-carbo-
nyl)-amino]-propionic acid (100 mg, 0.237 mmol),
2-aminocyclohexanol (58 mg, 0.5 mmol), EDC (100 mg, 0.52 mmol), and
HOBt (100 mg, 0.64 mmol) were combined. Dichloromethane (2 mL) was
added and then 4-methylmorpholine (0.2 mL). The mixture was stirred
at ambient temperature for 2 h. After dilution with ethyl acetate
(100 mL) the solution was washed with 1N aqu. HCl (30 mL), sat.
aqu. NaHCO.sub.3 (30 mL) and brine (30 mL), dried with MgSO.sub.4
and evaporated under vacuum. The crude product was dissolved in
dichloromethane (10 mL). Dess-Martin periodinane (300 mg, 0.71
mmol) was added, and the reaction mixture was stirred at ambient
temperature for 1 h. After dilution with ethyl acetate (100 mL),
the solution was washed with 0.26M Na.sub.2S.sub.2O.sub.3 in sat.
aqu. NaHCO.sub.3 (30 mL), sat. aqu. NaHCO.sub.3 and brine, dried
with MgSO.sub.4, and evaporated under vacuum. Purification by
flash-chromatography on silica gel (ethyl acetate/hexane) gave
morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclohexylcarbamoyl-
)-ethyl]-amide (78 mg, 0.151 mmol) as a white solid. Mixture of
diastereomers: .sup.1H NMR: (DMSO) [8.03 (d, J=7.2 Hz), 7.96 (d,
J=7.2 Hz), 1H], 7.50-7.42 (m, 2H), 7.30-7.21 (m, 2H), 7.10 (t,
J.sub.H,F=74 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.78-4.69 (m, 1H),
4.54 (s, 2H), 4.41-4.33 (m, 1H), 3.62-3.25 (m, 10H), 2.55-1.40 (m,
8H). MS: (M+H).sup.+ 518.
[0147] By proceeding in similar manner to Example 9 but using
2-aminocyclopentanol there was prepared morpholine-4-carboxylic
acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclopentylcarbamoy-
l)-ethyl]-amide (Compound 12) as a mixture of diastereomers:
.sup.1H NMR: (DMSO) [8.19 (d, J=8 Hz), 7.15 (d, J=8 Hz), 1H],
7.49-7.42 (m, 2H), 7.30-7.21 (m, 2H), 7.10 (t, J.sub.H,F=74 Hz,
1H), [7.02 (d, J=8.4 Hz), 7.00 (d, J=8.4 Hz), 1H], 4.77-4.70 (m,
1H), [4.53 (s), 4.52 (s), 2H], 4.10-3.91 (m, 1H), 3.60-3.23 (m,
10H), 2.28-1.70 (m, 6H). MS: (M+H).sup.+ 504.
[0148]
[0149] By proceeding in similar manner to Example 9 but using
2-aminocyclobutanol there was prepared morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(2-oxo-cyclobutylcarbamoyl-
)-ethyl]-amide (Compound 13) as a mixture of diastereomers: .sup.1H
NMR: (DMSO) 8.49 (d, J=7.6 Hz, 1H), 7.48-7.42 (m, 2H), 7.30-7.21
(m, 2H), 7.11 (t, J.sub.H,F=74 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H),
4.88-4.67 (m, 2H), 4.53 (s, 2H), 3.64-3.23 (m, 10H), 2.93-2.70 (m,
2H), 2.23-1.99 (m, 2H). MS: (M+H).sup.+
Example 10
Morpholine-4-carboxylic acid
[1-(2-benzylcarbamoyl-2-oxo-ethylcarbamoyl)-2-phenylmethanesulfonyl-ethyl-
]-amide
Compound 14
[0150] ##STR211##
[0151] Isoserine (3.11 g, 29.6 mmol) was dissolved in
1,4-dioxane/H.sub.2O 3:1 (40 mL). K.sub.2CO.sub.3 (0.5 g) and
NaHCO.sub.3 (0.5 g) was added. Di-tert-butyl dicarbonate (6.45 g,
29.6 mmol) was added and the mixture was stirred at ambient
temperature over night. The reaction mixture was extracted with
dichloromethane (3.times.100 mL). The combined organic phases were
washed with brine, dried with MgSO.sub.4, and evaporated under
vacuum. The crude 3-tert-butoxycarbonylamino-2-hydroxy-propionic
acid (4.76 g, 23.2 mmol) was obtained as a colorless oil, which
solidified on standing, and was used without further
purification.
