U.S. patent application number 11/296782 was filed with the patent office on 2006-04-27 for novel compounds and compositions as cathepsin inhibitors.
This patent application is currently assigned to Aventis Pharmaceuticals Inc.. Invention is credited to David J. Aldous, Michael Graupe, Frank Halley, Justine Lai, Jiayao Li, John Link, James T. Palmer, John W. Patterson, Stephen D. Pickett, Sukanthini Thurairatnam, Andreas P. Timm.
Application Number | 20060089357 11/296782 |
Document ID | / |
Family ID | 29999195 |
Filed Date | 2006-04-27 |
United States Patent
Application |
20060089357 |
Kind Code |
A1 |
Graupe; Michael ; et
al. |
April 27, 2006 |
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) ;
Patterson; John W.; (Mountain View, CA) ; Pickett;
Stephen D.; (Hitchin, GB) ; Aldous; David J.;
(Gillette, NJ) ; Thurairatnam; Sukanthini;
(Bedminster, NJ) ; Timm; Andreas P.; (Bridgewater,
NJ) ; Halley; Frank; (Chaville, FR) ; Lai;
Justine; (Epping, GB) ; Link; John; (San
Francisco, CA) ; Li; Jiayao; (Foster City,
CA) |
Correspondence
Address: |
ROSS J. OEHLER;AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
Aventis Pharmaceuticals
Inc.
Bridgewater
NJ
Axys Pharmaceuticals, Inc.
South San Francisco
CA
|
Family ID: |
29999195 |
Appl. No.: |
11/296782 |
Filed: |
December 7, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10183128 |
Jun 26, 2002 |
|
|
|
11296782 |
Dec 7, 2005 |
|
|
|
10035783 |
Dec 24, 2001 |
|
|
|
10183128 |
Jun 26, 2002 |
|
|
|
60257603 |
Dec 22, 2000 |
|
|
|
Current U.S.
Class: |
514/237.5 ;
544/168 |
Current CPC
Class: |
A61K 31/5375 20130101;
A61P 35/04 20180101; A61K 31/5377 20130101; C07D 205/08 20130101;
C07D 213/40 20130101; A61P 19/02 20180101; C07D 271/06 20130101;
C07D 271/10 20130101; C07D 413/04 20130101; C07C 323/60 20130101;
C07D 223/12 20130101; C07D 277/26 20130101; A61P 33/06 20180101;
C07D 213/75 20130101; C07D 413/12 20130101; A61P 1/02 20180101;
A61K 31/4245 20130101; C07D 295/185 20130101; A61P 21/04 20180101;
A61P 43/00 20180101; A61P 29/00 20180101; C07D 285/08 20130101;
C07C 317/44 20130101; C07D 207/24 20130101; C07D 263/32 20130101;
A61P 13/12 20180101; C07D 277/64 20130101; C07D 263/56
20130101 |
Class at
Publication: |
514/237.5 ;
544/168 |
International
Class: |
A61K 31/537 20060101
A61K031/537; C07D 265/30 20060101 C07D265/30 |
Claims
1. A compound or a related chemical entity of the compound, having
a backbone structure of a formula selected from the group
consisting of Formulae I and II: ##STR91## wherein X.sup.2,
X.sup.3, X.sup.4, X.sup.5 and X.sup.7 are general substituents.
2. A compound of claim 1 or a related chemical entity of a compound
of claim 1, having a backbone structure of Formula I: ##STR92##
wherein X.sup.2, X.sup.3, X.sup.4, X.sup.5 and X.sup.7 are general
substituents.
3. A compound of claim 1 or a related chemical entity of a compound
of claim 1, having a backbone structure of Formula II: ##STR93##
wherein X.sup.2 and X.sup.5 are general substituents.
4. A compound or a related chemical entity of the compound, having
a backbone structure of Formula III: ##STR94## wherein A.sup.1 is
--O--, --N(R)-- or --SO.sub.2--; A.sup.2 is --H, --F, --OH, or
--O--R; A.sup.3 is cyano or --C(O)--X.sup.3; and X.sup.2, X.sup.3,
X.sup.4, X.sup.7and R are general substituents.
5. A compound of claim 1 or a related chemical entity of a compound
of claim 1, wherein X.sup.2, X.sup.3, X.sup.4, X.sup.5 and X.sup.7
are popular substituents.
6. A compound of claim 2 or a related chemical entity of a compound
of claim 2, wherein X.sup.2, X.sup.3, X.sup.4, X.sup.7 and R are
popular substituents.
7. A compound of claim 1, wherein: X.sup.2 is a substituted alkyl
motif or a sulfonyl alkyl motif; X.sup.3 is a heterocyclic motif or
an amide motif; X.sup.4 and X.sup.7 are independently --H, --R or
##STR95## or X.sup.4 and X.sup.7 taken together with the carbon
atom to which both X.sup.4 and X.sup.7 are attached form a 3-6
membered cycloalkyl group; X.sup.5 is --H, --F, --OH or --O--R; and
R is an alkyl group with straight or branched-chain containing 1-6
carbon atoms.
8. A compound of claim 4, wherein: X.sup.2 is a substituted alkyl
motif or a sulfonyl alkyl motif; X.sup.3 is a heterocyclic motif or
an amide motif; X.sup.4 and X.sup.7 are independently --H, --R or
##STR96## X.sup.4 and X.sup.7 taken together with the carbon atom
to which both X.sup.4 and X.sup.7 are attached form a 3-6 membered
cycloalkyl group; and R is an alkyl group with straight or
branched-chain containing 1-6 carbon atoms.
9. A compound of claim 7, wherein X.sup.3 is a heterocyclic
motif
10. A compound of claim 8, wherein A.sup.3 is --C(O)--X.sup.3 and
X.sup.3 is a heterocyclic motif.
11. A compound of claim 7, wherein X.sup.3 is an amide motif.
12. A compound of claim 8, wherein A.sup.3 is --C(O)--X.sup.3 and
X.sup.3 is an amide motif.
13. A compound of claim 7, wherein X.sup.7 is --H, X.sup.4 is an
alkyl group with straight or branched-chain containing 1-4 carbon
atoms or ##STR97## and X.sup.5 is --H or --F.
14. A cmpound of claim 13, wherein X.sup.5 is --H.
15. A compound of claim 14, wherein X.sup.4 is --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3--(CH.sub.3).sub.3 or ##STR98##
16. A compound of claim 1, having a backbone structure of Formula
I, wherein X.sup.2 is a substituted alkyl motif or a sulfonyl alkyl
motif, X.sup.3 is a heterocyclic motif or an amide motif, X.sup.4
is --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3--C(CH.sub.3).sub.3 or ##STR99## X.sup.5
and X.sup.7 are --H.
17. A related chemical entity of a compound of claim 16.
18. A compound of claim 1 selected from the group consisting of:
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5--
phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl-
-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(5-trifluor-
omethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-
-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
N-[(S)-1-(5-Ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholin-4-yl-4-
-oxo-2-phenylmethanesulfonylmethyl-butyramide,
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(3-phen-
yl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[1-(3-phenyl-1-
,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-2-Cyclohexylmethyl-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-pro-
pyl]-4-morpholin-4-yl-4-oxo-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-
-morpholin-4-yl-4-oxo-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-phen-
yl-cyclopropylmethyl)-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid
[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-c-
arbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid
[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(S)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(5-methyl-thiophen-2-ylmet-
hyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethy-
l)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of
diastereoisomers),
4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl)-4-oxo-2-(2-ph-
enyl-cyclopropylmethyl)-butyramide (mixture of diastereoisomers),
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbonyl)-3-p-
henyl-propyl]-4-oxo-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl-amide,
3-Phenylmethanesulfonyl-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-p-
ropyl]-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(oxazole-2-carbonyl)-propyl]-amide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide,
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-N-[(S)-1-(3-Cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(2-met-
hyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-2-Cyclopropylmethanesulfonylmethyl-N-[(S)-1-(3-cyclopropyl-1,2,4-oxad-
iazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid
[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazo-
le-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-5-Cyclopropyl-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic
acid
[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-N-[(S)-1-(3-Cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(1-iso-
butyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,
R)-2-(1-Cyclopropylmethyl-cyclopropylmethyl)-N-[(S)-1-(3-cyclopropyl-1,2,-
4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-N-[(S)-1-(3-Ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(2-methyl-pr-
opane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-2-Cyclopropylmethanesulfonylmethyl-N-[(S)-1-(3-ethyl-1,2,4-oxadiazole-
-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(S)-2-(2-Benzenesulfonyl-ethyl)-N-[(S)-1-(3-ethyl-1,2,4-oxadiazole-5-carb-
onyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(S)-N-[(S)-1-(3-Ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4--
yl-4-oxo-2-[2-(propane-2-sulfonyl)-ethyl]-butyramide,
2-(1-Methyl-cyclopentylmethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyrid-
ine-2-carbonyl)-propyl]-4-oxo-butyramide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid (pyridin-4-ylmethyl)-amide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid diethylamide,
N-((S)-1-Ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl)-4-morpholin-4-yl-4-oxo-
-2-phenylmethanesulfonylmethyl-butyramide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid phenethyl-amide, and
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid (2-pyridin-2-yl-ethyl)-amide.
19. A compound of claim 1 selected from the group consisting of:
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5--
phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[1-(3-phenyl-1-
,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-
-morpholin-4-yl-4-oxo-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-phen-
yl-cyclopropylmethyl)-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of
diastereoisomers),
4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-(2-ph-
enyl-cyclopropylmethyl)-butyramide (mixture of diastereoisomers),
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbonyl)-3-p-
henyl-propyl]-4-oxo-butyramide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide,
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide, and
(R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide.
20. A related chemical entity of a compound of claim 18.
21. A related chemical entity of a compound of claim 19.
22. A method of synthesizing a compound of formula Y: ##STR100##
where Ry is benzyl, iso-butyl or cyclopropylmethyl, comprising the
steps of (a) reacting ##STR101## with ##STR102## to afford
##STR103## and then (b) reacting the ##STR104## with ##STR105## to
afford a compound of formula Y.
23. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 or a related chemcial
entity of a compound of claim 1, in combination with a
pharmaceutically acceptable excipient.
24. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 4 or a related chemcial
entity of a compound of claim 4, in combination with a
pharmaceutically acceptable excipient.
25. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 16 in combination with a
pharmaceutically acceptable excipient.
26. 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 a compound of claim 1 or a related chemical entity of a
compound of claim 1.
27. 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 a compound of claim 4 or a related chemical entity of a
compound of claim 4.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/035,783, filed on Dec. 24, 2001, which
claims priority from U.S. Provisional Application 60/257,603 filed
on Dec. 22, 2000. The two applications, 10/035,783 and 60/257,603,
are incorporated herein by reference.
[0002] This application relates to compounds and compositions for
treating diseases associated with cysteine protease activity,
particularly diseases associated with activity of cathepsin S and
the processes of making the compounds.
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
increased 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 that inhibit the
enzymatic activity of Cathapsin S and have a backbone structure of
formula I, II or III: ##STR1## where A.sup.1 is --O--, --N(R)-- or
--SO.sub.2--;
[0005] A.sup.2 is --H, --F, --OH, or --O--R;
[0006] A.sup.3 is --C(O)--X.sup.3 or cyano; and
[0007] X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.7 and R are
chemical groups or radicals.
[0008] The compounds of the present invention also include closely
related isomers and derivatives that are made from the compounds of
the above Formulae. They include, but not limited to, the N-oxide
derivatives, prodrug derivatives, protected derivatives, individual
isomers and mixture of isomers of the compounds, and the
pharmaceutically acceptable salts and solvates of such compounds.
For the purpose of this application, "a related chemical entity" of
Formula I, II or III means an N-oxide derivative, a produg
derivative, a protected derivative, an individual isomer, a mixture
of isomers, or a pharmaceutically acceptable salt or solvate, of a
compound of Formula I, II or III.
[0009] In one aspect of the present invention, the inventive point
is the backbone structures of Formulae I and II themselves, wherein
the substituents at the X.sup.2, X.sup.3, X.sup.4, X.sup.5 and
X.sup.7 positions can be any chemical groups or radicals which may
be substituted at those positions (or general substituents as
defined hereinafter), including those substitutions made possible
by any conventional means or by any new technologies developed in
the future. For the purpose of this application, a substituent
stated in a claim that does not serve as a claim element or
limitation of the claim is referred to as a "general
substituents."
[0010] In another aspect of the invention, the inventive point is
the backbone structures of Formula I and II plus popular
substituents at the X.sup.2, X.sup.3, X.sup.4, X.sup.5 and X.sup.7
positions. For the purpose of this application, "a popular
substituent" means a chemical group or radical which people of
ordinary skill in the art, by using the specific substitutions
disclosed hereinafter as guidance, would deem practical to
substitute at X.sup.2, X.sup.3, X.sup.4, X.sup.5 or X.sup.7 without
undue experimentation in practicing the present invention.
[0011] In another aspect of the invention, the inventive point is
the backbone structures of Formula I and II plus specific
substituents disclosed hereinafter at the X.sup.2, X.sup.3,
X.sup.4, X.sup.5 and X.sup.7 positions.
[0012] Another aspect of the invention is a compound of Formula
III, wherein A.sup.1 is --O--, --N(R)-- or --SO.sub.2--, A.sup.2 is
--H, --F, --OH, or --O--R, A.sup.3 is cyano or --C(O)--X.sup.3, and
X.sup.2, X.sup.3, X.sup.4, X.sup.7 and R are general substituents.
##STR2##
[0013] Another 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 a compound of the present
invention.
[0014] Another aspect of the invention are the processes for
preparing compounds of Formulae I, II and III.
DEFINITIONS
[0015] "Isomers", as used in this disclosure, mean compounds of
Formulae I, II and III having identical molecular formulae but
differ in the nature or sequence of bonding of their atoms or in
the arrangement of their atoms in space. Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereomers" and stereoisomers that are nonsuperimposable mirror
images are termed "enantiomers" or sometimes "optical isomers". A
carbon atom bonded to four nonidentical substituents is termed a
"chiral center". A compound, which has one chiral center has two
enantiomeric forms of opposite chirality. A "racemic mixture"
contains both enantiomers as a 1:1 ratio. However, in terms of this
application a racemic mixture has been employed when both
enantiomers were present irrespective of their ratios. A compound
that has more than one chiral center has 2.sup.n-1 enantiomeric
pairs, where n is the number of chiral centers. Compounds with more
than one chiral center may exist as either an individual
diastereomer or as a mixture of diastereomers, termed a
"diastereomeric mixture". When one chiral center is present a
stereoisomer may be characterized by the absolute configuration of
that chiral center. Absolute configuration refers to the
arrangement in space of the substituents attached to the chiral
center. Enantiomers are characterized by the absolute configuration
of their chiral centers and described by the R-- and S-sequencing
rules of Cahn, Ingold and Prelog. Conventions for stereochemical
nomenclature, methods for the determination of stereochemistry and
the separation of stereoisomers are well known in the art (e.g.,
see "Advanced Organic Chemistry", 4th edition, March, Jerry, John
Wiley & Sons, New York, 1992). It is understood that the names
and illustrations used in this disclosure to describe compounds of
Formulae I, II, and III are meant to encompass all possible
stereoisomers. Thus, for example, the name
2-cyclohexylmethyl-N-[1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-m-
orpholin-4-yl-4-oxo-butyramide is meant to include
(R)-2-cyclohexylmethyl-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-pro-
pyl]-4-morpholin-4-yl-4-oxo-butyramide and
(S)-2-Cyclohexylmethyl-N-[(R)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-pro-
pyl]-4-morpholin-4-yl-4-oxo-butyramide and any mixture, racemic or
otherwise, thereof.
[0016] "N-oxide derivatives" means derivatives of compounds of
Formulae I, II and III in which nitrogens are in an oxidized state
(i.e., N--O) and which possess the desired pharmacological
activity.
[0017] "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.
[0018] "Pharmaceutically acceptable salts" means salts of compounds
of Formulae I, II and III 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, tartaric acid, citric acid, benzoic acid,
o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methylsulfonic 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.
