Note: Descriptions are shown in the official language in which they were submitted.
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SUBSTITUTED BETA-AMINO~ACID INHIBITORS OF
METHIONINE AMINOPEPTIDASE-2
Field of the Invention
The present invention relates to organic compounds having biological activity,
to
compositions containing the compounds, and to medical methods of treatment.
More
particularly, the present invention concerns a class of substituted beta-amino
acids and their
pharmaceutically acceptable salts, phanmaceutical compositions containing the
compounds,
and methods of treating pathological conditions arising from or dependent upon
angiogenesis.
Background of the Invention
Angiogenesis is the fundamental process by which new blood vessels are formed
and is essential to a variety of normal body activities (such as reproduction,
development
and wound repair). Although the process is not completely understood, it is
believed to
involve a complex interplay of molecules which both stimulate and inhibit the
growth of
endothelial cells, the primary cells of the capillary blood vessels. Under
normal conditions,
these molecules appear to maintain the microvasculature in a quiescent state
(i.e. one of no
capillary growth) for prolonged periods which may last for as long as weeks or
in some
cases, decades. When necessary, however, (such as during wound repair), these
same cells
can undergo rapid proliferation and turnover within a 5 day period. (Folkman,
J. and Shing,
Y., The Journal of Biological Chemistry, 267: 10931-10934 (1987), and Folkman,
J. and
Klagsbrun, M., Science, 235: 442-447 (1987)).
Although angiogenesis is a highly regulated process under normal conditions;
many
diseases (characterized as "angiogenic diseases") are driven by persistent
unregulated
angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a
particular
disease directly or exascerbate an existing pathological condition. For
example, ocular
neovacularization has been implicated as the most common cause of blindness
and
dominates approximately 20 eye diseases. In certain existing conditions such
as arthritis,
newly formed capillary blood vessels invade the joints and destroy cartilage.
In diabetes,
new capillaries formed in the retina invade the vitreous, bleed, and cause
blindness.
Growth and metastasis of solid tumors are also angiogenesis-dependent
(Folkman, J.,
Cancer Research, 46: 467-473 (1986), Folkman, J., Journal of the National
Cancer
Institute, $2: 4-6 (1989)). It has been shown for example that tumors which
enlarge to
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greater than 2 mm, must obtain their own blood supply and do so by inducing
the growth
of new capillary blood vessels. Once these new blood vessels become embedded
in the
tumor, they provide a means for tumor cells to enter the circulation and
metastasize to
distant sites, such as liver, lung or bone (Weidner, N., et al., The New
England Journal of
Medicine, 324: 1-8 (1991)).
Because of this pivotal role played by neovasculurization in tumor formation
and
metastasis and in such other disease conditions as arthritis, inflammation,
maccular
degeneration of age, and diabetic retinopathy, agents which inhibit
angiogenesis have been
the subject of active current research for their clinical potential.
D. Ingber, et al., in Nature, 34$: 555-557 report that fumagillin, a natural
product
of fungal origin, and its synthetic analog, O-
(chloroacetylcarbamoyl)fumagillol, also known
as AGM-1470 or TNP-470, act as potent inhibitors of angiogenesis, with TNP-470
being
50-fold more potent than its natural precursor.
Ny Sin et al., Proc. Natl. Acad. Sci. USA 94: 6099-6103 (1997) and Eric C.
Griffith, et al., Chemistry and Biology, 4(6): 461-471 (1997) report that both
AGM-1470
and ovalicin, a sequiterpene isolated from the fungus Pseudorotium ocalis bind
to a
common bifunctional protein, type 2 methionine aminopeptidase, MetAP2, and
conclude
that MetAP2 plays a critical role in the proliferation of endothelial cells
and may serve as a
promising target for the development of new anti-angiogenic drugs.
J. Abe, et al., Cancer Research, 54: 3407-3412 (1994) report that fumagillin,
and its
derivative TNP-470, are effective in inhibiting neovascularization by
arresting the
endothelial cell cycle in the late G, phase.
The literature has thus established a casual link between inhibition of MetAP2
and
the resultant inhibition of endothelial cell proliferation and
neovascularization. There is a
need for discovery of new agents which inhibit MetAP2 for their potential as
new drugs in
combating angiogenesis or neovascularization and disease conditions such as
arthritis,
inflammation, macular degeneration of the eye, diabetic retinopathy, and tumor
growth
which depend upon neovasculaturization for their development. Compounds of the
current
invention are structurally novel, reversible inhibitors of MetAP2 which may
display
improved pharmaceutical properties and diminished side effects relative to the
currently
known irreversible inhibitors such as fumagillin and TNP-470.
Summary of The Invention
In its principle embodiment, the present invention provides a compound having
activity for inhibiting methionine aminopepfidase type 2 (MetAP2 or MetAP2-2)
having the
structural, formula I
-2-
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R~ X Y
N 1 R3
' 2~
~~E'~2~m
hhlii2
I,
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the
small numerals
denote chiral centers in the compound;
m is 1-3;
Ri is selected from the group consisting of
l0 (1) hydrogen,
(2) alkyl,
(3) carboxaldehyde,
(4) alkanoyl, where the alkanoyl can be optionally substituted with hydroxyl,
and
(5) -(CHZ)"C02R4, where n is (J-6, and R4 is selected from the group
consisting of
(a) hydrogen,
(b) alkyl,
(c) cycloallcyl,
(d) (cycloalkyl)alkyl,
(e) aryl,
and
(f) arylalkyl,
where (c) and (d) can be optionally substituted with 1, 2, or 3
substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkoxy,
and
(iii) aryl,
and
where (e) and (f) can be optionally substituted with 1, 2, or 3
substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
-3-
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(iii) alkoxy,
(iv) -C02R4~, where R4~ is selected from the group consisting of,
(a) hydrogen,
~) ~Yl~
(c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) aryh
and
(f) arylalkyl,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) arylsulfonylalkyl,
(xiv) aryloylalkyloxycarbonylalkyl,
(xv) -NR6R6~, where R6 and R6~ are independently selected from the
group consisting of
(1') hydrogen,
(2') alkyl optionally substituted with alkoxy,
(3') aryl,
~ (4') arylalkyl,
and
(5') a nitrogen-protecting group,
(xvi) -S02NR6R6~, where R6 and R6~ are defined above,
and
(xvii) -C(O)NR6R6~, where R6 and R6~ are defined above;
RZ is selected from the group consisting of
( 1 ) alkyl,
(2) cycloalkyl,
(3) (cycloalkyl)alkyl,
(4) -C(H)(SR15)(SR15~), where R15 and R15' are alkyl, or R15 and Risk together
with
the sulfurs to which they are attached, are a 1,3-dithiolane ring or a 1,3-
dithiane
-4-
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ring,
(5) aryl,
(6) arylalkyl,
and
(7) -SRS, where RS is selected from the group consisting of
(a) alkyl,
(b) cycloalkyl,
(c) (cycloalkyl)alkyl,
and
(d) benzyl, where the benzyl can be opdonaliy substituted with 1, 2, or 3
substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) allcoxy,
(iv) -C02R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) vitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) -NR6R6~, where R6 and R6~ are defined above,
(xiv) -S02NR6R6~, where R6 and R6~ are defined above,
and
(xv) -C(O)NR6R6~, where R6 and R6~ are defined above;
R3 is selected from the group consisting of
(1) an aminoacyl group optionally capped with a carboxyl protecting group,
(2) -N(R6)(CH2)pR~, where p is 0-6, R6 is defined above, and R~ is selected
from the
group consisting of
(a) hydrogen,
(b) alkyl, where the alkyl can be optionally substituted with 1, 2, 3, or
4 substituents independently selected from the group consisting of
(i) oxo,
(ii) thioxo,
-5-
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(iii) alkoxy,
(iv) -C02R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) vitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) -NR6R6~, where R6 and R6' are defined above,
(xiv) -S02NR6R6~, where R6 and R6~ are defined above,
(xv) -C(O)NR6R6~, where R6 and R6~ are defined above,
(xvi) aryl,
(xvii) hydroxy,
and
(xviii) heterocycle,
(c) cycloalkyl, where the aryl can be optionally substituted with 1, 2, or 3
substituents independently selected from the group consisting of
(i) alkyl,
(ii) halo,
(iii) oxo, and
(iv) aryl,
(d) aryl, where the aryl can be optionally substituted with 1, 2, or 3
substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
{iv) -COZR4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) vitro,
(xi) perfluoroalkyl,
(xii) .perfluoroalkoxy,
-6-
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(xiii) -NR6R6~, where R6 and R6~ are defined above,
(xiv) -S02NR6R6~, where R6 and R6~ are defined above,
(xv) -C(O)NR6R6~, where R6 and R6~ are defined above,
(xvi) aryloxy,
(xvii) arylalkoxy,
(xvi) aryl,
(xvii) hydroxy,
and
(xviii) heterocycle,
(e) -C02R4, where R4 is defined above,
(f) -CONR6Rg, where R6 is defined above, and Rg is selected from the group
consisting of
(i) hydrogen
(ii) alkyl,
Is (iii) aryl,
and
(iv) heterocycle,
where (ii)-(iv) can be optionally substituted with one, two, or three
groups independently selected from the group consisting of
{1') alkyl,
(2') alkanoyl,
(3') alkoxy,
(4') -C02R4, where R4 is defined above,
(5') alkanoyloxy,
(6') carboxaldehyde,
(T) cycloalkyl,
(8') cycloalkenyl,
{9') halo,
( 10') nitro,
( 11') perfluoroalkyl,
(12') perfluoroalkoxy,
(13') -NR6R6~, where R6 and R6~are defined above,
(14') -S02NR6R6~, where R6 and R6~ are defined above,
(15') -C(O)NR6R6~, where R~ and R6~ are defined above,
(16') aryloxy,
(17') arylalkoxy,
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(18') aryl,
(19') hydroxy,
and
(20') heterocycle,
(g) heterocycle, where the heterocycle can be optionally substituted with one,
two, or three groups independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
l0 (iv) -COZR4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) -NR6R6~, where R6 and R6~ are defined above,
(xiv) -S02NR6R6~, where R6 and R6~ are defined above,
(xv) -C(O)NR6R6~, where R6 and R6~ are defined above,
(xvi) aryloxy,
(xvii) arylalkoxy,
(xviii) aryl,
(xix) hydroxy,
and
(xix) heterocycle,
(h) -NR6Rg, where R6 and Rg are defined above,
and
(i) -N(R6)SOZR12, where R6 is defined previously, and R12 is selected from
the group consisting of
(i) alkyl,
(u) ~'Yh
(iii) arylalkyl,
(iv) heterocycle,
and
(v) (heterocycle)alkyl,
_g_
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where (ii)-(v) can be optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of
(1') alkyl,
(2') alkanoyl,
(3') alkoxy,
(4') -C02R4, where R4 is defined above,
(5') alkanoyloxy,
(6') carboxaldehyde,
(7') cycloalkyl,
(8') cycloalkenyl,
(9') halo,
(10') nitro,
(11') perfluoroalkyl,
( 12') perfluoroalkoxy,
(13') -NR6R6~, where R6 and R6~ are defined above,
(14') -S02NR6R6~, where R6 and R6~ are defined above,
(15') -C(O)NR6R6', where R6 and R6~ are defined above,
(16') aryloxy,
(17') arylalkoxy,
(18') aryl,
(19') hydroxy,
and
(20') heterocycle,
(3) -O(CH2)pR~ where p and R~ are defined above,
and
(4) -NR2~R21, where R2~ and R21, together with the nitrogen atom to which they
are
attached, are a 3- to 7-membered ring optionally containing therein 1 or 2
double
bonds and optionally containing therein a moiety selected from the group
consisting of
(a) oxygen,
(b) nitrogen
and
(c) -S(O)X , wherein x is 0-2,
where the ring formed by R2~ and R21 can be optionally substituted with 1, 2,
or
3 groups independently selected from the group consisting of
{ 1') alkyl,
(2') alkanoyl,
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(3') alkoxy,
(4') -C02R4, where R4 is defined above,
(5') alkanoyloxy,
(6') carboxaldehyde,
(7') cycloalkyl,
{8') cycloalkenyl,
(9') halo,
( 10') nitro,
(11') perfluoroalkyl,
( 12') perfluoroalkoxy,
(13') -NR6R6~, where R6 and R6~ are defined above,
(14') -S02NR6R6~, where R6 and R~~ are defined above,
(15') -C(O)NR6R6~, where R6 and R6~ are defined above,
(16') aryloxy,
(17') arylallcoxy,
( 18') aryl,
( 19') hydroxy,
and
. (20') heterocycle;
X is hydroxyl or sulfhydryl;
and
Y is hydrogen;
or
X and Y, taken together with the carbon atom to which they are attached, form
a carbonyl
or thiocarbonyl.
In another embodiment, the present invention provides a pharmaceutical
composition comprising a compound of formula I or a pharmaceutically
acceptable salt,
ester, or prodrug thereof, in combination with a pharmaceutically acceptable
carrier.
In another embodiment, the present invention provides a method of inhibiting
angiogenesis in a mammal in recognized need of such treatment comprising
adminstering to
the mammal a pharmaceuticlly acceptable amount of a compound of formula I.
Detailed Description
Definition of Terms
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When used throughout this specification and the appended claims, the following
terms have the ascribed meanings.
The term "alkanoyl," as used herein, denotes an alkyl group attached to the
parent
molecular group through a carbonyl group. The alkanoyl groups of this
invention can be
optionally substituted.
The term "allcanoyloxy," as used herein, denotes an alkanoyl group attached to
the
parent molecular group through an oxygen atom. The alkanoyloxy groups of this
invention
can be optionally substituted.
The term "alkyl," as used herein, denotes a radical formed by the removal of
one
hydrogen atom from a straight or branched saturated hydrocarbon of one to
twelve carbon
atoms. Representative hydrocarbon groups include methyl, ethyl, n-propyl, iso-
propyl, n-
butyl, sec-butyl, iso-butyl tert-butyl, and the like. The alkyl groups of this
invention can be
optionally substituted.
The term "alkoxy," as used herein, denotes a lower alkyl group, as defined
herein,
attached to the parent molecular moiety through an oxygen atom and includes
such groups
as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and the like. The alkoxy
groups of
this invention can be optionally substituted.
The term "aminoacyl group, " as used herein, denotes a radical derived from
naturally or unnaturally occuring amino acids. Representative aminoacyl groups
include
glycyl, alanyl, valyl, leucyl, iso-leucyl, methionyl, seryl, threonyl,
cysteinyl, phenylalanyl,
homophenylalanyl, and O-methyltyrosinyl in the racemic, S or L configurations.
The term "aryl," as used herein, denotes a mono- or bicyclic- carbocyclic ring
system having one or two aromatic rings. Aryl groups are exemplified by
phenyl,
naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,
and
indenyl. Bicyclic aryl groups of this invention can be attached to the parent
molecular
group through a saturated or unsaturated part of the group. The aryl groups of
this
invention can be optionally substituted.
The term "arylalkoxy," as used herein, denotes an aryl group, as defined
herein,
attached to the parent molecular group through an alkoxy group. The
arylallcoxy groups of
this invention can be optionally substituted.
The term "arylalkyl," as used herein, denotes an aryl group, as defined
herein,
attached to the parent molecular group through an alkyl group. The arylalkyl
groups of
this invention can be optionally substituted.
The term "aryloxy," as used herein, denotes an aryl group, as defined herein,
attached to the parent molecular group through an oxygen atom. The aryloxy
groups of
this invention can be optionally substituted.
-11-
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The term "aryloyl," as used herein, denotes an aryl group, as defined herein,
attached to the parent molecular group through a carbonyl group. The aryloyl
groups of
this invention can be optionally substituted.
The term "aryloyloxy," as used herein, denotes an aryloyl group, as defined
herein,
attached to the parent molecular group through an oxygen atom. The aryloyloxy
groups of
this invention can be optionally substituted.
The term "aryloyloxyalkyl," as used herein, denotes an aryloyloxy group, as
defined
herein, attached to the parent molecular group through an alkyl group. The
aryloyloxyalkyl
groups of this invention can be optionally substituted.
The term "aryloyloxyalkylcarbonyl," as used herein, denotes an aryloyloxy
group, as
defined herein, attached to the parent molecular group through a carbonyl
group. The
aryloyloxyalkylcarbonyl groups of this invention can be optionally
substituted.
The term "aryloyloxyalkylcarbonylalkyl," as used herein, denotes an
aryloyloxyalkylcarbonyl group, as defined herein, attached to the parent
molecular group
through an alkyl group. The aryloyloxyalkylcarbonylallcyl groups of this
invention can be
optionally substituted.
The term "arylsulfonyl," as used herein, denotes an aryl group, as defined
herein,
attached to the parent molecular group through an -S02- group. The
arylsulfonyl groups
of this invention can be optionally substituted.
The term "arylsulfonylalkyl," as used herein, denotes an arylsulfonyl group,
as
defined herein, attached to the parent molecular group through an alkyl group.
The
arylsulfonylalkyl groups of this invention can be optionally substituted.
The term "benzyl," as used herein, denotes a phenyl group, as defined herein,
attached to the parent molecular group through a methyl group. The benzyl
groups of this
invention can be optionally substituted.
The term "carboxaldehyde," as used herein, denotes -CHO.
The term "carbonyl," as used herein, denotes -C(O)-.
The term "carboxy," as used herein, denotes -C02H.
The term "cycloalkyl," as used herein, denotes a radical derived by the
removal of a
single hydrogen atom from a saturated cyclic or bicyclic hydrocarbon and
includes such
groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl,
norbornyl, and the
like. The cycloalkyl groups of this invention can be optionally substituted.
The term "(cycloalkyl)alkyl" denotes a cycloalkyl group as just defined,
attached to
the parent molecular moiety through an alkyl group as defined above and
includes such
representative groups as cyclopropylmethyl, cyclopentylethyl, 2-methyl-3-
cyclopentylbutyl,
cyclohexylmethyl, and the like. The (cycloaIkyl)alkyl groups of this invention
can be
optionally substituted.
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The term "cycloalkenyl," as used herein, denotes a monovalent cyclic or
bicyclic
hydrocarbon of four to twelve carbon atoms having at least one carbon-carbon
double
bond. The cycloalkenyl groups of this invention can be optionally substituted.
The term "halo," as used herein, denotes -F, ~-CI, -Br or -I.
The term "heterocycle" as used herein denotes any 5-, 6-or 7-membered
saturated
ring containing from one to three heteroatoms independently selected from the
group
consisting of 1, 2, or 3 nitrogens, one oxygen and one nitrogen, and one
sulfur and one
nitrogen; wherein the nitrogen and sulfur heteroatoms can be optionally
oxidized, and the
nitrogen heteroatom can be optionally quaternized. The term "heterocycle," as
used herein,
also includes and to 5-, 6-, or 7-membered aromatic rings having in the ring
one, two, or
three heteroatoms selected from N, O, and S, and also including benzo fused
analogs of
these 5-, 6-, or 7-membered heterocyclic aromatic rings. Representative
heterocycles of
this invention include, pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl,
pyridazinyl
morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl,
furyl, benzofuryl,
thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl,
oxadiazolyl,
oxazolyl, 1,2,3-oxadiazolyl, thienyl, triazolyl 1,3,4-thiadiazolyl, and
tetrazolyl, and the
like.
The term "heterocycle," as used herein, also includes compounds of formula
O_Y.
Z'
wherein Y* is selected from the group consisting of -C(O)- and
-(C(R30)(R31))~ , wherein R30 and R31 are independently selected from the
group
consisting of hydrogen and alkyl, and v is 1, 2, or 3, and Z* is selected from
the group
consisting of -CH2-, -O-, -CHZS(O),-, -CH20-, -CH2NR35-, and -NR35-, wherein,
at each
occurence, R35 is selected from the group consisting of hydrogen and alkyl.
The term "heterocycle," as used herein, also includes bicyclic or tricyclic
rings,
wherein any of the aformentioiled heteroaryl rings is fused to one or two
rings
independently selected from the group consisting of an aryl ring, a cycloalkyl
ring, a
cycloalkenyl ring, and another monocyclic heteroaryl ring. These heteroaryls
include
benzo[b]furanyl, benzo[b]thienyl, benzimidazolyl, cinnolinyl, imidazo[4,5-
c]pyridinyl,
quinazolinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3-
b]pyridinyl,indolizinyl, and imidazo[ 1,2-a]pyridine and can be attached to
the parent
molecular group through either the heretoaryl group or the aryl, cycloalkyl,
or
cycloalkenyl group to which it is fused. The heterocycle groups of this
invention can be
optionally substituted.
The term "hydroxy," as used herein, denotes -OH.
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The term "nitro," as used herein, denotes -NO2.
The term "nitrogen-protecting group," as used herein, denotes groups intended
to
protect an amino group against undersirable reactions during synthetic
procedures.
Commonly used nitrogen-protecting groups are disclosed in Greene, "Protective
Groups
In Organic Synthesis," (John Wiley & Sons, New York ( 1991 )). Common N-
protecting
groups comprise (a) acyl groups such as formyl, acetyl, propionyl, pivaloyl,
tert-
butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
phthalyl, o-
nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,
and 4-
nitrobenzoyl, (b) sulfonyl groups such as benzenesulfonyl, and para-
toluenesulfonyl, (c)
carbamate forming groups such as benzyloxycarbonyl,.para-
chlorobenzyloxycarbonyl, p
methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
p
bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-
dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-
methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-
trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-
dimethyl-
3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl,
allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-
nitrophenoxy
carbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,
and
phenylthiocarbonyl, (d) arylalkyl groups such as benzyl, triphenylmethyl, and
benzyloxymethyl, and (e) silyl groups such as trimethylsily. Preferred
nitrogen-protecting
groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl,
phenylsulfonyl, benzyl, tert-
butyloxycarbonyl (Boc) and benzyioxycarbonyl (Cbz).
The term "oxo," as used herein, denotes (=O).
The term "perfluoroalkoxy," as used herein, denotes a perfluoroalkyl group
attached to the parent molecular group through an axygen atom.
The term "perfluoroalkyl," as used herein, denotes an alkyl group in which all
of
the hydrogen atoms have been replaced by fluoride atoms.
The term "phenyl," as used herein, denotes a radical formed by the removal of
one
hydrogen atom from a benzene ring. The phenyl groups of this invention can be
optionally
substituted.
The term "prodrug" denotes compounds that are rapidly transformed in vivo to
yield the parent compounds of formula I, as for example, by hydrolysis in
blood. T.
Higuchi and V. Stella provide a thorough discussion of the prodrug concept in
"Prodrugs
as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, American
Chemical
Society (1975). Examples of esters useful as prodrugs for compounds containing
carboxyl
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WO 99/5709$ PCT/US99/09641
groups may be found on pages 14-21 of Bioreversible Carriers in Drug Design:
Theory
andApplication, edited by E.B. Roche, Pergamon Press (1987).
The term "prodrug ester group" denotes any of several ester-forming groups
that
are hydrolyzed under physiological conditions. Examples of prodrug ester
groups include
pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well
as other
such groups known in the art.
The term "pharmaceutically acceptable ester" denotes esters which hydrolyze in
vivo and include those that break down readily in the human body to leave the
parent
compound or a salt thereof. Suitable ester groups include, for example, those
derived from
1o pharmaceutically acceptable aliphatic carboxylic acids, particularly
alkanoic, alkenoic,
cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously
has not more than 6 carbon atoms. Examples of particular esters includes
formates,
acetates, propionates, butryates, acrylates and ethylsuccinates.
The term "sulfhydryl," as used herein, denotes -SH.
The term "thiocarbonyl," as used herein, denotes -C(S)-.
The term "thioxo," as used herein, denotes =S.
As shown in generic chemical structural formula I above, the compounds of the
invention have at least one chiral center designated by the numeral "1." When
Y is
hydrogen, the compounds also possess at least one additional chiral center
designated by
the numeral "2" in the generic formula. While compounds having either the "R,"
"S," or
"R,S" chirality at either site are described, preferred compounds of the
present invention
are those in which the chirality at the site designated "1" is R and the
chirality at the site
designated "2" is S. The "R" and "S" stereochemical designators follow the
convention
established by R. S. Cahn, et al., Angewandt Chemie. Int. Ed. End, 5: 385-415
(1966).
Diastereomers having the preferred (Site 1)R and (Site 2)S stereochemistry can
be
synthesized by judicious choice of optically pure starting materials,
asymmetric synthesis, or
may be separated from mixtures of diastereomers by methods well known in the
art as, for
example, by reverse phase HPLC techniques.
While compounds having a structure corresponding to the generic formula I
given
above are considered to fall within the scope of the present invention, a
preferred sub-
group of compounds is defined by structural formula I where R2 is -SRS where
RS is lower
alkyl, most preferably, methyl or ethyl.
Another preferred sub-group ofcompounds of the invention are compounds of
formula I where R2 is cycloalkyl, preferably cyclohexyl.
Another preferred sub-group of compounds of the invention are compounds of
formula I where m is one and R2 is lower alkyl, preferably n-propyl.
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Another preferred sub-group of compounds of the invention are compounds of
formula I where X is hydroxy or sulfhydryl, and Y is hydrogen, with X is
hydroxyl being
particularly preferred.
Another preferred sub-group of compounds of the present invention is defined
by
structural formula I above where X and Y, taken together with the carbon atom
to which
they are attached, form a carbonyl or thiocarbonyl group, with carbonyl being
particularly
preferred.
A preferred sub-group of compounds of the invention are defined by structural
formula I where R3 is an aminoacyl group derived from a naturally occurring
amino acid,
1o where the nitrogen atom at the N-terminus of the aminoacyl group is
attached to the
immediately adjacent carbonyl group of the parent molecular moiety, and the C-
terminus,
or carboxyl functionality of the aminoacyl residue is optionally and
preferably capped by a
carboxyl blocking group.
Carboxyl blocking groups are well known to practitioners of the organic
chemical
arts, and are described in some detail in Chapter 5, pages 224-276 of
"Protective Groups in
Organic Synthesis," Second Edition, by T. W. Greene and P. G. M. Wuts, Kohn
Wiley &
Sons, Inc., New York, 1991, the contents of which are incorporated herein by
reference.
Such carboxyl protecting groups include esters such as substituted methyl
esters,
substituted ethyl esters, substituted benzyl esters, silyl esters, oxazoles, 2-
alkyl-1,3-
oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxalanes,
ortho esters, and
amides such as N,N-dialkyl amides, pyrrolidinyl amides, piperidinyl amides,
5,6-
dihydropiperidinyl amides, o-nitroanilides, and hydrazides such as N-
phenylhydrazides and
N,N'-dialkylhydrazides.