[0152] 3-tert-butoxycarbonylamino-2-hydroxy-propionic acid (1.5 g,
7.31 mmol), benzylamine (1.1 mL, 100 mmol), EDC (2.5 g, 13.1 mmol),
and HOBt (2.0 g, 12.8 mmol) were combined. Dichloromethane (15 mL)
was added and then 4-methylmorpholine (2 mL). The mixture was
stirred at ambient temperature for 2 h. After dilution with ethyl
acetate (300 mL) the solution was washed with 1N aqu. HCl (100 mL),
sat. aqu. NaHCO.sub.3 (100 mL) and brine (100 mL), dried with
MgSO.sub.4 and evaporated under vacuum. Yield: 1.83 g, 6.22 mmol
(2-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl
ester.
[0153] (2-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl
ester (0.2 g, 0.68 mmol) was dissolved in dichloromethane (2 mL)
and trifluoroacetic acid (2 mL). After stirring for 2 h at ambient
temperature, the solution was evaporated under vacuum and the
residue was dried under high vacuum. To this residue were added EDC
(200 mg, 1.05 mmol), HOBt (200 mg, 1.28 mmol),
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic
acid (200 mg, 0.56 mmol), dichloromethane (5 mL) and
4-methylmorpholine (0.5 mL). The mixture was stirred at ambient
temperature for 2 h. After dilution with ethyl acetate (100 mL) the
solution was washed with 1N aqu. HCl (30 mL), sat. aqu. NaHCO.sub.3
(30 mL) and brine (30 mL), dried with MgSO.sub.4 and evaporated
under vacuum. The crude product was dissolved in dichloromethane
(10 mL). Dess-Martin periodinane (500 mg, 1.18 mmol) was added, and
the reaction mixture was stirred at ambient temperature for 1 h.
After dilution with ethyl acetate (100 mL), the solution was washed
with 0.26M Na.sub.2S.sub.2O.sub.3 in sat. aqu. NaHCO.sub.3 (30 mL),
sat. aqu. NaHCO.sub.3 and brine, dried with MgSO.sub.4, and
evaporated under vacuum. The product (morpholine-4-carboxylic acid
[1-(2-benzlcarbamoyl-2-oxo-ethylcarbamoy)-2-phenylmethanesulfonyl-ethyl]--
amide) was crystallized from ethyl acetate/diethylether and was
obtained as a white solid (153 mg, 0.29 mmol). .sup.1H NMR: (DMSO)
9.24 (t, J=6.4 Hz, 1H), 8.19 (t, J=5.6 Hz, 1H), 7.39-7.19 (m, 10H),
7.08 (d, J=8 Hz, 1H), 4.83-4.76 (m, 1H), 4.49 (s, 2H), 4.48-4.33
(m, 2H), 4.31 (d, J=6.8 Hz, 2H), 3.68-3.25 (m, 10H). MS:
(M+H).sup.+ 531.
Example 11
Acetic acid
3-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylami-
no}-4-oxo-azetidin-2-yl ester
Compound 15
[0154] ##STR212##
[0155] Acetic acid 3-benzyloxycarbonylamino-4-oxo-azetidin-2-yl
ester was prepared as outlined in J. C. Arnould et al. Eur. J. Med.
Chem 1992, 27, 131-140.