[0019] 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.
[0020] "Prodrug" means a compound which is convertible in vivo by
metabolic means to a compound of Formula I, II or III. For example
an ester of a compound of Formula I, II or III containing a hydroxy
group may be convertible by hydrolysis in vivo to the parent
molecule. Alternatively an ester of a compound of Formula I, II or
III containing a carboxy group may be convertible by hydrolysis in
vivo to the parent molecule. Suitable esters of compounds of
Formulae I, II and III 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, methylsulphonates, ethanesulphonates,
benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and
quinates. Suitable esters of compounds of Formulae I, II and III
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 Formulae I, II and III
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.
[0021] "Protected derivatives" means derivatives of compounds of
Formulae I, II and III in which a reactive site or sites are
blocked with protecting groups. Protected derivatives of compounds
of Formulae I, II and III are useful in the preparation of
compounds of Formulae I, II and III 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.
[0022] "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.
[0023] "Treatment" or "treating" means any administration of a
compound of the present invention and includes:
[0024] (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,
[0025] (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
[0026] (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:
[0027] The compounds of Formulae I, II and III 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 having the
following structure: ##STR3## is named
(R)-N-[(S)-1-(5-isopropyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholi-
n-4-yl-4-oxo-2-(tetrahydro-pyran-4-ylmethyl)-butyramide
[0028] However, it is understood that, for a particular compound
referred to by both a structural formula and a nomenclature name,
if the structural formula and the nomenclature name are
inconsistent with each other, the structural formula takes the
precedence over the nomenclature name.
[0029] The various features of novelty which characterize the
invention are pointed out with particularity in the claims annexed
to and forming a part of this disclosure. For a better
understanding of the invention, its operating advantages, and
specific objects attained by its use, reference should be made to
the following description in which there are illustrated and
described preferred embodiments of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Preferred Compounds:
[0030] One particular group of compounds, as preferred embodiments
of the present invention, are compounds of Formulae I, II and III,
##STR4## wherein:
[0031] X.sup.2 is a substituted alkyl motif or a sulfonyl alkyl
motif;
[0032] X.sup.3 is a heterocyclic motif or an amide motif;
[0033] X.sup.4 and X.sup.7 are independently --H, --R or ##STR5##
or X.sup.4 and X.sup.7 taken together with the carbon atom to which
both X.sup.4 and X.sup.7 are attached form a 3-6 membered
cycloalkyl group;
[0034] X.sup.5 is --H, --F, --OH or --O--R;
[0035] A.sup.1 is --O--, --N(R)-- or --SO.sub.2--;
[0036] A.sup.2 is --H, --F, --OH, or --O--R;
[0037] A.sup.3 is cyano or --C(O)--X.sup.3; and
[0038] R is an alkyl group with straight or branched-chain
containing 1-6 carbon atoms.
[0039] For the purpose of this application, a heterocyclic motif
is: ##STR6## ##STR7##
[0040] For the purpose of this application, an amide motif is
##STR8##
[0041] For the purpose of this application, a substituted alkyl
motif is: ##STR9## ##STR10##
[0042] For the purpose of this application, a sulfonyl alkyl motif
is: ##STR11##
[0043] This group of preferred embodiments also encompasses their
related chemcial entities as defined above.
[0044] Further preferred embodiments are the following compounds:
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5--
phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl-
-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl)-amide,
4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(5-trifluor-
omethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-
-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
N-[(S)-1-(5-Ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholin-4-yl-4-
-oxo-2-phenylmethanesulfonylmethyl-butyramide,
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(3-phen-
yl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[1-(3-phenyl-1-
,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-2-Cyclohexylmethyl-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-pro-
pyl]-4-morpholin-4-yl-4-oxo-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-
-morpholin-4-yl-4-oxo-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-phen-
yl-cyclopropylmethyl)-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
[0045]
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentano-
ic acid [(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid
[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-c-
arbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid
[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(S)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(5-methyl-thiophen-2-ylmet-
hyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethy-
l)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of
diastereoisomers),
4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-(2-ph-
enyl-cyclopropylmethyl)-butyramide (mixture of
diastereoisomers),
[0046]
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbon-
yl)-3-phenyl-propyl]-4-oxo-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl-amide,
3-Phenylmethanesulfonyl-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-p-
ropyl]-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(oxazole-2-carbonyl)-propyl]-amide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide,
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-N-[(S)-1-(3-Cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(2-met-
hyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-2-Cyclopropylmethanesulfonylmethyl-N-[(S)-1-(3-cyclopropyl-1,2,4-oxad-
iazole-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid
[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(3-cyclopropyl-1,2,4-oxadiazo-
le-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-5-Cyclopropyl-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic
acid
[(S)-1-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-N-[(S)-1-(3-Cyclopropyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(1-iso-
butyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,
R)-2-(1-Cyclopropylmethyl-cyclopropylmethyl)-N-[(S)-1-(3-cyclopropyl-1,2,-
4-oxadiazole-5-carbonyl)-propyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-N-[(S)-1-(3-Ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-2-(2-methyl-pr-
opane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide,
(R)-2-Cyclopropylmethanesulfonylmethyl-N-[(S)-1-(3-ethyl-1,2,4-oxadiazole-
-5-carbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(S)-2-(2-Benzenesulfonyl-ethyl)-N-[(S)-1-(3-ethyl-1,2,4-oxadiazole-5-carb-
onyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide,
(S)-N-[(S)-1-(3-Ethyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-4-morpholin-4--
yl-4-oxo-2-[2-(propane-2-sulfonyl)-ethyl]-butyramide,
2-(1-Methyl-cyclopentylmethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyrid-
ine-2-carbonyl)-propyl]-4-oxo-butyramide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid (pyridin-4-ylmethyl)-amide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid diethylamide,
N-((S)-1-Ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl)-4-morpholin-4-yl-4-oxo-
-2-phenylmethanesulfonylmethyl-butyramide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid phenethyl-amide,
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)-
-2-oxo-pentanoic acid (2-pyridin-2-yl-ethyl)-amide,
N-(1-Cyano-cyclopropyl)-4-morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmet-
hyl-butyramide, and their related chemical entities.
Pharmacology and Utility:
[0047] The compounds of the invention are 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 may be useful
in treating autoimmune disorders, including, but not limited to,
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
irritable bowel disease, 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.
[0048] Cathepsin S is also 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 may be of use in treatment of systemic
amyloidosis.
[0049] 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 46, 47, 48, 49,
infra.
Administration and Pharmaceutical Compositions:
[0050] In general, compounds of the present invention 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 the invention may range from
about 1 micrograms per kilogram body weight (.mu.g/kg) per day to
about 60 milligram per kilogram body weight (mg/kg) per day,
typically from about 1 .mu.g/kg/day to about 20 mg/kg/day.
Therefore, a therapeutically effective amount for a 80 kg human
patient may range from about 80 .mu.g/day to about 4.8 g/day,
typically from about 80 .mu.g/day to about 1.6 g/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 the
invention for treating a given disease.
[0051] The compounds of the invention 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 the
invention 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.
[0052] 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.
[0053] The amount of a compound of the invention 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 the invention 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 the invention are described
in, Example 50.
Chemistry:
PROCESSES FOR MAKING COMPOUNDS OF THE INVENTION
[0054] 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.
[0055] 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.
[0056] Compounds of the invention can be prepared by proceeding
according to Reaction Scheme 1:
Reaction Scheme 1
[0057] ##STR12## where each X.sup.2, X.sup.3, X.sup.4, and X.sup.5
are as defined for Formula I in the Summary of the Invention.
[0058] As indicated in the scheme, compounds of Formula I can be
prepared by condensing an acid of Formula 2 with an amino compound
of the formula NH.sub.2CX.sup.4X.sup.7--C(O)--X.sup.3. 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),
O-(7-azabenzotrizol-1-yl)-1,1,3,3,
tetra-methyluroniumhexafluorophosphate (HATU), or the like) and
optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole
(HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 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 1 to 10 hours to complete.
[0059] Compounds of the invention can be prepared by proceeding
according to Reaction Scheme 2: ##STR13##
[0060] The condensation reaction can be effected with an
appropriate coupling agent as above and the oxidation step can be
carried out with an oxidizing agent (e.g. Dess-Martin Periodinane
or Sodium hypochlorite and TEMPO) in a suitable solvent at ambient
temperature. Detailed descriptions for the synthesis of a compound
of Formula I by the processes in Reaction Scheme 2 are set forth in
the Examples 1, 2 and 10.
[0061] Similarly, compounds of Formulae II and III can be
synthesized by following the same schemes 1 and 2 with
corresponding starting materials, i.e. the corresponding acid and
amino compounds.
[0062] Compounds of Formula 2 can be prepared by reacting a
compound of Formula 3 with a compound of Formula X.sup.2L:
##STR14## in which L is a leaving group and X.sup.2 and X.sup.5 are
as defined in the Summary of the Invention. The reaction involves
alkylation followed by alkaline hydrolysis at a temperature during
which the dicarboxylic acid formed undergoes mono-decarboxylation.
The decarbalkoxylation can be effected under strongly basic
conditions (e.g. in the presence of 1N aqueous sodium hydroxide) in
a suitable solvent (e.g. ethanol).
[0063] Some of the compounds of Formula 2 can be prepared according
to the following reaction scheme: ##STR15## where Ry is, for
example, benzyl, iso-butyl, cyclopropylmethyl. Ry is not limited to
the examples provided. Other substituents at Ry may also provide
satisfactory results, and those sastisfactory substituents are
referred to as "equivalent substituents" for the purpose of this
application.
[0064] If applicable, compounds 2 can be resolved as their
individual stereoisomers by chiral HPLC or 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.
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 separation/resolution techniques
based upon differences in solubility. 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).
[0065] A compound of Formula I, II or III 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, II or III
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 Formulae I, II
and III are set forth in the definitions section of this
Application. Alternatively, the salt forms of the compounds of
Formulae I, II and III can be prepared using salts of the starting
materials or intermediates.
[0066] The free acid or free base forms of the compounds of
Formulae I, II and III can be prepared from the corresponding base
addition salt or acid addition salt form. For example, a compound
of Formula I, II or III 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, II or III 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).
[0067] The N-oxides of compounds of Formulae I, II and III 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, II or III 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 Formulae I, II and
III can be prepared from the N-oxide of an appropriate starting
material.
[0068] Compounds of Formulae I, II and III in unoxidized form can
be prepared from N-oxides of compounds of Formulae I, II and III 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.
[0069] Prodrug derivatives of the compounds of Formulae I, II and
III 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, II or III with a suitable
carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,
para-nitrophenyl carbonate, or the like).
[0070] Protected derivatives of the compounds of Formulae I, II and
III 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.
[0071] Compounds of the present invention may be conveniently
prepared, or formed during the process of practicing 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
dioxane, tetrahydrofuran or methanol.
[0072] The present invention is further exemplified, but not
limited by, the following examples that illustrate the preparation
of the compounds of the present invention (Examples) and their
corresponding intermediates (References). These specifically
exemplified embodiments are intended to provide guidance to carry
out the present invention to a greater extent.
REFERENCE 1
(S)-2-Amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol
[0073] ##STR16##
[0074] A solution of
(S)-3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (2.00 g,
8.57 mmol) and N-Hydroxy-cyclopropanecarboxamidine (1.03 g, 10.29
mmol) in dichloromethane (20 mL) was stirred at 0.degree. C. and
1.25 equivalents of N-cyclohexylcarbodiimide-N'-methyl polystyrene
(1.70 mmol/g, 6.30 g, 10.72 mmol) was added in portions. The
reaction mixture stirred under nitrogen for three hours while
warming to 15.degree. C. The reaction mixture was filtered, the
resin washed with dichloromethane and the filtrate evaporated under
vacuum to dryness. [LC/MS m/z=338 (M+H+Na)] The residue was
dissolved in tetrahydrofuran (20 mL) and heated in a microwave
reactor (Smith Creator) at 160.degree. C. for three minutes, cooled
to room temperature and evaporated under vacuum to dryness. [LC/MS
n/z=320 (M+H+Na)]. The residue was dissolved in dichloromethane (50
mL) and stirred at room temperature as a 50 mL solution of 50%
trifluoroacetic acid in dichloromethane was added dropwise. After
three hours the reaction was evaporated under vacuum to dryness and
dissolved in 50 mL of dichloromethane again. Three equivalents of
Silicycle triamine-3 was added and the mixture stirred at room
temperature overnight. The mixture was filtered and washed with
dichloromethane. Evaporate under vacuum to give 1.04 g (61%
overall). [LC/MS m/z=198 (M+H)]
REFERENCE 2
(S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol
[0075] ##STR17##
[0076] A solution of
(S)-3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (2.00 g,
8.57 mmol) and N-hydroxy-benzamidine (1.3 g, 9.5 mmol) in
dichloromethane (40 mL) was stirred at 0.degree. C.
N-cyclohexylcarbodiimide-N'-methyl polystyrene (1.90 mmol/g, 6 g,
11.4 mmol) was added in portions. The reaction mixture was stirred
under nitrogen for one hour. The reaction mixture was filtered, the
resin washed with dichloromethane and the filtrate evaporated under
vacuum to dryness. [LC/MS m/z=352 (M+H+),
296(M+H.sup.+-isobutene)]. The residue was dissolved in
tetrahydrofuran (20 mL) and heated in a microwave reactor (Smith
Creator) at 180.degree. C. for three minutes, cooled to room
temperature and evaporated under vacuum to dryness. The crude
product was purified via flash chromatography (eluted with a
gradient from 5% to 65% ethyl acetate in heptane) to give the
product as a white solid [LC/MS m/z=356 (M+Na.sup.+), 234
(M+H.sup.+-Boc)].
[0077] It was dissolved in dichloromethane (45 mL) and
trifluoroacetic acid (5 mL) was added. After two hours the reaction
was evaporated under vacuum to dryness. The residue was redissolved
in 50 mL of dichloromethane. Silicycle triamine-3 (9.9 g, 39 mmol)
was added and the mixture stirred at room temperature overnight.
The mixture was filtered and washed with dichloromethane. The
Filtrate was concentrated under vacuum to give 775 mg (38% overall)
product as a white solid. [LC/MS m/z=234 (M+H)]
[0078] .sup.1HNMR (CDCl.sub.3) 8.12-8.06 (m, 2H), 7.54-7.45 (m,
3H), 4.93 & 4.75 (2xd, J=5 Hz & 3.5 Hz, 1H), 3.25 &
3.11 (2xm, 1H), 1.78-1.42 (2xm, 2H), 1.04 & 1.01 (2x t, J=7.5
Hz, 3H).
REFERENCE 3
(S)-2-Amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol
[0079] ##STR18##
[0080] Reference 3 was synthesized as described in the following
reaction protocol: ##STR19##
{(S)-1-[Hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic
acid tert-butyl ester (2)
[0081] A solution of (2-cyano-1-ethyl-2-hydroxy-ethyl)-carbamic
acid tert-butyl ester (9.53 g, 44 mmol) in methanol (80 ml) was
cooled to 0.degree. C. and treated successively with hydroxylamine
hydrochloride (3.05, 44 mmol) in methanol (80 ml) and 25% sodium
methoxide solution in methanol (10.2 ml). Stirred at 0.degree. C.
for 5 minutes, cold bath removed and the reaction mixture stirred
at room temperature for 5 hours. Methanol evaporated off under
reduced pressure, crude partitioned between ethyl acetate and
water. Organic layer separated, dried (MgSO.sub.4) and evaporated
under reduced pressure to give yellow oil. Purified by mplc,
eluting with a mixture of ethyl acetate-heptane to give the title
compound as white solid (3.5 g); MS: M(H.sup.+) 248.