Specific examples of individual compounds falling within the scope of the
present
invention include, but are not limited to
(2RS,3S,1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3S,1'S)-N-((1-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R,1'S)-N-(( 1-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide
(2RS,3R,1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-((2-phenylethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
{2RS,3R)-N-((3-phenylpropyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
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(2RS,3R) N-(2-(4-methoxyphenyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-(2-(4-sulfonamidophenyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-(2-(2-pyridyl~thyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(2-(4-phenoxyphenyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R,1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(ethylthio)pentanamide,
(2RS,3R)-N-(4-phenyl)butyl)-3-amino-2-hydroxy-S-(ethylthio)pentanamide,
(2RS,3R)-N-{3-(carboethoxy)ethyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carbobenzyloxy)ethyl)-3-amino-2-hydroxy-5-
(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-5-
(ethylthio)pentanamide,
(2RS,3R,1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-heptanamide,
(2RS,3R)-3-amino-2-hydroxy-5-(methylthio)pentanoic acid,
(2RS,3R)-N-(2-(4-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R,1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-cyclohexyl-
butanamide,
(2RS,3R)-N-{2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-cyclohexyl-butanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cyclohexyl-
butanamide,
(2RS,3R,1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-phenyl-
butanamide,
(2RS,3R)-3-amino-2-hydroxy-N-(4-methoxyphenethyl)-5-
(methylsulfanyl)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hydroxy-5-
{ethylthio)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-acetylamino-2-hydroxy-5-(ethylthio)pentanamide,
{2RS,3 R)-N-((phenylbutyryl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
{2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hydroxy-M
ethylthio)pentanamide,
{2RS,3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
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(2RS,3R)-3-amino-2-hydroxy-N-methyl-5-(methylsulfanyl)-N-
phenethylpentanamide,
(2RS,3R,1'S)-N-((2-carboxyethyl)-3-amino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-N-((1-methyl-1-ethoxycarboxyethyl) 3-amino-2-hydroxy-4-
ethylthio)pentanamide,
(2RS,3R,1'S)-N-((1-(2-hydroxy)-1-ethoxycarboxyethyl) 3-amino-2-hydroxy-4-
ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-tert-butoxycarbonylamino-2-hydroxy-4-
ethylthio)pentanamide,
l0 (2RS,3R)-N-((phenylbutyryl)-3-formylamino-2-hydroxy-4-
ethylthio)pentanamide,
(2RS,3R)-N-Methyl-N-((ethoxycarbonylmethyl)-3-amino-2-hydroxy-4-
ethylthio)pentanamide,
(2RS,3R)-N-((Phenylhutyryl)-3-hydroxymethylcarbonylamino-2-hydroxy-4-
ethylthio)pentanamide,
15 (2RS,3R,1'R)-N-((1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-
ethylthio)pentanamide,
(2RS,3R,1'R)-N-(( 1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-
cyclohexyl)butanamide,
2RS,3R)-N-(( 1-methyl-1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-
2o cyclohexyl)butanamide,
(2RS,3R)-N-((Phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4-
ethylthio)pentanamide,
(2RS,3R,1'S)-N-((1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-
benzylthio)butanamide,
25 (2RS,3R,1'S)-N-((2-hydroxy-1-ethoxycarbonylethyl)-3-amino-2-hydroxy-4-
cyclohexyl)butanamide,
(2RS,3R,1'S)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2'S)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4-
cyclohexyl)butanamide,
30 (2RS,3R,2'S)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4-
cyclohexyl)butanamide,
(2RS,3R, 2'R)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4-
cyclohexyl)butanamide,
(2RS;3R,2'R)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4-
35 cyclohexyl)butanamide,
(2RS,3R,2'R)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2R5,3R,1'S)-N-(( 1-benzyloxycarbonylethyl)-3-amino-2-hydroxy-4-
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cyclohexyl)butanamide,
{2RS,3R,1'S)-N-(4-ethoxycarbonyl-2-( 1'-aminoethyl)thizole)-3-amino-2-hydroxy-
4-
cyclohexyl)butanamide,
(2RS,3R) N-(monodansylcadaveno)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R) N-(2-methyl-5-nitro imidazole-ethyl) 3-amino-2-hydroxy-4-
cyclohexyl)butanamide di,
(2RS,3R) N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4-
cyclohexyl)butanamide di,
(2RS,3R) N-(5-methoxy-tryptaminyl) 3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R) N-(3-O-methyl-dopaminyl) 3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R) N-(2-aminomethylbenzimidazolyl) 3-amino-2-hydroxy-4-
cyclohexyl)butanamide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-methyl-5-
nitroimidazolyl-ethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-
rutropyridylaminoethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-
(ethylisonipecotate)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyI)butanoyl-L-alanyl-(2-
pyrrolidinopropyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-
methoxytryptamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(3-O-
methoxydopamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-
benzimidazolemethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-{5-phenyl-pyrazole-
3)amide,
({2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-hydroxy-5-nitro-
1)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-bromothizole-
2)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(4-nitro-2-
hydroxyphenyl-1 )amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoylL-alanyl-(1-
ethylpyrazole)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide,
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((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(3-imidazolylpropyl)amide,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-carboxyl-2-(
1'amino)ethyl
thizole,
ethyl (2RS,3R,2'S)-2-((-3-(acetylamino)-4-cyclohexyl-2-
hydroxybutanoyl)amino)propanoate,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-
benzyloxycarbonylamino)butylamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-beta-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-monodansylcadaverine amide,
l0 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-(4-
toluenesulfonyl)aminobutyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-4-
toluenesulfonylaminoethyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-aminobutyl)amide ,
15 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-aminoethyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(((3-
(trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-({(3,4-
dimethoxyphenyl)sulfonyl)amino)butyl)-2-hydroxybutanamide,
20 (2RS,3R)-N-(4-{((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4-
cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-({2-
naphthylsulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-sulfonamide
25 benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclohexyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 2-
((phenylsulfonyl)methyl)benzyl ester,
30 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclopropyl
ester(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-tert-
butylbenzyl
ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-
methoxycarbonylbenzyl ester,
35 (2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-
trifluoromethylbenzyl ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-(4-(methyl)phenyl
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acetic acid phenacyl ester),
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenyl)butanamide,
methyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-4-
methylpentanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-furylmethyl)-2-hydroxybutanamide,
(2RS,3R,1'RS)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1-( 1-
naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-liydroxy-N-(3-(2-oxo-1-
pyrrolidinyl)propyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(1,2-dimethylpropyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine,
IS (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenylbutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(1,2,3,4-tetrahydro-1-
naphthalenyl)butanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)cyclohexyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethylhexyl)-2-hydroxybutanamide,
butyl (2RS,3R)-2-{(3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate,
2RS,3R)-3-amino-N-(1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-
hydroxybutanamide,
{2RS,3R)-3-amino-4-cyclohexyl-N-{2,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-5-
(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-decyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(( 1 R,4S)bicyclo(2.2.1 )hept-2-yl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-( 1-(4-fluorophenyl)ethyl)-2-
hydroxybutanamide,
(ZRS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(tetrahydro-2-
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furanylmethyl)butanamide,
ethyl (2RS,3R)-(4-((-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-1-
piperidinecarboxylate,
(2RS,3R)-3-amino-N-( 1,3-benzodioxol-5-yl)=4-cyclohexyl-2-hydroxybutanamide,
tert-butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate,
methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-
phenylpropanoate,
methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-
methylpentanoate,
l0 methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-
hydroxybutanoyl)amina)hexanoate,
methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-
methylbutanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(( 1 S)-1-(2-
15 naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(( 1 R)-1-(2-
naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(( 1 S)-1-( 1-
naphthyl~thyl)butanamide,
20 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((1R)-1-(1-
naphthyl)ethyl)butanamide,
ethyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino~3-
fluoropropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-hydroxy-1-
25 (hydroxymethyl~thyl)butanamide,
4-(tent-butyl)benzyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-
hydroxybutanoyl)amino)-3-hydroxypropanoate,
4-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-
3-hydroxypropanoate,
30 3-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-
hydroxybutanoyl)amino)-
3-hydroxypropanoate,
4-(trifluoromethyl)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-
hydroxybutanoyl)amino)-3-hydroxypropanoate,
3-(trifluoromethoxy)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-
35 hydroxybutanoyl)amino)-3-hydroxypropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenyl)butanamide,
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(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-{2-methoxyphenyl)butanamide,
(2RS,3R}-3-amino-N-(4-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)phenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)phenyl)butanamide,
2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-bromophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-(tort-butyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyl)benzyl)butanamide,
{2RS,3R)-3-amino-N-(2-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
{2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5
nitrophenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenoxyphenyl)butanamide,
(((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)(2,5-
dimethoxybenzyl)chloronium,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dichlorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3-fluorophenethyl}-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(3,4-bis(benzyloxy)phenethyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-
(trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methylphenyl)butanamide,
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WO 99/57098 PCT/US99/09641
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dimethylphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-iodo-2-methylphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-anilino-2-methoxyphenyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R}-3-amino-N-(4-chloro-2-methoxy-5-methylphenyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-N-(5-(acetylamino)-2-methoxyphenyl)-3-amino-4-cyclohexyl-2-
l0 hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxydibenzo(b,d)furan-3-
yl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2,4-dimethoxyphenyl}-4-cyclohexyl-2-
hydroxybutanamide,
15 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-diethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-phenoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methyl-5-nitrophenyl)butanamide,
20 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenyl)butanamide,
(2RS,3R}-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxybenzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylbenzyl)butanamide,
(2RS,3R)-3-amino-N-(3-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxybenzyl)butanamide,
25 (2RS,3R)-3-amino-N-(4-bromobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methylbenzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenethylbutanamide,
(2RS,3R)-3-amino-N-(4-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamid,
{2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-{4-methylphenethyl)butanamide,
30 {2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
35 (2RS,3R.)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)phenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-bromophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
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WO 99/57098 PCTNS99/09641
(2RS,3R)-N-( 1-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-N-(2-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-cycloheptyl-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(cycloheXylmethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N,4-dicyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-cyclopentyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-cyclobutyl-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1-methyl-3-
phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1-methyl-2-(3-
(trifluoromethyl)phenyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-( 1,5-dimethylhexyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1-methylhexyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isopropoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isobutoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(4-
morpholinyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,3-diphenylpropyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-( 1,4-dimethylpentyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-(1-
naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-(( 1 S)-1-( 1-
naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-
(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy( 1,1'-biphenyl)-3-
yl)butanamide,
{2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-
hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-(benzyloxy)phenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3-ethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3,4,5-trimethoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-{2-fluorophenyl)-1-methylethyl)-2-
hydroxybutanamide,
{2RS,3R)-3-amino-4-cyclohexyl-N-(2-(4-fluorophenyl)-l,l-dimethylethyl)-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro-1 H-inden-1-yl)-2-
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WO 99/57098 PCT/US99/09641
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(( 1 S,2R)-2-
phenylcyclopropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1,1,3,3-
tetramethylbutyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-( 1,3-dimethylbutyl)-2-hydroxybutanamide,
methyl 4-(((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3-
thiophenecarboxylate,
(2RS,3R)-N-( 1-( 1-adamantyl)ethyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
1o (2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-( (S)-(-)-(1-
naphthyl~thyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1-naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethoxy)benzyl)butanamide,
15 (2RS,3R)-3-amino-N-(3,5-bis(trifluoromethyl)benzyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-
(trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
20 (trifluoromethoxy)benzyl)butanamide,
(2RS,3R)-3-amino-N-(6-chloro-3-pyridinyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-Z-hydroxy-N-(6-methyl-2-pyridinyl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2-methoxyphenyl)-4-cyclohexyl-2-
hydroxybutanamide,
25 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-
methylphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-2-
hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dimethoxyphenyl)-2-hydroxybutanamide,
30 (2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-4-
methylphenyl)butanamide,
2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy-2-naphthyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-thienylmethyl)butanamide,
(2RS,3R)-3-amino-N-butyl-4-cyclohexyl-2-hydroxy-N methylbutanamide,
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WO 99/57098 PCT/US99/09641
(2RS,3R)-3-amino-4-cyclohexyl-1-(2,6-dimethyl-4-morpholinyl)-2-hydroxy-1-
butanone,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N,N bis(methoxymethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-1-[3,4-dihydro-2( 1,T~-isoquinolinyl]-2-hydroxy-
1-butanone,
(2RS,3R)-3-amino-1-( 1-azepanyl)-4-cyclohexyl-2-hydroxy-1-butanone,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-1-(4-phenyl-3,6-dihydro-1 (2H~-
pyridinyl]-1-butanone
(2RS,3R)-3-amino-N benzyl-N butyl-4-cyclohexyl-2-hydroxybutanamide
(2RS,3R)-3-amino-4-cyclohexyl-1-[(2R,6S)-2,6-dimethylmorpholinyl]-2-hydroxy-
1-butanone,
(2RS,3R)-3-amino-N-[(2-chioro-2,3,5-cyclohexatrien-1-yl)methyl]-4-cyclohexyl-
2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-N-( 1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxy-N
methylbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N (2,4-dichlorobenzyl)-N-ethyl-2-
hydroxybutanamide,
ethyl 3-[[(2RS,3R)-3-amino-4-cyclohexyl-2-
hydroxybutanoyl] (benzyl)amino]propanoate,
2o and
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-1-(1-piperidinyl)-1-butanone.
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
Biological Assay
The ability of compounds of the present invention to inhibit methionine
aminopeptidase 2 was evaluated using the following assay.
Recombinant methionine aminopeptidase-2 (MetAP2) was expressed as a secreted
protein with a baculovirus system and purified from the insect cell culture
supernatant as
previously described by R. L. Kendal, et al., 7. Biol. Chem., 267(29): 20667-
20673 (1992)
and Xuan Li, et al., Biochem. And Biophvs. Res. Comm., 227: 152-159 (1996),
the
contents of which are incorporated herein by reference.
Assays for MetAP2 enzyme activity and MetAP2 inhibition were performed in 96-
well microtiter plates. Compounds to be tested for MetAP2 inhibition were
dissolved in
dimethyl-sulfoxide at 10 mM and diluted ten-fold in assay buffer (50 nM HEPES,
pH 7.4,
100 mM NaCI). Ten microliters of solution of each compound to be tested for
inhibition
were introduced into each cell of the plate, with each compound being tested
in triplicate.
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WO 99/57098 PCT/US99/09641
Zero inhibition of enzyme activity was taken to be the result obtained in
cells in which 10
mL of assay buffer was placed, and 100 percent inhibition of enzyme activity
was taken to
be the result obtained in cells in which 10 mM of fumagillin (Sigma Chemical
Co., St.
Louis, MO, USA, Catalog No. F-6771) in assay buffer was placed.
A mixture totaling 901tL per well, and made up of of 84 mL of assay buffer, 1
~.L
of L-amino acid oxidase (Sigma Catalog No. A-9378, ~11 mg/mL), 1 ~L of
horseradish
peroxidase (Sigma Catalog No. P-8451, dissolved in assay buffer at a
concentration of 10
mglmL), 1 ~tL of the tripeptide Met-Ala-Ser (Bachem), dissolved in assay
buffer at
concentration of 50 mM), 1 mL of ortho-dianisidine (Sigma Catalog No. D-1954,
freshly
io made solution in water at a concentration of 10 mg,mL), and MetAP2 at a
final
concentration of 4 ~g/mL was rapidly mixed and added to each cell containing
test or
control compound. The absorbence at 450 nanometers was measured every 20
seconds
over a period of twenty minutes using an automaic plate reader (Molecular
Devices, CA,
USA). The V~"~ in mODlmin, calculated for each well was used to represent
MetAP2
activity. The ICso for each inhibitor was obtained by plotting the remaining
MetAP2
activity versus inhibitor concentration. The results of these tests appear in
Table 1.
Table 1
Inhibition of MetAP2 Activity by
Representative Compounds of the Invention
Example ICso(~M) Example ICso(p,M)
1 11. 126 13.
2 47. 127 28.
3 10. 128 14.
4 2.4 129 27.
5 2.6 130 4.3
6 3.0 131 0.99
7 2.0 132 4.1
8 2.3 133 0.27
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9 2.3 134 3.1
3.6 135 3.2
11 2.6 136 1.8
12 0.86 137 8.4
5
13 1.1 138 1.6
14 0.72 139 1.7
0.7 2 140 2.2
16 0.78 141 3.7
17 1.4 142 0.40
10
18 0.15 143 0.87
19 1.6 144 2.1
5.8 145 1.2
21 14. 146 1.5
22 3.4 147 1.0
15
23 1.3 148 0.52
24 1.0 149 0.93
1.9 150 3.1
26 4.7 151 0.43
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27 1.7 152 2.4
28 100 153 0.37
29 100 154 1.9
30 1.1 155 052
31 100 156 3.9
32 1.4 157 1.6
33 2.5 1 S 8 2.8
34 3.1 159 1.5
35 0.11 160 0.90
36 0.14 161 0.62
37 16. 162 1.2
38 100 163 0.48
39 5.1 164 0.65
40 81 165 0.26
41 .09 166 0.59
42 2.8 167 3.3
43 6.8 168 1.5
44 13 169 3.3
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45 5.2 170 1.0
46 1.1 171 0.95
47 1.5 172 5.0
48 1.5 173 0.58
49 2.2 174 1.5
50 3.7 175 2.1
51 5.0 176 3.4
52 6.1 177 2.0
53 1.8 178 11.
54 2.6 179 4.9
55 2.7 180 2.0
56 12. 181 9.8
57 3.1 182 8.0
58 3.5 183 8.7
59 1.5 184 0.43
60 18. 185 1.8
61 13. 186 1.1
62 7.6 187 1.2
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63 20. 188 1.6
64 19 189 1.5
65 5.6 190 1.3
66 10. 191 2.5
s
67 13. 192 1.2
68 3.8 193 2.5
69 5.3 194 1.4
70 5.4 195 1.3
71 12. 196 0.82
72 9.2 197 0.58
73 6.8 198 0.84
74 30. 199 1.0
75 9.4 200 1.5
76 100 201 0.71
77 3.3 202 8.3
78 1.8 203 4.9
79 0.10 204 3.8
80 1.3 205 2.5
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WO 99/57098 PCT/US99/09641
81 1.8 206 10.
82 38. 207 4.1
83 26. 208 2.7
84 3.3 209 14.
85 3.2 210 2.3
86 1.7 211 2.4
87 2.7 212 1.7
88 2.2 213 2.6
89 6.6 214 2.8
to
90 2.3 215 1.3
91 2.3 216 1.8
92 1.4 217 1.8
93 5.4 218 0.46
94 0.91 219 1.8
95 5.2 220 5.5
96 2.9 221 5.4
97 3.0 222 0.20
98 0.58 223 0.88
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WO 99/57098 PCT/US99/09641
99 35 224 0.43
100 5.9 225 0.35
101 0.31 226 0.97
102 13 227 0.88
103 100 228 0.93
104 28 229 1.2
105 19. 230 34.
106 100 231 2.5
107 1.2 232 100
108 0.63 233 2.7
109 1.7 235 0.97
110 1.0 236 1.9
111 8.2 237 5.1
112 1.5 238 2.7
is
113 5.5 239 4.2
114 20. 240 0.76
115 1.5 241 0.96
116 0.67 242 1.6
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117 0.87 243 1.1
118 16. 244 1.5
119 8.9 245 1.2
120 1.1 246 0.39
121 2.6 247 0.57
122 2.8 248 1.0
123 2.7 249 0.41
124 7.0
125 0.45
Pharmaceutical Compositions
The pharmaceutical compositions of the present invention comprise a
therapeutically effective amount of a compound of the present invention
formulated
together with one or more pharmaceutically acceptable Garners. As used herein,
the term
"pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-
solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of any type.
Some examples
of materials which can serve as pharmaceutically acceptable carriers are
sugars such as
lactose, glucose and sucrose; starches such as corn starch and potato starch;
cellulose and
its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and
cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and
suppository
waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil;
olive oil; corn oil
and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate
and ethyl
laurate; agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide;
alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and
phosphate buffer solutions, as well as other non-toxic compatible lubricants
such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents, releasing
agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives and
antioxidants can also
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WO 99/57098 PCTNS99/09641
be present in the composition, according to the judgment of the formulator.
The
pharmaceutical compositions of this invention can be administered to humans
and other
animals orally, rectally, parenterally, intracisternally, intravaginally,
intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an oral or
nasal spray.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the
active compounds, the liquid dosage forms may contain inert diluents commonly
used in the
art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl
l0 benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils
(in particular,
cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of
sorbitan, and
mixtures thereof. Besides inert diluents, the oral compositions can also
include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and
perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or
wetting agents and suspending agents. The sterile injectable preparation may
also be a
sterile injectable solution, suspension or emulsion in a nontoxic parenterally
acceptable
diluent or solvent, for example, as a solution in 1,3-butanedioi. Among the
acceptable
vehicles and solvents that may be employed are water, Ringer's solution,
U.S.P. and
isotonic sodium chloride solution. In addition, sterile, fixed oils are
conventionally
employed as a solvent or suspending medium. For this purpose any bland fixed
oil can be
employed including synthetic mono- or diglycerides. In addition, fatty acids
such as oleic
acid are used in the preparation of injectables. The injectable formulations
can be sterilized,
for example, by filtration through a bacterial-retaining filter, or by
incorporating sterilizing
agents in the form of sterile solid compositions which can be dissolved or
dispersed in
sterile water or other sterile injectable medium prior to use. In order to
prolong the effect
of a drug, it is often desirable to slow the absorption of the drug from
subcutaneous or
intramuscular injection. This may be accomplished by the use of a liquid
suspension of
crystalline or amorphous material with poor water solubility. The rate of
absorption of the
drug then depends upon its rate of dissolution which, in turn, may depend upon
crystal size
and crystalline form. Alternatively, delayed absorption of a parenterally
administered drug
form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable
depot forms are made by forming microencapsule matrices of the drug in
biodegradable
polymers such as polylactide-polyglycolide. Depending upon the ratio of drug
to polymer
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WO 99/57098 PC'f/US99/09641
and the nature of the particular polymer employed, the rate of drug release
can be
controlled. Examples of other biodegradable polymers include poly(orthoesters)
and
poly(anhydrides). Depot injectable formulations are also prepared by
entrapping the drug
in liposomes or microemulsions which are compatible with body tissues.
Compositions for
rectal or vaginal administration are preferably suppositories which can be
prepared by
mixing the compounds of this invention with suitable non-irntating excipients
or carriers
such as cocoa butter, polyethylene glycol or a suppository wax which are solid
at ambient
temperature but liquid at body temperature and therefore melt in the rectum or
vaginal
cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders,
and granules. In such solid dosage forms, the active compound is mixed with at
least one
inert, pharmaceutically acceptable excipient or carrier such as sodium citrate
or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose,
mannitol, and silicic acid, b) binders such as, for example,
carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as
glycerol, d) disintegrating agents such as agar-agar, calcium carbonate,
potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate, e) solution
retarding agents
such as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g)
wetting agents such as, for example, cetyl alcohol and glycerol monostearate,
h) absorbents
such as kaolin and bentonite clay, and i) lubricants such as talc, calcium
stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and
mixtures thereof.
In the case of capsules, tablets and pills, the dosage form may also comprise
buffering
agents. Solid compositions of a similar type may also be employed as fillers
in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high
molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can
be
prepared with coatings and shells such as enteric coatings and other coatings
well known in
the pharmaceutical formulating art. They may optionally contain opacifying
agents and can
also be of a composition that they release the active ingredients) only, or
preferentially, in
a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of
embedding compositions which can be used include polymeric substances and
waxes.
Solid compositions of a similar type may also be employed as fillers in soft
and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high
molecular weight polyethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more
excipients as noted above. The solid dosage forms of tablets, dragees,
capsules, pills, and
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granules can be prepared with coatings and shells such as enteric coatings,
release
controlling coatings and other coatings well known in the pharmaceutical
formulating art.
In such solid dosage forms the active compound may be admixed with at least
one inert
diluent such as sucrose, lactose or starch. Such dosage forms may also
comprise, as is
normal practice, additional substances other than inert diluents, e.g.,
tableting lubricants
and other tableting aids such a magnesium stearate and microcrystalline
cellulose. In the
case of capsules, tablets and pills, the dosage forms may also comprise
buffering agents.
They may optionally contain opacifying agents and can also be of a composition
that they
release the active ingredients) only, or preferentially, in a certain part of
the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions which can
be used
include polymeric substances and waxes.
Dosage forms for topical or transdenmal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders,
solutions, sprays,
inhalants or patches. The active component is admixed under sterile conditions
with a
pharmaceutically acceptable carrier and any needed preservatives or buffers as
may be
required. Ophthalmic formulation, ear drops, eye ointments, powders and
solutions are
also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active
compound of this invention, excipients such as animal and vegetable fats,
oils, waxes,
paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols,
silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this.
invention,
excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium
silicates and
polyamide powder, or mixtures of these substances. Sprays can additionally
contain
customary propellants such as chlorofluoro-hydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery
of a
compound to the body. Such dosage forms can be made by dissolving or
dispensing the
compound in the proper medium. Absorption enhancers can also be used to
increase the
flux of the compound across the skin. The rate can be controlled by either
providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
Therapeutic Administration
According to the methods of treatment of the present invention, disorders
caused by
undesirable angiogenesis are treated or prevented in a patient such as a human
or lower
mammal by administering to the patient a therapeutically effective amount of a
compound
of the invention, in such amounts and for such time as is necessary to achieve
the desired
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resultr By a "therapeutically effective amount" of a compound of the invention
is meant a
sufficient amount of the compound to inhibit angiogenesis, at a reasonable
benefidrisk ratio
applicable to any medical treatment. It will be understood, however, that the
total daily
usage of the compounds and compositions of the present invention will be
decided by the
attending physician within the scope of sound medical judgment. The specific
therapeutically effective dose level for any particular patient will depend
upon a variety of
factors including the disorder being treated and the severity of the disorder;
the activity of
the specific compound employed; the specific composition employed; the age,
body weight,
general health, sex and diet of the patient; the time of administration, route
of
administration, and rate of excretion of the specific compound employed; the
duration of
the treatment; drugs used in combination or coincidental with the specific
compound
employed; and like factors well known in the medical arts. However, a well-
known
technique utilized by medical practitioners is to "dose titrate" the patient;
that is, to start
with dose lower than that required to obtain the desired effect, and to
gradually increase the
dose until the dseired therapeutic benefit is obtained.
The total daily dose of the compounds of this invention administered to a
human or
other mammal in single or in divided doses can be in amounts, for example,
from 0.01 to 50
mg/kg body weight or more usually from 0.11 to 25 mg/kg body weight. Single
dose
compositions may contain such amounts or
submultiples thereof to make up the daily dose. In general, treatment regimens
according
to the present invention comprise administration to a patient in need of such
treatment from
about 1 mg to about 500 mg of the compounds) of this invention per day in
single or
multiple doses.
General ~nthetic Methods
As shown in Reaction Scheme 1, 3-amino-2-hydroxy-carboxylic acids used as
starting materials for the synthesis of compounds of the present invention are
available from
appropriately substituted alpha-aminoacids by conversion to the corresponding
aminoaldehyde, formation of the corresponding cyanohydrin, and hydrolysis.
Protection of
the free amino group, for example with a tert-butyl carbamate group, followed
by coupling
with an appropriate amine, amino acid derivative, or alcohol and deprotection
provides the
target compounds. The coupling partners may be purchased from commercial
sources or
prepared using known chemical transformations. Subsequent conversion of the 3-
amino-2-
hydroxy compounds to compounds of the present invention are by standard
methods well
known to practitioners of the organic chemical arts and are illustrated by the
Examples
which appear below.
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S~ S~
Boc~N OH --~ Boc~N OH --~ Boc~N OH
H H H
O O O
S~
--~ ~ Boc~N C02H
H
OH
S~
O O
Boc," ''
NHR HpN NHR
H H
The compounds and processes of the present invention will be better understood
in
connection with the following examples, which are intended as an illustration
of and not a
limitation upon the scope of the invention.
Example 1
(2RS,3S.1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(meth)rlthio?pentanamide
hydrochloride
Example lA
A solution of N (tert-butoicycarbonyl)-L-methionine (12.47 g, 50 mmol) and RED-
AL (50 mmol) in dry toluene (1,25 mL) was stirred at 0 °C for 30
minutes, then at ambient
temperature for 1 hour. The mixture was treated with aqueous Rochelle salt and
extracted
with ethyl ether. The extract was washed sequentially with brine and aqueous
NaHC03,
dried (MgS04), and concentrated to give a colorless syrup (9.05 g).
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Example 1B
A solution of the product of example lA (9.05 g, 38.5 mmol), sulfur trioxide
pyridine complex {30.64 g, 192.5 mmol) and triethylamine (26.8 mL, 192.5 mmol)
in
DMSO (30 mL) was stirred at ambient temperature for 30 minutes, cooled to 0
°C, then
treated sequentially with water (20 mL) and saturated aqueous KHS04 ( 120 mL),
and
extracted with ethyl acetate. The extract was washed sequentially with
saturated aqueous
KHSO4 and brine, dried (MgS04), and concentrated to give a colorless syrup
(9.00 g).
Example 1C
A solution of the product of example 1B (9.00 g, 38.5 mmol), and sodium
bisulfate
(3.80 g, 36.6 mmol) in water (200 mL) was stirred at 5 °C for 72 hours,
warmed to
ambient temperature, then treated with potassium cyanide (2.51 g, 38.6 mmol)
in ethyl
acetate (250 mL) for 4 hours. The separated ethyl acetate layer was washed
sequentially
with water and brine, dried (MgS04), and concentrated to give a colorless
syrup, which
was dissolved in dioxane (75 mL) and 12 N HCl (75 mL), then heated at reflux
for 16 h.
The mixture was concentrated in vacuo and redissolved in water (8 mL) and
acetone (300
mL), the pH adjusted to 5.5 with 1 N NaOH, and the resulting solid collected
by filtration
and dried to provide 5.81 g solid material.