[0156] Acetic acid 3-benzyloxycarbonylamino-4-oxo-azetidin-2-yl
ester (100 mg, 0.36 mmol) was hydrogenated on a Parr shaker over
10% palladium on carbon (100 mg) in ethyl acetate (20 mL) at 50 psi
for 5 h. The mixture was filtered through Celite and evaporated.
Acetic acid 3-amino-4-oxo-azetidin-2-yl ester was obtained in
quantitative yield.
[0157]
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propioni-
c acid (100 mg, 0.28 mmol), acetic acid 3-amino-4-oxo-azetidin-2-yl
ester (52 mg, 0.36 mmol), EDC (100 mg, 0.52 mmol), and HOBt (100
mg, 0.64 mmol) were combined. Dichloromethane (2 mL) was added and
then 4-methylmorpholine (0.2 mL). The mixture was stirred at
ambient temperature for 2 h. After dilution with ethyl acetate (100
mL) the solution was washed with 1N aqu. HCl (30 mL), sat. aqu.
NaHCO.sub.3 (30 mL) and brine (30 mL), dried with MgSO.sub.4 and
evaporated under vacuum. The residue was subjected to flash
chromatography on silica gel (ethyl acetate) to give acetic acid
3-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylami-
no}-4-oxo-azetidin-2-yl ester (17 mg, 0.035 mmol). .sup.1H NMR:
(DMSO) 9.18 (s, 1H), 8.72 (d, J=6.4 Hz, 1H), 7.41-7.30 (m, 5H),
7.08 (m, 1H), 5.76 (s, 1H), 4.80-4.61 (m, 2H), 4.49 (s, 2H),
3.63-3.22 (m, 10H), 2.08 (s, 3H). MS: (M+H).sup.+ 483.
Example 12
Morpholine-4-carboxylic acid
[1-(4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]--
amide
Compound 16
[0158] ##STR213##
[0159] 4-Amino-tetrahydro-furan-3-ol was prepared as outlined in
Marquis, Robert W. et al. J. Med. Chem 2001. 44, 725-736.
[0160]
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propioni-
c acid (100 mg, 0.28 mmol), 4-aminotetrahydrofuran-3-ol (100 mg,
0.96 mmol), EDC (200 mg, 1.04 mmol), and HOBt (200 mg, 1.28 mmol)
were combined. DMF (2 mL) was added and then 4-methylmorpholine
(0.2 mL). The mixture was stirred at ambient temperature for 2 h.
After dilution with ethyl acetate (100 mL) the solution was washed
with 1N aqu. HCl (30 mL), sat. aqu. NaHCO.sub.3 (30 mL) and brine
(30 mL), dried with MgSO.sub.4 and evaporated under vacuum. The
crude product was dissolved in dichloromethane (10 mL). Dess-Martin
periodinane (300 mg, 0.71 mmol) was added, and the reaction mixture
was stirred at ambient temperature for 1 h. After dilution with
ethyl acetate (100 mL), the solution was washed with 0.26M
Na.sub.2S.sub.2O.sub.3 in sat. aqu. NaHCO.sub.3 (30 mL), sat. aqu.
NaHCO.sub.3 and brine, dried with MgSO.sub.4, and evaporated under
vacuum. Purification by flash-chromatography on silica gel (ethyl
acetate) gave mornholine-4-carboxylic acid
[1-(4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]--
amide (8.6 mg, 0.020 mmol) as a colorless glass. Mixture of
diastereomers: .sup.1H NMR: (DMSO) [8.42 (d, J=6.8 Hz), 7.15 (d,
J=7.2 Hz), 1H], 7.40-7.32 (m, 5H), [7.06 (d, J=8 Hz), 7.05 (d, J=8
Hz), 1H], 4.78-4.68 (m, 1H), [4.49 (s), 4.48 (s), 2H], 4.32-3.75
(m, 5H), 3.60-3.23 (m, 10H). MS: (M+H).sup.+ 440.