{1-[Hydroxy-(N-benzoyloxycarbamimidoyl)-methyl]-propyl}-carbamic
acid tert-butyl ester (3)
[0082] A solution of
{1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid
tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethane (125 ml)
was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11
mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol)
and stirred at room temperature overnight. Reaction mixture was
washed with saturated sodium bicarbonate solution and then water
and dried over Na.sub.2SO.sub.4. Solvent evaporated under reduced
pressure, crude purified by mplc eluting with 1% triethylamine in
2:3 v/v ethyl acetate and heptane mixture to give yellow solid (850
mg); MS: MH.sup.+ 352.
2-Amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol (5)
[0083] A solution of (3) (1.5 g, 4.3 mmol) in diglyme was heated at
150.degree. C. in a microwave reactor (Smith Creator, S00219) for
40 minutes. Solvent evaporated under vacuum in Genevac Evaporator
at 80.degree. C. for 3 hours to give a brown solid. This was taken
in dichloromethane (40 ml) and treated with trifluoroacetic acid at
room temperature for 2 hours. Solvent evaporated to dryness under
reduced pressure, crude taken in water, washed with DCM, aqueous
layer basified with 1M NaOH solution and extracted with
dichloromethane. Organic layer dried over Na.sub.2SO.sub.4 and
evaporated under reduced pressure to give pale brown solid (300
mg); .sup.1HNMR (CDCl.sub.3) 8.14-8.10 (m, 2H), 7.59-7.47 (m, 3H),
4.83 & 4.65 (d, J=5 Hz, 1H), 3.18-3.05 (2m, 1H), 1.71-1.20(m,
2H), 1.05-0.97 (2Xt, J=7.2 Hz, 3H).
REFERENCE 4
(S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol;
compound with trifluoro-acetic acid
[0084] ##STR20##
[0085] A solution of
{(S)-1-[Hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic
acid tert-butyl ester (452 mg, 1.83 mmol) in dioxane (5 mL) was
treated with trifluoroacetic anhydride (0.349 ml, 2.47 mmol) and
heated at 100.degree. C. in a microwave reactor (Smith Creator,
S00219) for 7 minutes. Solvent evaporated under reduced pressure
and the crude was purified by flash chromatography eluting with a
mixture of ethyl acetate and heptane to give
{(S)-1-[Hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-pro-
pyl}-carbamic acid tert-butyl ester as a brown solid (476 mg)
(mixture of diastereoisomers).
[0086] .sup.1H NMR (CDCl.sub.3): 5.00 (d, J=4 Hz, 1H), 4.82, 4.65
(bd, J=7 Hz, 1H), 4.00, 3.85 (broad m, 1H), 1.78-1.52 (m, 1H),
1.52-1.32 (m, 1H), 1.44, 1.37 (2xs, 9H), 1.02 (2xt, J=7 Hz & 4
Hz, 3H).
[0087] MS: 348 (M+Na)
[0088] A solution of
{(S)-1-[Hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}--
carbamic acid tert-butyl ester (3.6 g, 0.011 mol) in methylene
chloride (15 mL) was treated with trifluoroacetic acid (8.53 ml,
0.111 mol) and stirred at room temperature for 3 h. Solvent
evaporated under reduced pressure to give
(S)-2-amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol;
compound with trifluoro-acetic acid as a brown oil (4.42 g)
(mixture of diastereoisomers).
[0089] .sup.1H NMR (CDCl.sub.3): 8.22 (bs, 2H), 7.04 (bs, 1H),
5.14, 4.90 (d, J=4 Hz & 7 Hz, 1H), 3.40-3.28 (m, 1H), 1.64-1.37
(m, 2H), 0.80 (2xt, J=7 Hz, 3H).
[0090] MS: 226 (MH.sup.+)
REFERENCE 5
(S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound
with trifluoroacetic acid
[0091] ##STR21##
[0092] A solution of
{(S)-1-[Hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic
acid tert-butyl ester (525 mg, 2.13 mmol) in dioxane (5 mL) was
treated with propionic anhydride (0.300 ml, 2.34 mmol) and heated
at 150.degree. C. in a microwave reactor (Smith Creator, S00219)
for 35 minutes. Solvent evaporated under reduced pressure and the
crude was purified by flash chromatography eluting with a mixture
of ethyl acetate and heptane to give
{(S)-1-[(5-Ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-carba-
mic acid tert-butyl ester as a yellow solid (406 mg) (mixture of
diastereoisomers).
[0093] .sup.1H NMR (CDCl.sub.3): 4.98-4.72 (m, 2H), 4.00, 3.88 (m,
1H), 3.64, 3.45 (bs, 1H), 2.89 (2xq, J=7.6 Hz, 2H), 1.69 (m, 1H),
1.47 (m, 1H), 1.45, 1.39 (2xs, 9H), 1.44-136 (m, 3H), 0.98 (2xt,
J=9 Hz & 7 Hz, 3H).
[0094] MS: 308 (M+Na)
[0095] A solution of
{(S)-1-[(5-Ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-carbamic
acid tert-butyl ester (214 mg, 0.751 mmol) in methylene chloride (5
mL) was treated with trifluoroacetic acid (0.578 ml, 7.504 mmol)
and stirred at room temperature for 3 h. Solvent evaporated under
reduced pressure to give
(S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol: compound
with trifluoro-acetic acid as a brown oil (224 mg) (mixture of
diastereoisomers).
[0096] MS: 186 (MH.sup.+)
[0097] .sup.1H NMR (CDCl.sub.3): 8.10-7.33 (2xbs, 3H), 5.24, 5.07
(d, J=3.5 Hz & 5.5 Hz, 1H), 3.77, 3.62 (bs, 1H), 2.91 (2xq, J=7
Hz, 2H), 1.78 (m, 1H), 1.76-1.40 (m, 1H), 1.39 (2xt, J=7 Hz, 3H),
1.02 (2xt, J=7.5 Hz, 3H).
[0098] Reference examples 6, 7, 8 were prepared according to the
scheme below ##STR22##
[0099] Ry=Benzyl, iso-butyl, cyclopropylmethyl
REFERENCE 6
4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric
acid
[0100] ##STR23##
[0101] Morpholine (23.6 g, 271 mmol) was slowly added to a stirred
solution of itaconic anhydride (30.36 g, 271 mmol) suspended in
dichloromethane (200 mL) below -5.degree. C. and stirred at that
temperature for 1 hr. The reaction mixture was allowed to slowly
warm up to room temperature and evaporated under reduced pressure
below 30.degree. C. to give a viscous oil. This was triturated with
ethyl acetate to give 2-Methylene-4-morpholin-4-yl-4-oxo-butyric
acid as white solid (36.8 g, 68%). The product was used without
further purification in the next step.
[0102] A mixture of 2-Methylene-4-morpholin-4-yl-4-oxo-butyric acid
(12.74 g, 64 mmol) and benzyl sulphinic acid (10.0 g, 64 mmol) was
suspended in anhydrous toluene (270 mL) and anhydrous acetonitrile
(55 mL). This mixture was warmed to 85.degree. C. and stirred
vigorously for 3 h (during this period the external bath
temperature climbes to 95.degree. C.). The reaction mixture was
allowed to cool to room temperature then concentrated under vacuum.
The solid residue was triturated with methanol (approximately 35
mL) and filtered. The solid was washed with 2.times.15 mL of
methanol then washed with ether to give 9.9 g of product. The
mother liquor was concentrated then taken up in 30 mL of methanol.
This solution was allowed to stand at -20.degree. C. overnight. The
resulting precipitate was filtered, washed with methanol and ether
to give 2.1 g of product. The combined product (9.9+2.1=12.0 g) was
86% pure by HPLC (UV analysis 254 nM). This material was taken up
in 400 mL of 20% methanol in CH.sub.2Cl.sub.2. The cloudy solution
was filtered and concentrated under vacuum. The residue was
triturated with about 50 mL of methanol, filtered and the solid
washed with ether then dried under vacuum to give 10.7 g of product
as a white solid, 96% pure by HPLC analysis. .sup.1H NMR (DMSO):
.delta. 12.63 (bs), 7.40 (m, 5H), 4.55 (dd, AB pattern, J=14 Hz,
2H), 3.53 (m, 4H), 3.40-3.2 (m, 7H), 2.78 (d, 2H). LC (C.sub.18
Dynamax column; CH.sub.3CN/H.sub.2O/0.1% TFA; 20-100 CH.sub.3CN
over 20 min; rt=7.59 min).
[0103] Chiral separation of the enantiomers on a Chiralpak AD
column using 80% ethanol/20% heptane/0.01% TFA gave
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric
acid (6a) and
(S)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric
acid (6b).
REFERENCE 7
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid
[0104] ##STR24##
[0105] A mixture of 2-Methylene-4-morpholin-4-yl-4-oxo-butyric acid
(3.98 g, 20 mmol) and isobutyl-sulphinic acid (2.44 g, 20 mmol)
were suspended in anhydrous toluene (80 mL) and anhydrous
acetonitrile (20 mL). This mixture was warmed to 85.degree. C. and
stirred vigorously for 4.5 h. The reaction mixture was allowed to
cool to room temperature and concentrated under vacuum. The residue
was purified by flash chromatography using a 90 g silica gel column
eluting with 10% methanol/CH.sub.2Cl.sub.2. Recovered 3.7 g of
product as an oil. Triturated residue with isopropanol (5 mL)/ether
(100 mL). Product began to precipitate out. Cooled this to
5.degree. C. for 17 hrs(overnight). Product was collected by
filtration, washed with ether and dried under vacuum to give
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid as a white solid (1.8 g).
[0106] .sup.1H NMR (DMSO): .delta. 12.59 (bs, 1H), 3.56-3.52 (m,
5H), 3.43-3.40 (m, 4H), 3.3-3.1 (m 2H), 3.08 (d, 2H), 2.79 (m, 2H),
2.20 (m, 1H), 1.06 (d, 6H). MS: m/z 320 (M-H).sup.-.
[0107] Chiral separation of the enantiomers on a Chiralpak AD
column using 70% ethanol/70% heptane/0.01% TFA gave
(R)-2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid (7a) and
(S)-2-(2-Methyl-propane-1-sulfonylmethyl)4-morpholin-4-yl-4-oxo-butyric
acid (7b)
REFERENCE 8
2-Cyclopropylmethanesulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric
acid
[0108] ##STR25##
[0109] To a solution of cyclopropylmethylsulphinic acid (1.8 g, 15
mmol) in anhydrous toluene (45 mL) and anhydrous acetonitrile (9
mL) was added 2-Methylene-4-morpholin-4-yl-4-oxo-butyric acid (2.98
g, 15 mmol). The resulting solution was warmed to 85.degree. C. and
stirred at this temperature for 4.5 h. The heterogeneous reaction
mixture is then allowed to cool to room temperature then
concentrated under reduced pressure. The residue is then purified
by flash chromatography eluting with 7% methanol in dichloromethane
to give
2-Cyclopropylmethanesulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric
acid (1.92 g) as viscous oil which was re crystallized from hot
ethyl acetate to give a white solid.
[0110] .sup.1HNMR (CDCl.sub.3): .delta. 8.23 (bs, 1H), 3.80-3.55
(m, 8H), 3.55-3.40 (m, 2H), 3.4-3.2 (m, 1H), 3.2-2.84 (m, 2H), 2.95
(d, 2H), 1.28-1.15 (m, 1H), 0.84-0.64 (m, 2H), 0.45-0.35(m,
2H).
[0111] MS: 320 (MH.sup.+), 342 (M+Na).
[0112] Combustion Analysis: Calculated: C; 48.9, H; 6.6, N; 4.4.
Found: C; 48.9, H; 6.8, N; 4.3
[0113] Chiral separation of the enantiomers on a Chiralpak AD
column using 70% ethanol/70% heptane/0.01% TFA gave
(R)-2-Cyclopropylmethanesulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric
acid (8a) and
(S)-2-Cyclopropylmethanesulfonvlmethyl4-morpholin-4-yl-4-oxo-butyric
acid (8b)
[0114] Reference examples (9)-(14) were made according to the
scheme below. ##STR26##
[0115] References: Angew. Chem. Int. Ed. 1998, 37(13/14),
1931-1933.
[0116] Angew. Chem. Int. Ed. 2000, 39(11), 1981-1984
(Amido-derivatives).
REFERENCE 9
(R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid
[0117] ##STR27##
[0118] To a warmed solution (75.degree. C.) of tBuOK 1M in tBuOH
(1.3 eq., 16.0 mmol, 16.0 mL) under N2 was added slowly a mixture
of dimethyl succinate (2.42 g, 14.7 mmol, 1.2 eq) and
1-Benzyl-cyclopropanecarbaldehyde (1.97 g, 12.3 mmol). After the
addition, the mixture was heated to 85.degree. C. for another 5 hr,
cooled and concentrated in vacuum. The residue was diluted with
water (150 mL), and extracted with ether (50 mL). The aqueous layer
was acidified to pH 1 and extracted with ether (2.times.75 mL). The
acidic extracts were dried (MgSO4) and concentrated in vacuum. The
residue was purified over 90 g silica gel, eluted with ethyl
acetate and heptane (1:1 then 2:1) to afford
2-[1-(1-Benzyl-cyclopropyl)-meth-(Z)-ylidene]-succinic acid
1-methyl ester as a light yellow oil (3.096 g, 91.8% yield).
[0119] .sup.1H NMR (CDCl.sub.3) 7.2 (m, 5H), 7.0 (s, 1H), 3.75 (s,
3H), 3.2 (s, 2H), 2.75 (s, 2H), 0.85 (m, 2H), 0.75 (m, 2H).
[0120] A solution of
2-[1-(1-Benzyl-cyclopropyl)-meth-(Z)-ylidene]-succinic acid
1-methyl ester (2.686 g, 9.79 mmol) and sodium methoxide (0.1 eq.,
0.98 mmol, 52.9 mg) in dry methanol (25 mL) was degassed with N2
for 5 min then (+)-(2S,5S)-2,5-Diethylphospholanobenzene
(cyclooctadiene) Rhodium tetrafluoroborate (25 mg) was added. The
mixture was hydrogenated at 60 psi for 24 hr, then concentrated in
vacuum. The residue was diluted with NaHCO.sub.3 (150 mL) and the
solution was made basic with NaOH and extracted with ether (80 mL).
The aqueous layer was acidified to pH 1 and extracted with ether
(2.times.100 mL). The acidic extracts were dried (MgSO4) and
concentrated in vacuum to afford
(R)-2-(1-Benzyl-cyclopropylmethyl)-succinic acid 1-methyl ester as
a yellow oil (2.465 g, 91% yield).
[0121] .sup.1HNMR (CDCl.sub.3) 7.3 m (5H), 3.75 (s, 3H), 3.15 (m,
1H), 2.9 (d, J=14.3 Hz, 1H), 2.75 (dd, J=17.2, 9.8 Hz, 1H), 2.5 (d,
J=14.3 Hz, 1H), 1.58 (dd, J=14.1, 6.5 Hz, 1H), 1.4 (dd, J=14.2, 9.3
Hz, 1H), 0.6 (m, 1H), 0.4 (m, 3H).
[0122] To a solution of (R)-2-(1-Benzyl-cyclopropylmethyl)-succinic
acid 1-methyl ester (2.453 g, 8.88 mmol), di-isopropyl amine (1.1
eq, 9.76 mmol, 1.26 g) and morpholine (1.5 eq., 13.3 mmol, 1.16 g)
in dry dichloromethane under N.sub.2 was added PyBOP (1.1 eq., 9.76
mmol, 5.08 g). The mixture was stirred at room temperature for 5
hr, and concentrated in vacuum. The residue was dissolved in ethyl
acetate (150 mL) and washed with water (100 mL), NH.sub.4Cl (100
mL), NaHCO.sub.3 (2.times.100 mL), then water (100 mL). The organic
layer was dried (MgSO.sub.4) and concentrated in vacuum. The
residue was purified over 120 g silica gel, eluted with ethyl
acetate:heptane (1:1.5, 1:1, to 2:1) to afford the desired compound
contaminated with PyBOP residues. A solution of the mixture in
ether containing ethyl acetate (250 mL total) was washed with
dilute HCl (150 mL), water (150 mL) dilute NaOH (150 mL) then water
(150 mL). The organic layer was dried (MgSO4) and concentrated in
vacuum to afford
(R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid methyl ester as a white solid (2.292 g, 74.7 % yield).