MS (ESI+Q1MS) m/e 180: (M+ H)+, 202 (M+ Na)+; (ESI-Q1MS) m/e: 178 (M- H)-
1H NMR (300 MHz, D20) 8 4.25 (d, 0.5H), 4.14 (d, 0.5H), 3.78 (m, 0.5H), 3.66
(m,
0.5H), 2.65 (m, 2H), 2.13 (s, 1.5H), 2.09 (s, 1.5H), 1.93 (m, 2H).
Example 1D
A solution of the product of example 1C (5.81 g, 32.4 mmol), BOC-ON (9.58 g,
38.9 mmol) and triethylamine (6.77 mL, 48.6 mmol) in water (70 mL) and dioxane
(70 mL)
was stirred at 45 °C for 5 hours, diluted with ethyl acetate and 10%
aqueous KHS04 then
extracted with ethyl acetate. The extract was washed sequentially with water
and brine,
dried {MgS04), and concentrated to give (2RS,3S) 3-(tert-butoxycarbonylamino)-
2-
hydroxy-5-(methylthio)pentanoic acid. (4.05 g).
MS (ESI+Q1MS) m/e 280: (M+ H)+, 302 (M+ Na)+, 581 (2M+ Na)+; (ESI-Q1MS) m/e
278: (M- H)-.
Example lE
A solution of example 1D {2.79 g, 10 mmol), L-alanine ethylester hydrochloride
(1.84 g, 12 mmol), EDCI (2.30 g, 12 mmol), HOBT (1.84 g, 12 mmol) and NMM
(1.32
mL, 12 mmol) in CH2C12 (35 mL) was stirred at ambient temperature for 16
hours,
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evaporated to dryness, redissolved in ethyl acetate then washed sequentially
with aqueous
NaHC03, brine, 10% aqueous KHS04 and brine, dried (MgS04), and concentrated.
The
residue was purified by flash chromatography on silica gel with 50% ethyl
acetate/toluene
to provide the designated compound (2.74g).
MS (ESI+Q1MS) m/e 379 (M+H)+, 396 (M+Na)+, 279 (M+H-BOC)+.
Example 1 F
A solution of the product of example lE (0.40 g, 1.1 mmol), in hydrogen
chloride
saturated dioxane (8 mL) was stirred at ambient temperature for 1 hour,
evaporated to
dryness, suspended in ethyl ether then concentrated and vacuum dried to give
the title
compound (0.24 g).
MS (ESI+Q1MS) m/e 279 (M+H)+, 557 (2M+H)+;
1H NMR (300 MHz, DMSO-d6) b 8.46 (d. 0.6H), 8.43 (d, 0.4H), 8.14 (br. 1H),
7.97 (br.,
1H), 6.63 (d, 0.6H), 6.51 (d, 0.4H), 4.05-4.38 {m, 5H), 2.42-2.67 (m, 2H),
2.04 (s, 1.8H),
2.01 (s, 1.2H), 1.65-1.96 (m, 2H), 1.35 (d, 0.6H), 1.33 (d,l.2H), 1.17-1.23
(dt, 1.8H).
Example 2
(2RS.3S.1'S)-N-(~1-Ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5
(methylthio)pentanamide hydrochloride
The product of example 1D and alanine ethylamide were processed as in examples
lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 278 (M+H)+, 300 (M+Na)+; .
1H NMR (300 MHz, D20) 8 4.28-4.52 (m, 2H),. 3.83-3.88 (m, 0.5H), 3.72-3.78 (m,
0.5H), 3.22 (q, 2H), 2.52-2.73 (m, 2H), 1.83-2.17 (m, 5H), 1.41 (d, 3H), 1.11
(t, 1.5H),
1.10 (t, 1.5H).
Example 3
(2RS,3R,1'S)-N-(( 1-Ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5
(methylthio)~entanamide hydrochloride
Example 3A
N (tert-butoxycarbonyl)-D-methionine was processed as in examples lA through
1D to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-
(methylthio)pentanoic
acid.
Example 3B
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The product of example 3A and L-alanine ethylamide wem processed as in example
2 to provide the title compound.
MS (ESI+Q1MS) m/e 278 (M+H)+, 300 (M+Na)+;
1H NMR (300 MHz, D20) 8 4.27-4.52 (m, 2H), 3.85-3.92 (m, O.SH), 3.74-3.81 (m,
O.SH), 3.17-3.26 (m, 2H), 2.52-2.74 (m, 2H), 1.85-2.17 (m, SH), 1.42 (d, 3H),
1.12 (t,
3H).
Example 4
(2RS.3R.1'S)-N-(( 1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-S-
(methylthio)pentanamide
hydrochloride
The product of example 3A and L-alanine ethylester hydrochloride were
processed
as in example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 279 (M+H)+, 301 (M+Na)+;
1H NMR (300 MHz, D20) 8 4.37-4.53 (m, 2H), 4.24 (q, 2H), 3.86-3.93 (m, 0.4H),
3.73-
3.78 (m, 0.6H), 2.53-2.77 (m, 2H), 1.89-2.17 (m, SH), 1.48 (d, 3H), 1.28 (t,
3H).
Example 5
s2RS.3R)-N-((2-phenylethvl)-3-amino-2-hvdroxy-5-(meth ly thio)pentanamide
l~drochloride
The product of example 3A and 1-amino-2-phenylethane were processed as in
example 2 to provide the title compound.
MS (APCI+) m/e 283 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.20 (m, 1H), 7.80 (m, 2H), 7.30 (m, 2H), 7.21 (m,
3H), 6.50 (m, 1H), 4.09 (m, 1H), 3.40 (m, 3H), 2.79 (m, 2H), 2.53 (m, 2H),
2.04 (s, 3H),
1.68 (m, 2H).
Example 6
(2RS.3R~)-N-ll3-phenylpropyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide
hydrochloride
The product of example 3A and 1-amino-3-phenylpropane were processed as in
example 2 to provide the title compound.
MS (APCI+) m/e 297 (M+H)+;
iH NMR (300 MHz, DMSO-d6) 8 8.20 (m, 1H), 7.82 (m, 2H), 7.28 (m, SH), 6.54 (d,
0.6H), 6.47 (d, 0.4H), 4.09 (m, 1H), 3.40 (m, 2H), 2.68 (m, 2H), 2.57 (m, 2H),
2.05 (s,
1.8H), 1.98 (s, 1.2H), 1.68 (m, 2H).
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Example 7
2RS.3R)-N-(4-phenvlhut r~-1~-3-amino-2-hvdroxv-5-(methvlthio)pentanarnide
hydrochloride
The product of example 3A and 1-amino-4-phenylbutane were processed as in
example 2 to provide the title compound.
MS (APCI+) m/e 311 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.18 (m, 1H), 7.82 (m, 2H), 7.22 (m, SH), 6.45 (m,
1H), 4.09 (m, 1H), 3.39 (rn, 1H), 3.15 (m, 2H), 2.56 (m, 4H), 2.03 (s, 3H),
1.80 (m, 2H),
1.51 (m, 4H).
. Example 8
(2RS.3R) N-(2-(4-methoxyphenvl)ethyl)-3-amino-2-hvdroxv-5-
(methylthio)nentanamide
hydrochloride
The product of example 3A and 1-amino-2-(4-methoxyphenyl)ethane were
processed as in example 2 to provide the title compound.
MS (APCI+) m/e 313 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.17 (m, 1H), 7.87 (bds, 2H), 7.12 (s, 2H), 6.86
(d,
2H), 6.5 (m, 1H), 4.1 (m, 1H), 3.72 (s, 3H), 3.30 (m, 2H), 2.70 (m, 2H), 2.54
(m, 2H),
2.05 (s, 3H), 1.78 (m, 2H).
Example 9
(2RS.3R)-N-(2-(4-sulfonamidophen~lethyl)-3-amino-2-hydroxy-5
(methylthio)pentanamide hydrochloride
The product of example 3A and 1-amino-2-(4-sulfonamidophenyl)ethane were
processed as in example 2 to provide the title compound.
MS (APCI+} m/e 362 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.24 (m, 1H), 7.84 (m, 2H}, 7.75 (d, 2H), 7.42 (d,
2H),
7.32 (s, 2H), 6.52 (d, 1H), 4.09 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 2.86 (m,
2H), 2.58
(m, 2H), 2.04 (s, 3H), 1.67 (m, 2H).
Example 10
(2RS.3R)-N-(2-(2-pvridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide
dihydrochloride
The product of example 3A and 1-amino-2-(2-pyridyl)ethane were processed as in
example 2 to provide the title compound.
MS (APCI+) m/e 284 (M+H)+;
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1H NMR (300 MHz, DMSO-d6) 8 8.74 (m, 1H), 8.38 (m, 2H), 8.10 (m, 1H), 7.90 (m,
2H), 7.78 (m, 2H), 4.09 (m, 1H), 3.70 (m, 2H), 3.57 (m, 2H), 3.49 (m, 2H),
2.57 {m, 1H),
2.04 {s, 3H), 1.80 (m, 2H).
Example 11
~2RS 3R)-N-(2-(4=pheno~rphenvl)ethyl)-3-amino-2-hvdroxy-5-(meth lty
hio)pentanamide
hydrochloride
The product of example 3A and 1-amino-2-(4-phenoxyphenyl)ethane were
processed as in example 2 to provide the title compound.
to MS (APCI+) m/e 375 (M+H)+;
iH NMR (300 MHz, DMSO-d6) 8 8.17 (m, IH), 7.69 (m, 2H), 7.39 (m, 2H), 7.23 (m,
2H), 7.13 (m, 1H), 6.98 (m, 4H), 6.50 (m, 1H), 4.09 (m, 1H), 3.38 (m,3H), 2.75
(m, 2H),
2.56 (m, 2H), 2.04 (s, 3H), 1.74 (m, 2H).
15 Example 12
~2RS,3Ri1'S)-N-((1-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-(eth
l~pentanamide
hydrochloride
Example 12A
20 N-(tert-butoxycarbonyl)-D-ethionine was processed as in examples IA through
ID
to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-
(ethylthio)pentanoic acid.
Example 12B
The product of example 12A and L-alanine ethylester hydrochloride were
processed
25 as in example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 293 (M+H)+, 585 (2M+H)+;
iH NMR (300 MHz, D20) 8 4.37-4.53 (m, 2H), 4.24 (q, 2H), 3.87-3.92 (m, 0.4H),
3.73-
3.79 (m, 0.6H), 2.68-2.82 (m, 2H), 2.52-2.65 (m, 2H), 1.91-2.16 (m, 2H), 1.47
(d, 3H),
1.20-1.30 {m, 6H).
Example 13
(2RS.3R)-N-(4-phen r~l)butyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide
hydrochloride
The product of example 12A and 1-amino-4-phenylbutane were processed as in
example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 325 (M+H)+, 347 (M+Na)+, 649 (2M+H)+, 671 (2M+Na)+;
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1H NMR (300 MHz, DMSO-d6) S 7.16-7.31 (m, 5H), 6.77 {br., 1H), 5.22 (br.d.,
0.6H),
5.01 (br.d., 0.4H), 4.23 (d. 0.4H), 4.12 (d, 0.6H), 3.94 (br.m. 1 H), 3.24-
3.36 (m, 2H),
2.46-2.68 (m, 6H), 1.94-2.16 (m, 2H), 1.47-1.62 (m, 4H), 1.19-1.28 (m, 3H).
Example 14
~2RS.3R)-N-l3-(carboethoxy)ethyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide
hydrochloride
The product of example 12A and ethyl 3-amino-propionate were processed as in
example 2 to provide the title compound.
l0 MS (ESI+Q1MS) m/e 293 (M+H)+" 315 (M+Na)+;
1H NMR (300 MHz, D20) 8 4.45 (d. 0.4H), 4.31 (d, 0.6H), 4.17 (q, 2H), 3.81-
3.87 (m,
0.4H), 3.67-3.77 (m, 0.6H), 3.44-3.63 (m, 2H), 2.52-2.74 (m, 6H), 1.75-2.12
(m, 2H),
1.19-1.28 (m, 6H).
15 Example 15
(2RS.3R)-N-(3-(carbobenz~y)ethyll-3-amino-2-h day 5-~ethylthio)pentanamide
hydrochloride
The product of example 12A and benzyl 3-amino-propionate were processed as in
example 2 to provide the title compound.
20 MS (ESI+Q1MS) m/e 355 (M+H)+, 377 (M+Na)+;
1H NMR (300 MHz, DMSO-d6) 8 7.45 (br.m., 5H), 5.18 (s, 2H), 4.41 (d. 0.4H),
4.21 (d,
0.6H), 3.46-3.87 (m, 3H), 2.43-2.72 (m, 6H), 1.70-2.03 (m, 2H), 1.16-1.26 (m,
3H).
Example 16
25 (2RS.3R)-N-(3-(carboethoxy)propel)-3-amino-2-hydroxy-5-
(ethylthio)pentanamide
hydrochloride
The product of example 12A and ethyl 4-amino-butyrate were processed as in
example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 307 (M+H)+, 325 (M+Na)+;
30 1H NMR (300 MHz, DMSO-d6) 8 4.46 (d. 0.4H), 4.32 (d, 0.6H), 4.17 (q, 2H),
3.83-3.88
(m, 0.4H), 3.71-3.80 (m, 0.6H), 3.20-3.41 (m, 2H), 2.58-2.79 (m, 2H), 2.52-
2.55 (m, 2H),
2.44 (t, 2H), 1.81-2.13 (m, 4H), 1.20-1.29 (m, 6H).
Example 17
35 (2RS.3R,1'S)-N-((1-ethoxycarbon ly )ethyl)-3-amino-2-h dy roxy-he~tanamide
hydrochloride
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Example 17A
N (tert-butoxycarbonyl)-D-norleucine was processed as in examples .lA through
1D
to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-heptanoic acid.
Example 17B
The product of example 17A and L-alanine ethyl ester hydrochloride were
processed as in example lE to provide the title compound.donnerg
MS (APCI) m/e 295 (M+H)+ ;
1H NMR (300 MHz, DMSO-d6) 8 8.39 (m, 1H), 7.89 (m, 1H), 7.74 (m, 1H), 6.48 (m,
l0 1H), 4.13 (m, 1H), 4.08 (m, 3H), 3.60 (m, 1H), 1.34 (m, 9H), 1.19 (m, 3H),
0.88 (m, 3H).
Example 18
(2RS,3R)-3-amino-2-hydroxy-5-fmethylthio)pentanoic acid
N (tert-butoxycarbonyl)-D-methionine was processed as in examples lA through
1C to provide (2RS,3R) 3-amino-2-hydroxy-5-(methylthio)pentanoic acid.
MS (APCI) m/e 180 (M+H)+ ;
iH NMR (300 MHz, DMSO-d6) 8 7.52 (bs, 2H), 3.64 (d, 1H), 3.50 (m, IH), 3.30
(m, 2H),
2.58 (m, 2H), 2.03 (s, 3H).
Example 19
(2RS.3R)-N-(2-(4-pvrid ly )ethyl)-3-amino-2-hydroxv-5-(methylthio)nentanamide
The product of example 3A and 1-amino-2-(4-pyridyl)ethane were processed as in
example 2 to provide the title compound.
MS (APCI) m/e 284 (M+H)+ ;
tH NMR (300 MHz, DMSO-d6) 8 8.78 (m, 2H), 8.32 (m, 1H), 8.10 (m, 1H), 7.90 (m,
1H), 7.84 (m, 2H), 4.22 (m, 1H), 4.08 (m, 1H), 3.49 {m, 2H), 3.04 (m, 2H),
2.55 (m, 2H),
2.04 (s, 3H), 1.75 {m, 2H).
Example 20
(2RS.3R)-N-(2-(carboethoxv)ethvl)-3-amino-2-hydroxy-4-phenyl-butanamide
hydrochloride
Example 20A
N (tert-Butoxycarbonyl)-D-phenylalanine was processed as in examples lA
through
1D to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-
butanoic acid.
Example 20B
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The product of example 20A and ethyl 3-amino-propionate were processed as in
example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 295 (M+H)+, 317 (M+Na)+
1H NMR (300 MHz, MeOH-d4) 8 1.19-1.26 (m, 3H), 2.49-2.58 (m, 2H), 2.80-3.10
(m,
2H), 3.41-3.53 (m, 2H), 3.78-3.85 (m, 1H), 4.03 (d, 0.6H), 4.07-4.16 (m, 2H),
4.27 (d,
0.4H), 7.25-7.40 (m, 5H); 3.10-3.19 (m, 1H), 4.02 (d, 1H), 4.29 (m, 1H); 7.10-
7.27 (m,
SH).
Example 21
(2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdrox~phenyl-butanamide
hvdrochloride
The product of example 20A and ethyl 4-amino-butyrate were processed as in
example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 309 (M+H)+, 325 (M+NH4)+
1H NMR (300 MHz, MeOH-d4) S 1.23 (dt, 3H), 1.75-1.87 (m, 2H), 2.32-2.38 (m,
2H),
2.82-3.38 (m ), 3.79-3.86 (m, 1H), 4.05-4.15 (m, 3H), 4.28 (d, 0.3H), 7.25-
7.40 (m, SH).
Example 22
~2RS,3R)-N-(4-phenylbutyl)-3-amino-2-h~droxy-4-phenyl-butanamide hydrochloride
The product of example 20A and 4-phenylbutylamine were processed as in example
2 to provide the title compound.
MS (ESI+Q1MS) m/e 327 (M+H)+, 653 (2M+H)+
iH NMR (300 MHz, MeOH-d4) b 1.47-1.69 (m, 4H), 2.65 (t, 2H), 2.80-3.39 (m ),
3.75-
3.84 (m, 1H), 4.03 (d, 0.7H), 4.29 (d, 0.3H), 7.08-7.39 (m, lOH).
Example 23
S2RS,3R,1'S)-N-((1-ethoxycarbon l~thyl)-3-amino-2-hydroxy-4-cycIohexyl-
butanamide
hydrochloride
Example 23A
N (tert-Butoxycarbonyl)-D-cyclohexylalanine was processed as in examples lA
through 1D to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-
cyclohexyl-
butanoic acid.
Example 23B
The product of example 23A and L-alanine ethyl ester hydrochloride were
processed as in example lE to provide the title compound.
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MS (ESI+Q1MS) m/e 301 (M+H)+, 601 (2M+H)+
iH NMR (300 MHz, MeOH-d4) S 0.90-1.82 (m, 19H, includes 1.27,t, 3H; 1.45, d,
3H)
3.57-3.65 (m, 3H), 4.15-4.23 {m, 3H), 4.45 (q, 2H);
Example 24
~,2RS 3R)-N-(2-(carboethoxyLthyl)-3-amino-2-hvdroxv-4-cyclohexyl-butanamide
hydrochloride
The product of example 23A and ethyl 3-amino-propionate were processed as in
example 2 to provide the title compound.
MS {ESI+Q1MS) m/e 301 (M+H)+, 323 (M+Na)+
1H NMR (300 MHz, MeOH-d4) b 0.93-1.84 (m, 16H, includes 1.26,t, 3H) 2.55-2.61
(m,
2H), 3.47-3.54 (m, 2H), 4.11-4.24 (m, 3H).
Example 25
(2RS 3R)-N-(3-(carboethoxy)oropyl)-3-amino-2-hvdroxv-4-cvclohexyl-butanamide
hydrochloride
The product of example 23A and ethyl 4-amino-butyrate were processed as in
example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 335 (M+Na-H)+;
1H NMR (300 MHz, MeOH-d4) 8 0.82-1.88 (m, 18H, includes 1.25,t, 3H), 2.34-2.39
(m,
2H), 3.18-3.38 {m, overlapped with MeOH peak), 3.57-3.67 (m, 2H), 4.08-4.25
(m, 3H).
Example 26
(2RS 3R 1'S)-N-((1-ethoxycarbon l~yl)-3-amino-2-hydroxy-4-phenyl-butanamide
hydrochloride
The product of example 20A and L-alanine ethyl ester hydrochloride were
processed as in example lE to provide the title compound.
MS (ESI+Q1MS) m/e 295 (M+ H)+;
1H NMR {300 MHz, MeOH-d4) 8 1.25 (dt, 3H), 1.44 (d, 3H), 2.83-3.17 (m, 2H),
3.76-
3.83 (m, 1H), 4.0$-4.21 (m, 3H), 4.35-4.47 (m, 1H), 7.25-7.40 (m, SH).
Example 27
y2RS,3R)-3-amino-2-hydroxy-N ~4-methoxv~henethyl)-5-
(methvlsulfanyl)pentanamide
hydrochloride
The product of example 23A and 1-amino-2-(4-methoxyphenyl~thane were
processed as in example 2 to provide the title compound.
MS (APCI) m/e 313 (M+H)+;
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1H NMR (300 MHz, DMSO-d6) 8 8.24 (m, 1H), 7.82 (m, 2H), 7.I2 (d, 2H), 6.86 (d,
2H),
6.53 (d, 1H), 4.08 (m, 1H), 3.72 (s, 3H), 3.38 (m, 2H), 2.70 (m, 2H), 2.54 (m,
2H), 2.04
(s, 3H), 1.75 (m, 2H).
Example 28
(2RS,3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hydroxv-S
(ethylthio)pentanamide
The product of examp1e12A and 4-phenylbutyl amine were processed as in example
lE to provide the title compound.
MS (APCI-Q1MS) m/e 459 (M+2NH4-H)+
iH NMR (300 MHz, MeOH-d4) 8 1.16-1.25 (dt, 3H), 1.39 (s, 0.4x9H), 1.43 (s,
0.6x9H),
1.52-1.84 (m, 6H), 2.43-2.55 (m, 3H), 3.14-3.26 (m, 1H), 3.99 (brd, 0.6H),
4.09 (brd,
0.4H), 7.10-7.27 (m, SH);
Example 29
(2RS,3RD-((2-nhenvlbutvl)-3-acetvlamino-2-hvdroxv-5-(ethvlthio)nentanamide
The product of example 13 and acetic anhydride were reacted in methylene
chloride
in the presence of triethylamine and purified on silica gel column
chromatography, eluting
with 1 % methanol in chloroform to provide the title compound.
MS (ESI+Q1MS) m/e 367 (M+H)+, 389 (M+Na)+, 733 (2M+H)+, 755 (2M+Na)+
1H NMR (300 MHz, MeOH-d4) 8 1.23 (t, 3H), 1.48 -1.68 (m, 4H), 1.73-1.93 (m,
SH,
includes, 1.87, s, 3H), 2.49-2.57 (m, 4H), 2.63 (t, 2H), 3.10-3.19 (m, 1H),
4.02 (d, 1H),
4.29 (m, 1H), 7.10-7.27 (m, SH);
Example 30
2RS,3R)-N-l(nhenvlbutvrvl)-3-amino-2-hvdroxv-4-cvclohexvl)butanamide
hydrochloride
The product of example 23A and 4-phenylbutyl amine were processed as in
examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 333 (M+ H)'", 665 (2M+ H)+
3o iH NMR (300 MHz, CDC13) 8 7.14-7.30 (m, SH), 5.04 (br. 0.7H), 4.82 (br.d,
0.3H), 4.17
(br., 0.3H), 4.04 (br.d, 0.7H), 3.86 (br.m, 1H), 3.22-3.36 (m, 2H), 2.63 (t,
2H), 0.80-1.83
(m, I9H).
Example 31
(2,RS,3R)-N-((nhenylbutyryl)-3-methoxycarbonylamino-2-hydroxY 4-
ethylthio)pentanamide hydrochloride
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The product of example 13 and methyl chloroformate were reacted in
tetrahydrofuran in the presence of triethylamine and purified on silica gel
column
chromatography, eluting with 0.5-0.75 % methanol in chloroform to provide the
title
compound.
MS (ESI+Q1MS) m/e 383 (M+ H)+, 400 (M+ NH4)+
1H NMR (300 MHz, CDCl3) 8 7.16-7.30 (m, SH), 6.73 (br.d, 1H), 5.1$ and 5.35
(both
br. d.,total 1H), 4.25 (br.d, 0.3H), 4.14 (d, 0.7H), 3.97-4.07 (m, 1H), 3.59
and 3.67 (both
s, total 3H), 3.23-3.37 (m, 2H), 2.45-2.68 (m, 6H), 1.90-2.12 (m, 2H), 1.52-
1.71 (m, 6H),
1.25 (tit, 3H).
Example 32
2RS,3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio~pentanamide
The product of example 3A and 1-amino-2-(3-pyridyl)ethane were processed as in
example 2 to provide the title compound.
MS (APCI) m/e 284 (M+H)+ ;
1H NMR (300 MHz, DMSO-d6) 8 8.74 (m, 1H), 8.38 (m, 2H), 8.10 (m, 1H), 7.90 (m,
2H), 7.78 {m, 2H), 4.09 (m, 1H), 3.70 (m, 2H), 3.57 (m, 2H), 3.49 (m, 2H),
2.57 (m, 1H),
2.04 (s, 3H), 1.80 (m, 2H).
Example 33
f2RS.3R)-3-amino-2-hydroxy-N-methyl-S-(methvlsulfan Iy )~N-
phenethylpentanamide
hydrochloride
The product of example 3A and 1-(N-methylamino)-2-phenylethane were processed
as in example 2 to provide the title compound.
MS (APCI) m/e 297 (M+H)+ ;
1H NMR (300 MHz, DMSO-d6) b 7.88 (m, 1H), 7.76 (m, 2H), 7.37 (m, SH), 6.38 (m,
1H), 4.42 (m, 1H), 4.23 (s, 3H), 3.70 (m, 4H), 3.49 {m, 3H), 3.05 (m, 1H),
2.92 (m, 1H),
2.04 (m, 3H).
Example 34
(2RS,3R.1'S)-N-((2-carboxvethyl)-3-amino-2-hydroxv-4-ethylthio~pentanamide
h d~loride
Following example 12B an intermediate product tert-butoxycarbonyl derivative
was
obtained. This was saponified by 1N lithium hydroxide in methanol-water to
obtain N
protected carboxylic acid derivative, which was then treated in the same
method described
in example 1F provide the title compound.
MS (ESI+Q1MS) m/e 265 (M+ H)+, 287 (M+ Na)+ ,529 (2M+ H)+, 551 (2M+Na)+
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iH NMR (300 MHz, D20) 8 2.75-2.50 (m, 4H), 2.12-1.90 (m, 2H), 1.40 (d, 3H),
1.24
(dt, 3H);
Example 35
(2RS,3R)-N-((1-methyl-1-ethoxycarboxyethyl) 3-amino-2-hydroxy-4
ethylthio)pentanamide hydrochloride
The product of example 12A and alpha aminoisobutyric acid ethyl ester
hydrochloride were.processed as in examples lE and 1F to provide the title
compound.
MS (ESI+Q1MS) m/e 307 (M+ H)+
1H NMR (300 MHz, MeOH-d4) 8 4.26-4.14 (m, 3H), 3:77-3.53 (m, 4H), 2.77-2.55
(m,
4H), 2.14-1.84 (m, 2H), 1.54-1.51 (m, 6H), 1.29-1.22 (m, 6H);
Example 36
(2RS,3R,1'S)-N-((1-(2-hvdroxv)-1-ethoxycarboxvethvl) 3-amino-2-h day-4
i5 ethylthio)pentanamide hydrochloride
The product of example 12A and L-serine ethyl ester hydrochloride were
processed
as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 309 (M+ H)+
iH NMR (300 MHz, D20) 8 4.67-4.63, (m, 1H) 4.57 (d, 0.3), 4.44 (d, 0.7H), 4.24-
4.15
(m, 2H), 4.06-3.87 (3H), 3.76-3.84 (m, 1H), 2.52-2.83 (m, 4H), 2.18-1.93 (m,
2H), 1.32-
1.20 (m, 6H);
Example 37
12RS,3R)-N-((phenylbut~ryl)-3-tert-butoxycarbonylamino-2-hydroxy-4
ethylthio)pentanamide
The product of example 12A and 4-phenylbutyl amine were processed as in
example lE to provide the title compound.
MS (ESI+Q1MS) m/e 439 (M+ H)+
iH NMR (300 MHz, CDCl3) 8 7.30-7.15 (m, SH), 7.03 (t, 1H), 3.34-3.26 (m, 2H),
2.73-
2.47 (m, 6H), 1.98-1.85 (m, 2H}, 1.73-1.53 (m, 6H), 1.46 (s, 9H), 1.28-1.21
(m, 3H).