Example 13
Morpholine-4-carboxylic acid
[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethan-
esulfonyl-ethyl]-amide
Compound 17
[0161] ##STR214## Step 1 To a flask fitted with a septum and
stirbar under a nitrogen atmosphere containing 4.1 g (20 mmol) of
2-phenyl-1,3-dithiane (Aldrich) was added dry distilled THF (20
mL). The solution was cooled to -30.degree. C. and n-butyl lithium
(1.6M in pentane, 16.8 mmol, 10.5 mL) was added slowly by syringe.
The reaction mixture was warmed to -20.degree. C. and held at that
temperature for 30 minutes, and then held at -10.degree. C. for 15
minutes. The yellow solution was cooled to -78.degree. C. and
(1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.5 g, 8
mmol, in 5 ml THF) was added rapidly (over 30 seconds) and 60
seconds later a solution of 2 mL acetic acid and 5 mL THF was added
rapidly. The cooling bath was removed and 4 minutes later water was
added and the mixture was extracted with ethyl acetate. The solvent
was removed under reduced pressure and then recrystallized from 10
ml of ethyl acetate. The white crystals were washed three times
with ethyl acetate and dried under reduced pressure to afford
[2-hydroxy-1,1-dimethyl-2-(2-phenyl-[1,3]dithian-2-yl)-ethyl]-carbamic
acid tert-butyl ester (1.6 g, 52%). Step 2 To
[2-hydroxy-1,1-dimethyl-2-(2-phenyl-[1,3]dithian-2-yl)-ethyl]-carbamic
acid tert-butyl ester (1 g, 2.6 mmol) in 4.8 mL dioxane at
10.degree. C. was added hydrochloric acid (4.8 mL, 4M in dioxane).
The solution was warmed to 23.degree. C. After 2 hours the solution
was concentrated to 4 ml and diluted with ether to afford a white
precipitate that was collected by filtration. The mother liquor was
concentrated to a paste and triturated with ether. The solids were
combined to afford 726 mg of
2-amino-2-methyl-1-(2-phenyl-[1,3]dithian-2-yl)-propan-1-ol (98%
yield). Step 3
2-Amino-2-methyl-1-(2-phenyl-[1,3]dithian-2-yl)-propan-1-ol and
2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic
acid were coupled using the standard peptide coupling conditions
hereinbefore described to afford morpholine-4-carboxylic acid
{1-[2-hydroxy-1,1-dimethyl-2-(2-phenyl-[1,3]dithian-2-yl)-ethylcarbamoyl]-
-2-phenylmethanesulfonyl-ethyl}-amide (270 mg, 78%). Step 4 To
morpholine-4-carboxylic acid
{1-[2-hydroxy-1,1-dimethyl-2-(2-phenyl-[1,3]dithian-2-yl)-ethylcarbamoyl]-
-2-phenylmethanesulfonyl-ethyl}-amide (200 mg, 0.32 mmol) in 5.25
ml of 4:1 acetonitrile:water at 23.degree. C. was simultaneously
added finely ground HgCl.sub.2 (192 mg, 0.7 mmol) and finely ground
calcium carbonate (80 mg, 0.8 mmol) with stirring. The mixture was
stirred for 10 minutes and then diluted with ethyl acetate.
Methylene chloride was added and the organics were washed with
water. After separation the organic layer concentrated to a gum
that solidified upon addition of ether. The ether was removed under
reduced pressure to afford a white solid. The solid was dissolved
in a minimum of hot methylene chloride and filtered to remove
insoluble material. The solution was concentrated to afford
morpholine-4-carboxylic acid
[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethan-
esulfonyl-ethyl]-amide (165 mg, 100% yield). Step 5
[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethan-
esulfonyl-ethyl]-amide was oxidized in the usual manner to afford
morpholine-4-carboxylic acid
[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethan-
esulfonyl-ethyl]-amide. .sup.1HNMR: (CDCl.sub.3) [8.0 (d, J=8 Hz)
1H], 7.7-7.2 (m, 10H), [5.9 (d, J=6 Hz) 1H], [4.8 (d, J=6 Hz) 1H],
[4.3 (d, J=14, Hz) 1H], [4.1 (d, J=14 Hz) 1H], 3.7 (m, 4H), 3.36
(m, 4H), [3.3 (d, J=2 Hz) 1H], [3.29 (d, J=2 Hz) 1H], 1.7(s, 6H).