[0123] .sup.1H NMR (CDCl.sub.3) 7.3 (m, 5H), 3.8 (s, 3H), 3.6 (m,
6H), 3.4 (m, 2H), 3.2 (m, 1H), 3.0 (d, J=14.4 Hz, 1H), 2.7 (dd,
J=16.1, 10.3 Hz, 1H), 2.5 (d, J=14.5 Hz, 1H), 2.3 (dd, J=16.2, 3.9
Hz, 1H), 1.6 (dd, J=14, 5.9 Hz, 1H), 1.27 (dd, J=14, 10 Hz, 1H),
0.55 (m, 1H), 0.4 (m, 3H).
[0124] To a solution of
(R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid methyl ester (2.29 g, 6.63 mmol) in MeOH:H2O (2:1 vol, 21 mL)
was added THF (5 mL) followed by lithium hydroxide monohydrate (3.0
eq., 19.9 mmol, 834.5 mg). The mixture was stirred at rt for 19 hr,
then concentrated in vacuum. The residue was diluted with water
(100 mL) and extracted with ether (60 mL). The aqueous layer was
acidified to pH 1 and extracted with ethyl acetate (2.times.70 mL).
The acidic extracts were dried (MgSO4) and concentrated in vacuum
to afford
(R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid as colorless oil (2.128 g, 96.8% yield).
[0125] .sup.1H NMR (CDCl.sub.3) 7.25 (m, 5H), 3.65 (m, 6H), 3.45
(m, 2H), 3.2 (m, 1H), 2.9 (d, J=1.4.4 Hz, 1H), 2.78 (dd, J=16.3,
10.0 Hz, 1H), 2.55 (d, J=14.5 Hz, 1H), 2.48 (dd, J=16.5, 4.0 Hz,
1H), 1.6 (m, 2H), 0.5 (m, 4H).
REFERENCE 10
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic
acid
[0126] ##STR28##
[0127] Similarly prepared according to the general procedure for
Reference 9 but using dimethyl succinate and
2,2-Dimethyl-propionaldehyde as the aldehyde component.
[0128] .sup.1H NMR (CDCl.sub.3) 3.7 (m, 6H), 3.5 (m, 2H), 3.0 (m,
1H), 2.7 (dd, J=16.2, 9.0 Hz, 1H), 2.5 (dd, J=16.3, 4.5 Hz, 1H),
1.9 (dd, J=14.1, 7.4 Hz, 1H), 1.3 (dd, J=14.1, 4.2 Hz, 1H), 1.0 (s,
9H).
REFERENCE 11
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid
[0129] ##STR29##
[0130] Similarly prepared according to the general procedure for
Reference 9 but using dimethyl succinate and
2,2-Dimethyl-3-phenyl-propionaldehydeas the aldehyde component.
[0131] .sup.1H NMR (CDCl.sub.3) 7.3 (m, 3H), 7.15 (m, 2H), 3.7 (m,
6H), 3.5 (m, 2H), 3.0 (m, 1H), 2.8 (dd, J=16.4, 9.2 Hz, 1H), 2.6
(s, 2H), 2.5 (dd, J=16.5, 4.4 Hz, 1H), 2.0 (dd, J=14.3, 7.5 Hz,
1H), 1.3 (dd, J=14.3, 3.9 Hz, 1H), 0.95 (s, 3H), 0.93 (s, 3H).
REFERENCE 12
[0132] ##STR30##
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-et-
hyl)-pentanoic acid
[0133] Similarly prepared according to the general procedure for
Reference 9 but using dimethyl succinate and
3-(2-Difluoromethoxy-phenyl)-2,2-dimethyl-propionaldehyde as the
aldehyde component.
[0134] .sup.1H NMR (CDCl.sub.3) 7.2 (m, 4H), 6.5 (t, J=74 Hz, 1H),
3.65 (m, 6H), 345 (m, 2H), 3.1 (m, 1H), 2.77 (dd, J=16.4, 9.2 Hz,
1H), 2.7 (d, J=13 Hz, 1H), 2.6 (d, J=13 Hz, 1H), 2.5 (dd, J=16.4,
4.4 Hz, 1H), 2.0 (dd, J=14.1, 7.6 Hz, 1H), 1.38 (dd, J=14.2, 3.7
Hz, 1H), 0.95 (s, 6H).
REFERENCE 13
[0135] ##STR31##
[0136]
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
Similarly prepared according to the general procedure for Reference
9 but using dimethyl succinate and 2,2,4-Trimethyl-pentanal as the
aldehyde component.
[0137] .sup.1H NMR (CDCl.sub.3) 3.7 (m, 6H), 3.5 (m, 2H), 2.9 (m,
1H), 2.75 (dd, J=16.3, 9.6 Hz, 1H), 2.45 (dd, J=16.2, 4.0 Hz, 1H),
2.8-1.0 (m, 8H), 0.9 (m, 8H).
REFERENCE 14
(S)-2-(5-Methyl-thiophen-2-ylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid
[0138] ##STR32##
[0139] Similarly prepared according to the general procedure for
Reference 9 but using dimethyl succinate and
5-Methyl-thiophene-2-carbaldehyde as the aldehyde component.
[0140] .sup.1H NMR (CDCl.sub.3) 6.6 (m, 2H), 3.7 (m, 6H), 3.4 (m,
2H), 3.3 (dd, J=14.2, 5.0 Hz, 1H), 3.2 (m, 1H), 3.02 (dd, J=14.3,
8.7 Hz, 1H), 2.68 (dd, J=16.6, 8.5 Hz, 1H), 2.58 (dd, J=16.5, 4.1
Hz, 1H), 2.45 (d, J=0.6 Hz, 3H).
REFERENCE 15
2-Amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-ol
[0141] ##STR33##
[0142] A mixture of 2-amino-3-hydroxy pyridine (25 g, 227 mmol),
triethylorthoformate (75 ml) and p-toluenesulfonic acid (61 mg) was
heated at 140.degree. C. for 8 hours. Excess triethylorthoformate
was removed under vacuum. The product was crystallized from ethyl
acetate to yield 22.5 g of oxazolo[4,5-b]pyridine; H.sup.1 NMR
(DMSO-6): 9.26 (1H, s), 8.78 (1H, d), 8.45 (1H, d), 7.7(1H, dd);
MS: 120.8 (M+1).
[0143] Oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in 30 ml THF was
cooled to 0.degree. C. before the addition of isopropanyl magnesium
chloride (2M in THF, 2.5 ml, 5 mmol). After stirring for 1 hour at
0.degree. C., (S)-(1-formyl-propyl)-carbamic acid tert-butyl ester
(573 mg, 3 mmol) in 20 ml THF was added. The ice bath was removed
and the reaction allowed to warm to room temperature. The reaction
mixture was stirred for 2 hours and quenched with saturated
ammonium chloride solution. Excess THF was removed and the residue
was extracted with EtOAc, washed with brine, dried with anhydrous
MgSO.sub.4, filtered and concentrated. The crude residue was
purified by chromatography to yield 383 mg product;
[0144] H1 NMR (DMSO-.delta.): 8.42(1H, m), 8.18(1H, m), 7.3(1H, m),
6.8, 6.6(1H, dd, d, OH, diastereomeric), 6.3, 6.02(1H, d, d, NH,
diastereomeric), 4.82, 4.5(1H, m, m, diastereomeric), 1.8-1.3(2H,
m), 1.2, 1.05(9H, s,s, diastereomeric), 0.89(3H, m); MS:
306.2(M-1), 308.6(M+1).
[0145] Alternative procedure: To a stirred solution of the
oxazolo[4,5-b]pyridine (12 g, 100 mmol) in THF (300 ml) was added
n-BuLi (1.6M solution in 62.5 ml of hexane) drop wise under N.sub.2
at -78.degree. C. After 1 hour, MgBr.Et.sub.2O (25.8 g, 100 mmol)
was added and the reaction mixture was allowed to warm to
-45.degree. C. for 1 hour before being treated with
(S)-(1-formyl-propyl)-carbamic acid tert-butyl ester (11.46 g, 60
mmol) in THF (50 ml). The reaction mixture was stirred for 1 hour,
quenched with saturated NH.sub.4Cl, and extracted with ethyl
acetate. The organic layer was washed with brine, dried with
MgSO.sub.4 and concentrated. The residue was purified by silica gel
column chromatography to yield
(S)-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic
acid tert-butyl ester (14.1 g).
[0146]
(S)-[1-(Hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbami-
c acid tert-butyl ester (311 mg, 1 mmol) and MeCl.sub.2 (5 ml) were
mixed and TFA (1 ml) was added at room temperature. After stirring
for 1 hour, the solvent and excess TFA were removed under vacuum to
produce 355 mg of 2-Amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-ol
TFA salt.
REFERENCE 16
3-Benzylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic
acid
[0147] ##STR34##
2-(Tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethyl ester (1)
[0148] NaH added to a solution of 4-hydroxy tetrahydropyran (5 g,
49 mmol) in THF (40 ml) stirred at room temperature for 30 minutes.
A solution of ethyl 2-(bromomethyl)acrylate (9.6 g, 49 mmol) in THF
(30 ml) was added and stirred at room temperature overnight.
Reaction mixture cooled in ice, quenched with saturated NH.sub.4Cl
solution and extracted with ethyl acetate. Organic extracts dried,
(Na.sub.2SO.sub.4) and purified by mplc eluting with 1:9 to 2:8 v/v
ethyl acetate-heptane mixture to give the title compound as yellow
oil (6.56 g, 61%). MS: MH.sup.+ 215; LCMS retention time 3.29
minutes.
3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid
ethyl ester (2a)
[0149] A suspension of 2-(tetrahydro-pyran-4-yloxymethyl)-acrylic
acid ethyl ester (2.2 g, 10.2 mmol) in ethanol (100 ml) was treated
with a solution of NaHCO.sub.3 (0.86 g, 10.2 mmol) in water ml (10
ml) and benzyl mercaptan (1.21 ml, 10.2 mmol) at room temperature
overnight. Ethanol evaporated off under reduced pressure, crude
partitioned between ethyl acetate and water, organic layer
separated and purified by mplc eluting with 1:9 to 2:8 v/v ethyl
acetate-heptane mixture to give the title compound as pale yellow
oil (1.27 g). MS: 339 (MH.sup.+); LCMS (Protocol B) retention time
4.3 minutes.
3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid
(3a)
[0150] A solution of
3-benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid
ethyl ester (1.27 g) in ethanol (30 ml) was treated with 2N NaOH
(9.4 ml) overnight. Usual water work up gave the title compound as
white solid; MS: 333 (M+Na), 311 (M+1); LCMS retention time 3.7
minutes.
3-Benzylsulfonyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid
(Reference 15)
[0151] A solution of
3-Benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid
(1.16 g, 3.7 mmol) in a mixture of MeOH (10 ml) and water (30 ml)
was treated oxone (3.5 g, 5.6 mmol) overnight. Methanol evaporated
off under reduced pressure, aqueous layer extracted with ethyl
acetate, dried (Na.sub.2SO.sub.4) and evaporated under reduced
pressure to give the title compound as white solid (1.36 g); MS:
365 (M+Na), 343 (MH.sup.+); LCMS retention time 3.1 minutes.
REFERENCE 17
2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid
[0152] ##STR35##
[0153] A 0.05 M solution of
1-(4-benzyl-2-oxo-oxazolidin-3-yl)-2-cyclohexylmethyl-4-morpholin-4-yl-bu-
tane-1,4-dione (1 g) in 3:1-THF/H.sub.2O was treated at 0.degree.
C. with 8 equivalents of 30% H.sub.2O.sub.2 followed by 2.0
equivalents of LiOH. The resulting mixture was stirred at
0-25.degree. C. until the substrate had been consumed
(approximately 1 hour). The excess peroxide was quenched at
0.degree. C. with a 10% excess of 1.5 N aqueous Na.sub.2SO.sub.3.
After buffering to pH 9-10 with aqueous NaHCO.sub.3 and evaporation
of the THF, the oxazolidone chiral auxiliary was recovered by
MeCl.sub.2 extraction. The carboxylic acid was isolated by EtOAc
extraction of the acidified (pH 1-2) aqueous phase, then
recrystallized from EtOAc and hexane to yield 0.58 g of
2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid;
[0154] H.sup.1 NMR (DMSO-.delta.): 12(1H, s, COOH), 3.6-3.3(8H, m),
2.8-2.3(3H, m), 1.8-1.1(11H, m), 0.9-0.7(2H, m); MS: 282.2(M-1),
284.1 (M+1).
[0155] Reference Examples (18)-(19) were prepared according to the
scheme below. ##STR36##
REFERENCE 18
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[0156] ##STR37##
2-(2-Morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl ester (1)
[0157] To a solution of n-tetra butyl ammonium hydrogen sulfate
(1.18 g, 3.48 mmol) and NaOH (560 mg, 13.9 mmol) in water (8 ml)
was added a solution of 4-(2-bromoacetyl morpholine) (1.45 g, 6.97
mmol) and diethyl malonate (1.34 g, 8.36 mmol) in DCM (8 ml). The
mixture was stirred at room temperature for 3 hours, diluted with
water (30 ml) and extracted with DCM (2.times.30 ml). The organic
layer was dried (MgSO.sub.4) and concentrated in vacuum. The
residue was purified by chromatography (silica) eluting with 1:2
v/v ethyl acetate-heptane to give
2-(2-morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl ester as a
colorless oil (1.19 g, 59%); .sup.1H NMR (CDCl.sub.3) 4.25 (m, 4H),
4.0 (t, J=7.2 Hz, 1H), 3.8-3.45 (m, 8H), 3.0 (d, J=7.4 Hz, 2H), 1.3
(t, J=7.1 Hz, 6H).
2-(2-Morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid
diethyl ester (2)
[0158] To a mixture of Pd(OAc).sub.2 (17.5 mg, 0.078 mmol) and
PPh.sub.3 (40.9 mg, 0.156 mmol) in dry THF (2 ml) under N.sub.2,
cinnamyl alcohol (105.1 mg, 0.78 mmol) was added followed by a
solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-malonic acid diethyl
ester (250 mg, 0.87 mmol) and NaH (17.4 mg, 0.43 mmol) in dry THF
(3 ml). BF.sub.3 (1M in THF, 1 ml, 1 mmol) was then added and the
yellow solution was stirred at room temperature for 6.5 hours. The
mixture was diluted with ethyl acetate (50 ml) and washed with 1N
HCl (10 ml) and brine (2.times.20 ml). The organic layer was dried
(MgSO.sub.4), concentrated in vacuum and purified by chromatography
eluting with 1:1 v/v ethyl acetate-heptane mixture to give
2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid
diethyl ester as a thick, yellow oil (266.5 mg, 85%); .sup.1H NMR
(CDCl.sub.3) 7.25 (m, 5H), 6.40 (d, J=15.6 Hz, 1H), 6.1 (dt,
J=15.8, 7.7 Hz), 4.2 (q, J=7.1 Hz, 4H), 3.6 (m, 6H), 3.45 (m, 2H),
3.05 (d, J=7.6 Hz, 2H), 3.0 (s, 2H), 1.25 (t, J=7.1 Hz, 6H). MS:
404 (MH.sup.+)
2-(2-Morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid
diethyl ester (3)
[0159] A solution of
2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid
diethyl ester (257 mg, 0.637 mmol) in EtOH (15 ml) was hydrogenated
over Pd/C at 55 Psi for 7.5 hrs. The catalyst filtered off over a
pad of Celite and the filtrate evaporated under vacuum to give
2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid
diethyl ester as a light yellow oil (260 mg); .sup.1H NMR
(CDCl.sub.3) 7.4-7.1 (m, 5H), 4.20 (q, J=7.1 Hz, 4H), 3.7-3.4 (m,
8H), 3.0 (s, 2H), 2.6 (t, J=7.6 Hz, 2H), 2.2 (m, 2H), 2.55 (m, 2H),
1.20 (t, J=7.1 Hz, 6H). MS: 406 (MH.sup.+).