Example 38
(2RS.3R)-N-((phenylbut~ryl)-3-formvlamino-2-hydroxy-4-eth~lthio)nentanamide
The product of example 13 and formic acid-acetic anhydride in methylene
chloride
in the presence of triethylamine were processed as in example lE, and purified
by silica gel,
eluting with 2% methanol in chloroform to provide the title compound.
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MS {ESI+Q1MS) m/e 353 (M+ H)+ , 375 (M+ Na)+ , 727 (2M+ Na)''
iH NMR (300 MHz, MeOH-d4) 8 7.26-7.11 (m, 5H), 4.44-4.38 (m, 1H), 4.05 (d,
0.7H),
4.00 (d, 0.3H), 3.27-3.12 (m, 2H), 2.63-2.49 (m, 4H), 1.93-1.30 (m, 8H), 1.26-
1.20 (m,
3H).
Example 39
(2RS.3R)-N-Methyl-N-((ethoxycarbonylmethvl)-~-amino-2-hydroxy-4
~thvlthio)pentanamide hydrochloride
The product of example 12A and sarcosine ethyl ester hydrochloride were
l0 processed as in examples 1 E and 1 F to provide the title compound.
MS (ESI+Q1MS) m/e 293 (M+ H)''
iH NMR (300 MHz, D20) 8 4.22-4.27 (m, 1H), 3.76 (s, 3H), 3.24-2.98 (m, 2H),
2.83-
2.54 (m, 6H), 2.23-1.92 (m, 4H), 1.31-1.19 (m, 6H).
Example 40
(2RS.3R)-N-((Phenylbutvryl)-3-hydroxymethylcarbonylamino-2-h,Ydroxy-4
eth lty hio)pentanamide hydrochloride
The product of example 13 and glycolic acid were processed as in examples lE
and
1F to provide the title compound.
MS (ESI+Q1MS) m/e 383 (M+ H)+, 405 (M+ Na)+, 787 (2M+ Na)+
iH NMR (300 MHz, MeOH-d4) 8 8.01 (br.t, 1H), 7.68 (d, 1H), 7.26-7.13 (m, 5H),
4.43-
4.32 (m, 1H), 3.94-3.85 (m, 1H), 3.78-3.65 (m, 1H), 3.26-3.15 {m, 2H), 3.24-
2.98 (m,
2H), 2.64-2.48 (m, 6H), 1.97-1.49 (m, 6H), 1.22 (t, 3H).
Exam.,ple 41
(2RS,3R,1'R)-N-((1-ethoxvcarbonvlethyl)-3-amino-2-hydroxy-4-
ethylthio)oentanamide
hydrochloride
The product of example 12A and D-alanine ethyl ester hydrochloride were
processed as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 293 (M+ H)+ ,
iH NMR (300 MHz, MeOH-d4) S 4.55-4.15 (m, 4H), 3.76-3.67 (m, 2H), 2.75-2.51
(m,
4H), 2.05-2.17 (m, 1H), 1.97-1.85 (m, 1H), 1.45 (t, 3H), 1.31-1.22 (m, 6H).
Example 42
(2RS,3R,1'R)-N-((1-ethoxycarbon l~,thvl)-3-amino-2-hydrox~r-4-
~clohexvl)butanamide
hydrochloride
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The product of example 23A and D-alanine ethyl ester hydrochloride were
processed as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 301 (M+ H)+ ,
1H NMR (300 MHz, MeOH-d4) 8 4.54-4.42 (m, 1H), 4.28-4.16 (m, 2H), 3.76-3.57
(m,
2H), 1.82-0.83 (m, 19H ).
Example 43
(2RS.3R)-N-((1-methyl-1-ethox c~nxlethvl)-3-amino-2-hydroxy-4
cyclohexyl)butanamide hydrochloride
The product of example 23A and alpha aminoisobutyric acid ethyl ester
hydrochloride were processed as in examples lE and 1F to provide the title
compound.
MS (ESI+Q1MS) m/e 315 {M+ H)+ , 629 (2M+ H)+ ,
1H NMR (300 MHz, MeOH-d4) 8 4.23-4.09 (m, 3H), 3.76-3.57 (m, 1H), 1.82-0.82
(m,
22H).
Example 44
(2RS.3R)-N-((Phenylbutyryl)-3-methox_ycarhonylmethylamino-2-hydrox
ethvlthio)pentanamide hydrochloride
The product of example 13 and methyl bromoacetate were reacted in
dimethylsulfoxide in the presence of sodium hydride and processed as in
example lE to
provide the title compound.
MS (ESI+Q1MS) m/e 397 (M+ H)+ , 419 {M+ Na)+,
1H NMR {300 MHz, CDC13) b 8.01(s, 1H), 7.31-7.16 (m, SH), 6.53 (br. 1H), 4.35-
4.25
(m, 1H), 3.85-3.71 (m, 4H), 3.33-3.25 (m, 2H), 2.68-2.48 (m, 6H), 1.97-1.49
(m, 6H),
1.22 (t, 3H), 1.99-1.50 (m, 8H), 1.28-1.19 (m, 3H).
Exam In a 45
(2RS,3R,1'S)-N-((1-ethoxvcarbon I~vl)-3-amino-2-hvdroxy-4-
benzylthio)butanamide
hydrochloride
Example 45A
N (tert-Butoxycarbonyl)-S-benzyl-D-cysteine was processed as in Example lA
through 1B to prepare N (tert-hutoxycarbonyl)-S-benzyl-D-cysteinal.
Example 45B
The product of example 286491.1A (3.56g, 12.1 mmol) was suspended in ice-cold
water (70 mL) and sodium bisulfate (1.26g, 12.1 mmol) was added, and stirred
at 0 °C for
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1.5 hours, and was then kept in a refrigerator for one over night. Ethyl
acetate (70 mL)
and potassium cyanide (0.79g, 12.1 mmol) were added and vigorously stirred for
4 hours.
The separated ethyl acetate layer was washed sequentially with water and
brine, dried
(MgS04), and concentrated to give a colorless syrup-to provide 3.40 g solid
material.
Example 45C
The product of example 45B (3.40g) was dissolved in 50 mL of methanol in an
ice
bath and hydrogen chloride gas was bubbled through the reaction mixture until
saturated.
It was then stirred at 0 °C for 3 hours and at room temperature for one
over night. Solvent
was evaporated dryness and 20 mL of water was added to the residue. 10%-Sodium
hydrogen carbonate was added to the mixture to adjust pH over 9, an oil was
extracted
with ethyl acetate (50 mLx2). The combined ethyl acetate layer was washed with
10%-
sodium hydrogen carbonate (2X), brine (3X), quickly dried over sodium sulfate
anhydrous.
Ethyl acetate was removed by evaporation to yield 1.77g of dark brown oil.
This was processed as in Example 1D, and purified by silica gel column
chromatography, eluting with 12.5 % acetone in hexane to yield 0.12g of (2RS,
3R)-3-(tert-
butoxycarbonylamino)-2-hydroxy-4-benzylthio-butanoic acid methyl ester.
Example 45D
The product of example 45C was treated with 1N-lithium hydroxide in methanol-
water to provide its free carboxylic acid derivatives and coupled with L-
alanine ethyl ester
as in example lE and deprotection was carned out according to the method
described in
example 1F to provide the title compound.
MS (ESI+Q1MS) m/e 341 (M+ H)+, 363 (M+ Na)+, 681 (2M+ H)+,
1H NMR (300 MHz, MeOH-d4) 8 7.38-7.22 (m, SH), 4.51-4.38 (m, 2H), 4.23-4.05
(m,
2H), 3.76-3.56 (m, 4H), 2.86-2.77 (m, 1H), 2.72-2.61 (m, 1H), 1.46-1.38 (m,
3H), 1.32-
1.16 (m, 3H).
Example 46
(2RS,3R,1'S)-N-((2-hydroxy-1-ethoxycarbonylethyl)-3-amino-2-hydrox
cyclohexyl)butanamide hydrochloride
The product of example 23A and L-serine ethyl ester hydrochloride were
processed
as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 317 (M+ H)+ , 633 (2M+ H)+,
1H NMR (300 MHz, MeOH-d4) 8 4.45-4.55 (m, 1H), 4.26-4.18 (m, 3H), 4.00-3.87
(m,
2H), 3.69-3.63 (m, 1H), 0.94-1.83 (m, 16H, includes 1.29 t, 3H).
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Example 47
(2RS,3R.1'S)-N-((2-acetoxvpropvl)-3-amino-2-hydrox~r-4-cyclohexyl)butanamide
hydrochloride
Example 47A
N (tert-Butoxycarbonyl)-L-alaninol (438 mg, 2.Smmo1) was dissolved in 5 mL of
methylene chloride in an ice bath and acetyl chloride (0.294 mL, 3.75 mmol),
followed by
triethylamine (0.7mL, 5 mmol) were added. It was then reacted at 0 °C
for 1 hour and at
room temperature for 2 days. The mixture was diluted with 25 mL of ethyl
acetate and the
organic layer was washed with 10%-sodium hydrogen carbonate (3x), brine (2x),
dried
over magnesium sulfate anhydrous, and then evaporated to dryness to yield 380
mg of N-
(tert-butoxycarbonyl)-O-acetyl-L-alaninol.
Example 47B
The product of example 47A (380 mg) was processed as in example 1F to yield
0.26g of its corresponding salt. This (0.26g, 1.69 mmol) was coupled with the
product of
example 23A (509mg, 1.69 mmol) according to the method described in example lE
and
purified by silica gel column eluting with 15% acetone in hexane to yield 0.35
g of N-(tert-
butoxycarbonyl) derivative. The obtained product (0.35 g) was processed as in
example
1F to give the title product (290mg).
MS (ESI+Q1MS) m/e 301 (M+ H)'' , 601 (2M+ H)+,
iH NMR (300 MHz, MeOH-d4) S 4.26-3.97 (m, 4H), 3.74-3.56 (m, 2H), 2.05, 2.03
(2.05, s, major, 2.03 s, minor, total 3H), 1.83-0.94 (m, 16H).
Example 48
(2RS.3R,2'S)-N-((2-nronionvloxypropyl)-3-amino-2-hydroxy-4-
cyclohexyl)butanamide
hydrochloride
Following the procedure of example 47A, but replacing acetyl chloride with
propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-L-alaninol.
This was
followed the procedure described in example 47B to give the title compound.
MS (ESI+Q1MS) m/e 315 {M+ H)+ , 629 (2M+ H)'',
1H NMR (300 MHz, MeOH-d4) S 4.25-3.97 (m, 4H), 3.74-3.56 (m, 2H), 2.40-2.32
(m,
2H), 1.83-0.94 (m, 19H).
Example 49
(2RS.3R.2'S)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4-~clohexyl)butanamide
hydrochloride
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Following the procedure of example 47A, but replacing acetyl chloride with
benzoyl
chloride, provided N (tert-butoxycarbonyl)-O-benzoyl-L-alaninol. This was
followed the
procedure described in example 47B to give the title compound.
MS (ESI+Q1MS) m/e 363 (M+ H)+, 725 (2M+ H)+; 747 (2M+ Na)'',
1H NMR (300 MHz, MeOH-d4) b 8.07-8.02 (m, 2H), 7.65-7.58 (m, 1H), 7.52-7.45
(m,
2H), 4.44-4.07 (m, 4H), 3.60-3.54 (m, 1H), 1.78-0.82 (m, 16H).
Example 50
(2RS.3R. 2'R)-N-((2-benzoylox~rpropvl)-3-amino-2-~droxy-4-
cvclohexyl)butanamide
hydrochloride
Following the procedure of example 47A, but replacing N (tert-butoxycarbonyl)-
L-
alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with
benzoyl chloride,
provided N-(tert-butoxycarbonyl)-O-benzoyl-D-alaninol. This was followed the
procedure
described in example 47B to give the title compound.
MS (ESI+Q1MS) m/e 363 (M+ H)+ , 725 (2M+ H)+,
1H NMR (300 MHz, MeOH-d4) 8 8.07-8.02 (m, 2H), 7.65-7.58 (m, 1H), 7.53-7.44
(m,
2H), 4.43-4.12 (m, 4H), 3.62-3.48 (m, 1H), 1.74-0.82 (m, 16H).
Example 51
f2RS,3R,2'R)-N-((2-nropionvloxypropvl)-3-amino-2-hvdroxy-4-
cvclohexyl~butanamide
hydrochloride
Following the procedure of example 47A, but replacing N (tert-butoxycarbonyl)-
L-
alaninol with N (tert-butoxycarbonyl)-D-alaninol and acetyl chloride with
propionyl
chloride, provided N (tert-butoxycarbonyl)-O-propionyl-D-alaninol. This was
followed the
procedure described in example 47B to give the title compound.
MS (ESI+Q1MS) m/e 315 (M+H)+, 629 (2M+ H)'',
1H NMR (300 MHz, MeOH-d4) b 4.23-4.00 (m, 4H), 3.62-3.53 (m, 1H), 2.43-2.32
(m,
2H), 1.82-0.94 (m, 19H).
Example 52
(2RS,3R,2'R)-N-((2-acetoxypropvl)-3-amino-2-hydroxy-4-cyclohex~)butanarnide
hydrochloride
Following the procedure of example 47A, but replacing N (tert-butoxycarbonyl)-
L-
alaninol with N-(tert-butoxycarbonyl)-D-alaninol, provided N (tert-
butoxycarbonyl)-D-
acetyl-D-alaninol. This was followed the procedure described in example 47B to
give the
title compound.
MS (ESI+Q1MS) m/e 301 (M+ H)+ , 601 (2M+ H)+,
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1H NMR (300 MHz, MeOH-d4) b 4.25-3.99 (m, 4H), 3.74-3.54 {m, 2H), 2.06, 2.04
(2.04, s, major, 2.06 s, minor, total 3H), 1.83-0.82 (m, 16H).
Example 53
(2RS.3R.1'S)-N-((1-benzvloxycarbonvlethyl)-3-amino-2-hydroxv-4-
cyclohex~,rl)butanamide
hydrochloride
The product of example 23A and L-alanine benzyl ester hydrochloride were
processed as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 363 (M+ H)+ , 725 {2M+ H)+,
l0 1H NMR (300 MHz, MeOH-d4) 8 7.38-7.32 (m, SH), 5.21-5.17 {m, 2H), 4.57-4.48
(m,
1H), 4.27-4.15 (m, 1H), 3.63-3.56 (m, 1H), 1.82-0.87 (m, 16H).
Example 54
~2RS.3R,1'S)-N-(4-ethoxycarbonvl-2-( 1'-aminoethylZthizole)-3-amino-2-hydroxv-
4
c~clohexyl)butanamide hydrochloride
Example 54A
N (tert-Butoxycarbonyl)-L-alanine amide (3.76g, 20 mmol) was suspended in 70
mL of methylene chloride in an ice bath and triethyloxonium
hexafluorophosphate (4.978,
20 mmol) was added. It was stirred at 0 oC for 30 minutes and at room
temperature for
one over night. Methylene chloride layer was washed with water (2x), 10%-
sodium
hydrogen carbonate (2x), water (2x), dried over sodium sulfate anhydrous. It
was then
evaporated to dryness, dried under high vaccum to yiels 2.72 g of iminoether.
MS
{ESI+Q1MS) m/e 217 (M+ H)+ , 433 (2M+ H)+, 455 (2M+Na)+
Example 54B
The product of example 54A (2.72g, 12.6 mmol) was dissolved in 40 mL of
ethanol
and L-cysteine ethyl ester hydrochloride (2.57g, 13.86 mmol) was added. It was
stirred at
room temperature for 2 days. Ethanol was removed by evaporation, and the
residue was
dsimcdy purified by silica gel column chromatography, eluting with 30% ethyl
acetate in
hexane to yield 2.91 g of pure thizoline analogue. MS (ESI+Q1MS) m/e 303 (M+
H)+ ,
325 (M+ Na)+,
Example 54C
To the product of example 54B (604mg, 2 mmol) in a 50 mL of round bottle flask
were addwd copper (I) bromide (316 mg, 1.1 mmol) and copper (II) acetate
anhydrous
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(0.40g, 2.2 mmol). The flask was evacuated with argon repeatedly and 15 mL of
benzene
was added via syringe. While stirring at 60 °C, tert-butyl perbenzoate
was carefully added
in a period of 15 minutes, and gently refluxed for 4 hours. The crude product
was directly
purified by silica gel column chromatography, eluting eith 30 % ethyl acetate
in hexane to
yield 390 mg of pure thiazole derivative. The obtained product (320 mg ) was
treated
according to the method as in example 1F and coupled with the product of
exariiple 23A as
in example lE to give N-(tert-butoxycarbonyl) derivative of the title compound
(220 mg).
Example 54D
The product of example 54C (60 mg) was processed as in example 1F to yield the
title compound.
MS (ESI+Q1MS) m/e 384 (M+ H)+ , 767 (2M+ H)+,
1H NMR (300 MHz, MeOH-d4) 8 8.38 , 8.34 (8.34, s, major, 8.38, s, minor both
1H),
5.51-5.27 (m, 1H), 4.43-4.23 (m, 4H), 3.71-3.57 (m, 1H), 1.70, d, 3H), 1.86-
0.88 (m,
19H, includes 1.37 t, 3H).
Example 55
(2RS.3R) N-(monodansylcadaveno)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide
dih~drochloride
The product of example 23A and monodansyl cadaverive were processed as in
examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 519 (M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 8.90 (d, 1H), 8.58 (d, 1H), 8.36 (d, 1H), 8.06 (d,
1H),
7.87 (q, 2H), 4.23 (d, 0.3H), 4.12 (d, 0.7H), 3.72-3.44 (m, 8H), 3.23-2.97 (m,
2H), 2.87 (t,
2H), 1.81-0.77 (m, 19H).
Example 56
(2RS.3R) N-(2-methvl-5-nitro imidazole-eil~l) 3-amino-2-hvdroxy-4
c cly ohexyl)butanamide dihydrochloride
The product of example 23A and 1-(2-aminoethyl)-2-methyl-5-nitro imidazole
were
processed as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 354 (M+ H)+, 707 (2M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 8.63 (mn, 1H), 8.52, 8.50 (both s, total 1H), 4.75-
4.56
(m, 2H), 4.1 I (d, 0.4H), 4.00 (d, 0.6H), 3.96-3.72 (m, 2H), 3.63-3.53 (m,
2H), 2.72 (s,
3H), 1.82-0.77 (m, 13H).
Example 57
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(2RS,3R) N-(5-nitrotwridvl-2-aminoethyl~ 3-amino-2-hydroxy-4-
cyclohexyl)butanamide
dihYdrochloride
The product of example 23A and 2-(2-aminoethylamino)-S-nitro-pyridine were
processed as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 366 (M+ H)+, 731 (2M+ H)+;
iH NMR (300 MHz, MeOH-d4) 8 8.94 (br.d, 1H), 8.41 (br. 1H), 7.90 (d, IH), 7.77
(d,
1H), 7.61-7.49 (m, 2H), 6.98 (br., 1H), 4.28 (d, 0.4H), 4.18 (d, 0.6H), 3.96-
3.72 (m, 2H),
3.77-3.42 (m, 6H), 2.72 (s, 3H), 1.80-0.77 (m, 13H).
Example 58
(2RS.3R) N-(5-methoxv-trwtaminyl) 3-amino-2-hydroxy-4-~rclohexyl)butanamide
dih drochloride
The product of example 23A and 5-methoxy tryptamine were processed as in
examples lE and 1F to provide the title compound.
is MS {ESI+Q1MS) m/e 374 (M+ H)+ , 747 (2M+ H)+ ,
iH NMR (300 MHz, MeOH-d4) 8 7.91 (m, 1H), 7.78 (d, 1H), 7.63-7.52 (m, 2H),
7.25-
7.06 (m, 1H), 4.24 (d, 0.3H), 4.13 (d, 0.7H), 3.93-3.82 (m, 4H, includes 3.84,
s, 3H),
3.75-3.44 (m, 4H), 3.00-2.87 (m, 2H), 1.76-0.66 (m, 13H).
Example 59
~2RS.3R) N-(3-O-methvl-dopaminyl) 3-amino-2-hydro~-4-cvclohexyl)butanamide
h dy rochloride
The product of example 23A and 3-O-methyl dopamine hydrochloride were
processed as in examples lE and 1F to provide the title compound.
MS (ESI+Q 1 MS) m/e 351 (M+ H)+ , 701 (2M+ H)'" ;
iH NMR (300 MHz, MeOH-d4) 8 7.90-7.74 (m, 1H), 7.60-7.46 (m, 1H), 6.84-6.65
(m,
3H), 4.21 (d, 0.3H), 4.10 (d, 0.7H), 3.85 (s, 3H), 3.62-3.34 (m, 4H), 2.75 (t,
2H), 1.82-
0.76 (m, 13H).
Example 60
(2RS.3R) N-(2-aminomethylbenzimidazolyl) 3-amino-2-hydroxy-4-
cyclohexyl)butanamide
hydrochloride
The product of example 23A and 2-(aminomethyl)benzimidazole dihydrochloride
monohydrate were processed as in examples lE and 1F to provide the title
compound.
MS (ESI+Q1IVIS) m/e 331 (M+ H)+ , 661 (2M+ H)+ ;
iH NMR (300 MHz, MeOH-dq,) 8 7.92-7.47 (m, SH), 4.46 (d, 0.3H), 4.39 (d,
0.7H),
3.77-3.56 (m, 2H), 1.84-0.83 (m, 13H).
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Example 61
((2RS,3R)-3-amino-2-hydroxv-4-c c~hexrl)butanoyl-L-alanyl-(2-methyl-5
nitroimidazol~thylLide~hydrochloride
Example 61A
The product of example 23A and L-alanine benzyl ester hydrochloride were
processed as in example lE to yield N (tert-butoxycarbonyl) drivative (3.80
g), which was
hydrogenated in 50 mL of ethanol in the presence of 0.3g of 10°!o
palladium on charcoal as
a catalyst for 3.5 hours. The mixture was passed through celite S4S and
evaporated to
dryness to yield (2RS,3R) N [(3-tent-butoxycarbonylamino-2-hydroxy-4-
cyclohexyl)butanoyl-L-alanine (3.16g)
Example 61B
The product of example 61A and 1-(2-aminoethyl)-2-methyl-S-vitro imidazole
were
processed as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 425 (M+ H)+, 849 (2M+ H)+,
1H NMR (300 MHz, MeOH-d4) b 8.58, 8.56 (both s, total 1H), 4.73-4.57 (m, 2H),
4.26-
4.17 (rn, 2H), 3.84-3.56 (m, 4H), 2.77 (s, 3H), 1.85-0.82 (m, 16H includes
1.34, d).
Example 62
((2RS,3R)-3-amino-2-h dy r~xv-4-cxclohexyl)butanoyl-L-alanyl-(5
nitropyridylaminoethyl)amide dihvdrochloride
The product of example 61 A and 2-(2-aminoethylamino)-S-vitro-pyridine were
processed as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 437 (M+ H)+ , 873 (2M+ H)+ ,
1H NMR (300 MHz, MeOH-d4) 8 8.94-8.37 (br. m, 1H), 7.92-7.75 (m, 1H), 7.62-
7.50
(m, 1H), 4.37-4.17 (m, 3H), 3.78-3.50 (m, SH), 1.85-0.80 (m, 16H).
Example 63
~(2RS.3R)-3-amino-2-hvdroxy-4-cyclohexyl)hutan~l-L-alanyl-(eth-
ylisonipecotate)amide
hydrochloride
The product of example 61A and ethyl isonipecotate were processed as in
examples
lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 412 (M+ H)+ , 823 (2M+ H)'
tH NMR (300 MHz, MeOH-d4) b 4.41-3.93 (m, 4H), 3.76-3.57 (m, 3H), 3.00-2.82
(m,
1H), 2.72-2.53 (m, 1H), 2.08-1.92 (m, 2H), 1.85-0.80 (m, 23H).
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Example 64
f(2RS.3R)-3-amino-2-hydroxv-4-c cl~vl)butano~rl-L-alan~l-(2
pyrrolidinoprop~)amide
. hydrochloride-
The product of example 61A and 1-(3-aminopropyl)-2-pyrrolidone were processed
as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 397 (M+ H)+, 793 (2M+ H)+,
1H NMR (300 MHz, MeOH-d4) b 4.38-4.24 (m, 2H), 3.74-3.56 (m, 2H), 3.52-3.43
(m,
2H), 3.27-3.08 (m, 2H), 2.41 (t, 2H), 2.12-2.00 (m, 2H), 1.84-1.70 (m, 8H),
1.53-0.91 (m,
lOH includes 1.42, d, 3H).
Example 65
f (2RS.3R)-3-amino-2-hydroxv-4-cyclohexvl)butanoyl-L-alanyl-(5
methoxytryptamine)amide hydrochloride
The product of example 61A and 5-methoxy tryptamine were processed as in
examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 455 (M+ H)+ , 889 (2M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 4.38-4.24 (m, 2H), 3.74-3.56 (m, 2H), 3.52-3.43
(m,
2H), 3.27-3.08 (m, 2H), 2.41 (t, 2H), 2.12-2.00 (m, 2H), 1.84-1.70 (m, 8H),
1.53-0.91 (m,
lOH includes 1.42, d, 3H).
Example 66
((2RS.3R)-3-amino-2-hvdroxv-4-cyclohexyl)butanoyl-L-alanvl-(3-O
methoxvdopamine)amide hydrochloride
The product of example 61A and 3-O-methoxydopamine hydrochloride were
processed as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 422 (M+ H)+ , 843 (2M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 6.80-6.63 (m, 4H), 4.38-4.16 (m, 2H), 3.84 (s,
3H),
3.67-3.56 (m, 1H), 3.44-3.35 (m, 2H), 2.72 (t, 2H), 1.85-0.82 (m, 16H includes
1.34, d,
3H).
Example 67
~(2RS,3R)-3-amino-2-hydroxy-4-cyclohe~cyl)butan ~l-L-alanyl-(2
henzimidazolemethyl)amide hydrochloride
The product of example 61A and 2-(aminomethyl)benzimidazole dihydrochloride
monohydrate were processed as in examples lE and 1F to yield the title
compound.
MS (ESI+Q1MS) m/e 402 (M+ H)+, 803 (2M+ H)+;
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iH NMR (300 MHz, MeOH-d4) 8 7.90-7.46 (m, SH), 4.54-4.44 (m, 1H), 4.24 (d,
0.7H),
3.75-3.48 (m, 2H), 1.80-0.83 (m, 16H includes 1.50, d, 3H).
Example 68
(l2RS.3R)-3-amino-2-hvdroxv-4-cvclohexyl)butanoyl-L-alanvl-(S=phenyl-pvrazole-
3~amide
hydrochloride
The product of example 61A and 3-amino-S-phenyl pyrazole were processed as in
examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 414 (M+ H)+ , 827 (2M+ H)+ ;
i0 1H NMR (300 MHz, MeOH-d4) 8 7.92-7.46 (m, SH), 6.80 (br., 1H), 4.64-4.56
(m, 1H),
4.33 (d, 0.3H), 4.24 (d, 0.7H), 3.75-3.56 (m, 2H), 1.84-0.93 (m, 16H).
Example 69
(2RS,3R)-3-amino-2-hydroxy-4-cyclohex l~tanoyl-L-alan~2-hydroxY S-nitro-
1)amide
iS hydrochloride
The product of example 61A and 2-amino-4-nitrophenol were processed as in
examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 409 (M+ H)+ , 817 (2M+ H)+ ,
iH NMR (300 MHz, MeOH-d4) b 9.03-8.96 (m, 1H), 7.98-7.77 (m, 2H), 7.47-7.60
(m,
20 1H), 4.SS-4.65 (m, 1H), 4.33 (d, 0.3H), 4.23 (d, 0.7H), 3.75-3.SS (m, 2H),
1.84-0.69 (m,
16H).
Example 70
(2RS.3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-L-alanyl-(S-bromothizole-
2)amide
25 ~drcxhloride
The product of example 61A and 2-amino-S-bromothiazole hydrobromide were
processed as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 433 (M+ H)+ , 867 {2M+ H)+ ;
iH NMR (300 MHz, MeOH-d4) 8 7.42 (s, 1H), 4.65-4.57 (m, 1H), 4.31 (d, 0.3H),
4.20
30 (d, 0.7H), 3.76-3.49 (m, 2H), 1.84-0.76 (m, 16H).