LCMS: elution time=3.71 min. 527.6(M-1), 529.6(M+1). (MS: API
150EX. LC: HP Agilent 1100 Series. Column: Phenomenex, 5 u ODS3
100A 100.times.3 mm.; Flow Rate: 2 ml/min. Two solvent gradient:
Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH. Solvent B, 99%
actonitrile, 1% water, 0.1% AcOH. Gradient from 100% A, 0% B to 0%
A, 100% B from t=0 to t=6 min. Then gradient back to 100% A, 0% B
from t=7 to t=15 min.).
[0162] By proceeding in a similar manner to Example 13 but using
3-(2-difluoromethoxy-phenylmethanesulfonyl)-2-[(morpholine-4-carbonyl)-am-
ino]-propionic acid in step 3 there was prepared
morpholine-4-carboxylic acid
[2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(1,1-dimethyl-2,3-dio-
xo-3-phenyl-propylcarbamoyl)-ethyl]-amide. LC-MS: elution time=3.95
min. 593.4(M-1), 596.2(M+1). (MS: API 150EX. LC: HP Agilent 1100
Series. Column: Phenomenex, 5 u ODS3 100A 100.times.3 mm.; Flow
Rate: 2 ml/min. Two solvent gradient: Solvent A, 99% water, 1%
acetonitrile, 0.1% AcOH. Solvent B, 99% actonitrile, 1% water, 0.1%
AcOH. Gradient from 100% A, 0% B to 0% A, 100% B from t=0 to t=6
min. Then gradient back to 100% A, 0% B from t=7 to t=15 min.)
Example 14
Cathepsin S Assay
[0163] 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 ambient temperature.
Z-Val-Val-Arg-AMC (9 nMoles in 25 .mu.L of assay buffer) was added
to the assay solutions and hydrolysis was followed
spectrophotometrically at (.lamda. 460 nm) for 5 minutes. Apparent
inhibition constants (K.sub.i) were calculated from the enzyme
progress curves using standard mathematical models.
Example 15
Cathepsin B Assay
[0164] 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-aminoethanesulfonic 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 ambient 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 (.lamda. 460 nm) for 5
minutes. Apparent inhibition constants (K.sub.i) were calculated
from the enzyme progress curves using standard mathematical
models.
Example 16
Cathepsin K Assay
[0165] 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 cathepsin 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 ambient temperature. Z-Phe-Arg-AMC
(4 nMoles in 25 .mu.L of assay buffer) was added to the assay
solutions and hydrolysis was followed spectrophotometrically at
(.lamda. 460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
Example 17
Cathepsin L Assay
[0166] 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 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 ambient 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
(.lamda. 460 nm) for 5 minutes. Apparent inhibition constants
(K.sub.i) were calculated from the enzyme progress curves using
standard mathematical models.
[0167] Some of the compounds of the invention tested according to
the above-described assays for protease inhibition were observed to
exhibit selective cathepsin S inhibitory activity. The apparent
inhibition constants (K.sub.i) for compounds of the invention,
against Cathepsin S, were in the range from about 10.sup.-10M to
about 10.sup.-7M.
Example 18
[0168] Representative Pharmaceutical Formulations Containing a
Compound of Formula I
Oral Formulation
[0169] TABLE-US-00004 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
[0170] TABLE-US-00005 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
[0171] TABLE-US-00006 Compound of Formula I 1% Microcrystalline
Cellulose 73% Stearic Acid 25% Colloidal Silica 1%.
* * * * *