2-(2-Morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid
monoethyl ester (4)
[0160] To a solution of
2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid
diethyl ester (934 mg, 2.3 mmol) in a 2:1 mixture of ethanol and
water (12 ml) LiOH.H.sub.2O (193.3 mg, 4.61 mmol) was added and
heated at 40.degree. C. for 19 hrs. Ethanol was evaporated under
reduced pressure, the residual aqueous mixture was acidified to pH
1 and extracted with methylene chloride (2.times.40 ml). The
organic extract was dried with MgSO.sub.4 and evaporated under
reduced pressure to give
2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid
monoethyl ester as a thick, yellow oil (831 mg); .sup.1H NMR
(CDCl.sub.3) 7.4-7.1 (m, 6H), 4.25 (q, J=7.1 Hz, 2H), 3.8-3.4 (m,
8H), 3.20 (d, J=16.4 Hz, 1H), 2.9 (d, J=16.4 Hz, 1H), 2.6 (m, 2H),
2.1-1.8 (m, 4H), 1.25 (t, J=7.1 Hz, 3H). MS: 378 (MH.sup.+).
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl
ester (5)
[0161] A Solution of
2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid
monoethyl ester (809 mg, 2.14 mmol) in toluene (25 ml) was heated
under reflux for 23 hours. The colorless solution was concentrated
under reduced pressure, the residue was taken up in diethyl ether
(50 ml), washed with saturated NaHCO.sub.3 and dried over
MgSO.sub.4. The solvent was evaporated under reduced pressure to
give 2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl
ester as yellow oil (617 mg); .sup.1H NMR (CDCl.sub.3) 7.3-7.1 (m,
5H), 4.2 (m, 2H), 3.8-3.4 (m, 8H), 3.0 (m, 1H), 2.75 (dd, J=15.9,
9.4 Hz, 1H), 2.65 (m, 2H), 2.35 (dd, J=15.9, 5.1 Hz, 1H), 1.8-1.55
(m, 4H), 1.29 (t, J=7.1 Hz, 3H). MS: 334 (MH.sup.+).
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid (6)
[0162] To a solution of
2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid ethyl
ester (604 mg, 1.81 mmol) in a 2:1 mixture of MeOH--H2O (12 ml)
LiOH.H2O (228 mg, 5.43 mmol) was added and stirred overnight at
room temperature. Ethanol was removed under reduced pressure,
residue diluted with water (40 ml) and washed with ether. The
aqueous layer was acidified to pH1 with 1N HCl and extracted with
diethyl ether (3.times.25 ml). The combined organic extracts were
dried with MgSO4 and concentrated under reduced pressure to give
2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as a white
solid (492 mg); 1H NMR (CDCl3) 8.0-7.5 (1H), 7.4-7.1 (m, 5H),
3.8-3.4 (m, 8H), 3.0 (m, 1H), 2.8 (dd, J=16.4, 9.6 Hz, 1H), 2.65
(t, J=7.2 Hz, 2H), 2.40 (dd, J=16.4, 4.3 Hz, 1H), 1.9-1.5 (m, 4H).
MS: 306 (MH.sup.+).
REFERENCE 19
2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid
[0163] ##STR38##
[0164] Similarly prepared according to the Scheme illustrated for
Reference Example 18 as colorless oil.
[0165] .sup.1H NMR (CDCl.sub.3) 7.25 (m, 5H), 3.65 (m, 6H), 3.45
(m, 2H), 3.2 (m, 1H), 2.9 (d, J=14.4 Hz, 1H), 2.78 (dd, J=16.3,
10.0 Hz, 1H), 2.55 (d, J=14.5 Hz, 1H), 2.48 (dd, J=16.5, 4.0 Hz,
1H), 1.6 (m, 2H), 0.5 (m, 4H).
REFERENCE 20
2-(1-methyl-cyclopentylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid
[0166] ##STR39##
[0167] To 1-methylcyclopentanol (5 g, 50 mmol) was added 48% aqu.
HBr (15 mL). The mixture was stirred rapidly for 30 min and then
was extracted with hexane (2.times.50 mL). The combined organic
layers were washed with water, dried with MgSO.sub.4 and evaporated
under vacuum. The crude 1-bromo-1-methyl-cyclopentane (6.6 g, 40.5
mmol) was used without further purification.
[0168] Tributyltinhydride (2.69 mL, 10 mmol), AIBN (164 mg, 1
mmol), and 1-bromo-1-methyl-cyclopentane (2.4 g, 15 mmol) were
added to a solution of itaconic anhydride (1 g, 8.93 mmol) in dry
benzene (20 mL) and heated at reflux for 3 hours. After cooling,
the benzene was removed under vacuum and the residue was dissolved
in dry dichloromethane (20 mL). The solution was cooled to
-78.degree. C. and morpholine (1.5 mL) was added dropwise over
2min. The mixture was allowed to warm to room temperature over 2
hours. The mixture was partitioned between diethylether (100 mL)
and sat. aqu. NaHCO.sub.3 solution (100 mL). The aqueous layer was
extracted two more times with diethylether, was acidified with 6N
aqu. HCl and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were washed with brine, dried with MgSO4
and evaporated under vacuum. The crude
2-(1-methyl-cyclopentylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid
(400 mg, 1.41 mmol) was used without further purification.
REFERENCE 21
2-Amino-1-benzoxazol-2-yl-butan-1-one; hydrochloride
[0169] ##STR40##
[0170] Prepared according to the general procedure for oxidation of
amino alcohol to aminoketone template. ##STR41##
[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid
tert-butyl ester (step 1)
[0171] DIPEA (0.35 ml, 2 mmol) and di-tret-butyl dicarbonate (355
mg, 1.63 mmol) were added to a solution of
2-Amino-1-benzooxazol-2-yl-butan-1-ol (320 mg, 1.55 mmol) in dry
methylene chloride (10 ml) and stirred at room temperature for 4
hrs. The reaction was quenched with saturated aqueous NH.sub.4Cl
and the pH was adjusted to neutral. Oraganic layer separated and
the aqueous layer extracted with methylene chloride. The organic
extracts were dried over MgSO.sub.4 and concentrated under reduced
pressure to give
[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid
tert-butyl ester (500 mg).
[1-(Benzooxazole-2-carbonyl)-propyl]-carbamic acid tert-butyl ester
(step2)
[0172] Dess-Martin Periodinane (15 wt % in DCM, 8.8 g, 3.1 mmol)
was added to a solution of
[1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid
tert-butyl ester (475 mg, 1.55 mmol) in dry methylene chloride (15
ml) and stirred at room temperature for 4 hrs. The reaction was
quenched with a solution of Na.sub.2S.sub.2O.sub.3 in aqueous
NaHCO.sub.3. The organic layer was separated and the aqueous
extracted with dichloromethane. The organic extracts were dried
over sodium sulfate and concentrated under reduced pressure. Column
chromatography on silica eluting with a mixture of heptane and
methylene chloride gave the title compound as a off-white powder
(0.38 g).
2-Amino-1-benzoxazol-2-yl-butan-1-one; hydrochloride (step3)
[0173] Hydrogen chloride (4M in 1,4 dioxane, 1 ml) was added to a
solution of [1-(Benzooxazole-2-carbonyl)-propyl]-carbamic acid
tert-butyl ester (100 mg, 0.33 mmol) in dry methylene chloride and
the reaction mixture was stirred for 4 hours at rt. The reaction
mixture was concentrated under reduced pressure to gave the title
compound as a yellowish solid (65 mg).
[0174] .sup.1H NMR (DMSO) .delta. 0.99 (t, J=7.5 Hz, 3H), 2.20-2.05
(m, 2H), 4.96 (m, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz,
1H), 7.95 (d, J=8.2 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.75 (m, 3H);
MS: 207(M.sup.+)
[0175] Reference Examples (22)-(25) were made as shown in the
scheme below ##STR42## ##STR43##
(S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (1a) and
(S)-2-Acetoxy4-morpholin-4-yl-4-oxo-butyric acid (1b)
[0176] Morpholine (14.48 ml) and Triethylamine (23.14 ml, 166 mmol)
were added to an ice-cold solution of Acetic acid
(S)-2,5-dioxo-tetrahydro-furan-3-yl ester (25 g, 158.12 mmol) in
dry THF (600 ml) and the solution was stirred at room temperature
over the week end. Solvent was evaporated under reduced pressure,
residue diluted with water, acidified to pH 2 with 1N HCl and
extracted with ethyl acetate. Combined organic extracts were dried
over MgSO.sub.4 and evaporated under reduced pressure to give a
mixture of (S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid and
2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (14 g) as white
solid.
(S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester
(2a)
[0177] To a mixture of (S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric
acid and 2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (11 g, 44.8
mmol) in dry methanol (30 mL) HCl in dioxane (4M, 7.3 ml, 29.16
mmol) was added and stirred at room temperature for 5 hrs. The
reaction mixture was neutralized with solid NaHCO.sub.3, filtered
through a mixture of Celite/Na.sub.2SO.sub.4 (1:1) and concentrated
under reduced pressure. Column chromatography on silica eluting
with a mixture of ethyl acetate and methylene chloride gave
(S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (6
g).
(E)-(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pent-4-eno-
ic acid methyl ester (3a)
[0178] Lithium hexamethyldisilazide (1M in THF, 14.5 ml, 14.5 mmol)
was added to a solution of
(S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (1.5
g, 6.9 mmol) in dry THF (15 ml) at -78.degree. C. under N.sub.2 and
stirred for 30 min. Cinnamyl bromide (1.6 g, 7.32 mmol) was then
added, the reaction mixture stirred at -78.degree. C. for 2 hrs,
warmed up to room temperature and stirred overnight at room
temperature. The reaction was quenched with saturated ammonium
chloride solution, adjusted the pH to 6 with 1N HCl and extracted
with ethyl acetate. Combined ethyl acetate extracts were dried over
MgSO.sub.4 and concentrated under reduced pressure to give yellow
solid. Column chromatography on silica eluting with a mixture of
ethyl acetate and methylene chloride gave the title compound as
pale yellow solid (1.15 g).
(E)-(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-o-
xo-ethyl)-pent-4-enoic acid methyl ester (3b)
[0179] It is similarly prepared according to the procedure above
but replacing cinnamyl bromide with
1-((E)-3-Bromo-propenyl)-2-difluoromethoxy-benzene.
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (4a)
[0180] A solution of
(E)-(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pent-4-en-
oic acid methyl ester (1.55 g, 4.65 mmol) in methanol (15 ml) was
hydrogenated at 50 psi over Pd/C for 4 hrs. The catalyst was
removed by filtration through celite and the filtrate concentrated
under reduced pressure to give
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester as yellow solid (1.45 g).
(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid methyl ester (4b)
[0181] It is similarly prepared according to the procedure above
but using
(E)-(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-
-yl-2-oxo-ethyl)-pent-4-enoic acid methyl ester.
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid (22)
[0182] A solution of
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (230 mg, 0.69 mmol) and LiOH.H.sub.2O (57.5 mg,
1.37 mmol) in a mixture of THF and water (2:1, 6 ml) was stirred at
room temperature for 2.5 hrs. The reaction was diluted with water
and THF removed under reduced pressure. The pH of the aqueous
solution was adjusted to 5 with 1N HCl and extracted with ethyl
acetate. The combined organic extracts were dried over MgSO.sub.4
and evaporated under reduced pressure to give the title compound as
white solid (180 mg).
[0183] .sup.1H NMR (CDCl.sub.3) .delta. 1.92-1.60 (m, 4H),
2.75-2.60 (m, 3H), 3.78-3.45 (m, 9H), 4.5 (d, J=8 Hz, 1H),
7.35-7.18 (m, 5H);
[0184] MS: 322(M.sup.+).
(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid (23)
[0185] It is similarly prepared according to the procedure above
but using
(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl--
2-oxo-ethyl)-pentanoic acid methyl ester.
[0186] .sup.1H NMR (CDCl.sub.3) .delta. 1.90-1.65 (m, 4H),
2.77-2.68 (m, 3H), 3.70-3.53 (m, 9H), 4.51 (d, J=4.4 Hz, 1H), 6.52
(t, J=74 Hz, 1H), 7.28-7.14 (m, 4H);
[0187] MS: 388(M.sup.+).
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester 16a)
[0188] (Diethylamino)sulfur trifluoride (2.0 ml, 15.2 mmol) was
added to a ice cold solution of
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (4a) (0.85 g, 2.5 mmol) in dry methylene chloride
(15 ml) and the reaction mixture was stirred overnight while
warming to room temperature. The reaction was quenched with aqueous
NaHCO.sub.3 solution and extracted with methylene chloride. The
organic extracts were dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Column chromatography on silica eluting
with a mixture of ethyl acetate and methylene chloride gave the
title compound as a off-white solid (230 mg). .sup.1H NMR
(CDCl.sub.3) .delta. 1.90-1.58 (m, 4H), 2.78-2.57 (m, 2H),
3.28-3.10 (m, 1H), 3.75 (s, 3H), 3.74-3.45 (m, 8H), 5.40-5.12 (m,
1H), 7.35-7.18 (m, 5H);
[0189] MS: 338(M.sup.+).
(R)-2-(1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (6b)
[0190] Sodium hydride (60% in mineral oil, 114 mg, 2.86 mmol) was
added to a solution of
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (800 mg, 2.38 mmol) in dry dimethylformamide
followed by addition of methyl iodide (0.74 ml, 11.9 mmol) and the
reaction mixture was stirred for two hours at rt. The reaction was
diluted with water and extracted with Ethyl acetate. The organic
extracts were washed with water and brine, dried over MgSO4 and
concentrated under reduced pressure to give the title compound as a
colorless oil solid (660 mg).
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid (24)
[0191] It is similarly prepared according to the procedure of (22),
but using
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (6a).
[0192] .sup.1H NMR (CDCl.sub.3) .delta. 1.88-1.62 (m, 4H),
2.78-2.64 (m, 2H), 3.30-3.15 (m, 1H), 3.80-3.50 (m, 8H), 5.40-5.16
(m, 1H), 7.36-7.18 (m, 5H), 8.78-8.50 (b, 1H);
[0193] MS: 324 (M.sup.+).
(R)-2-(1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid (25)
[0194] It is similarly prepared according to the procedure of (22),
but using
(R)-2-(1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid methyl ester (6b).
[0195] .sup.1H NMR (CDCl.sub.3) .delta. 1.90-1.58 (m, 4H),
2.74-2.60 (m, 2H), 2.98-2.84 (m, 1H), 3.36 (s, 3H), 3.78-3.40 (m,
8H), 4.32 (m, 1H), 7.38-7.16 (m, 5H), 9.94-9.56 (b, 1H); MS: 336
(M.sup.+).
REFERENCE 26
2-Amino-1-oxazol-2-yl-butan-1-ol
[0196] ##STR44##
[0197] 2-Amino-1-oxazol-2-yl-butan-1-ol was prepared according to
the following reaction scheme: ##STR45##
Step 1
[0198] Triethylborane (1.0 M in THF, 149.5 ml, 149.5 mmol) was
added to oxazole (10.33 g, 149.5 mmol) and stirred for 45 minutes
at room temperature. The mixture was then cooled to -78.degree. C.
and n-BuLi (2.5 M in hexane, 59.8 ml, 149.5 mmol) was added
dropwise and allowed to stir for one hour under nitrogen. Compound
(1) (8.0 g, 42.7 mmol) was dissolved in 25 ml of THF and added to
the reaction mixture. The reaction was stirred for 5 hours at
-78.degree. C. then it was allowed to warm to 0.degree. C. for one
hour. The reaction was then cooled back to -78.degree. C. and
quenched with 7% acetic acid in ethanol (700 ml) which was allowed
to stir overnight at room temperature. The mixture was concentrated
in vacuum and the residue was dissolved in ether and filtered. The
filtrate was concentrated in vacuum and the residue was dissolved
in ethyl acetate washed twice with 0.005 N HCl, twice with
saturated sodium bicarbonate and brine. The organic layer was dried
over magnesium sulfate, filtered and concentrated in vacuum. The
residue was purified on silica using 10-40% ethyl acetate/heptane
to give [(S)-1-(Hydroxy-oxazol-2-yl-methyl)-propyl]-carbamic acid
tert-butyl ester ((2), 3.85 g).