Example 71
(2RS.3R)-3-amino-2-hvdroxy-4-cyclohexvl)butanoyl-L-alanyl-(4-nitro-2-h
d~ro_xyphenyl
1 )amide hydrochloride
35 The product of example 61A and 2-amino-S-nitrophenol were processed as in
examples lE and 1F to yield the title compound.
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MS (ESI+Q1MS) m/e 409 (M+ H)+, 817 (2M+ H)+
1H NMR (300 MHz, D20) 8 8.08-7.98 (m, 1H), 7.85-7.68 (m, 2H), 4.68-4.57 (m,
1H),
3.76-3.49 (m, 2H), 1.88-0.80 (m, 16H).
Example 72
((2RS.3R)-3-amino-2-hvdroxy-4-cyclohexvl)butanoylL-alanvl-(,l-
ethylpyrazole)amide
hydrochloride
The product of example 61A and 5-amino-1-ethylpyrazole were processed as in
examples 1 E and 1 F to yield the title compound.
MS (ESI+Q1MS) m/e 366 (M+ H)+;
1H NMR (300 MHz, D20) 8 7.74-7.70 (br., 1H), 7.55 (br., 1H), 4.52-3.98 (m,
4H), 3.71-
3.b2 (m, 1H), 1.76-0.86 (m, 19H).
Example 73
((2RS.3R)-3-amino-2-hvdroxv-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide
hvdrochloride
The product of example 23A and ethyl isonipecotate were processed as in
examples
lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 341 (M+ H)+,
1H NMR (300 MHz, MeOH-d4) 8 4.14 (q, 2H), 3.73-3.48 (m, 2H), 0.83-1.93 (m,
20H).
Example 74
(2RS.3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(3-imidazolylpropyl)amide
dihydrochloride
The product of example 23A and 1-(3-aminopropyl)imidazole were processed as in
examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 309 (M+ H)+, 617 (2M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 9.04 (s, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 4.35-
4.21 (m,
3H), 3.42-3.16 (m, 2H), 2.18-2.07 (m, 2H), 0.82-1.83 (m, 15H).
Example 75
(2RS.3R)- 3-amino-2-hvdroxv-4-cyclohexyl)butanovl-(4-carboxyl-2-( 1'amino)e>~1
thizole
hydrochloride
The product of example 54C (0.2g, 0.414 mmol) was treated with 1N lithium
hydroxide (0.5 mL, 0.5 mmol) in methanol for 3 hours. 8 mL of water was added
to the
mixture, and methanol was removed by evaporation. The aqueous layer was washed
with
ethyl acetate, and acidified by an addition of 10 % potassium hydrogen
sulfate. The
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product was extracted with ethyl acetate ( 15 mL x2), and ethyl acetate layer
was washed
with brine (2x), dried over magnesium sulfate anhydrous. Evaporation of
solvent gave 160
mg, which was then precessed as in example 1F to obtain the title compound
(120 mg).
MS (ESI+Q1MS) m/e 356 (M+ H)+, 378 (M+ Na)+, 711 (2M+ H)+, 733 (2M+ Na)+ ;
1H NMR (300 MHz, D20) 8 8.20 (s, 1H), 5.40-5.29 (m, 1H), 4.34 (d, 0.3H), 4.27
(d,
0.7H), 3.69-3.53 (m, 2H), 1.72-0.73 (m, 16H).
Example 76
ethyl (2RS.3R.2'S)-2-y-3-(acetylamino)-4-cyclohexvl-2-
hvdroxvbutanovl)amino)propanoate
The product of example 23 (O.OSOg, 0.15 mmol), diisopropylethylamine (O.OSSmL,
0.31 mmol) and acetyl chloride (0.012 mL, 0.16 mmol) in dichloromethane was
stirred at
0°C for 2 hours, washed sequentially with aqueous sodium bicarbonate,
water and brine,
dried (MgS04), and concentrated to give the title compound.
MS (APCI) m/e 343 (M+ H)+ ;
IH NMR (300 MHz, MeOH-d4) 8 7.81 (m, 1H), 7.32 (m, 2H), 5.92 (d, 1H), 4.30 (m,
1H), 4.11 (m, 4H), 3.95 (m, 1H), 3.73 (m, 2H), 3.38 (m, 1H), 1.78 (s, 3H),
1.63 (6H), 1.32
(m, 2H), 1.23 (m, 9H), 0.89 (m, 1 H).
Example 77
(2RS.3R)-3-amino-2-hvdroxY-4-cyclohex~)butanoyl-(4
t~enzyloxycarbonylamino)butylamide hydrochloride
The product of example 23A and N-benzyloxycarbonyl-1,4-diaminobutane
hydrochloride were processed as in examples lE and 1F to yield the title
compound.
MS (ESI+Q1MS) m/e 406 (M+ H)+, 428 (M+ Na)'", 811 (2M+ H)'' ;
IH NMR (300 MHz, MeOH-d4) S 7.39-7.27 (m, SH), 5.06 (s, 2H), 4.23 (d, 0.3H),
4.14
(d, 0.7H), 3.73-3.56 (m, 2H), 3.27-3.08 (m, 4H), 1.84-0.80 (m, 17H).
Example 78
~2RS.3R)-3-amino-2-hydroxy-4-cyclohexvl)butanoyl-beta-alanine benzyl ester
hydrochloride
The product of example 23A and benzyl N-(2-aminoethyl)carbamate hydrochloride
were processed as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 378 (M+ H)+, 400 (M+ Na)+
IH NMR (300 MHz, MeOH-d4) 8 7.39-7.27 (m, SH), 5.07 (s, 2H), 4.22 (d, 0.3H),
4.14
(d, 0.7H), 3.76-3.56 (m, 2H), 3.45-3.15 (m, 4H overlapped with MeOH peak ),
1.84-0.91
(m, 13H).
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Example 79
~2RS.3R)-3-amino-2-h dy roxy-4-cyclohexyl)butanoyl-monodansylcadaverine amide
dihvdrochloride
The product of example 12A and monodansyl cadaverine were processed as in
examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 511 (M+ H)+, 533 (M+ Na)+ ;
1H NMR (300 MHz, MeOH-d4) b 8.87 (d, 1H), 8.55 (d, 1H), 8.35 (d, 1H), 8.02 {d,
1H),
7.88-7.82 (m, 2H), 4.26 (d, 0.4H), 4.18 {d, 0.6H), 3.70-3.56 (m, 2H), 3.43 (s,
6H), 3.22-
2.98 (m, 2H), 2.87 (t, 2H), 2.73-2.63 (m, 2H), 2.59-2.46 (m, 2H), 2.12-1.78
(m, 3H),
1.50-1.34 (m, 4H), 1.29-1.18 (m, 4H).
Example 80
(2RS.3R)-3-amino-2-h d~ r~xy-4-cyclohexyl)butanoyl-(4-(4
taluenesulfonvl)aminobutvl)amide hydrochloride
Example 80A
Following example 77, the product of example 23A and N benzyloxycarbonyl-1,4-
diaminobutane hydrochloride were coupled as in examples lE to yield the both
protected
compound. The product (260 mg) was hydrogenated in 10 mL of ethanol in the
presence
of 30 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same
method
described in Example 61A to yield 200 mg. MS {ESI+Q1MS) m/e 372 (M+ H)+
Example 80B
The product of example 80A (92.8 mg, 0.25 mmol) was dissolved in 5 mL of
methylene chloride in an ice bath, and diisopropylethylamine (0.048 mL, 0.275
mmol) and
p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol) were added. It was reacted at
0 °C for 3
hours and at room temperature for over night. Methylene chloride was removed
and the
residue was purified by silica gel column chromatography, eluting with 15-30%
acetone in
hexane. The obtained product was processed as in example 1F to yield the title
compound
(70 mg).
MS (ESI+Q1MS) m/e 426 (M+ H)+, 448 (M+Na)+, 533 (M+ Na)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.73 (d, 2H), 7.37 (d, 2H), 4.22 (d, 0.4H), 4.13
(d,
0.6H), 3.74-3.56 (m, 2H), 3.25-3.07 (m, 1 H), 2.84 (t, 2H), 2.43 (s, 3H), 1.84-
0.81 (m,
17H).
Example 81
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(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-4-
toluenesulfonylaminoethyDamide
hydrochloride
Example 81A
Following example 77, the product of example 23A and benzyl N (2-
aminoethyl)carbamate hydrochloride were coupled as in example lE to yield the
protected
compound. The product (220 mg) was hydrogenated in 10 mL of. ethanol in the
presence
of 20 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same
method
described in example 61A to yield 130 mg. MS (ESI+Q1MS) m/e 344 (M+ H)+
Example 81B
The product of example 81A (42.8 mg, 0.125 mmol) and p-toluenesulfonyl
chloride
(23.8 mg, 0.125 mmol) were processed as in example 80B to yield the title
compound (20
mg).
MS (ESI+Q1MS) m/e 426 (M+ H)+, 448 (M+Na)'', 533 (M+ Na)+ ;
iH NMR (300 MHz, MeOH-d4) 8 7.73 (d, 2H), 7.38 (d, 2H), 4.23 (d, 0.4H), 4.15
(d,
0.6H), 3.76-3.56 (m, 2H), 3.25-3.07 (m, 1 H), 3.02-2.93 (m, 2H), 2.84 (t, 2H),
2.43 (s,
3H), 1.84-0.92 (m, 13H).
Example 82
2RS.3R)-3-amino-2-hydrox~-4-cyclohexyl)butanoyl-(4-aminobutvl)amide
dihvdrochloride
The product of example 80A (100 mg) was processed as in example 1F to yield
the
title compound (70 mg).
MS (ESI+Q1MS) m/e 272 (M+ H)+ ;
iH NMR (300 MHz, MeOH-d4) 8 4.28 (d, 0.4H), 4.16 (d, 0.6H), 3.77-3.56 (m, 2H),
3.46-3.14 (m, 2H overlapped with MeOH peak), 2.96 (t, 2H), 1.84-0.80 (m, 17H).
Example 83
(2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-(2-aminoethvl)amide
dihydrochloride
The product of example 81A (60 mg) was processed as in example 1F to yield the
title compound (45 mg).
MS (ESI+Q1MS) m/e 244 (M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 4.33 (d, 0.2H), 4.24 (d, 0.8H), 3.75-3.56 (m, 3H),
3.48-3.38 (m, 1H), 3.18-3.03 (m, 2H), 1.84-0.92 (m, 13H).
Example 84
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(2RS,3R)-3-amino-4-cyclohex~h~droxy~N-(4-(((3-
~trifluorometh~phenyllsulfonyl)amino)but,~rl)butanamide hydrochloride
The product of example 81A and m-(trifluoromethyl)benzenesulfonyl chloride
were
processed as in example 80B to yield the title compound.
MS (APCI) m/e 480 (M+ H)+ ;
1H NMR (300 MHz, DMSO-d6) 8 8.08 (m, 4H), 7.86 (m, 2H), 7.73 (m, 1H), 6.41 (d,
1H), 3.99 (m, 1H), 3.70 (m, 2H), 3.49 (m, 1H), 3.06 (m, 2H), 2.76 (m, 2H),
1.65 (m, 4H),
1.40 (m, SH), 1.15 (m, 3H), 0.84 (m, 3H).
Exam In a 85
(2RS.3R)-3-amino-4-cyclohexyl-N-(4-(((3,4-dimethoxyphenyl)sulfonyl)amino)bu~l)-
2
hydroxvbutanamide hydrochloride
The product of example 81A and 3,4-dimethoxybenzenesulfonyl chloride were
processed as in example 80B to yield the title compound.
MS (APCI) m/e 472 (M+ H)+ ;
1H NMR (300 MHz, DMSO-ds) 8 8.10 (m,.1H), 7.92 (m, 1H), 7.73 (m, 1H), 7.44 (m,
1H), 7.42 (m, 1H), 7.12 (m, 1H), 6.42 (m, 1H), 3.98 (m, 1H), 3.84 (s, 3H),
3.81 (s, 3H),
3.70 (m, 2H), 3.49 (m, 1H), 3.08 (m, 2H), 2.67 (m, 2H), 1.65 (m, 4H), 1.40 (m,
5H), 1.18
(m, 3H), 0.84 (m, 3H).
Examgle 86
(2RS.3R)-N-(4-(((4-(acetylamino)phenyl)sulfon~rl~amino)butyl)-3-amino-4-
cyclohexyl-2
hydroxybutanamide hydrochloride
The product of example 81A and 4-acetamidobenzenesulfonyl chloride were
processed as in example 80B to yield the title compound.
MS (APCI) m/e 469 (M+ H)+ ;
1H NMR (300 MHz, DMSO-d6) 8 7.72 (m, 4H), 7.41 (m, 1H), 5.93 (d, 1H), 3.79 (m,
3H), 3.04 (m, 2H), 2.73 (s, 3.H), 2.68 (m, 1H), 2.09 (s, 3H), 1.60 (m, 2H),
1.24.(m, 4H),
1.I3 (m, SH), 0.85 (m, 3H).
Example 87 (2RS.3R)-3-amino-4-cvclohexvl-2-hydroxy-N-(4-(~2
naphthylsulfonvl)amino)butvl butanamide h dy rochloride
The product of example 81A and 2-naphthylsulfonyl chloride were processed as
in
example 80B to yield the title compound.
MS (APCI) m/e 462 (M+ H)+ ;
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1H NMR (300 MHz, DMSO-d6) $ 8.61 (s, 1H), 8.15 (m, 2H), 8.04 (m, 2H), 7.82 (m,
1H), 7.70 (m, 4H), 6.41 (m, 1H), 3.99 (m, 1H), 3.69 (m, 2H), 3.50 (m, 1H),
3.04 (m, 2H),
2.77 (m, 2H), 1.64 (m, 4H), 1.42 (SH), 1.14 (m, 3H), 0.85 (m, 3H).
Example 88
(2RS,3R)-3-amino-2-hvdroxy-4-cyclohexvl)butanovl-L-alanine 4-sulfonamide benzf
ester
hydrochloridg
The product of example 23A and 4-(2-aminoethyl)benzenesulfonamide were
processed as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 384 (M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 4.20 (d,), 4.10 (d,), 3.75-3.56 (m, 3H), 3.85-3.37
(m,
2H), 2.93 (t, 2H), 1.8-0.91 (m, 15H).
Example 89
(2RS,3R)-3-amino-2-h d~,y-4-cvclohexyl)butanoyl-L-alanine benzyl ester
hydrochloride
The product of example 23A and amino isobutyric acid benzyl ester were
processed
as in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 377 (M+ H)+, 753 (2M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.39-7.30 (m, SH), 5.17 (s, 2H), 4.22 (d, 0.3H),
4.08
(d, 0.7H), 3.76-3.46 (m, 2H), 1.81-0.74 (m, 19H).
Example 90
(2RS,3R)-3-amino-2-hvdroxy-4-cvclohexvl)butanoyl-L-alanine c~clohex ly ester
hydrochloride
Example 90A
N (tart-Butoxycarbnnyl)-L-alanine (0.945g, 5 mmol) was dissolved in 10 mL of
methanol and 2 mL of water was added, and pH was then adjusted to 7.0 by an
addition of
20% cesium carbonate. The mixture was evaporated to dryness, re-evaporated
twice from
5 mL of N,N dimethylformamide, and suspended into 10 mL of N,N-
dimethylformamide.
Cyclohexyl bromide (0.677 mL, 5.5 mmol) was added and stirred at room
temperature for over night. The mixture was diluted with 40 mL of ethyl
acetate, the
organic layer was washed with brine (2x), 10% sodiun hydrogen carbonate (2x),
brine (2x),
dried over magnesium sulfate anhydrous. It was then evapotated to dryness to
yield 0.97 g
of N-(tart-butoxycarbonyl)-L-alanine cyclohexyl ester. All was processed as in
example 1F
to obtain L-alanine cyclohexyl ester hydrochloride (0.68 g).
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Example 90B
The product of example 23A and the product of example 90A were processed as in
examples lE and 1F to yield the title compound.
MS {ESI+Q1MS) m/e 355 (M+ H)+, 709 (2M+H)+.;
1H NMR (300 MHz, MeOH-d4) S 4.46-4.35 (m, 1H), 4.28 (d, 0.3H), 4.17 (d, 0.7H),
3.78-3.56 (m, 2H), 0.74-1.81 (m, 27H includes 1.45 d, 3H).
Example 91
f2RS,3R)-3-amino-2-h day-4-cyclohexvl)butanoyl-L-alanine 2-
~(phenylsulfonyl)methyl}benzyl ester hydrochloride
Following the procedure of example 90A, but replacing cyclohexyl bromide with
1-
bromomethyl-2-[(phenylsulfonyl)methyl]benzene, followed by the procedure of
example 1F
provided the desired title compound.
MS (ESI+Q1MS) m/e 517 (M+ H)+, 539 (M+Na}+, 1033 (2M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.75-7.68 (m, 3H), 7.62-7.53 (m, 2H), 7.46-7.32
(m,
2H), 7.27-7.18 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.18 {m, 2H), 4.69-4.66 (m,
2H), 4.54-
4.44 (m, 1H), 4.27 (d, 0.3H), 4.16 {d, 0.7H), 3.76-3.54 (m, 2H), 1.83-0.74 (m,
16H).
Example 92
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclopronvl ester
hydrochloride
Following the procedure of example 90A, but replacing cyclohexyl bromide with
cyclopropyl bromide, and followed by the procedure of example 1F provided the
desired
title compound.
MS {ESI+Q1MS) m/e 315 (M+ H)+, 629 (2M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 5.06-4.97 (m, 1H), 4.45-4.36 (m, 1H}, 4.17 {d,
0.7H),
3.63-3.57 (m, 1H), 1.84-0.90 (m, 20H).
Example 93
~2RS,3R)-3-amino-2-hydroxv-4-cyclohexyl)butano~l-L-alanine 4-tert-but I~zyl
ester
hydrochloride
Following the procedure of example 90A, but replacing cyclohexyl bromide with
4-
tert-butylbenzyl bromide, followed by the procedure of example 1F provided the
desired
title compound.
MS (ESI+Q1MS) m/e 419 (M+ H)+, 837 (2M+H)+ ;
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1H NMR (300 MHz, MeOH-d4) 8 7.42-7.28 (m, 4H), 5.15 (s, 2H), 4.56-4.47 (m,
1H),
4.28 (d, 0.3H), 4.16 (d, 0.7H), 3.74-3.55 (m, 2H), 1.84-0.90 (m, 25H includes
1.32 s, 9H
and 1.45 d, 3H).
Example 94
(2RS.3R)- 3-amino-2-hvdroxv-4-cvcIohexvl)butanoyl-L-alanine 4-
metho~carbonylbenzvl
ester hydrochloride
Following the procedure of example 90A, but replacing cyclohexyl bromide with
4-
methoxycarbonylbenzyl bromide, followed by the procedure of example 1F
provided the
desired title compound.
MS (ESI+Q1MS) m/e 421 (M+'H)'', 841 (2M+H)+;
1H NMR (300 MHz, MeOH-d4) S 8.04-7.46 (m, 4H), 5.26 (s, 2H), 4.62-4.51 (m,
1H),
4.29 (d, 0.3H), 4.16 (d, 0.7H), 3.90 (s, 3H), 3.75-3.55 (m, 2H), 0.66-1.79 {m,
16H).
Example 95
~2RS,3R)- 3-amino-2-hvdroxv-4-cyclohexyl)butan~l-L-alanine 4-
trifluorometh~benzvl
ester hydrochloride
Following the procedure of example 90A, but replacing cyclohexyl bromide with
4-
trifluoromethylbenzyl bromide, followed by the procedure of example 1F
provided the
desired title compound.
MS (ESI+Q1MS) m/e 431 (M+ H)+, 861 (2M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.70-7.56 (m, 4H), 5.27 (s, 2H), 4.62-4.52 (m,
1H),
4.31 (d, 0.3H), 4.16 (d, 0.7H), 3.76-3:56 (m, 2H), 1.81-0.66 (m, 16H).
Example 96
(2RS.3R)- 3-amino-2-hydrox -~4-cyclohexyl)butan~rl-L-alanine-(4-(methvl)phenvl
acetic
acid phenacyl ester) hydrochloride
Following the procedure of example 294115.1 A, but replacing cyclohexyi
bromide
with 4-(bromomethyl)phenyl acetic acid phenacyl ester, followed by the
procedure of
example 1 F provided the desired title compound.
MS (ESI+Q1MS) m/e 539 (M+ H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.96-7.32 (m, 9H), 5.46-5.17 (m, 4H), 4.59-4.48
(m,
1H), 4.28 (d, 0.3H), 4.16 (d, 0.7H), 3.84 (s, 2H), 3.76-3.54 (m, 2H), 1.80-
0.75 (m, 16H).
Example 97
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(2RS.3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 2,4-dichlorobenzylamine were processed as in
example 101 to provide the title compound.
MS (ESI+Q1MS) m/e 359 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.47 (d, 1H), 7.39 (d, 1H), 7.30 (dd, 1H), 4.54(q,
2H),
4.13 (d, 1H), 3.49 (m, 1H), 3.0 (br s, 1H), 0.82-1.80 (m, 13H).
Example 98
(2RS.3R)-3-amino-4-cvclohexyl-2-hydroxv-N-(3-m~thoxyphenyl)butanamide
hydrochloride
The product of example 23A and 3-methoxyaniline were processed as in example
101 to provide the title compound.
MS (ESI+Q1MS) m/e 307 (M+H)+, 329 (M+Na)~
'H NMR (300MHz, MeOH-d4) 8 7.37 (t, 1H), 7.23 (dd, 1H), 7.16 (m, 1H), 6.72 (m,
1H),
4.24 (d, 1H), 3.79 (s, 3H), 3.66 (m, 1H), 0.80-1.85 (m, 13H).
Example 99
methyl (2RS.3R,2'R)-2-((3-amino-4-cyclohexyl-2-h d~ybutanoyl)amino)-4-
methylpentanoate hydrochloride
The product of example 23A and L-leucine methyl ester were processed as in
example l0I to provide the title compound.
MS (ESI+Q1MS) m/e 329 (M+H)+, 351 (M+Na)+
'H NMR (300MHz, MeOH-d4) 8 4.50 (m, 1H), 4.10 (d, 1H), 3.73 (s, 3H), 3.39 (m,
1H),
1.2-1.81 (m, 13H), 0.9-1.0 (m, 9H).
Example 100
2RS,3R)-3-amino-4-cvclohexvl-N-(2-furvlmethvl)-2-hvdroxvbutanamide
hydrochloride
The product of example 23A and furfurylamine were processed as in example 101
to provide the title compound.
MS (ESI+Q1MS) m/e 281 (M+H)+, 303 (M+Na)+
'H NMR (300MHz, MeOH-d4) 8 7.42 (m, 1H), 6.35 (m, 1H), 6.28 (d, 1H), 4.47 (q,
2H),
4.13 (d, 1H), 3.51 (m, 1H), 0.90-1.80 (m, 13H).
Example 101
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(2RS,3R,1'RS)-3-amino-4-c cl~xvl-2-hydroxy N-(1-(1-naphthvl)ethyl)butanamide
hydrochloride
The product of example 23A (2.4g, 8.64mmo1) was dissolved in N,N
dimethylacetamide to give 48m1 (solution A). 1-Hydroxy-7-azabenzotriazole
(HOAT
1.928, 13.2mmol), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU-4.8g, 13.4mmo1), and disopropylethylamine (2.4m1,
13.4mmol) were dissolved in N,N-dimethylacetamide to make 48m1 (solution B).
Solution
A was distributed equally into 48 individual reactors. Solution B was then
added to these
same reactors in equal portions. The reactors were shaken lOmin at room
temperature. To
one of these reactors, 1-(1-naphthyl~thylamine( 0.04m1, 0.275mmo1) was added
and the
mixture was shaken ca. 75h. Dichloromethane (Sml) and water (Sml) were added
to the
reaction and shaken. The aqueous layer was removed and the reactor placed on a
liquid
phase extractor to wash twice with 1N hydrochloric acid, once with water, and
finally,
twice with 2N sodium carbonate. Any residual water was removed and the solvent
was
concentrated to dryness. The residue was dissolved in dichloromethane (lml)
and placed
on a solid phase extractor to be eluted on a lg silica gel cartridge with 13%
ethyl acetate in
hexane. The appropriate fractions were collected and dried down. The residue
was
dissolved in 4M hydrochloric acid in dioxane (lml) to cleave the protecting
group. After
one hour, the solvent was concentrated to dryness. 48 amines were processed at
one time
in batch mode. Based on HPLC purity, the material was either submitted as is,
or sent for
preparative HPLC purification prior to submission.
MS (ESI+Q1MS) m/e 355 (M+H)+, 377 (M+Na)+
'H NMR (300MHz, MeOH-d4) 8 8.16 (m, 1H), 7.89 (d, 1H), 7.81 (d, 1H), 7.44-7.63
(m,
4H), 5.90 (q, 1 H), 4.08 (dd, 1 H), 3.48 (m, 1 H), 2.98 (br s, 1 H), 0.85-1.91
(m, 17H).
Example 102
(2RS.3R)-3-amino-4-cvclohexvl-2-h~droxy-N-(3-(2-oxo-1-
pyrrolidinxl~propyl)butanamide
hydrochloride
The product of example 23A and 1-(3-aminopropyl)-2-pyrrolidone were processed
as in examples lE and 1F to provide the title compound.
MS (ESI+Q1MS) m/e 326 (M+ H)'" , 651 (2M+ H)+ ;
iH NMR (300 MHz, MeOH-d4) 8 4.24 (d, 0.4H), 4.15 (d, 0.6H), 3.54-3.41 (m, 2H),
3.27-3.15 (m, 2H), 2.44-2.34 (m, 2H), 2.12-2.02 (m, 2H), 1.86-0.72 (m, 19H).
Example 103
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(2RS.3R)-3-amino-4-cyclohexyl-N-( 1.2-dirneth~nrop ly )-2-hydroxybutanamide
hydrochloride
The product of example 23A and 1,2-dimethylpropylamine were processed as in
example 101 to provide the title compound.
MS (ESI+Q1MS) m/e 271 (M+H)+, 293 (M+Na)+
'H NMR (300MHz, MeOH-d4) S 4.28 (d, 1H), 3.74 (m, 1H), 1.05-1.80 (m, 13H),
0.8$-
0.94 (m, 11 H).
Example 104
(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine hydrochloride
The product of example 61A was processed as in example 1F to yield the title
compound.
MS (ESI-Q1MS) m/e 271 (M- H)+, 307 (M+Na- H)+, 543 (2M-H)+, 565 (2M+Na-H)+ ;
iH NMR (300 MHz, D20) b 4.28-4.47 (m, 2H), 3.86-3.62 (m, 2H), 1.75-0.78 (m,
16H).
IS
Example 105
2RS.3R)-3-amino-2-hvdroxv-4-cvclohexvl)butanovl-L-alanine benzvl ester
hydrochloride
The product of example 20A and L-alanine benzyl ester were processed as in
examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m1e 357 (M+H)+, 713 (2M+H)+;
1H NMR (300 MHz, D20) 8 7.39-7.17 (m, lOH), 5.16 (s, 2H), 4.53-4.43. (m, 1H),
4.35
(d, 0.3H), 4.07 (d, 0.7H), 3.82-3.63 (m, 2H), 3.12-2.76 (m, 2H),1.45 (d, 3H).
Example 106
~2RS.3R1-3-amino-2-h~v-4-cyclohexyl)butanovl-L-alanine hydrochloride
Example 106A
The product of example 20A and L-alanine benzyl ester were processed as in
examples lE to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-
cyclohexyl)butanoyl-L-alanine benzyl ester. O.Sg of the above product was
hydrogenated
in 20 mL of isopropyl alcohol in the presence of 20 mg of 10%-palladium on
charcoal to
yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-
alanine
(0.4g).
Example 1068
The product of example 106.1A was processed as in example 1F to yield the
title
compound.
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MS (ESI+Q1MS) m/e 267 (M+H)+, 289 (M+Na)+,533 (2M+H)+, 555 (2M+Na)+ ;
1H NMR (300 MHz, D20) 8 7.46-7.27 (m, SH), 4.52-4.13 (m, 2H), 4.03-3.85 (m,
2H),
3.19-2.88 (m, 2H), 1.45-1.38 (dt, 3H).