Step 2
[0199] To a solution of
[(S)-1-(Hydroxy-oxazol-2-yl-methyl)-propyl]-carbamic acid
tert-butyl ester (2) (1.1 g, 4.29 mmol) in dry methylene chloride
(10.0 mL), stirring under nitrogen at room temperature, was added
4M HCl (in dioxane, 10.73 ml) dropwise followed by 5 ml of
methanol. The reaction was stirred overnight then concentrated in
vacuo to give (S)-2-Amino-1-oxazol-2-yl-butan-1-ol (1.2 g) as a
brown solid.
REFERENCE 27
(S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol
[0200] ##STR46##
[0201] It is similarly prepared according to the procedure for
Reference Example 26 LCMS RT=1.1 min., 231 (M+1).
REFERENCE 28
(S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride
[0202] ##STR47##
[0203] It is similarly prepare daccording to the general procedurre
for Reference Example 21 but using
[(S)-1-(Hydroxy-oxazol-2-yl-methyl)-propyl]-carbamic acid
tert-butyl ester.
EXAMPLE 1
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-p-
henyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide
[0204] ##STR48##
[0205] A suspension of PS-bound N-cyclohexylcarbodiimide (HL
200-400 mesh cross linked with 2% DVB) from Novabiochem (436 mg,
0.841 mmol, 1.93 mmol/g loading) in methylene chloride (6 mL) was
treated with
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid (154 mg, 0.480 mmol) in methylene chloride (3 mL) and stirred
at room temperature for 10 minutes. A solution of
(S)-2-Amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol (96 mg,
0.412 mmol) in methylene chloride (3 mL) was added and the reaction
mixture was stirred at room temperature for 3 h. The mixture was
filtered and the filtrate was evaporated under reduced pressure.
Crude purified by flash chromatography eluting with a mixture of
ethyl acetate and heptane to give
N-{(S)-1-[Hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-2--
(2-methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide
as an off white solid (41 mg) (mixture of diastereoisomers).
[0206] MS: 537 (MH.sup.+)
[0207] A solution of
N-{(S)-1-[Hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-2-(2-me-
thyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyramide
(41 mg, 0.076 mmol) in methylene chloride (6 mL) was treated with
Dess-Martin periodinane (39 mg, 0.092 mmol) and stirred at room
temperature for 90 minutes. The reaction mixture was washed with a
solution of Na.sub.2S.sub.2O.sub.3 in water (0.26M), saturated
aqueous bicarbonate solution and water, dried over Na.sub.2SO.sub.4
and the solvent evaporated under reduced pressure. The residue was
purified by flash chromatography eluting with a mixture of ethyl
acetate and heptane to give
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)--
1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide as an
off white solid (18 mg) (mixture of diastereoisomers).
[0208] MS: 535 (MH.sup.+).
[0209] .sup.1H NMR (CDCl.sub.3): 8.21 (d, J=7 Hz, 2H), 7.80, 7.64
(d, J=7 Hz, 1H), 7.56 (t, J=7 Hz, 3H), 5.32 (m, 1H), 3.79-3.51 (m,
8H), 3.51-3.36 (m, 2H), 3.08 (2xdd, J=14 Hz & 6 Hz, 1H),
2.97-2.91 (m, 2H), 2.97-2.70 (m, 2H), 2.38 (m, 1H), 2.08 (m, 1H),
1.88 (m, 1H), 1.26 (m, 1H), 1.15-1.09 (2xd, J=7 Hz, 6H), 1.03 (2xt,
J=7.5 Hz, 3H).
EXAMPLE 2
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl--
1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide
[0210] ##STR49##
[0211] A solution of
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (223 mg,
0.788 mmol) in dimethylformamide (10 ml) was treated successively
with
(S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol;
compound with trifluoroacetic acid (267 mg, 0.788 mmol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (299 mg, 0.787 mmol) and diisopropylethylamine
(0.274 ml, 1.576 mmol). Reaction stirred at room temperature
overnight. Solvent evaporated under reduced pressure. Residue taken
up in ethyl acetate and washed with 1N hydrochloric acid, saturated
aqueous bicarbonate solution and water, dried over Na.sub.2SO.sub.4
and solvent evaporated under reduced pressure to give
(R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiaz-
ol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide as a
yellow solid (324 mg).
[0212] MS: 491 (MH.sup.+)
[0213] A solution of
(R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiaz-
ol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide (324 mg,
0.661 mmol) in methylene chloride (10 ml) was treated with Dess
Martin periodinane (308 mg, 0.726 mmol) and stirred at room
temperature for 90 minutes. The reaction mixture was washed with an
aqueous solution of Na.sub.2S.sub.2O.sub.3 (0.26M), saturated
aqueous bicarbonate solution and water, dried over Na.sub.2SO.sub.4
and the solvent evaporated under reduced pressure. The crude was
purified by flash chromatography eluting with a mixture of ethyl
acetate and heptane to give
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl-
-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide as an off white
solid (10 mg).
[0214] .sup.1H NMR (CDCl.sub.3): 6.68 (d, J=6 Hz, 1H), 5.19 (m,
1H), 3.73-3.60 (m, 4H), 3.60-3.52 (m, 2H), 3.52-3.40 (m, 2H), 2.97
(m, 1H), 2.71 (dd, J=16 Hz & 10 Hz, 1H), 2.26 (dd, J=16 Hz
& 3 Hz, 1H), 2.14-1.96 (m, 1H), 1.88-1.44 (m, 7H), 1.32-1.07
(m, 5H), 1.02 (t, J=7 Hz, 3H), 0.95-0.76 (m, 2H).
[0215] MS: 489 (MH.sup.+)
EXAMPLE 3
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0216] ##STR50##
[0217] It is similarly prepared according to general procedure
given for Example 2 above but using
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
and
(S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol;
compound with trifluoroacetic acid,
[0218] .sup.1H NMR (CDCl.sub.3): 6.79 (d, J=5 Hz, 1H), 5.16 (m,
1H), 3.86-3.51 (m, 6H), 3.51-3.28 (m, 2H), 2.96 (m, 1H), 2.72 (dd,
J=16 Hz & 10 Hz, 1H), 2.28 (dd, J=16 HZ & 3 Hz, 1H),
2.15-1.96 (m, 1H), 1.96-1.72 (m, 2H), 1.14 (m, 1H), 1.00 (t, J=7
Hz, 3H), 0.88 (s, 9H).
[0219] MS: 463 (MH.sup.+).
EXAMPLE 4
4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(5-trifluoro-
methyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide
[0220] ##STR51##
[0221] It is similarly prepared according to general procedure
given for Example 2 above but using
4-Morpholin-4-yl4-oxo-2-phenylmethanesulfonylmethyl-butyric acid
and
(S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol;
compound with trifluoroacetic acid.
[0222] .sup.1H NMR (CDCl.sub.3): 7.82, 7.61 (d, J=6 Hz, 1H), 7.40
(m, 5H), 5.08 (m, 1H), 4.28 (m, 2H), 3.78-3.47 (m, 7H), 3.47-3.30
(m, 3H), 2.91 (dd, J=14 Hz & 7 Hz, 1H), 2.82-2.56 (m, 2H),
2.14-1.96 (m, 1H), 1.94-1.76 (m, 1H), 1.02 (t, J=7.5 Hz, 3H).
[0223] MS: 561 (MH.sup.+).
EXAMPLE 5
(R)-2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1--
(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide
[0224] ##STR52##
[0225] It is similarly prepared according to general procedure
given for Example 2 above but using
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid and
(S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
[0226] .sup.1H NMR (CDCl.sub.3) .delta. 8.12 (d, 2 H), 7.66 (d, 1
H), 7.54-7.46 (m, 3 H), 5.27 (m, 1 H), 3.67-3.57(m, 7H), 3.51-3.4
(m, 3 H), 3.08 (dd, 1 H), 2.92-2.79 (m, 4H), 2.36 (m, 1 H), 2.11
(m, 1 H), 1.90 (m, 1 H), 1.10 (d, 6 H), 1.05 (t, 3 H).
[0227] MS: m/z 535 (M.sup.++H)
EXAMPLE 6
N-[(S)-1-(5-Ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-4-morpholin-4-yl-4--
oxo-2-phenylmethanesulfonylmethyl-butyramide
[0228] ##STR53##
[0229] It is similarly prepared according to general procedure
given for Example 2 above but using
4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid
and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol.
[0230] 1H NMR (CDCl.sub.3): .delta. 0.98 (t, 3H), 1.43 (t, 3H),
1.80 (m, 1H), 2.03 (m, 1H), 2.74 (m, 2H), 2.95 (m, 1H), 2.98 (q,
2H), 3.4-3.71 (m, 10H), 4.25 (dd, 1H), 4.30 (dd, 1H), 5.22 (m, 1H),
7.39 (m, 5H), 7.66 (d, 1H).
[0231] LC/MS (2.82 min) m/z=521 (M+H).
EXAMPLE 7
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[(S)-1-(3-pheny-
l-1,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide
[0232] ##STR54##
[0233] It is similarly prepared according to general procedure
given for Example 2 above but using
4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyric acid
and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
[0234] 1H NMR (CDCl.sub.3): .delta. 1.03 (t, 3H), 1.91 (m, 1H),
2.13 (m, 1H), 2.72 (dd, 1H), 2.79 (dd, 1H), 2.95 (dd, 1H), 3.40 (m,
3H), 3.65 (m, 7H), 4.27 (d, 1H), 4.30 (d, 1H), 5.29 (m, 1H), 7.40
(m, 3H), 7.54 (m, 5H), 8.14 (m, 2H).
[0235] MS m/z=569 (M+H).
EXAMPLE 8
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0236] ##STR55##
[0237] A solution of
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
(200 mg, 0.778 mmol) in dimethylformamide (10 ml) was treated
successively with
(S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound
with trifluoro-acetic acid (233 mg, 0.779 mmol),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (296 mg, 0.779 mmol) and diisopropylethylamine
(0.271 ml, 1.559 mmol). Reaction stirred at room temperature
overnight. Solvent evaporated under reduced pressure. Residue taken
up in ethyl acetate and washed with 1N hydrochloric acid, saturated
aqueous bicarbonate solution and water, dried over Na.sub.2SO.sub.4
and solvent evaporated under reduced pressure to give
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
{(S)-1-[(5-ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-amide
as a yellow solid (277 mg).
[0238] MS: 425 (MH.sup.+)
[0239] A solution of
(R)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
{(S)-1-[(5-ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-amide
(277 mg, 0.653 mmol) in methylene chloride (6 ml) was treated with
Dess-Martin periodinane (332 mg, 0.783 mmol) and stirred at room
temperature for 90 minutes. The reaction mixture was washed with a
solution of Na.sub.2S.sub.2O.sub.3 in water (0.26M), saturated
aqueous bicarbonate solution and water, dried over Na.sub.2SO.sub.4
and solvent evaporated under reduced pressure. The residue was
purified by flash chromatography eluting with a mixture of ethyl
acetate and heptane to give
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide as a yellow
solid (44 mg) (mixture of diastereoisomers).
[0240] .sup.1H NMR (CDCl.sub.3): 6.60 (d, J=7 Hz, 1H), 5.24 (m,
1H), 3.66-3.54 (m, 4H), 3.54-3.46 (m, 2H), 3.44-3.28 (m, 2H), 2.91
(q, J=8 Hz, 2H), 2.93-2.83 (m, 1H), 2.68 (dd, J=16 Hz & 10 Hz,
1H), 2.20 (dd, J=16 Hz & 4 Hz, 1H), 1.96 (m, 1H), 1.82 (m, 1H),
1.70 (m, 1H), 1.37 (t, J=7 Hz, 3H), 1.09 (m, 1H), 0.88 (t, J=7 Hz,
3H), 0.82 (s, 9H).
[0241] MS: 423 (MH.sup.+).
EXAMPLE 9
(R)-2-Cyclohexylmethyl-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-prop-
yl]-4-morpholin-4-yl-4-oxo-butyramide
[0242] ##STR56##
[0243] It is similarly prepared according to general procedure
given for example 8 above but using
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid and
(S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound
with trifluoro-acetic acid.
[0244] .sup.1H NMR (CDCl.sub.3): 6.53 (d, J=7 Hz, 1H), 5.35 (m,
1H), 3.70-3.61 (m, 4H), 3.61-3.53 (m, 2H), 3.50-3.40 (m, 2H),
3.01-2.92 (m, 1H), 2.99 (q, J=8 Hz, 2H), 2.74 (dd, J=16 Hz & 10
Hz, 1H), 2.25 (dd, J=16 Hz & 3.5 Hz, 1H), 2.05 (m, 1H),
1.85-1.69 (m, 1H), 1.70-1.48 (m, 6H), 1.44 (t, J=7.5 Hz, 3H),
1.32-1.04 (m, 5H), 0.97 (t, J=7.5 Hz, 3H), 0.96-0.78 (m, 2H).
[0245] MS: 449 (MH.sup.+).
EXAMPLE 10
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4--
morpholin-4-yl-4-oxo-butyramide
[0246] ##STR57##
[0247] To a solution of
2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid
(53 mg, 0.16 mmol) in dry DCM (4.5 mL) under N.sub.2 was added
PS-bound N-cyclohexylcarbodiimide (HL 200-400 mesh cross-linked
with 2% DVB) from Novabiochem (188 mg, 0.0.32 mmol, 1.93 mmol/g
loading) followed by Hydroxybenzotriazole (36.7 mg, 0.27 mmol).
After stirring at room temperature for 15 min,
(S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol (35.2 mg,0.16 mmol) was
added and the reaction mixture was stirred over night at room
temperature. Silacycle trisamine (222 mg, 0.8 mmol, 3.6 mmol/g
loading) was then added and the mixture was stirred for 2 hrs.
Solid filtered off and the filtrate evaporated under reduced
pressure to give yellow solid (80 mg). The crude was purified by
silica gel column chromatography eluting with a mixture of ethyl
acetate and heptane to give
N-[(S)-1-(Benzoxazol-2-yl-hydroxy-methyl)-butyl]-2-(1-benzyl-cyclopr-
opylmethyl)-4-morpholin-4-yl-4-oxo-butyramide (55 mg).
[0248] To a solution of
N-[(S)-1-(Benzoxazol-2-yl-hydroxy-methyl)-butyl]-2-(1-benzyl-cyclopropylm-
ethyl)-4-morpholin-4-yl-4-oxo-butyramide (55 mg, 0.103 mmol) in dry
dichloromethane under N.sub.2 was added a solution of Dess-Martin
Periodinane solution in dichloromethane (15% wt in DCM, 0.206 mmol)
and stirred at room temperature for lhr. The mixture was quenched
with a solution Na.sub.2SO.sub.3 (65.4 mg) in saturated NaHCO.sub.3
(20 mL). The aqueous layer was extracted with dichloromethane
(2.times.25 mL). Organic extracts dried (MgSO.sub.4) and
concentrated under reduced pressure. Residue purified by silica gel
column chromatography eluting with a mixture of ethyl acetate and
heptane (1:1 then 2:1) to give
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-
-morpholin-4-yl-4-oxo-butyramide as white solid (43 mg).
[0249] .sup.1H NMR (CDCl.sub.3): 7.92 (d, J=8 Hz, 1H), 7.67 (d, J=8
Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.42-7.14
(m, 5H), 6.78, 6.64 (d, J=7 Hz, 1H), 5.63 (m, 1H), 3.84-3.53 (m,
6H), 3.53-3.32 (m, 2H), 3.18 (m, 1H), 2.88-2.58 (m, 2H), 2.50 (d,
J=14.5 Hz, 1H), 2.30 (m, 1H), 2.08 (m, 1H), 1.82 (m, 1H), 1.58-1.36
(m, 4H), 0.98 (t, J=7 Hz, 3H), 0.58-0.26 (m, 4H).