Example 107
(2RS.3R)-3-amino-4-cyclohexvl-2-hydroxy-N-phenylbutanamide hydrochloride
The product of example 23A and aniline were processed as in example 101 to
provide the title compound.
MS (APCI) m/e 277 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.64 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 4.22 (d,
1H),
3.61 (m, 1H), 0.91-1.85 (m, 13H).
Example 108
(2RS,3R)-3-amino-N-(2-chlorophenethvl)-4-cyclohex~-hydroxybutanamide
hydrochloride
The product of example 23A and 2-(2-chlorophenyl)ethylamine were processed as
in example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.2-7.4 (m, 4H), 4.04 (d, 1H), 3.00 {m, 1H), 0.9-
1.81
(m, I3H).
Example 109
2RS.3R)-3-amino-4-cyclohexvl-2-hydroxv-N-(3-nhenv~ronvl)butanamide
hydrochloride
The product of example 23A and 3-phenyl-1-propylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 319 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.12-7.3 (m, 5H), 4.1 (d, 1H), 3.25 (m, 1H), 2.65
(m,
6H), 0.90-1.90 (m, I3H).
Example 110
(2RS,3R)-3-amino-4-c cl~exyl-2-hvdroxy-N-(1 2,3 4-tetrahydro-1
naphthalenyl)butanamide hydrochloride
The product of example 23A and 1,2,3,4-tetrahydro-1-naphthylamine were
processed as in example l0I to provide the title compound.
MS (APCI) m/e 3661 (2M+H)+
'H NMR (300MHz, MeOH-d4) b 7.15 (m, 4H), 5.12 (m, 1H), 4.14 (m, 1H), 3.58 (m,
1H),
2.81 (m, 2H), 2.05 (m, 1H), 0.90-1.90 (m, 16H).
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Example 111
2RS.3R)-3-amino-N-(4-(tert-butyl)cyclohex,Yl)-4-cyclohexvl-2-h d~Kbutanamide
hydrochloride
The product of example 23A and 1-amino-4-(1,1-dimethylethyl)cyclohexane were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+, 677.3 (2M+H)+
'H NMR (300MHz, MeOH-d4) S 4.03 (d, 1H), 3.62 (m, 1H),3.49 (m, 1H), 0.90-2.00
(m,
22H), 0.89 (m, 9H).
Example 112
(2RS,3R)-3-amino-4-cvclohexvl-N-(3,5-dichlorophenyl)-2-hydrox~rbutanamide
hydrochloride
The product of example 23A and 3,4-dichloroaniline were processed as in
example
101 to provide the title compound.
MS (APCI) m/e 345 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.74 (d, 2H), 7.20 (t, 1H), 4.23 (d, 1H), 3.58 (m,
1H),
0.92-1.85 (m, 13H).
Example 113
(2RS,3R)-3-amino-4-cvclohexvl-N-(2-ethylhexyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 2-ethylhexylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 313 (M+H)+ .
'H NMR (300MHz, MeOH-d4) 8 4.03 (dd, 1H), 3.13(m, 1H), 0.89-1.85 (m, 29H).
Example 114
butyl (2RS,3R)-2-((3-amino-4-cvclohexyl-2-hydroxybutanoyl)amino)acetate
hydrochloride
The product of example 23A and glycine n-butyl ester were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 315 (M+H)''
'H NMR (300MHz, MeOH-d4) 8 4.16 (m, 2H), 4.02 (m, 1H), 3.50 (m, 1H), 0.90-1.85
(m,
1~H), 0.95 (t, 3H).
Example 115
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l2RS.3R)-3-amino-N-( 1.3-benzodioxol-5-vlmethyl)-4-cvclohexyl-2-
hydroxybutanamide
hydrochloride
The product of example 23A and piperonylamine were processed as in example 101
to provide the title compound.
MS (APCI) m/e 335 (M+H)+, (669 (2M+H)+
'H NMR~(300MHz, MeOH-d4) 8 6.80 (m, 2H), 5.92 (s, 1H), 4.32 (q, 2H), 4.11 (d,
1H),
3.50 (m, 1H), 0.85-1.80 (m, 13H).
Example 116
(2RS.3R)-3-amino-4-c cly ohex~rl-N-(2.4-dimethoxyphenyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 2,4-dimethoxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 673 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.09 (d, 1H), 6.63 (d, 1H), 6.51 (dd, 1H), 4.27 (d,
1H),
3.89 (s, 3H), 3.79 (s, 3H), 3.67 (m, 1H), 0.95-1.87 (m, 13H).
Example 117
(2RS,3R)-3-amino-4-c cl~ohexvl-2-hydroxy-N-(3-methoxv-5-
(trifluoromethyl)phenyl)butanamide hydrochloride
The product of example 23A and 3-methoxy-5-(trifluoromethyl)aniline were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 375 (M+H)+, 748 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.55 (m, 1H), 7.47 (t, 1H), 6.85 (m, 1H), 4.10 (d,
1H),
3.45 (m, 1H), 0.80-1.75 (m, 13H).
Example 118
(2RS.3R)-3-amino-4-cyclohexvl-N-decvl-2-hvdroxvbutanamide hydrochloride
The product of example 23A and undecylamine were processed as in example 101
to provide the title compound.
MS (APCI) m/e 681 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 3.85 (d, 1H), 3.22 (m, 2H), 3.13 (m, 1H), 0.85-1.85
(m,
32H).
Example 119
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(2RS,3R)-3-amino-N-((1R,4S)bicyclo(2.2.1)hept-2-vl)-4-cyclohexyl-2-h dy
roxwbutanamide
The product of example 23A and 2-aminonorbornane were processed as in example
101 to provide the title compound.
MS (APCI) m/e 295 (M+H)+, 589 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 4.05 (t, 1H), 3.66 (m, 1H), 3.51 (m, 1H), 2.30 (br
s, 1H),
2.22 (m, 1 H), 0.90-1.80 (m, 21 H).
Example 120
l2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorohenzyl)-2-hydro~butanamide
hydrochloride
The product of example 23A and 2-fluorobenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 309 (M+H)+, 616 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.32 (m, 2H), 7.11 (m, 2H), 4.5 (q, 2H), 4.14 (d,
1H),
3.52 (m, 1H), 0.87-1.80 (m, 13H).
Example 121
~2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2
hydroxybutanamide hydrochloride
The product of example 23A and 3-(trifluoromethyl)-4-fluorobenzylamine were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 377 (M+H)+
1H NMR (300MHz, MeOH-d4) 8 7.64 (m, 2H), 7.29 (t, 1H), 4.45 (q, 2H), 4.12 (d,
1H),
3.49 (m, 1H), 0.80-1.80 (me, 13H).
Example 122
(2RS,3R)-3-amino-4-cvclohexyl-N-(1-(4-fluorophenvl)ethyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 4-fluoro-a-methylbenzylamine were processed as
in example 101 to provide the title compound.
MS (APCI) m/e 645 (2M+H)+
~H NMR (300MHz, MeOH-d4) b 7.36 (m, 2H), 7.04 (t, 2H), 5.06 (m, 1H), 4.05 (d,
1H),
3.47 (m, 1H), 0.80-1.85 (m, 17H).
Example 123
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L2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(tetrahydro-2-
furanvlmethyl)butanamide
hydrochloride
The product of example 23A and tetrahydrofurfurylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 285 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 4.07 (m, 1H), 3.88 (m, 1H), 3.75 (m, 1H), 3.48 (m,
1H),
1.92 (m, 1H), 0.90-185 (m, 19H).
Example 124
ethyl (2RS,3R)-(4-((-3-amino-4-cyclohexyl-2-hydrox butanov_1)aminoy-1-
piperidinecarboxylate ~drochloride
The product of example 23A and ethyl 4-amino-1-piperidinecarboxylate were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 356 (M+H)+
'H NMR (300MHz, MeOH-d4) b 4.1 (q, 2H), 4.05 (t, 1 H), 3.91 (m, 1 H), 3.4$ (m,
1 H),
2.94 (m, 2H), 1.26-1.90 (m, 17H), 1.25 (t, 3H), 0.95 (m, 2H).
Example 125
(2RS.3R)-3-amino-N-( 1,3-benzodioxol-5-yl)-4-cyclohexyl-2-hydroxybutanamide
hydrochloride
The product of example 23A and 3,4-methylenedioxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+, 640 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.32 (d, 1H), 7.00 (dd, 1H), 6.77 (dd, 1H), 5.94
(s, 2H),
4.25 (d, 1H), 3.68 (m, 1H), 0.90-1.85 (m, 13H).
Example 126
tert-butyl (2RS.3R)-2-((3-amino-4-cyclohexyl-2-h d~ybutanovl)amino)acetate
hydrochloride
The product of example 23A and glycine tert-butyl ester were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 315 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 4.10 (d, 1H), 3.91 (q, 2H), 3.45 (m, 1H), 1.48 (s,
9H),
0.90-1.85 (m, 13H).
Example 127
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methyl (2RS.3R)-2-((3-amino-4-cyclohexyl-2-l~droxybutanoyl)aminoy-3
phenylpropanoate hydrochloride
The product of example 23A and phenylalanine methyl ester were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 363 (M+H)+
1H NMR (300MHz, MeOH-d4) S 7.23 (m, SH), 4.74 (m, 1H), 4.17 (d, 1H), 3.73 (s,
3H),
3.47 (m, 1H), 3.01-3.25 (m, 2H), 0.70-1.78 (m, 13H).
Example 128
methyl (2RS.3R,2'S)-2-((3-amino-4-cyclohexvl-2-hvdroxybutanovl)amino)-3-
methylpentanoate hydrochloride
The product of example 23A and L-isoleucine methyl ester were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 657 (2M+H)+
'H NMR (300MHz, MeOH-d4) 8 4.41 (m, 2H), 4.33 (d, 1H), 4.17 (m, 1H), 3.95 (s;
3H),
3.73 (d, 2H), 0.90-1.78 (m, 22H).
Example 129
methyl (2RS.3R.2'S)-2-((3-amino-4-cvclohexyl-2-hydroxybutanovl)amino)hexanoate
hydrochloride
The product of example 23A and L-norleucine methyl ester were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 657 (2M+H)+
1H NMR (300MHz, MeOH-d4) 8 4.44 (m, iH), 4.13 (d, 1H), 3.74 (s, 3H), 3.45 (m,
1H),
0.90-1.82 (m, 22H).
Example 130
methyl (2RS.3R)-2-((3-amino-4-cyclohexyl-2-hydroxyhutanovl)amino)-3-
methvlbutanoate
hydrochloride
The product of example 23A and L-valine methyl ester were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 315 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 4.36 (d, 2H), 4.05 (d, 1H), 3.72 (s, 3H), 2.20 (m,
2H),
0.98 (s, 3H), 0.96 (s, 3H), 0.87-1.84 (m, 13H).
Example 131
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~2RS,3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-((1 S)-1-(2-naphthvl~thyl)butanamide
The product of example 23A and (S)-1-amino-1-(2-naphthyl)ethane were processed
as in example 24 to provide the title compound.
MS (ESI) m/e 355 (M+H)+;
iH NMR (300 MHz, DMSO-d6) 8 8.63 (d, 1H), 7.88 (m, 2H), 7.78 (m, 3H), 7.54
(dd,
1H), 7.48 (m, 2H), 6.46 (d, 1H), 5.13 (m, 1H), 4.02 (m; 1H), 3.28 (m, 1H),
1.58 (m, 2H),
1.52 (d, 3H), 1.38-1.06 (m, 9H), 0.77 (m, 1H), 0.63 (m, 1H);
Anal. calcd for C22H30N202S~HCI: C, 67.59; H, 7.99; N, 7.17. Found: C, 67.42;
H,
8.03; N, 7.08.
to
Example 132
(2RS.3R)-3-amino-4-cyclohexyl-2-hydroxy-NN~(1R)-1-(2-naphth l~thyl)butanamide
hydrochloride
The product of example 23A and (R)-1-amino-1-(2-naphthyl)ethane were processed
as in example 24 to provide the title compound.
MS (ESI) m/e 355 (M+H)+;
iH NMR (300 MHz, DMSO-d6) 8 8.67 (d, 1H), 7.83 (m, 5H), 7.56 (dd, 1H), 7.48
(m,
2H), 6.49 (d, 1H), 5.13 (m, 1H), 4.09 (t, 1H), 3.28 (m, 1H), 1.58 (m, 2H),
1.50 (d, 3H),
1.38-1.06 (m, 9H), 0.77 (m, 1H), 0.63 (m, 1H).
Example 133
f2RS.3R)-3-amino-4-cvclohex~ydroxy-N-((1S)-1-(1-naphth l~yl)butanamide
hydrochloride
The product of example 23A and (S)-1-amino-1-(1-naphthyl~thane were processed
as in example 24 to provide the title compound.
MS (ESI) m/e 355 (M+H)+;
iH NMR (300 MHz, DMSO-d6) S 8.69 (d, 1H), 8.13 (d, 1H), 7.94 (dd, 1H), 7.81
(m,
3H), 7.60 (d, 1H), 7.52 (m, 2H), 6.47 (d, 1H), 5.77 (m, 1H), 3.99 (t, 1H),
3.23 (m, 1H),
1.61 (m, 2H), 1.57 (d, 3H), 1.38-1.11 (m, 9H), 0.78-0.60 (m, 2H);
Anal. calcd for C22H30N202S~HCI: C, 67.59; H, 7.99; N, 7.17. Found: C, 67.25;
H,
7.92; N, 6.96.
Example 134
2RS.3R)-3-amino-4-cvclohex~vdroxv-N=(~ 1 R)-1-( 1-naphthyl)ethyl)butanamide
hydrochloride
The product of example 23A and (R)-1-amino-1-(1-naphthyl)ethane were processed
as in example 24 to provide the title compound.
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MS (ESI) m/e 355 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.71 (d, 1H), 8.14 (d, 1H), 7.94 (dd, 1H), 7.82
(d, 1H),
7.79 (bds, 2H), 7.60 (d, 1H), 7.52 (m, 2H), 6.43 (d, 1H), 5.76 (m, 1H), 4.11
(t, 1H, J=5
Hz), 3.23 (m, 1H), 1.61 (m, 2H), 1.53 (d, 3H), 1.38-1.11 (m, 9H), 0.81 (m,
1H), 0.63 (m,
1H);
Anal. calcd for C22H30N202S~HCl~0.33 H20: C, 66.58; H, 8.04; N, 7.06. Found:
C,
66.46; H, 8.07; N, 6.81.
Example 135
io ethyl (2RS.3R.2'R)-2-((3-amino-4-cyclohexvl-2-hvdroxvbutanoyl)amino,-3-
fluoropropanoate trifluoroacetate
Example 135A
XB-fluoro-DL-alanine was processed as in example 1D to provide the title
compound.
MS (APCI+) m/e 208 (M+H)+.
Example 135B
The product of example 135A was processed as in example 137A to provide the
title compound.
MS (APCI+) m/e 236 (M+H)+.
Example 135C
The product of example 1358 was processed as in example 1F to provide the
title
compound.
MS (APCI+) m/e 136 (M+H)+.
Example 135D
The product of example 23A and the product of example 135C were processed as
in example lE to provide the title compound.
MS (APCI+) m/e 419 (M+H)+.
Example 135E
A solution of example 135D (0.27 g, 0.62 mmol) in dichloromethane (3 mL)
containing trifluoroacetic acid (2 mL) was stirred at ambient temperature for
3 hours,
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evaporated to dryness, suspended in ethyl ether, then concentrated and vacuum
dried to
give the title compound (0.24 g).
MS (APCI) m/e 336 (M+H)+;
IH NMR (300 MHz, DMSO-d6) 8 7.75 (m, 2H), 6.43 (m, 1H), 6.18 (m, 2H), 5.84 (m,
1H), 4.26 (m, 1H), 4.13 (m, 3H), 3.38 (m, 1H), 1.67 (m, 8H), 1.28 (m, 1H),
1.19 (m, 3H),
1.10 (m, 2H).
Example 136
(2RS.3R)-3-amino-4-cvclohex~hvdroxy-N-(2-hydrox~ 1
(hydroxvmethyl)ethvl)butanamide trifluoroacetate
Example 136A
N-(Benzyloxycarbonyl)-O-(t-butyl)-L- Serine was processed as in example lA to
provide the title compound.
MS (ESI+Q1MS) m/e 282 (M+H)+
Example 1368
The product of examp1e136A was processed as in example 106.1A to provide the
title compound.
MS (APCI+) m/e 311 (M+H)+
Examgle 136C
The product of example 23A and the product of example 1368 were processed as
in examples lE and 135B to provide the title compound.
MS (APCI) m/e 275 (M+H)+ ;
1H NMR (300 MHz, D20) & 7.64 (m, 2H), 6.49 (m, IH), 4.70 (m, 1H), 4.04 (m,
2H), H),
3.78 (m, 2H), 3.42 (m, 2H), 3.35 (m, 2H), 1.64 (m, 4H), 1.41 (m, 3H), I.22 (m,
3H), 0.89
(m, 1H).
Example 137
4-(tert-butvl)benzvl (2RS.3R.2'R)-2-((3-amino-4-cyclohexvl-2-
hydroxvbutanoyl)amino)-3
hydroxypropanoate trifluoroacetate
Example 137A
A solution of N {t-butyloxycarbonyl)-O-(t-butyl-L- Serine (0.54 g, 2.1 mmol)
and
DCC (0.478, 2.2mmo1) in CH2C12 (5 mL) was stirred at 0 °C for 15
minutes, treated with
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para-t-butyl benzyl alcohol (0.33 g, 2.0 mmol) and catalytic DMAP and stirred
for 16
hours. The solution was evaporated to dryness and the residue was purified by
flash
chromatography on silica gel with 5% ethyl acetate/toluene to provide the
designated
compound (0.49g).
MS (APCI+) m/e 311 (M+H)+
Example 1378
The product of example 137A was processed as in examples 1F, IE, and 135B to
provide the title compound.
MS (APCI) m/e 435 (M+H)+ ;
1H NMR (300 MHz, D20) S 7.72 (m, 2H), 7.41 (m, 3H), 7.28 (m, 1H), 5.40 (s,
2H), 5.14
(m, 2H), 4.89 (m, 1H), 4.70 (m, 2H), 4.12 (m, 1H), 3.76 (m, 1H), 1.64 (m, 6H),
1.42 (m,
2H), 1.28 (s, 9H), 1.14 (m, 1H), 0.84 (m, 2H).
Example 138
4-nitrobenzvl (2RS.3R,2'S)-2-((3-amino-4-cvclohexyl-2-hydrox,~rbutanoyl)amino)-
3
h dy roxypropanoate trifluoroacetate
Example 138A
N BOC-O-(t-Butyl)-L-Serine and 4-nitro-benzyl alcohol were processed as in
example 137A to provide the title compound.
Example 1388
The product of example 23A~ and the product of example 138 were processed as
in
example 1388 to provide the title compound.
MS (APCI) m/e 424 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.86 (m, IH), 8.23 (d, 2H), 7.67 (m, 1H), 7.63 (d,
2H),
5.32 (s, 2H), 4.93 (m, 1H), 4.76 (m, 2H), 4.48 (m, 1H), 4.13 (m, 1H), 3.78 (m,
2H), 1.62
(m, 6H), 1.40 (m, 2H), 1.18 (m, 3H).
Example 139
3-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cvclohexvl-2-h~roxvbutanoyl)amino)-3-
hydroxypropanoate trifluoroacetate
N BOC-O-(t-Butyl)-L-Serine and 3-nitro-benzyl alcohol were processed as in
examples 137A and 1378 to provide the title compound.
MS (APCI) m/e 424 (M+H)+;
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iH NMR (300 MHz, DMSO-d6) 8 8.80 (m, ~1H), 8.24 (m, 1H), 7.86 (m, 1H), 7.70
(m,
2H), 5.32 (m, 2H), 4.91 (m, 1H), 4.74 (m, 2H), 4.13 (m, 1H), 3.32 {m, 2H),
1.63 (m, 6H),
1.40 (m, 2H), 1.15 (m, 2H) 0.80 (m, 1H).
Example 140
4-(trifluoromethvl)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2
hydroxybutanoyl)amino -3-h ~~dro~nropanoate trifluoroacetate
N BOC-O-(t-Butyl)-L-Serine and 4-(trifluorornethyl)benzyl alcohol were
processed
as in examples 137A and 137B to provide the title compound.
MS (APCI) m/e 447 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 8.82 (m, 1H), 7.74 (m, 3H), 7.58 (m, 1H), 5.28 (s,
2H),
4.91 (m, 1H), 4.48 (m, 1H), 4.23 (m, 2H), 4.21 (m, 1H), 3.83 (m, 2H), 1.65 (m,
6H), 1.40
(m, 2H), 1.18 (m, 2H), 0.79 (m, 1H).
Example 141
3-(trifluoromethoxy)benzyl (2RS 3R 2'S)-2-((3-amino-4-cyclohexyl-2
h dy rox,vbutanoyl)amino)-3-hydroxy_piopanoate trifluoroacetate
N BOC-O-(t-Butyl)-L-Serine and 3-(trifluoromethoxy)benzyl alcohol were
processed as in examples 137A and 137B to provide the title compound.
2o MS (APCI) m/e 463 (M+H)~;
1H NMR (300 MHz, DMSO-d6) S 8.78 (m, 1H), 7.73 {m, 2H), 7.50 (m, 1H), 7.37 (m,
3H), 5.24 (m, 2H), 4.90 (m, 1H), 4.83 (m, 2H), 4.11 (m, 1H), 4.05 (m, 1H),
3.99 (m, 2H),
1.62 (m, 6H), 1.40 (m, 2H), 1.15 (m, 2H), 0.82 (m, 1H).
Example 142
~2RS.3R)-3-amino-4-cyclohexyl-N-(4-fluorophenethyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and4-fluoro phenethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 323 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 7.25 (m, 2H), 7.00 (m, 2H), 4.10 (d, 1H), 3.60 (m,
2H),3.40 (m, 2H), 2.85 (t, 2H), 1.70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 143
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(2RS,3R)-3-amino-4-cyclohexYl-2-hydroxy-N ~4-meth~nhenyl)butanamide
The product of example 23A and p-toluidine were processed as in example 101 to
provide the title compound.
MS (APCI) m/e 291 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.52 (d, 2H), 7.16 (d, 2H), 4.28 (d, 1H), 3.65 (m,
1H),
2.31 (s, 3H), 0.92-1.86 (m, 13H).
Example 144
(2RS.3R)-3-amino-4-cvclohexyl-N-(4-fluoronhem lr )-2-hydroxybutanamide
The product of example 23A and 4-fluoroaniline were processed as in example
101
to provide the title compound.
MS (APCI) m/e 295 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.65 (q, 2H), 7.07 (t, 2H), 4.29 (d, 1H), 3.74 (m,
1H),
0.92-1.88 (m, 13H).
I5
Example 145
(2RS.3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenvl)butanamide
The product of example 23A and p-anisidine were processed as in example 101 to
provide the title compound.
MS (APCI) m/e 307 (M+H)+
'H NMR (300MHz, MeOH-d4) b 7.54 (d, 2H), 6.90 (d, 2H), 4.29 (d, 1H), 3.80 (s,
3H),
3.67 (m, 1H), 0.92-1.88 (m, 13H).
Example 146
(2RS,3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(2-methoxyphenyl)butanamide
The product of example 23A and o-anisidine were processed as in example 101 to
provide the title compound.
MS (APCI) m/e 307 (M+H)+
1H NMR (300MHz, MeOH-d4) 8 8.28 (dd, 1H), 7.03-7.15 (m, 2H), 6.94 (td, 1H),
4.34 (d,
1H), 3.91 (s, 3H), 3.77 (m, 1H), 0.96-1.89 (m, 13H).
Example 147
(2RS,3R)-3-amino-N-(4-chlorophen ly )-4-c cly ohexyl-2-hydrox_ybutanamide
The product of example 23A and 4-chloroaniline were processed as.in example
101
to provide the title compound.
MS (APCI) m/e 311 (M+H)+
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'H NMR (300MHz, MeOH-d4) 8 7.67 (d, 2H), 7.33 (d, 2H), 4.30 (d, 2H), 3.74 (m,
1H),
0.92-1.86 (m, 13H).
Example 148
l2RS,3R)-3-amino-N-(3-chlorophenvl)-4-cvclohexvl-2-hvdroxvbutanamide
The product of example 23A and 3-chloroaniline were processed as in example
101
to provide the title compound.
MS (APCI) m/e 311 (M+H)+
'H NMR (300MHz, MeOH-d4) S 7.87 (t, 1H), 7.15 (qd, 1H), 7.32 (t, 1H), 7.14
(qd, 1H),
4.31 (d, 1H), 3.73 (m, 1H), 0.93-1.87 (m, 13H).
Example 149
(2RS.3R)-3-amino-N-(2-chlorophenvl)-4-c~lohexvl-2-hvdroxvbutanamide
The product of example 23A and 2-chloroaniline were processed as in example
101
to provide the title compound.
MS (APCI) m/e 311 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.33 (dd, 1H), 7.48 {dd, 1H), 7.34 (dt, 1H), 7.16
(dt,
1 H), 4.40 (d, 1 H), 3.80 (m, 1 H), 2.69 (s, 1 H), 0.96-1.88 (m, 13H).
Example 150
(2RS.3R)-3-amino-N-(4-(tort-butyl)phenyl)-4-cvclohexvl-2-hvdroxvbutanamide
The product of example 23A and 4-tert-butylaniline were processed as in
example
101 to provide the title compound.
MS (APCI) m/e 333 (M+H)+
'H NMR (300MHz, MeOH-d4) b 7.57 (d, 2H), 7.54 (d, 2H), 4.28 (d, 1H), 3.72 (m,
1H),
1.33 (s, 9H), 0.92-1.88 (m, 13H).
Example 151
2RS,3R)-3-amino-4-cvclohexvl-2-hvdroxv-N-(3-(trifluaromethvl)phenvl)butanamide
The product of example 23A and 3-(trifluoromethyl)aniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 345 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.16 (s, 1H), 7.86 (d, 1H), 7.54 (t, 1H), 7.43 (d,
1H),
4.33 (d, 1H), 3.77 (m, 1H), 0.93-1.87 (m, 13H).
Example 152
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(2RS.3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyl)phenyl)butanamide
The product of example 23A and 4-(trifluoromethyl)aniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 345 {M+H)+
'H NMR (300MHz, MeOH-d4) S 7.89 (d, 2H), 7.64 {d, 2H), 4.34 (d, 1H), 3.74 (m,
1H),
0.95-1.87 (m, 13H).
Example 153
~2RS.3R)-3-amino-4-cyclohexvl-N-(3.4-dichlorophenyl)-2-hydroxybutanamide
The product of example 23A and 3,4-dichloroaniline were processed as in
example
101'to provide the title compound.
MS {APCI) m/e 345 (M)+
'H NMR (300MHz, MeOH-d4) S 8.04 (d, 1H), 7.55 (dd, 1H), 7.47 (d, 1H), 4.32 (d,
1H),
3.75 (m, 1H), 0.92-1.83 (m, 13H).
Example 154
l2RS.3R)-3-amino-4-cvclohexvl-N-~2 4-dichloronhenvl)-2-hvdroxvbutanamide
The product of example 23A and 2,4-dichloroaniline were processed as in
example
101 to provide the title compound.
2o MS (APCI) m/e 345 (M)+
'H NMR (300MHz, IVIeOH-d4) 8 8.32 (d, 1H), 7.55 (d, 1H), 7.37 (dd, 1H), 4.40
(d, 1H),
3.66 (m, 1H), 0.95-1.87 (m, 13H).
Example 155
(2RS.3R)-3-amino-N-(4-bromaphenvl)-4-cvclohexvl-2-hvdroxvbutanamide
The product of example 23A and 4-bromoaniline were processed as in example I01
to provide the title compound.
MS (APCI) m/e 356 (M+H)+
'H NMR (300MHz, MeOH-d4) S 7.62 (d, 2H), 7.47 (d, 2H), 4.30 (d, 1H), 3.73 (m,
IH),
0.92-1.85 (m, 13H).