[0250] MS: 532 (MH.sup.+).
EXAMPLE 11
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-pheny-
l-cyclopropylmethyl)-butyramide
[0251] ##STR58##
[0252] It is similarly prepared according to general procedure
given for example 10 above but using
4-Morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyric acid
and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
[0253] LC/MS: RT=3.39 min, MH.sup.+=518.
EXAMPLE 12
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide
[0254] ##STR59##
[0255] It is similarly prepared according to general procedure
given for example 10 above but using
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
[0256] .sup.1H NMR (CDCl.sub.3): 7.91 (d, J=8 Hz, 1H), 7.66 (d, J=8
Hz, 1H), 7.55 (dt, J=8 Hz & 1.2 Hz, 1H), 7.47 (dt, J=8 Hz &
1.2 Hz, 1H), 6.79 (d, J=7 Hz, 1H), 5.61 (m, 1H), 3.75-3.58 (m, 6H),
3.56-3.42 (m, 2H), 3.01 (m, 1H), 2.78 (dd, J=16 Hz & 10 Hz,
1H), 2.30 (dd, J=16 Hz & 4 Hz, 1H), 2.11-2.01 (m, 1H),
1.99-1.74 (m, 2H), 1.54-1.41 (m, 2H), 1.18 (dd, J=14 Hz & 3 Hz,
1H), 0.97 (t, J=7 Hz, 3H), 0.90 (s, 9H).
[0257] MS: 458 (MH.sup.+).
EXAMPLE 13
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide
[0258] ##STR60##
[0259] It is similarly prepared according to general procedure
given for example 10 above but using
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid and
(S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
[0260] .sup.1H NMR (CDCl.sub.3): 8.15 (dd, J=8 Hz & 1.6 Hz,
2H), 7.57-7.52 (m, 3H), 6.86 (d, J=6 Hz, 1H), 5.36 (dd, J=12 Hz
& 7 Hz, 1H), 3.76-3.54 (m, 6H), 3.54-3.34 (m, 2H), 3.07-2.93
(m, 1H), 2.78 (dd, J=16 Hz & 10 Hz, 1H), 2.32 (dd, J=16 Hz
& 3 Hz, 1H), 2.15 (m, 1H), 2.00-1.80 (m, 2H), 1.19 (dd, J=14 Hz
& 3 Hz, 1H), 1.05 (t, J=7.5 Hz, 3H), 0.91 (s, 9H).
[0261] MS: 471 (MH.sup.+).
EXAMPLE 14
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide
[0262] ##STR61##
[0263] It is similarly prepared (as mixture of diastereoisomers)
according to general procedure given for example 10 above but using
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid and 2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol
[0264] .sup.1H NMR (CDCl.sub.3): 8.15 (dd, J=8 Hz & 1.6 Hz,
2H), 7.61-7.44 (m, 3H), 7.32-7.16 (m, 3H), 7.09 (d, J=6.6 Hz, 2H),
6.93 (d, J=6.5 Hz, 1H), 5.35 (dd, J=12 Hz & 7 Hz, 1H),
3.76-3.54 (m, 6H), 3.52-3.34 (m, 2H), 3.11 (m, 1H), 2.76 (dd, J=16
Hz & 10 Hz, 1H), 2.53 (s, 2H), 2.29 (dd, J=16 Hz & 3 Hz,
1H), 2.07 (m, 1H), 2.01 (m, 1H), 1.90 (m, 1H), 1.22 (dd, J=14 Hz
& 3Hz, 1H), 1.05 (t, J=7 Hz, 3H), 0.88 (s, 6H)
[0265] MS: 547 (MH.sup.+).
EXAMPLE 15
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide
[0266] ##STR62##
[0267] It is similarly prepared according to general procedure
given for example 10 above but using
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid and (S)-2-Amino-1-benzoxazol-2-yl-pentan-1-ol.
[0268] .sup.1H NMR (CDCl.sub.3): 7.91 (d, J=7.6 Hz, 1H), 7.66 (d,
J=8.1 Hz, 1H), 7.55 (dt, J=7 Hz & 1 Hz, 1H), 7.47 (dt, J=8 Hz
& 1 Hz, 1H), 7.30-7.15 (m, 3H), 7.09 (d, J=8 Hz, 2H), 6.86 (d,
J=7 Hz, 1H), 5.62 (m, 1H), 3.75-3.55 (m, 6H), 3.54-3.38 (m, 2H),
3.12 (m, 1H), 2.77 (dd, J=16 Hz, & 10 Hz, 1H), 2.52 (s, 2H),
2.27 (dd, J=16 Hz & 4 Hz, 1H), 2.13-1.94 (m, 2H), 1.81 (m, 1H),
1.47 (m, 2H), 1.21 (dd, J=14 Hz & 3 Hz, 1H), 0.98 (t, J=7 Hz,
3H), 0.88 (s, 6H).
[0269] MS: 534 (MH.sup.+), 0.88(2xS, 6H).
EXAMPLE 18
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0270] ##STR63##
[0271] It is similarly prepared according to the general procedure
for Example 10.
[0272] .sup.HNMR (CDCl.sub.3), (ppm): 7.20-7.29(m, 3H),
7.10-7.19(d, 2H), 6.78-6.80(d, H), 5.31-5.35(m, H), 3.61-3.68 (m,
6H), 3.44-3.48(m, 2H), 3.06-3.21(m, H), 2.96-3.03(q, 2H),
2.73-2.82(dd, H), 2.53(s, 2H), 2.24-2.31(dd, H), 1.98-2.18(m, 2H),
1.78-1.85(m, H), 1.43-1.48(t, 3H), 1.19-1.24(dd, H), 0.96-1.01(t,
3H), 0.89(s, 3H), 0.88(s, 3H).
[0273] MS: 499 (MH.sup.+).
EXAMPLE 19
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid
[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0274] ##STR64##
[0275] It is similarly prepared according to the general procedure
for Example 10.
[0276] .sup.HNMR (CDCl.sub.3), (ppm): 7.19-7.30(m, 3H),
7.10-7.13(d, 2H), 6.89-6.91(d, H), 5.15-5.32(m, H), 3.60-3.73 (m,
6H), 3.44-3.46(m, 2H), 3.05-3.14(m, H), 2.70-2.78(dd, H), 2.53(s,
2H), 2.25-2.32(dd, H), 1.98-2.15(m, H), 1.78-1.90(m, H),
1.27-1.32(m, H), 1.17-1.22(dd, H), 1.01-1.06(t, 3H), 0.89(s, 3H),
0.87(s, 3H).
[0277] MS: 539 (MH.sup.+).
EXAMPLE 20
(R)-2-(1-Benzyl-cyclopropylmethyl)-N-[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-ca-
rbonyl)-propyl]-4-morpholin-4-yl-4-oxo-butyramide
[0278] ##STR65##
[0279] It is similarly prepared according to general procedure
given for example 10 above but using
(R)-2-(1-Benzyl-cyclopropylmethyl)-4-morpholin-4-yl-4-oxo-butyric
acid and (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol;
compound with trifluoro-acetic acid.
[0280] .sup.HNMR (CDCl3), (ppm): 7.19-7.36(m, 5H), 6.39-6.55(d, H),
5.30-5.44(m, 1H), 3.52-3.67 (m, 6H), 3.37-3.52(m, 2H), 3.06-3.17(m,
1H), 2.98-3.06(q, 2H), 2.66-2.83(dd, 1H), 2.55-2.85(dd, 2H),
2.25-2.32(dd, H), 2.03-2.15(m, 1H), 1.74-1.84(m, 1H), 1.44-1.49(t,
3H), 1.25-1.59(m, 2H), 0.96-1.01(t, 3H), 0.30-0.56(m, 4H).
[0281] MS: 497 (MH.sup.+).
EXAMPLE 21
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-et-
hyl)-pentanoic acid
[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0282] ##STR66##
[0283] It is similarly prepared according to general procedure for
Example 10 above.
[0284] .sup.HNMR (CDCl.sub.3), (ppm): 7.05-7.28(m, 4H),
6.85-6.87(d, 1H), 6.26-6.76(t, H), 5.27-5.34(m, 1H), 3.55-3.68 (m,
6H), 3.41-3.52(m, 2H), 3.08-3.15(m, 1H), 2.96-3.08(q, 2H),
2.72-2.80(dd, H), 2.52-2.69(dd, 2H), 2.29-2.35(dd, 1H),
1.99-2.19(m, 2H), 1.71-1.86(m, 1H), 1.42-1.47(t, 3H), 1.22-1.30(m,
1H), 0.96-1.04(t, 3H), 0.89(s, 3H), 0.86(s, 3H).
[0285] MS: 565 (MH.sup.+).
EXAMPLE 22
(S)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(5-methyl-thiophen-2-ylmeth-
yl)-4-morpholin-4-yl-4-oxo-butyramide
[0286] ##STR67##
[0287] It is similarly prepared according to general procedure for
Example 10 above.
[0288] .sup.HNMR (CDCl.sub.3), (ppm): 7.90-7.92(d, 1H),
7.66-7.69(d, 1H), 7.46-7.58(m, 2H), 6.90-6.92(d, 1H), 6.53-6.54(d,
1H), 6.35-6.36(d, 1H), 5.52-5.59(m, 1H), 3.60-3.68 (m, 6H),
3.38-3.60(m, 2H), 3.07-3.20(m, 2H), 2.77-2.91(m, 2H), 2.39-2.46(dd,
H), 2.28(s, 3H), 1.94-2.04(m, 1H), 1.73-1.86(m, 1H), 1.39-1.67(m,
2H), 0.93-0.98(t, 3H).
[0289] MS: 498 (MH.sup.+).
EXAMPLE 23
(R)-N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl-
)-4-morpholin-4-yl-4-oxo-butyramide
[0290] ##STR68##
[0291] It is similarly prepared according to general procedure for
Example 10 above.
[0292] .sup.1H NMR (CDCl.sub.3): 7.92 (d, J=8 Hz, 1H), 7.67 (d, J=8
Hz, 1H), 7.56 (dt, J=7 Hz & 1 Hz, 1H), 7.47 (dt, J=7 Hz & 1
Hz, 1H), 7.37-7.15 (m, 5H), 6.61 (d, J=7 Hz, 1 H), 5.64 (m, 1H),
3.76-3.63 (m, 4H), 3.63-3.56 (m, 2H), 3.52-3.36 (m, 2H), 3.14 (m
1H), 2.80-2.67 (m, 2H), 2.51 (d, J=15 Hz, 1H), 2.28 (dd, J=16 Hz
& 3.5 Hz, 1H), 2.14-1.98 (m, 1H), 1.90-1.75 (m, 1H), 1.60-1.37
(m, 4H), 0.98 (t, J=7 Hz, 3H), 0.62-0.27 (m, 4H).
[0293] MS: 532 (MH.sup.+).
EXAMPLE 24
(R)-5-(2-Difluoromethoxy-phenyl)-4,4-dimethyl-2-(2-morpholin-4-yl-2-oxo-et-
hyl)-pentanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide
[0294] ##STR69##
[0295] It is similarly prepared according to general procedure for
Example 10 above.
[0296] .sup.HNMR (CDCl.sub.3), (ppm): 7.89-7.91(d, H), 7.64-7.67(d,
H),7.43-7.64(m, 2H),7.04-7.23(m 4H), 6.86-6.88(d, H), 6.256-6.74(t,
H), 5.58-5.65(m, H), 3.57-3.68 (m, 6H), 3.46-3.57(m, 2H),
3.11-3.17(m, H), 2.73-2.82 (dd, H), 2.52-2.68(dd, 2H),
2.29-2.36(dd, H), 1.99-2.11(m, 2H), 1.76-1.86(m, H), 1.42-1.54(m,
2H), 0.95-1.00(t, 3H), 0.89(s, 3H), 0.86(s, 3H). 1.34-1.10 (dd,
1H).
[0297] MS: 600 (MH.sup.+).
EXAMPLE 25
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of
diastereoisomers)
[0298] ##STR70##
[0299] It is similarly prepared according to general procedure for
Example 10 above but using
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and
(S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol.
[0300] .sup.1H NMR (CDCl.sub.3): 7.80 (d, J=4.5 Hz, 1H), 7.34 (d,
J=6 Hz, 1H), 7.30-7.25 (m, 1H), 7.25-7.20 (m, 3H), 7.20-7.12 (m,
5H), 7.12-7.06 (m, 1H), 6.92, 6.69 (d, J=8 Hz, 1H), 5.54 (m, 1H),
3.73-3.60 (m, 4H), 3.60-3.52 (m, 2H), 3.48-3.38 (m, 2H), 3.00-2.80
(m, 1H), 2.80-2.32 (m, 5H), 2.43-2.22 (m, 2H), 2.05 (m, 1H),
1.87-1.53 (m, 3H), 1.53-1.37 (m, 1H).
[0301] MS: 518 (MH.sup.+).
EXAMPLE 26
4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-(2-phe-
nyl-cyclopropylmethyl)-butyramide (mixture of diastereoisomers)
[0302] ##STR71##
[0303] It is similarly prepared according to general procedure
given for example X above but using
4-Morpholin-4-yl-4-oxo-2-(2-phenyl-cyclopropylmethyl)-butyric acid
and (S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol.
[0304] .sup.1H NMR (CDCl.sub.3): 7.80 (t, J=2 Hz, 1H), 7.34 (d, J=6
Hz, 1H), 7.25-7.17 (m, 4H), 7.15-7.08 (m, 2H), 7.08-6.97 (m, 3H),
6.96-6.83 (m, 1H), 6.77, 6.52 (d, J=7 Hz, 1H), 5.47 (m, 1H),
3.73-3.60 (m, 4H), 3.60-3.53 (m, 2H), 3.53-3.32 (m, 2H), 3.04 (m,
1H), 2.89-2.51 (m, 3H), 2.46-2.14 (m, 2H), 2.12-1.77 (m, 2H),
1.75-1.56 (m, 2H), 1.54-1.33 (m, 1H), 1.01-0.73 (m, 2H).
[0305] MS: 530 (MH.sup.+).
EXAMPLE 27
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbonyl)-3-ph-
enyl-propyl]-4-oxo-butyramide
[0306] ##STR72##
[0307] It is similarly prepared according to the general procedure
for example 10 but using
(S)-2-Amino-1-oxazol-2-yl-4-phenyl-butan-1-ol and
2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid.
[0308] .sup.1H NMR: (CDCl.sub.3) 7.80 (s, 1H), 7.40(s, 1H),
7.30-7.05 (m, 5H), 6.70 (d, 1H), 5.65-5.50 (m, 1H), 3.75-3.3(m,
8H), 3.10-2.90(m, 1H), 2.90-2.60(m, 3H), 2.45-2.20(m, 2H),
2.10-1.90 (m, 1H), 1.90-1.45(m, 6H), 1.35-1.00(m, 5H), 1.00-0.75(m,
2H)
[0309] LCMS:RT=3.25 min. M+1=496.4.
EXAMPLE 28
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl-amide
[0310] ##STR73##
[0311] It is similarly prepared according to the general procedure
for example 10.
[0312] .sup.1HNMR: (CDCl.sub.3) 8.10 (d, 2H), 7.50-7.70 (m, 3H),
6.73 (d, 1H) 5.40 (m, 1H), 3.58-3.70 (m, 6H), 3.45 (m, 2H), 2.96
(m, 1H), 2.75 (dd, 1H), 2.30 (dd, 1H), 2.10 (m, 1H), 1.75-1.95(m,
2H), 1.18 (dd, 1H), 0.98(t, 3H), 0.90(s, 9H).
[0313] LCMS: RT=3.20 min. M+1=471.2.
EXAMPLE 29
3-Phenylmethanesulfonyl-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-pr-
opyl]-2-(tetrahydro-pyran-4-yloxymethyl)-propionamide
[0314] ##STR74##
[0315] It is similarly prepared according to general procedure
given for Example 1 above but using
2-Phenylmethanesulfonylmethyl-3-(tetrahydro-pyran-4-yloxy)-propionic
acid and
(S)-2-amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol.
[0316] .sup.1H NMR (CDCl.sub.3): 8.20 (d, J=7 Hz, 2H), 7.64 (m,
1H), 7.55 (t, J=7 Hz, 2H), 7.47-7.33 (m, 6H), 5.49 (m, 1H), 4.28
(m, 2H), 3.98-3.85 (m, 2H), 3.81-3.65 (m, 2H), 3.64-3.50 (m, 2H),
3.49-3.37 (m, 2H), 3.19 (m, 1H), 2.92 (2xdd, J=14 Hz & 6.5 Hz,
1H), 2.24-2.04 (m, 1H), 2.00-1.77 (m, 3H), 1.72-1.51 (m, 2H), 0.98
(2xt, J=10 Hz & 7.5 Hz, 3H).
[0317] MS: 556 (MH.sup.+).
EXAMPLE 30
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(5-ethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0318] ##STR75##
[0319] It is similarly prepared according to the general procedure
for example 10.
[0320] LCMS: RT=3.35 min. M+1=465.
EXAMPLE 31
N-[(S)-1-(Benzoxazole-2-carbonyl)-2,2-dimethyl-propyl]-4-morpholin-4-yl-4--
oxo-2-phenylmethanesulfonylmethyl-butyramide
[0321] ##STR76##
[0322] It is similarly prepared according to the procedure for
Example 34.
[0323] LCMS: RT=3.2 min. M+1=570.
EXAMPLE 32
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(oxazole-2-carbonyl)-propyl]-amide
[0324] ##STR77##
[0325] It is similarly prepared according to the general procedure
for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one;
hydrochloride as the amino component and
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
as the acidic component but without further oxidation step.
[0326] LCMS: RT=8.13 min. M+1=436. M+Na=458.
EXAMPLE 33
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide
[0327] ##STR78##
[0328] It is similarly prepared according to general procedure
given for example 10.
[0329] LCMS: RT=3.65 min. M+1=500
EXAMPLE 34
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(benzoxazole-2-carbonyl)-propyl]-amide
[0330] ##STR79##
[0331] PyBOP (86 mg, 0.16 mmol), DIPEA (0.065 ml, 0.37 mmol) and
2-Amino-1-benzoxazol-2-yl-butan-1-(36 mg, 0.15 mmol) were added to
a solution of
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid (7a) (50 mg, 0.15 mmol) in dry methylene chloride (4 ml) and
the reaction mixture was stirred overnight at room temperature. The
reaction was quenched with water, the solvent remove under reduced
pressure, the aqueous was extracted with ethyl acetate, and the
organic extracts were dried over MgSO4 and evaporated under reduced
pressure. Column chromatography on silica eluting with a mixture of
ethyl acetate and heptane gave
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(benzoxazol-2-yl-hydroxy-methyl)-propyl]-amide as a white
solid (38 mg).
[0332] Dess-Martin Periodinane (15 wt % in DCM, 0.15mmol, 424 mg)
was added to a solution of
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(benzoxazol-2-yl-hydroxy-methyl)-propyl]-amide (0.074 mmol)
in dry methylene chloride and stirred for three hours. The reaction
was quenched with Na.sub.2S.sub.2O.sub.3 (0.37 mmol, 56 mg) in
aqueous NaHCO.sub.3, the organic layer was separated, the aqueous
extracted once more with methylene chloride, the organic extracts
were dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Column chromatography on silica eluting with a mixture of
ethyl acetate and methylene chloride gave the title compound as a
white solide (30 mg).
[0333] .sup.1H NMR (CDCl.sub.3) .delta. 1.02 (t, 3H), 2.26-1.40 (m,
2+2+2H), 2.78-2.58 (m, 2H), 3.24-3.02 (m, 1H), 3.75-3.48 (m, 8H),
5.38-5.08 (m, 1H), 5.78-5.52 (m, 1H), 6.88-6.56 (m, 1H), 7.36-7.15
(m, 5H), 7.60-7.42 (m, 2H), 7.70 (m, 1H), 7.94 (m, 1H);
[0334] MS 510 (M.sup.+). 532 (M+23).
EXAMPLE 35
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide
[0335] ##STR80##
[0336] It is similarly prepared according to the procedure for
Example 34.
[0337] .sup.1H NMR (CDCl.sub.3) .delta. 0.98 (t, 3H), 2.18-1.40 (m,
2+2+2+2H), 2.74-2.58 (m, 2H), 3.96-2.98 (m, 1H), 3.78-3.46 (m, 8H),
5.36-5.16 (m, 1H), 5.80-5.58 (m, 1H), 6.72-6.48 (m, 1H), 7.36-7.14
(m, 5H), 7.60-7.48 (m, 2H), 7.65 (m, 1H), 7.92 (m, 1H);
[0338] LCMS: RT=3.5 & 3.4 min. M+1=524
EXAMPLE 36
(R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide
[0339] ##STR81##
[0340] It is similarly prepared according to the procedure for
Example 34.
[0341] .sup.1H NMR (CDCl.sub.3) .delta. 0.98 (t, 3H), 2.18-1.46 (m,
2+2+2+2H), 2.74-2.52 (m, 1+2H), 3.34 (s, 3H), 3.78-3.52 (m, 8H),
4.32 (d, 1H), 5.80-5.70 (m, 1H), 6.56 (d, 1H), 7.36-7.14 (m, 5H),
7.62-7.46 (m, 2H), 7.68 (m, 1H), 7.92 (m, 1H);
[0342] LCMS: RT=3.37 min. M+1=536
EXAMPLE 37
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[(S)-1-(oxazole-2-carbonyl)-propyl]-amide
[0343] ##STR82##
[0344] It is similarly prepared according to the general procedure
for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one;
hydrochloride as the amino component and
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid as the
acidic component but without further oxidation.
[0345] LCMS: RT=2.86 min. M+1=442
EXAMPLE 38
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(oxazole-2-carbonyl)-propyl]-amide
[0346] ##STR83##
[0347] It is similarly prepared according to the general procedure
for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one;
hydrochloride as the amino component and
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid as the acidic component but without further oxidation.
[0348] .sup.1H NMR (CDCl.sub.3) .delta. 1.0 (t, 3H), 2.22-1.64 (m,
2+2+2H), 2.75-2.55 (m, 2+1H), 3.75-3.45 (m, 8H), 4.44 (m, 1H),
4.98-4.64 (b, 1H), 5.55-5.45 (m, 1H), 6.98-6.72 (m, 1H), 734-7.15
(m, 5H), 7.38 (d, 1H), 7.84 (d, 1H).
[0349] MS: 458 (M.sup.+).
EXAMPLE 39
(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-e-
thyl)-pentanoic acid [(S)-1-(oxazole-2-carbonyl)-propyl]-amide
[0350] ##STR84##
[0351] It is similarly prepared according to the general procedure
for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one;
hydrochloride as the amino component and
(R)-5-(2-Difluoromethoxy-phenyl)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo--
ethyl)-pentanoic acid as the acidic component but without further
oxidation step.
[0352] .sup.1H NMR (CDCl.sub.3) .delta. 1.2 (t, 3H), 2.22-1.164 (m,
2+2+2H), 2.75-2.55 (m, 2+1H), 3.75-3.45 (m, 8H), 4.38-4.10 (b, 1H),
4.44 (m, 1H), 5.55-5.45 (m, 1H), 6.80-6.28 (t, 1H), 7.08-6.70 (m,
1H), 726-7.10 (m, 4H), 7.38 (d, 1H), 7.85 (d, 1H).
[0353] MS: 524 (M.sup.+).
EXAMPLE 40
2-(1-Methyl-cyclopentylmethyl)-4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridi-
ne-2-carbonyl)-propyl]-4-oxo-butyramide
[0354] ##STR85##
[0355]
2-(1-Methyl-cyclopentylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid
(100 mg, 0.35 mmol) was combined with EDC (250 mg, 1.3 mmol), HOBt
(250 mg, 1.6 mmol), and
(2S)-2-amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-ol (100 mg, 0.48
mmol). Dichloromethane (4 mL) was added and then 4-methylmorpholine
(0.5 mL). The mixture was stirred at ambient temperature for 2
hours. After dilution with ethyl acetate (150 mL), the solution was
washed with 1N aqueous HCl, water, saturated aqueous NaHCO.sub.3
solution and brine, dried with MgSO.sub.4 and evaporated under
vacuum. The crude product was dissolved in dry dichloromethane (10
mL) and Dess-Martin Periodinane (500 mg, 1.2 mmol) was added. After
stirring at ambient temperature for 1 hour, the mixture was diluted
with ethyl acetate (150 mL) and treated with 0.26M
Na.sub.2S.sub.2O.sub.3 solution in saturated aqueous NaHCO.sub.3.
The organic phase was washed with saturated aqueous NaHCO.sub.3 and
brine, dried with MgSO.sub.4 and evaporated. The product was
purified by flash chromatography on silica gel (hexane/ethyl
acetate 1:1) to yield the title compound (40 mg; 0.085 mmol) as a
mixture of diastereomers.
[0356] LC-MS: elution time diastereomer 1=3.90 min. 469.6(M-1),
471.4(M+1).
[0357] Elution time diastereomer 2=3.97 min. 469.6(M-1),
471.4(M+1).
[0358] (MS: API 150EX. LC: HP Agilent 1100 Series. Column:
Phenomenex, 5u 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% acetonitrile, 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 41
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butrylamino)-2-
-oxo-pentanoic acid (pyridin-4-ylmethyl)-amide
[0359] ##STR86##
[0360] The synthesis was performed in analogy to Harbeson, S. L. et
al. J. Med. Chem. 1994, 37, 2918-2929.
[0361] .sup.1H NMR (CDCl.sub.3) .delta. 8.5-8.4(m, 2H), 7.5-7.0 (m,
9H), 5.05 (m, 1H), 4.6-4.0 (m, 4H), 3.7-3.1(m, 7H), 2.9-2.5(m, 2H),
2.1-1.9(m, 2H), 1.8-1.5(m, 2H), 1.3-1.0(m, 2H), 1.0-0.8(m, 3H).
[0362] MS: 559 (MH.sup.+).
EXAMPLE 42
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)--
2-oxo-pentanoic acid diethylamide
[0363] ##STR87##
[0364] The synthesis was performed in analogy to Harbeson, S. L. et
al. J. Med. Chem. 1994, 37, 2918-2929.
[0365] .sup.1H NMR (CDCl.sub.3) .delta. 7.37-7.19(m, 6H), 4.7-4.59
(m, 1H), 4.25-4.1 (m, 2H), 3.6-3.05 (m, 13H), 2.96-2.55 (m, 3H),
1.8-1.7 (m, 2H), 1.3-0.8 (m, 10H).
[0366] MS: 525 (MH.sup.+), 546 (M+Na).
EXAMPLE 43
N-((S)-1-Ethyl-2,3-dioxo-3-pyrrolidin-1-yl-propyl)-4-morpholin-4-yl-4-oxo--
2-phenylmethanesulfonylmethyl-butyramide
[0367] ##STR88##
[0368] The synthesis was performed in analogy to Harbeson, S. L. et
al. J. Med. Chem. 1994, 37, 2918-2929.
[0369] .sup.1H NMR (CDCl.sub.3) .delta. 7.2-7.0 (m, 6H), 4.7 (m,
1H), 4.2 (m, 2H), 3.6-3.2 (m, 10H), 2.95 (m, 1H), 2.85-2.6 (m, 2H),
2.0-1.3 (m, 7H), 1.3-1.1 (m, 3H), 1.0-0.8 (m, 3H).
[0370] MS: 522 (MH.sup.+), 544 (M+Na).
EXAMPLE 44
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)--
2-oxo-pentanoic acid phenethyl-amide
[0371] ##STR89##
[0372] The synthesis was performed in analogy to Harbeson, S. L. et
al. J. Med. Chem. 1994, 37, 2918-2929.
[0373] .sup.1H NMR (CDCl.sub.3) .delta. 7.4-6.8 (m, 12H), 5.15 (m,
1H), 4.25-4.15 (m, 2H), 3.6-3.2 (m, 12H), 2.94-2.5 (m, 5H), 2.0-1.8
(m, 1H), 1.65-1.55 (m, 1H), 0.90-0.8 (m, 3H).
[0374] MS: 572, 596.
EXAMPLE 45
(S)-3-(4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-butyrylamino)--
2-oxo-pentanoic acid (2-pyridin-2-yl-ethyl)-amide
[0375] ##STR90##
[0376] The synthesis was performed in analogy to Harbeson, S. L. et
al. J. Med. Chem. 1994, 37, 2918-2929.
[0377] .sup.1H NMR (CDCl.sub.3) .delta. 8.51 (m, 1H), 7.86 (m, 1H),
7.5 (m, 1H), 7.4-7.1 (m, 7H), 5.2 (m, 1H), 4.3-4.2 (m, 3H), 3.8-3.3
(m, 9H), 3.1-2.6 (m, 4H), 2.0 (m, 2H), 1.7 (m, 2H), 1.3-1.1 (m,
2H), 0.90 (m, 3H).
[0378] MS: 573 (MH.sup.+).
EXAMPLE 46
Cathepsin S Assay
[0379] 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. Based on essays
carried out by Applicants, the following compounds showed a K.sub.i
value below 100 nM:
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5--
phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide,
(R)-4-Morpholin-4-yl-4-oxo-2-phenylmethanesulfonylmethyl-N-[1-(3-phenyl-1-
,2,4-oxadiazole-5-carbonyl)-propyl]-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-2-(1-benzyl-cyclopropylmethyl)-4-
-morpholin-4-yl-4-oxo-butyramide,
N-[(S)-1-(Benzoxazole-2-carbonyl)-butyl]-4-morpholin-4-yl-4-oxo-2-(2-phen-
yl-cyclopropylmethyl)-butyramide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid
[1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [1-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)-propyl]-amide,
4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
2-(2-Morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid
[(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide (mixture of
diastereoisomers),
4-Morpholin-4-yl-N-[1-(oxazole-2-carbonyl)-3-phenyl-propyl]-4-oxo-2-(2-ph-
enyl-cyclopropylmethyl)-butyramide (mixture of diastereoisomers),
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-N-[(S)-1-(oxazole-2-carbonyl)-3-p-
henyl-propyl]-4-oxo-butyramide,
(R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid
[(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide,
(R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(oxazole-2-carbonyl)-3-phenyl-propyl]-amide,
(S)-2-(1-Fluoro-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide, and
(R)-2-((S)-1-Methoxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic
acid [(S)-1-(benzoxazole-2-carbonyl)-butyl]-amide.
EXAMPLE 47
Cathepsin B Assay
[0380] 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 48
Cathepsin K Assay
[0381] Solutions of test compounds in varying concentrations were
prepared in 10 VL 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 49
Cathepsin L Assay
[0382] 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.
EXAMPLE 50
[0383] Representative Pharmaceutical Formulations Containing a
Compound of Formula I, II or III:
Oral Formulation
[0384] TABLE-US-00001 Compound of Formula I, II or III 10-100 mg
Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring
Water q.s. to 100 mL
Intravenous Formulation
[0385] TABLE-US-00002 Compound of Formula I, II or III 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
[0386] TABLE-US-00003 Compound of Formula I, II or III 1%
Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica
1%.
[0387] While there have been described and pointed out fundamental
novel features of the invention as applied to a preferred
embodiment thereof, it will be understood that various omissions
and substitutions and changes, in the form and details of the
composition and methods illustrated, may be made by those skilled
in the art without departing from the spirit of the invention. For
example, it is expressly intended that chemcial radical
substitutions and/or method steps which perform substantially the
same function in substantially the same way to achieve the same
results are within the scope of the invention.
[0388] The invention is not limited by the embodiments described
above which are presented as examples only but can be modified in
various ways within the scope of protection defined by the appended
patent claims.
* * * * *