Example 156
~2RS,3R)-3-amino-N-(4-(tert-butyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide
The product of example 23A and 4-tertbutylbenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 347 (M+H)+
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1H NMR (300MHz, MeOH-d4) 8 7.35 (d, 2H), 7.24 (d, 2H), 4.39 (q, 2H), 4.16 (d,
1H),
3.58 (m, 1H), 1.39 (s, 9H), 0.87-1.80 (m, 13H).
Example 157
(2RS.3R)-3-amino-4-cvclohexvl-2-hvdroxv-N-(3-
(trifluoromethvl)benzvl)butanamide
The product of example 23A and 3-(trifluoromethyl)benzylamine were processed
as
in example 101 to provide the title compound.
MS (APCI) m/e 359 (M+H)+
'H NMR (300MHz, MeOH-d4) S 7.64 (s, 1H), 7.57 (m, 3H), 4.50 (q, 2H), 4.20 (d,
1H),
3.58 (m, 1H), 0.82-1.80 (m, 13H).
Example 158
(2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(4-
(trifluoromethvl)benzyl)butanamide
The product of example 23A and 4-(trifluoromethyl)benzylamine were processed
as
in example 101 to provide the title compound.
MS (APCI) m/e 359 (M+H)+
1H N1VIR (300MHz, MeOH-d4) 8 7.63 (d, 2H), 7.51 (d, 2H), 4.50 (q, 2H), 4.20
(d, 1H),
3.62 (m, 1H), 0.86-1.80 (m, 13H).
Example 159
(2RS.3R)-3-amino-N-(2-chlorobenzvl)-4-cyclohexyl-2-hvdroxvbutanamide
The product of example 23A and 3-chlorobenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m1e 325 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.40 (m, 2H), 7.27 (m, 2H), 4.55 (q, 2H), 4.22 (d,
1H),
3.61 (m, 1H), 0.88-1.81 (m, 13H).
Example 160
(2RS.3R)-3-amino-4-c cl~exvl-2-hydrox~N-(2-methoxv-5-nitronhenvl)butanamide
hydrochloride
The product of example 23A and 2-methoxy-5-nitroaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 352 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 9.30 (d, O.SH), 8.10 (m, 1H), 7.25 (d, 1H), 4.40
(d,
1H), 4.08 (s, 3H), 3.82 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.58 (m, 1H),
1.75 (m, SH),
1.40 (m, 6H), 1.05 (m, 2H).
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Example 161
(2RS,3R)-3-amino-4-cyclohexyl-N-(3.5-dimethoxyphen~)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 3,5-dimethoxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 337 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 6.92 (d, 2H), 6.60 (t, 1H), 4.28 (d, 1H), 3.78 (s,
6H),
3.73 (m, 1H), 3.65 (m, 1H), 3.58 (m, 1H), 1.75 (m, 5H), 1.40 (m, 6H), 1.00 (m,
2H).
Example 162
2RS,3R)-3-amino-4-cvclohexvl-2-hvdrox~N-(3-phenoxvnhenvl)butanamide
hydrochloride
The product of example 23A and 3-phenoxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 369 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.40 (m, 5H), 7.10 (m, 4H), 6.75 (m, 1H), 4.28 (d,
1H),
3.72 (m, 1H), 3.66 (m, 2H), 3.58 (m, 1H), 1.75 (m, 5H), 1.50 (m, 2H), 1.30 (m,
4H), 1.00
(m, 2H).
Example I63
(((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoYl)amino)(2.5-
dimethoxybenzyl)chloronium hydrochloride
The product of example 23A and 2,5-dimethoxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 365 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 6.42 (d, 2H), 6.35 (t, 1H), 4.11 (d, 1H), 3.75 (s,
6H),
3.65 (m, 1H), 3.55 (m, 2H), 3.40 (m, 1H), 2.78 (t, 2H), 1.75 (m, 5H), 1.40 (m,
6H), 0.90
m, 2H).
Example 164
SRS,3R)-3-amino-4-cyclohexy,1-N-(2,4-dichlorophenethyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 2,4-dichloro phenethylamine were processed as
in
example 101 to provide the title compound.
MS (APCI) m/e 373 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.45 (d, 1H), 7.30 (m, 2H), 4.00 (d, 1H), 3.60 (m,
2H),
3.45 (m, 2H), 3.00 (m, 2H), 1.70 (m, 5H), 1.40 {m, 6H), 0.90 (m, 2H).
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Example 165
(2RS.3R)-3-amino-4-cyclohexyl-N-(2,6-dichloropheneth~)-2-hvdroxybutanamide
hydrochloride
The product of example 23A and 2,6-dichloroaniline were processed as in
example
101 to provide the title compound.
MS (APCI) m/e 373 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.38 (d, 2H), 7.20 (t, 1H), 4.10 (d, 1H), 3.60 (m,
3H),
3.40 (m, 1H), 3.25 (m, 2H), 1.75 (m, 7H), 1.45 (m, 2H), 1.30 (m, 2H), 1.00 (m,
2H).
Example 166
2RS.3R)-3-amino-4-cyclohexyl-N-(3-fluorophenethyl)-2-hydroxvbutanamide
hydrochloride
The product of example 23A and 3-fluorophenethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 323 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.30 (m, 1H), 7.00 (m, 3H), 4.10 (d, 1H), 3.65 (m,
1H),
3.58 (m, 2H), 3.40 (m, 1H), 2.85 (t, 2H), 1.75 (m, SH), 1.60 (m, 2H), 1.45 (m,
2H), 1.28
(m, 2H), 0.95 (m, 2H).
Example 167
(2RS,3R)-3-amino-N-(3,4-bis(henzvloxv)phenethyl)-4-c cl~yl-2-hvdroxybutanamide
hydrochloride
The product of example 23A and 3,4-dibenzyloxy phenethylamine were processed
as in example 101 to provide the title compound.
MS (APCI) m/e 517 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.45 (t, SH), 7.35 (m, SH), 6.95 (m, 2H), 8.78 (d,
1H),
5.10 (d, 4H), 4.10 (d, 1H), 3.65 (m, 1H), 3.55 (m, 2H), 3.40 (m, 1H), 2.75 (m,
2H), 1.75
(m, 5H), 1.60 (m, 2H), 1.40 (m, 4H), 0.90 (m, 2H).
Example 168
~2RS,3R)-3-amino-4-cyclohexvl-2-hydrox~N-(4-phenoxyphenethyl)butanamide
hydrochloride
The product of example 23A and 4-phenoxy phenethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 397 (M+H)+;
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1H NMR {300 MHz, MeOH-d4) S 7.35 (t, 2H), 7.25 (d, 2H), 7.08 (t, 1H), 6.95 (t,
4H),
4.12 (d, 1H), 3.65 (m, 4H), 2.85 (m, 2H), 1.75 (m, 5H), 1.50 (m, 6H), 0.95 (m,
2H).
Example 169
l2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxv-N-(2-
ftrifluoromethoxy)phenyl)butanamide
hydrochloride
The product of example 23A and 2-(trifluoromethoxy)aniline were processed as
in
example 101 to provide the title compound.
MS (APCI) m/e 361 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.34 (dd, 1H), 7.38 (dt, 2H), 7.26 (dt, 1H), 4.39
(d, 1H),
3.78 (m, 1H), 0.94-1.86 (m, 13H).
Example 170
2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(3-
(trifluoromethoxv)nhenvl)butanamide
hydrochloride
The product of example 23A and 3-(trfluoromethoxy)aniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 361 (M+H)+
'H NMR (300MHz, MeOH-da) 8 7.85 (s, 1H), 7.57 {qd, 1H), 7.43 (t, 1H), 7.05
(td, 1H),
4.33 (d, 1H), 3.76 (m, 1H), 0.91-1.87 (m, 13H).
Example 171
(2RS.3R)-3-amino-4-c cl,~ ohexyl-2-hydroxv-N-(2-methvlphenvl)butanamide
hydrochloride
The product of example 23A and o-anisidine were processed as in example 101 to
provide the title compound.
MS (APCI) m/e 291 (M+H)+
'H NMR (300MHz, MeOH-d4) S 7.68 (dd, 1H), 7.22 (dq, 2H), 7.13 (dq, 1H), 4.37
(d,
1H), 3.74 (m, 1H), 2.30 (s, 3H), 0.94-1.88 (m, 13H).
Example 172
(2RS,3R)-3-amino-4-cvclohexyl-N-(2,6-dimethylphen l~vdroxybutanamide
hydrochloride
The product of example 23A and 2,6-dimethyianiline were processed as in
example
101 to provide the title compound.
MS (APCI) m/e 305 (M+H)+
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'H NMR (300MHz, MeOH-d4) 8 7.14 (s, 3H), 4.38 (d, 1H), 3.61 (m, 1H), 2.24 (s,
6H),
0.89-1.$9 (m, 13H).
Example 173
(2RS.3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-iodo-2-methvlohenyl)butanamide
hydrochloride
The product of example 23A and 2-methyl-4-iodoaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 416 (M)+
1H NMR (300MHz, MeOH-d4) b 8.16 (d, 1H), 7.47 (dd, 1H), 7.03 (d, 1H), 4.38 (d,
1H),
3.74 (m, 1H), 2.25 (s, 3H), 0.91-1.86 (m, 13H).
Example 174
2RS,3R)-3-amino-N-(4-anilino-2-methoxyphen l~vclohexvl-2-hvdroxvbutanamide
h~nehloride
The product of example 23A and 1-amino-2-methoxy-4-(N phenylamino)benzene
were processed as in example 101 to provide the title compound.
MS (APCI) m/e 398 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.05 (d, 1H), 7.24 (t, 2H), 7.10 (d, 2H), 6.88 (m,
1H),
6.78 (d, 1H), 6.70 (dd, 1H), 4.32 (d, 1H), 3.76 (s, 3H), 3.74 (m, 1H), 0.85-
1.89 (m, 13H).
Example 175
(2RS.3R)-3-amino-4-cyclohexyl-N-(2-ethoxyphenvl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 2-ethyoxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.30 (dd, 1H), 7.09 (dt, 1H), 7.03 (t, 1H), 6.93
(dt, 1H),
4.34 (d, 1H), 4.14 (q, 2H), 3.79 (m; 1H), 1.45 (t, 3H), 0.92-1.88 (m, 13H).
Example 176
(2RS.3R)-3-amino-N-(4-chloro-2-methox -y 5methvlphenyl)-4-cvclohex
hydroxybutanamide hydrochloride
The product of example 23A and 2-methoxy-4-chloro-5-toluidine were processed
as in example 101 to provide the title compound.
MS (APCI) m/e 355 (M+H)+
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~H NMR (300MHz, MeOH-d4) 8 8.24 (s, 1H), 7.05 {s, 1H), 4.34 (d, 1H), 3.89 (s,
3H),
3.78 (m, 1H), 2.30 (s, 3H), 0.94-1.89 (m, 13H).
Example 177
(2RS.3R)-3-amino-4-cyclohexyl-N-(2,5-dimethox n~ henyly-2-)~droxvbutanamide
hydrochloride
The product of example 23A and 2,5-dimethoxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 337 (M+H)~
1H NMR (300MHz, MeOH-d4) S 8.00 (d, 1H), 6.95 (d, 1H), 6.67 (dd, 1H), 4.34 (d,
1H),
3.86 (s, 3H), 3.79 (m, 1H), 3.75 (s, 3H), 0.94-1.86 (m, 13H).
Example 178
(2RS.3R)-N-(5-(acetylamino)-2-methoxyphenvl)-3-amino-4-cvclohexyl-2
hydroxybutanamide hydrochloride
The product of example 23A and 1-amino-2-methoxy-4-(N acetylamino)benzene
were processed as in example 101 to provide the title compound.
1H NMR (300MHz, MeOH-d4) 8 8.00 (d, 1H), 7.54 (d, 1H), 7.44 (dt, 1H), 7.42
(td, 1H),
4.48 (d, 1H), 4.41 (d, 1H), 4.06 (s, 3H), 3.83 (m, 1H), 3.15 (s, 3H), 0.89-
1.88 (m, 13H).
Example 179
(2RS.3R)-3-amino-4-cyclohexvl-2-hydroxv-N-(2-methoxvdibenzo(b.d)furan-3
yl)hutanamide hydrochloride
The product of example 23A and 3-amino-2-methoxydibenzofuran were processed
as in example 101 to provide the title compound.
MS (APCI) m/e 397 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.67 (s, 1H), 7.98 (qd, 1H), 7.69 (s, 1H), 7.54 (q,
1H),
7.43 (qd, 1H), 7.43 (dt, 1H), 4.41 (d, 1H), 4.06 (s, 3H), 3.84 (m, 1H), 0.98-
1.90 (m, 13H).
Example 180
(2RS.3R)-3-amino-N-(5-chloro-2,4-dimethoxvphenyl)-4-cyclohexyl-2-
hydroxvbutanamide
hydrochloride
The product of example 23A and 2,4-dimethoxy-5-chloroaniline were processed as
in example 101 to provide the title compound.
MS (APCI) m/e 371 (M+H)+
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'H NMR (300MHz, MeOH-d4) 8 8.29 (s, 1H), 6.80 (s, 1H), 4.33 (d, 1H), 3.95 (s,
3H),
3.90 (s, 3H), 3.74 (m, 1H), 0.82-1.88 (m, 13H).
Example 181
12RS,3R)-3-amino-4-cyclohexvl-N-(2.5-diethoxyphenvl)-2-hydrox~ butanamide
hydrochloride
The product of example 23A and 2,5-diethoxyaniline were processed as in
example
101 to provide~the title compound.
MS (APCI) m/e 365 (M+H)+
'H NMR (300MHz, MeOH-d4) S 8.00 (d, 1H), 6.92 (d, 1H), 6.63 (dd, 1H), 4.34 (d,
1H),
4.09 (q, 2H), 4.01 (q, 2H), 3.81 (m, 1H), 1.42 (t, 3H), i.36 (t, 3H), 0.93-
1.89 (m, 13H).
Example 182
(2RS,3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cyclohe~l-2-
hydroxybutanamide
hydrochloride
The product of example 23A and 32-methoxy-5-tert-butylaniline were processed
as
in example 101 to provide the title compound.
MS (APCI) m/e 363 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.42 (d, 1H), 7.15 (dd, 1H), 6.95 (d, 1H), 4.34 (d,
1H),
3.89 (s, 3H), 3.76 (m, 1H), 1.30 (s, 9H), 0.93-1.89 (m, 13H).
Example 183
2RS.3R)-3-amino-4-cvclohexvl-2-hvdroxv-N-f2-phenoxvnhenvl)butanamide
hydrochloride
The product of example 23A and 2-phenoxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 369 (M+H)+
'H NMR (300MHz, MeOH-d4) b 8.35 (dd, 1H), 7.37 (m, 2H), 7.14 (m, 3H), 7.02 (m,
2H),
6.92 (d, 1H), 4.31 (d, 1H), 3.71 (m, 1H), 0.89-1.81 (m, 13H).
Example 184
2RS.3R)-3-amino-4-cvclohexvl-2-hvdroxv-N-(2-methyl-5-nitronhenvl)butanamide
hydrochloride
The product of example 23A and 2-methyl-5-nitroaniline were processed as in
example .101 to provide the title compound.
MS (APCI) m/e 336 {M+H)''
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'H NMR (300MHz, MeOH-d4) 8 8.77 (d, 1H), 8.00 (dd, 1H), 7.50 (d, 1H), 4.44 (d,
1H),
3.79 (m, 1H), 3.19 (d, 1H), 3.06 {d, 1H), 2.42 (s, 3H), 0.82-1.88 (m, 13H).
Example 185
(2RS.3R)-3-amino-4-cyclohexyl-2-hvdrox -~phenoxyphenvl)butanamide
hydrochloride
The product of example 23A and 4-phenoxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 369 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.63 (d, 2H), 7.34 (t, 2H), 7.09 (t, 1H), 6.96 (d,
3H),
4.20 (d, 1H), 3.58 (m, 1H), 0.93-1.91 (m, 13H).
Example 186
2RS.3R)-3-amino-4-cvclohexvl-2-hvdroxv_-N-(4-methoxvbenzvl)butanamide
hydrochloride
The product of example 23A and 4-methoxybenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.25 (d, 2H), 6.87 (d, 2H), 4.35 (q, 2H), 4.15 (d,
1H),
3.77 (s, 3H), 3.57 (m, 1H), 0.85-1.78 (m, 13H).
Example 187
2RS.3R)-3-amino-4-cyclohexyl-2-hydroxy-N-~4-methvlbenzvl)butanamide
hydrochloride
The product of example 23A and 4-methylbenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 305 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.20 (d, 2H), 7.12 (d, 2H), 4.38 (q, 2H), 4.11 (d,
1H),
3.53 (m, 1H), 2.30 (s, 3H), 0.86-1.80 (m, 13H).
Example 188
(2RS.3R)-3-amino-N-(3-chlorobenzvl)-4-cyclohexyl-2-hydroxybutanamide
hydrochloride
The product of example 23A and 3-chlorobenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 325 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.34 (s, 1H), 7.26 {m, 3H), 4.41 (q, 2H), 4.17 {d,
1H),
3.55 (m, 1H), 0.87-1.80 (m, 13H).
Example 189
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(2RS.3R)-3-amino-4-cyclohexvl-2-hydroxy-N-(3-methoxybenzyl)butanamide
hydrochloride
The product of example 23A and 3-methoxybenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)''
'H NMR (300MHz, MeOH-d4) b 7.22 (t, 1H), 6.88 (m, 2H), 6.80 (m, 1H), 4.38 (q,
2H),
3.99 (d, 1H), 3.77 (s, 3H), 0.82-1.80 (m, 13H).
Example 190
2RS.3R)-3-amino-N-(4-bromobenzvl)-4-cvclohexvl-2-hvdroxvbutanamide
hydrochloride
The product of example 23A and 4-bromo benzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 371 ~ (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.40 (d, 2H), 7.25 (d, 2H), 4.45 (d, 1H), 4.37 (d,
1H),
4.02 (d, 1H), 3.35 (m, 2H);1:70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 191
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxv-N-(3-methvlbenzyl)butanamide
hydrochloride
The product of example 23A and 3-methyl benzylamine were processed as in
example 101 to~provide the title compound.
2o MS (APCI) m/e 305 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.25 (m, 4H), 4.90 (d, 1H), 4.30 (d, 1H), 4.12 (d,
1H),
3.55 (m, 2H), 2.35 (s, 3H), 1.70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H)..
Example 192
SRS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N;phenethvlbutanamide hydrochloride
The product of example 23A and phenethylamine were processed as in example 101
to provide the~title compound.
MS (APCI) m/e 305 (M+H)+;
1H NMR (300 MHz, MeOH-d4)S 7.25 (m, SH), 4.00 (d, 1H), 3.50 (m, 4H), 2.85 (t,
2H),
1.70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 193
(2RS.3R)-3-amino-N-(4-chlorobenz 1~ c~exyl-2-hydroxybutanamide hydrochloride
The product of example 23A and 4-chlorobenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 325 (M+H)+
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'H NMR (300MHz, MeOH-d4) 8 7.32 (s, 4H), 4.40 (q, 2H), 4.18 (d, 1H), 3.59 (m,
1H),
0.87-1.80 (m, 13H).
Example 194
(2RS.3R)-3-amino-4-c~lohexyl-2-hvdroxy-N-l4-meth~ahenethvl)butanamide
~drochloride
The product of example 23A and 3-methyl phenethylamine were processed as in
example 101 to provide the title compound.
MS {APCI) m/e 319 (M+H)+;
l0 1H NMR (300 MHz, MeOH-d4) 8 7.10 (s, 4H), 4.05 (d, 1H), 3.50 (m, 4H), 2.80
(t, 2H),
2.30 (s, 3H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 195
(2RS,3R)-3-amino-4-c cly ohex~-2-hvdroxy-N-(4-methoxyphenethyl)butanamide
hydrochloride
The product of example 23A and 4-methoxy phenethylamine were processed as in
example 101 to provide the title compound. .
MS (APCI) m/e 335 (M+H), 669 (2M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.15 (d, 2H), 6.80 (d, 2H), 4.05 (d, 1H), 3.75 (s,
3H),
3.50 (m, 2H), 3.40 (m, 2H), 2.78 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m,
2H).
Example 196
(2RS.3R)-3-amino-4-cyclohexvl-2-hydroxy-N-(3-methoxyphenethyl)butanamide
hydrochloride
The product of example 23A and 3-methoxy phenethylarnine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.15 (d, 2H), 6.85 (d, 2H), 4.05 (d, 1H), 3.75 (d,
3H),
3.45 (m, 4H), 2.78 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 197
(2RS.3R)-3-amino-4-cyclohexvl-2-hydroxv-N-(2-methoxyphenethvl)butanamide
hydrochloride
The product of example 23A and 2-methoxy phenethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+;
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iH NMR (300 MHz, MeOH-d4) S 7.19 (m, 2H), fi.90 (m, 2H), 4.05 (d, 1H), 3.85
(s, 3H),
3.45 (m, 4H), 2.85 (t, 2H), 1.70 (m, SH), 1.40 (m, 6H), 0.90 {m, 2H).
Example 198
~2RS,3R)-3-amino-N-(4-chloropheneth l~yclohexvl-2-hydroxvbutanamide
h dy rochloride
The product of example 23A and 4-chloro phenethylamine were processed as in
example lOl to provide the title compound.
MS (APCI) m/e 339 (M+H)+;
l0 1H NMR (300 MHz, MeOH-d4) 8 7.25 (m, 4H), 3.92 (d, 1H), 3.48 (m, 4H), 2.82
(t, 2H),
1.71 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 199
(2RS.3R)-3-amino-N-(3-chlorophenethyl)-4-cyclohexvl-2-hydroxybutanamide
15 hydrochloride
The product of example 23A and 3-chloro phenethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.25 (m, 4H), 4.05 (d, 1H), 3.55 (m, 2H), 3.45 (m,
2H),
20 2.85 (t, 2H), 1.70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 200
(2RS.3R)-3-amino-4-cyclohexyl-2-hydroxv-N-(3-
(trifluoromethyl'phenethyl)butanamide
h~rdrochloride
25 The product of example 23A and 3-trifluoromethyl phenethylamine were
processed
as in example 101 to provide the title compound.
MS (APCI) m/e 373 (M+H)+;
iH NMR (300 MHz, MeOH-d4) b 7.55 (m, 4H), 4.05 (d, 1H), 3.6 (m, 2H), 3.45 (m,
2H),
2.95 (t, 2H), 1.70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 201
(2RS.3R)-3-amino-N-(4-bromopheneth~~l)-4-cyclahex~rl-2-hydroxybutanamide
hydrochloride
The product of example 23A and 4-bromo phenethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 385 (M+H)+;
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iH NMR (300 MHz, MeOH-d4) 8 7.41 (d, 2H), 7.16 (d, 2H), 3.90 (d, 1H), 3.50 (m,
4H),
2.80 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 202
(2RS.3R)-N-(1-adamantvl)-3-amino-4-c cy lohexvl-2-hydroxybutanamide
hydrochloride
The product of example 23A and 1-adamantanamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 3.95 (d, 1H), 3.45 (m, 2H), 2.09 (s, lOH), 1.75
(s,
lOH), 1..40 (m, 6H), 0.90 (m, 2H).
Example 203
2RS.3R)-N-(2-adamantvl)-3-amino-4-cyclohexyl-2-hvdroxvbutanamide hydrochloride
The product of example 23A and 2-adamantamine were processed as in example
i5 101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 4.15 (d, 1H), 4.00 (s, 1H), 3.55 (m, 2H), 1.80 (m,
19H),
1.40 (m, 6H), 0.90 (m, 2H).
Example 204
(2RS.3R)-3-amino-N-cyclohentvl-4-cyclohexyl-2-hydroxybutanamide ~drochloride
The product of example 23A and cycloheptylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 297 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 4.00 (d, 1H), 3.90 (m, 1H), 3.41 (m, 2H), 1.50 (m,
23H), 0.90 (m, 2H).
Example 205
~2RS,3R)-3-amino-4-cvclohexyl-N-(c cy_lohexylmethyl)-2-hvdroxybutanamide
hydrochloride
The product of example 23A and cyclohexylmethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 297 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 4.02 (d, 1H), 3.40 (m, 2H), 3.15 (m, 1H), 3.00 (m,
1H),
1.50 (m, 24H).
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Example 206
f2RS.3R)-3-amino-N.4-dicvclohex~il-2-hydroxyhutanamide hydrochloride
The product of example 23A and cyclohexylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 283 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 4.05 (d, 1H), 3.70 (m, 1H), 3.45 (m, 2H), 1.50 (m,
21H), 0.90 (m, 2H).
Example 207
f2RS.3R)-3-amino-4-cvclohexvl-N-cyclopentyl-2-hydroxybutanamide hydrochloride
The product of example 23A and cyclopentylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 269 (M+H)+;
1H NMR (300 MHz, MeOH-d4) S 4.15 (m, 1 H), 3.95 (d, 1 H), 3.35 (m, 2H), 1.50
(m,
19H), 0.90 (m, 2H).
Example 208
f2RS,3R)-3-amino-N-cvclobutyl-4-c cly ohexyl-2-h droxybutanamide hydrochloride
The product of example 23A and cyclobutylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 255 (M+H)+;
1H NMR (300 MHz, MeOH-d4) S 4.35 (m, 1H), 4.00 (d, 1H), 3.45 (m, 1H), 2.30 (m,
2H),
2.05 (ni, 2H), 1.75 (m, 7H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 209
(2RS.3R)-3-amino-4-cyclohexyl-2-h~x~-N-!1-methyl-3-phenylpropyl)butanamide
hydrochloride
The product of example 23A and 4-phenyl-2-aminopropane were processed as in
example 101 to provide the title compound.
MS (ESI) m/e 333 (M+H)+;
tH NMR (300 MHz, MeOH-d4) $ 7.40 (m, 5H), 4.10 (d, 1H), 3.90 (m, 1H), 3.75 (m,
1H),
3.68 (m, 1H), 3.55 (m, 2H), 2.65 (m, 2H), 1.75 (m, 7H), 1.45 (m, 2H), 1.20 (m,
5H), 0.90
(m, 2H).
Example 210
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(2RS,3R)-3-amino-4-cyclohexyl-2-l~dro~-N-( 1-methyl-2-(3
(trifluoromethvl)phenyl)ethyl)butanamide hydrochloride
The product of example 23A and 3(3-triflouromethylphenyl)-2-aminopropane were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 387 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 7.50 (m, 4H), 4.25 (m, 2H), 4.10 (d, 1H), 4.00 (d,
1H),
3.50 (m, 2H), 3.00 (m, 1H), 2.90 (m, 2H), 1.75 (m, 5H), 1.30 {m, 9H), 0.90 (m,
2H).
Example 211
f2RS.3R)-3-amino-4-cvclohexvl-N-(15-dimethylhe~l)-2-hydrox_ybutanamide
hydrochloride
The product of example 23A and 1,5-dimethylhexylamine were processed as in
example 101 to provide the title compound.
MS (ESI) m/e 313 (M+H)+;
iH NMR (300 MHz, MeOH-dq) 8 4.10 (m, 1H), 3.95 (m, 1H), 3.55 {m, 2H), 1.75 (m,
7H), 1.25 (m, 7H), 1.00 (m, 2H), 0.80 (m, 6H).
Example 212
(2RS,3R)-3-amino-4-cvclohexvl-2-hydroxy-N~1-meth~rlhexyl)butanamide
hydrochloride
The product of example 23A and 1-methylhexylamine were processed as in example
101 to provide the title compound.
MS (ESI) m/e 299 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 4.10 (d; 1H), 3.95 {m, 1H), 3.55 (m, 2H), 1.75 (m,
8H),
1.45 (m, 2H), 1.35 (m, 8H), 1.15 (m, 4H), 0.80 (m, SH).
Example 213
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isopropoxypropvl)hutanamide
hydrochloride
The product of example 23A and 3-isopropoxypropylamine were processed as in
example 101 to provide the title compound.
MS (ESI) m/e 301 (M+H)+;
iH NMR (300 MHz, MeOH-d4) 8 4.15 (d, 1 H), 3.60 (m, 2H), 3.55 (m, 4H), 1.75
(m, 6H),
1.40 (m, 8H), 1.I5 (d, 6H), 1.00 (m, 2H).
Example 214
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(2RS,3R)-3-amino-4-cvclohexvl-2-hvdroxy-N-(3-isobutoxypropyl)butanamide
hydrochloride
The product of example 23A and 3-isobutoxypropylamine were processed as in
example 101 to provide the title compound.
MS (ESI) m/e 315 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 4.15 (d, 1H), 3.62 (m, 1H), 3.50 (t, 2H), 3.40 (m,
1H),
3.20 (d, 2H), 1.80 (m, 9H), 1.45 (m, 2H), 1.30 (m, 3H), 0.90 {m, lOH).
Example 215
~2RS.3R)-3-amino-4-cvclohexvl-2-hvdroxv-N-(4-(4-moroholinyl~phenvl)butanamide
hydrochloride
The product of example 23A and 4-morpholinoaniline were processed as in
example
101 to provide the title compound.
MS (APCI) m/e 362 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.85 (d, 2H), 7.60 (d, 2H), 4.32 (d, 1H), 4.05 (t,
4H),
3.75 (m, 2H), 3.65 (m, 2H), 3.58 (m, 4H), 1.50 (m, 11H), 1.00 (m, 2H).
Example 216
f2RS.3R)-3-amino-4-cvclohexvl-N-(3 3-diphen~propvl)-2-hydroxvbutanamide
hydrochloride
The product of example 23A and 3,3-diphenylpropylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 395 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.30 (m, 8H), 7.15 (m, 2H), 4.10 (d, 1H), 4.00 (t,
1H),
3.55 (m, 2H), 3.25 (m, 1H), 3.15 (m, 1H), 2.30 (q, 2H), 1.75 (m, 7H), 1.45 (m,
2H), 1.25
(m, 2H), 0.90 (m, 2H).
Example 217
(2RS.3R)-3-amino-4-cyclohexyl-N-( 1 4-dimethy~ntyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 1,4-dimethylpentylamine were processed as in
example 101 to provide the title compound.
MS (ESI) m/e 299 (M+H)+;
1H NMR (300 MHz, MeOH-d4) b 4.10 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 1.75 (m,
6H), 1.50 (m, SH), 1.20 (m, 8H), 0.90 (m, 8H).
Example 218
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(2RS.3R)-3-amino-4-cvclohexyl-2-h dery-N-methyl-N-(1-
na_phthvlmethyl)butanamide
hydrochloride
The product of example 23A and N methyl-N (1-naphthyl)methyl amine were
processed as in example 24 to provide the title compound.
MS (ESI) m/e 355 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 7.90 (m, 3H), 7.68 (d, 1H), 7.52 (m, 3H), 6.51 (m,
1H),
5.08 (dd, 1.2H), 4.96 (dd, 0.8H), 4.45 (m, 0.6H), 4.20 (m, 0.4H), 3.03 (s,
1.8H), 2.98 (s,
1.2H), 1.80 (m, 1H), 1.63 (m, 3H), 1.43 (m, 2H), 1.31 (m, 2H), 1.17 (m, 4H),
0.81 (m,
2H);
to Anal. calcd for C22H30N202S~HCl~O.SC2H80: C, 66.27; H, 8.11; N, 6.44.
Found: C,
65.96; H, 7.82; N, 6.31.
Example 219
(2RS.3R)-3-amino-4-cyclohexyl-2-hydro~-N-methyl-N-(( 1 S)-1-( 1
nanhthvl)ethyl)butanamide hydrochloride
The product of example 23A and (,S~-N-methyl-N 1-(1-naphthyl)ethyl amine were
processed as in example 24 to provide the title compound.
MS (ESI) m/e 369 (M+H)+;
1H NMR (300 MHz, DMSO-d6) 8 7.90 (m, 3H), 7.68 (d, 1H), 7.52 (m, 3H), 6.43 (m,
1H),
4.20 (t, 1H), 2.59 ($, 3H), 1.80 (m, 1H), 1.63 (m, 3H), 1.53 (d, 3H), 1.43 (m,
2H), 1.31
(m, 2H), 1.17 (m, 4H), 0.81 (m, 2H);
Anal. calcd for C23H32N2O2S~HCl~0.75H20: C, 66.01; H, 8.31; N, 6.69. Found: C,
66.25; H, 8.09; N, 6.31.
Example 220
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-l2-methoxlr--5-,
(trifluoromethyl)phenyi)hutanamide hydrochloride
The product of example 23A and 2-methoxy-5-(trifluoromethoxy)aniline were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 375 (M+H)+
1H NMR (300MHz, MeOH-d4) 8 8.70 (d, 1H), 7.44 (dd, 1H), 7.20 (d, 1H), 4.35 (d,
1H),
4.00 (s, 3H), 3.72 (m, 1H), 0.92-1.86 (m, 13H).
Example 221
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(2RS,3R)-3-amino-4-cvclohexvl-2-hydroxy-N-(4-methoxv(,1 1'-biphenyl)-3-
yl~butanamide
hydrochloride
The product of example 23A and 2-methoxy-5-phenylaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 383 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.60 (d, 2H), 7.40 (t, 4H), 7.15 (m, 1H), 7.05 (d,
1H),
4.25 (d, 1H), 3.95 (s, 3H), 3.55 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.90 (m,
2H).
Example 222
(2RS,3R)-3-amino-4-cvclohexyl-N-(2 3-dihydro-1 4-benzodioxin-6-yl)_2-
hydroxybutanamide hvdrochloride
The product of example 23A and 3,4-ethylenedioxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.25 (s, 1H), 7.00 (d, 1H), 6.80 (d, 1H), 4.25 (m,
SH),
3.70 (m, 2H), 1.75 (m, SH), 1.40 (m, 6H), 1.00 (m, 2H).
Example 223
(2RS,3R)-3-amino-N-(3-(benzylo_xy)phenyl~~clohe~l-2-hydroxybutanamide
hydrochloride
The product of example 23A and 3-benzyloxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 383 (M+H)+;
1H NMR (300 MHz, MeOH, d4) 8 7.20 (m, 6H), 6.90 (d, 1H), 6.40 (m, 2H), 5.05
(d, 2H),
4.30 (d, 1H), 3.70 (m, 2H), I.75 (m, SH), 1.40 (m, 6H), 1.00 (m, 2H).
Example 224
(2RS,3R)-3-amino-4-cvclohexvl-N-(3-ethoxyphenyl)-2-~dro~butanamide
hydrochloride
The product of example 23A and 3-ethoxyaniline were processed as in example
101
to .provide the title compound.
MS (APCI) m/e 321 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.40 (d, 1H), 7.20 (m, 2H), 6.70 (d, 1H), 4.25 (d,
1H),
4.00 {q, 2H), 3.70 (m, 2H), 1.75 (m, SH), 1.40 (m, 6H), 1.05 (m, 2H).
Example 225
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(2RS.3R)-3-amino-4-cvclohexvl-2-hydroxv-N-(3 4 5-trim~thoxyphenvl)butanamide
hydrochloride
The product of example 23A and 3,4, 5-trimethoxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 367 (M+H)+;
tH NMR (300 MHz, MeOH-d4) $ 7.10 (s, 2H), 4.30 (d, 1H), 3.80 (m, 11H), 1.80
(m, SH),
1.50 (m, 2H), 1.30 (m, 4H), 1.00 (m, 2H).
Example 226
f2RS.3R)-3-amino-4-cvclohexyl-N-l2-(2-fluorophenvl)-1-methvleth 1
hvdrox b~amide hydrochloride
The product of example 23A and 3(2-flourophenyl)-2-aminopropane were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 337 (M+H)+;
1H NMR (300 MHz, DMSO) b 7.60 (m, 1H), 7.30 (m, 2H), 7.10 (m, 1H), 4.10 (m,
1H),
2.80 (m, 2H), 1.80 (m, 6H), 1.40 (m, 1 H), 1.10 (m, SH), 0.80 (m, 2H).
Example 227
(2RS,3R)-3-amino-4-cvclohexyl-N-(2-(4-fluorophenyl)-1 1-dimeth ly ethyl) 2
hydroxybutanamide hydrochloride
The product of example 23A and 2-(4-flourophenyl)-1,1-dimethylethylamine were
processed as in example I01 to provide the title compound.
MS (APCI) m/e 351 (M+H)+;
ZH NMR (300 MHz, DMSO) 8 7.20 (m, 2H), 7.05 (m, 2H), 3.60 (d, 1H), 3.00 (s,
2H),
1.65 (m, 5H), 1.40 (m, 2H), 1.20 (m, IOH), 0.80 (m, 2H).
Example 228
f2RS,3Rl-3-amino-4-cvclohexyl-N-(2 3-dihvdro-1H-inden-1-vl)-2
hvdroxybutanamide
hydrochloride
The product of example 23A and 1-aminoindane were processed as in example 101
to provide the title compound.
MS (APCI) m/e 317 (M+H)+;
iH NMR (300 MHz, DMSO) 8 7.95 (m, 1H), 7.20 (m, 3H), 5.30 (m, 1H), 3.75 (d,
1H),
3.00 (m, 2H), 2.80 (m, 2H), 2.38 (m, 1H), 1.95 (m, 1H), 1.70 (m, SH), 1.20 (m,
6H), 0.90
(m, 2H).
Example 229
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(2RS,3R)-3-amino-4-cvclohexvl-2-hydroxy-N-((IS 2R)-
2"phenvlcyclopropyl)butanamide
hydrochloride
The product of example 23A and trans-2-phenylcyclopropylamine were processed
as in example 101 to provide the title compound.
MS (APCI) m/e 317 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.25 (t, 2H), 7.15 (m, 3H), 4.12 (d, 1H), 3.SS (m,
2H),
2.95 (m, 1H), 2.15 (m, 1H), 1.75 (m, 7H), 1.45 (m, 2H), 1.25 (m, 4H), 1.00 (m,
2H).
Exa ale 230
(2RS.3R)-3-amino-4-cvclohex~2~hydroxv-N-(1 1 ~ 3-tetramethvlbutyl)butanamide
~drochloride
The product of example 23A and tert-octylamine were processed as in example
101
to provide the title compound.
MS (APCI) m/e 3I3 (M+H)+;
1H NMR (300 MHz, DMSO) 8 3.60 (d, IH), 2.95 (m, 1H), 1.75 (m, 7H), 1.35 (s,
6H),
1.20 (m, 6H), 0.98 (s, 9H), 0.80 (m, 2H).
Example 231
(2RS,3R)-3-amino-4-cvclohexyl-N-(I 3-dimethvlbutvl)-2-hvdroxvbutanamide
hydrochloride
The product of example 23A and 1,3-dimethylbutylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 285 (M+H)+;
1H~NMR (300 MHz, DMSO) S 3.70 (m, IH), 2.95 (m, 1H), I.80 (m, 8H), 1.40 (m,
2H),
1.20 (m, 4H), 1.05 (d, 3H), 0.85 {m, 8H).
Example 232
methvl4-(((2RS,3R)-3=amino-4-cvclohex 1-~2-h_ dy rox,ybutanoyl)amino)-3
thiophenecarboxylate hydrochloride
The product of example 23A and methyl 3-aminothiophene-4-carboxylate were
processed as in example 101 to provide the title compound.
MS (APCI) m/e 341 (M+H)+;
1H NMR (300 MHz, MeOH-d4) b 8.40 (s, 1H), 8.10 (s, 1H), 3.95 {d, 1H), 3.80 (s,
3H),
3.10 (m, 1H), 1.70 (m, SH), 1.20 (m, 6H), 0.90 (m, 2H).
Example 233
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(2RS.3R)-N-( 1-( 1-adamantyl)ethyl)-3-amino-4-c,~rclohex~hvdroxybutanamide
hydrochloride
The product of example 23A and 1-(1-adamantyl)ethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 363 (M+H)+;
1H NMR (300 MHz, DMSO) 8 3.75 (d, 1 H), 3.50 (m, 2H), 2.90 (m, 2H), 1.95 (s,
2H),
1.65 (m, 10H), 1.45 (m, 8H), 1.20 (m, SH), 0.95 (d, 3H), 0.80 (m, 2H).
Example 234
to (2RS,3R)- 3-amino-2-hvdroxv-4-cyclohexyl)butanoyl-( (S)-(-)-(1-naphth ly
)ethyl)amide
The product of examp1e12A and (S)-(-)-(1-naphthyl)ethylamine were processed as
in examples lE and 1F to yield the title compound.
MS (ESI+Q1MS) m/e 347 (M+ H)+ , 693 (2M+ H)+ ;
1H NMR (300 MHz, DMSO-d6) 8 8.75-7.47 (m, 7H), 6.55 (br., 1H), 4.82-4.75 (m,
1H),
4.15 (d, 1H), 3.60-3.33 (br.m, 3H), 2.68-2.34 (m, 3.6H), 2.18 (q, 0.4H), 1.87-
1.68 (m,
2H), 1.58-1.53 (m, 3H), 1.13 (t, 0.6H), 0.98 (t, 0.4H).
Example 235
(2RS.3R)-3-amino-4-cvclohexvl-2-hydroxy-N-(1-nanhthylmethvl)butanamide
hvdrochlorid~
The product of example 23A and 1-naphthylmethylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 341 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 8.15 (d, 1H), 7.85 (q, 2H), 7.50 (m, 4H), 4.90 (m,
2H),
4.15 (d, 1H), 3.50 (m, 2H), 1.70 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 236
(2RS.3R)-3-amino-4-cyclohex~rl~2-hydroxy-N-(3-
(trifluoromethoxy)benzyl)butanamide
hydrochloride
The product of example 23A and 3-trifluoromethoxy benzylamine were processed
as in example 101 to provide the title compound.
MS (APCI) m/e 375 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.40 (t, 1H), 7.30 (d, 1H), 7.22 (s, 1H), 7.19 (d,
1H),
4.55 (d, 1H), 4.40 (d, 1H), 4.15 (d, 1H), 3.50 (m, 2H), 1.75 (m, SH), 1.40 (m,
6H), 0.95
(m, 2H).
Example 237
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2RS.3R)-3-amino-N-(3,5-bis(trifluoromethvl)benz l~vclohe~l-2-hydroxybutanamide
hydrochloride
The product of example 23A and 3-methylbenzylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 427 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.95 (s, 2H), 7.85 (s, 1H), 4.65 (d, 1H), 4.50 (d,
1H),
4.10 (d, 1H), 3.40 (m, 2H), 1.75 (m, SH), 1.40 (m, 6H), 0.90 (m, 2H).
Example 238
(2RS.3R)-3-amino-4-cvcIohexvl-2-hvdroxy-N-(2-
(trifluoromethyl)benzyl)butanamide
The product of example 23A and 2-trifluoromethyl benzylamine were processed as
in example 101 to provide the title compound.
MS (APCI) m/e 359 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.70 (d, 1H), 7.58 (m, 2H), 7.45 (t, 1H), 4.75 (d,
1H),
4.55 (d, 1H), 4.19 (d, 1H), 3.55 (m, 2H), 1.75 (m, SH), 1.40 (m, 6H), 0.95 (m,
2H).
Example 239
(2RS,3R)-3-amino-4-cvclohexvl-2-hydroxv-N-(4-
(trifluoromethoxy)benzvl)butanamide
hydrochloride
The product of example 23A and 2-trifluoromethoxy benzylamine were processed
as in example 101 to provide the title compound.
MS (APCI) m/e 375 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 7.45 (d, 2H), 7.22 (d, 2H), 4.50 (d, 1H), 4.38 (d,
1H),
4.10 (d, 1H), 3.45 (m, 2H), 1.75 (m, SH), 1.40 (m, 6H), 0.95 (m, 2H).
Example 240
(2RS.3R)-3-amino-N-(6-chloro-3-pyridinyl)-4-cyclohexyl-2-hydro~butanamide
hydrochloride
The product of example 23A and 3-amino-6-chloropyridine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 312 (M+H)+;
1H NMR (300 MHz, MeOH-d4) 8 8.70 (s, 1H), 8.20 (d, 1H), 7.40 (d, 1H), 4.30 (d,
1H),
3.80 (m, 2H), 1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 3H), 1.00 (m, 2H).
Example 241
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2RS.3R)-3-amino-4-cyclohexvl-2-hvdroxy-N-(6-meth,~rl-2-p, m~'dinvl)butanamide
hydrochloride
The product of example 23A and 2-amino-6-methylpyridine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 292 (M+H)+;
1H NMR (300 MHz, MeOH-d4) b 8.05 (d, 2H), 7.30 (m, 1H), 4.45 (d, 1H), 3.70 (m,
2H),
2.60 (s, 3H), 1.80 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).
Example 242
(2RS.3R)-3-amino-N-(5-chloro-2-methoxvnhenvl)-4-cvclohexvl-2-hvdroxvbutanamide
hydrochloride
The product of example 23A and 2-methoxy-5-chloroaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 341 (M+H)+
1H NMR (300MHz, MeOH-d4) 8 8.39 (d, 1H), 7.11 (dd, 1H), 7.02 (d, 1H), 4.36 (d,
1H),
3.82. (s, 3H), 3.79 (m, 1H), 0.98-1.88 (m, 13H).
Example 243
2RS.3R)-3-amino-4-cvclohexvl-2-hydroxv-N-(2-methoxv-5-methvlohenyl)butanamide
hydrochloride
The product of example 23A and 2-methoxy-5-methylaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 8.13 (s, 1H), 6.92 (s, 2H), 4.33 (d, 1H), 3.89 (s,
3H),
3.78 (m, 1H), 2.28 (s, 3H), 0.92-1.88 (m, 13H).
Example 244
2RS.3R)-3-amino-N-(4-chloro-2 5-dimethoxvphenvl)-4-cvcIohexvl-2-
hvdroxvbutanamide
hydrochloride
The product of example 23A and 2,5-dimethoxy-4-chloroaniline were processed as
in example 101 to provide the title compound.
MS (APCI) m/e 370 (M)'"
'H NMR (300MHz, MeOH-d4) b 8.23 (s, 1H), 7.09 (s, 1H), 4.36 (d, 1H), 3.88 (s,
3H),
3.85 (s, 3H), 3.79 (m, 1H), 0.97-1.88 (m, 13H).
Example 245
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(2RS.3R)-3-amino-4-cyclohexyl-N-(2 3-dimethoxyphe~l)-2-hydroxvbutanamide
hydrochloride
The product of example 23A and 2,3-dimethoxyaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 337 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.93 (d, 1H), 7.04 (t, 1H), 6.83 (d, 1H), 4.35 (d,
1H),
3.88 (m, 6H), 3.79 (m, 1H), 0.94-1.88 (m, 13H).
Example 246
(2RS.3R)-3-amino-4-cvclohexyl-N-(3 4-dimethoxyphenyl)-2-hydroxybutanamide
hydrochloride
The product of example 23A and 3,4-dimethoxyaniline processed as in example
101
to provide the title compound.
MS (APCI) m/e 337 (M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.39 (d, 1H), 7.14 (dd, 1H), 6.91 (d, 1H), 4.27 (d,
1H),
3.83 (s, 3H), 3.81 (s, 3H), 3.72 (m, 1H), 0.95-1.86 (m, 13H).
Example 247
(2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(3-rnethoxy-4-meth~phenyl)butanamide
hydrochloride
The product of example 23A and 3-methoxy-4-methylaniline were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
'H NMR (300MHz, MeOH-d4) b 7.35 (s, 1H), 7.06 (d, 2H), 4.28 {d, 1H), 3.82 (s,
3H),
3.72 (m, 1H), 2.14 (s, 3H), 0.91-1.86 (m, 13H).
Example 248
(2RS.3R)-3-amino-4-cvclohexyl-2-h~roxy-N-(4-methoxy-2-n~hthyl)butanamide
hydrochloride
The product of example 23A and 4-methoxy-2-naphthylamine were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 357 (M+H)''
'H NMR (300MHz, MeOH-d4) 8 8.13 (dd, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.47 (m,
1H),
7.38 (m, 1H), 7.24 (d, 1H),.4.35 (d, 1H), 4.02 (s, 3H), 3.77 (m, 1H), 0.95-
1.88 (m, 13H).
Example 249
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2RS.3R)-3-amino-4-cvclohexvl-2-hvdroxy-N-(2-thienylmethyl~butanamide
hydrochloride
The product of example 23A and 2-(aminomethyl)thiophene were processed as in
example 101 to provide the title compound.
MS (APCI) m/e 297 {M+H)+
'H NMR (300MHz, MeOH-d4) 8 7.29 (dd, 1H), 7.02 (dd, 1H), 6.95 (dd, 1H), 4.59
(q,
2H), 4.15 (d, 1H), 3.58 (m, 1H), 0.82-1.80 (m, 13H).
Example 250
f2RS.3R)-3-amino-N hutvl-4-cyclohexyj,~ hydrox~,N, methylbutanamide
The product of example 23A (2.4g, 8.64mmole) was dissolved in anhydrous
dichloromethane to give 24m1 ( solution A). 1-Hydroxybenzotriazole hydrate
(HOBT-
0.96g, 7.78mmole) and 4-(dimethylamino)-pyridine (DMAP-0.096 g, catalytic)
were
dissolved in 2:1 dichloromethane:N,N dimethylformamide to make 48m1 (solution
B). 1-
[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI-2.30g,
12.96mmole)
was dissolved in anhydrous dichloromethane to give 4$ml (solution C). Solution
A was
distributed equally into 48 individual reactors. Solution B and solution C
were added
respectively to these same reactors in equal portions. The reactors were
shaken l5min at
room temperature. To one of these reactors, N methylbutylamine( 0.022m1,
0.27mmol)
was added and the mixture was shaken ca. 20h. Dichloromethane (2.Sm1) was
added to the
reaction and shaken. The reactor placed on a liquid phase extractor to wash
twice with 1M
sodium bisulfate, once with water, and finally, twice with 2N sodium
bicarbonate. Any
residual water was removed and the solvent was concentrated to dryness. The
residue was
dissolved in 4M hydrochloric acid in dioxane (lml) to cleave the protecting
group. After
one hour, the solvent was concentrated to dryness. 48 amines were processed at
one time
in batch mode. Based on HPLC purity, the material was either submitted as is,
or sent for
preparative HPLC purification prior to submission.
MS (APCI) m/e 271 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 4.45 (t, 1H), 3.45 (m, 3H), 3.14 (s, 2H), 2.95 (s,
1H),
1.7 (m, SH), 1.4 (m, 4H), 0.95 (m, 6H).
Example 251
R _ _4_ I_4_ r
The product of example 23A and 2,6-dimethylmorpholine were processed as in
Eample 250 to provide the title compound.
MS (APCI) m/e 299 (M+H)+ ;
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1H NMR (300 MHz, MeOH-d4) b 4.4 (m, 2H), 3.95 (m, 1H), 3.55 (m, 3H), 2.85 (m,
1H),
2.4 (m, 1H), 1.7 (m, 5H), 1.5 (m, 3H), 1.2 (m, 9H), 0.95 (m, 2H).
Example 252
L2RS.3R)-3-amino-4-cvclohexvl-2-hvdro~v-N.N bislmethoxvmerhvllhnrar,at";rlP
The product of Example 23A and bis(2-methoxyethyl)amine were processed as in
Example 250 to provide the title compound.
MS (APCI) m/e 317 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) b 4.65 (d, 1H), 3.9 (m, IH), 3.55 (m, 9H), 3.35 (m,
6H),
1.7 (m, 5H), 1.4 (m, 6H), 0.95 (m, 2H).
Example 253
R - i -4- h 4- 'h I 'no '
~u none
The product of example 23A and 1,2,3,4-tetrahydroisoquinoline were processed
as
in example 250 to provide the title compound.
MS (APCI) m/e 317 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.2 (m, 4H), 4.7 (m, 2H), 4.55 (d, 1H), 3.8 (m,
2H), 3.5
(m, 1H), 2.95 (m, 2H), 1.7 (m, 5H), 1.4 (m, 6H), 0.95 (m, 2H).
Example 254
~2RS.3Rl-3-amine-I-ll-aze~n lv )-4-~yclohexy -~- y~3r 1 butanone
The product of example 23A and hexamethyleneimine were processed as in
example 250 to provide the title compound.
MS (APCI) m/e 283 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) S 4.45 (d, 1H), 3.65 (m, 2H), 3.55 (m, 3H), 1.6-1.8
(m,
13H), 0.95-1.5 (m, 8H).
Example 255
R = i o- 1 d - 4- h - i 2
n n
The product of example 23A and 4-phenyl-1,2,3,6-tetrahydropyridine
hydrochloride
were processed as in example 250 to provide the title compound.
MS (APCI) m/e 343 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.35 (m, 5H), 6.15 (m, 1H), 4.45 (dd, 1H), 4.25
(m,
2H), 3.85 (m, 2H), 3.55 (m, 1H), 2.6 (m, 2H), 1.7 (m, 5H), 0.95 -I.5 (m, 8H).
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Example 256
l2RS.3Rl-3-amino-N benzyl-N butyl-4-cvslohexyl-2 ~ r xvlputanamide
The product of example 23A and n-butylbenzylamine were processed as in
Example 250 to provide the title compound.
MS (APCI) m/e 347 (M+H)' ;
iH NMR (300 MHz, MeOH-d4) 8 7.4 (m, 5H), 4.7 (m, 2H), 4.4 (dd, 1H), 3.5 (m,
2H),
3.25 (m, 1H), 2.1-1.7 (m, 15H), 0.92 (m, SH).
Example 257
l2RS.3Rl-3-amino-4-cvclohe_x_yi_-1-r«R~,~-2 ~-~;n,pthylmon, holin~rll-2-h3~,~~
butan ~r
The product of example 23A and cis-2,6-dimethylmorpholine were processed as in
example 250 to provide the title compound.
MS (APCI) m/e 299 (M+H)'' ;
1H NMR (300 MHz, MeOH-d4) 8 4.5 (dd, 1H), 4.35 (m, 1H), 3.95 (m, 1H), 3.55 (m,
1H),
2.9 (m, 1H), 2.4 (m, 1H), 1.5-1.7 (m, 8H), 0.95- 1.3 (m, 11H).
Example 258
R - -N 'i 5- _4_
hydroxy-N methylbutanamide
The product of example 23A and 2-chloro-N methylbenzylamine were processed as
in example 250 to provide the title compound.
MS (APCI) m/e 339 (M+H)+ ;
iH NMR (300 MHz, MeOH-d4) 8 7.35 (m, 4H), 4.75 (m, 2H), 4.4-4.55 (dd, 1H), 3.5
(m,
1H), 3.14 (s, 2H), 2.99 (s, 1H), 1.7 (m, 5H), 0.95- 1.5 (m, 8H).
Example 259
3R - -N _5_ _4_ -N
methyl~utanamide
The product of example 23A and N ethyl-3,4 (methylenedioxy)aniline were
processed as in example 250 to provide the title compound.
MS (APCI) m/e 349 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4)~ b 6.9 (d, 1H), 6.83 (d, 1H), 6.78 (dd, 1H), 6.04
(d, 2H),
4.19 (d, 1H), 3.9 m, 1H), 3.5 (m, 1H), 3.25 (m, 1H), 1.65 (m, SH), 1.4 (m,
2H), 1.0- 1.25
(m, 7H), 0.8 (m, 2H)
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Example 260
12RS.3R)-3-amino-4-cvclohexvl-N 12.4-dichlorobenzvl)-N ethyl-2-
hvdroxvhutanamide
The product of example 23A and 2,4-dichloro-N ethylbenzylamine were processed
as in example 250 to provide the title compound.
MS (APCI) m/e 387 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.29-7.52 (m, 3H), 4.65 (m, 2H), 4.3-4.5 (dd, 1H),
3.55
(m, 2H), 3.45 (m, 1H), 1.7 (m, SH), 1.5 (m, 2H), 1.1-1.4 (m, 7H), 0.95 (m,
2H).
Example 261
lI~2R~.3R~~-amln0-4-CVClOhexvl-2-livdrnxvhntas1nv11lhc~nwllaminnlnrnnannatP
The product of example 23A and N benzyl-3-aminopropionic acid ethyl ester were
processed as in example 250 to provide the title compound.
MS (APCI) m/e 391 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 7.3 (m, SH), 4.7 (m, 3H), 4.1 (m, 2H), 3.4 (m,
1H), 2.6
(m, 2H), 1.7 (m, SH), 1.15-1.5 (m, 9H), 0.95 (m, 2H).
Example 262
12RS.3R)-3-amino-4-cyclohexy)~y~r~y-1-ll-~ eridinX],)-1-butanone
The product of example 23A and piperidine were processed as in example 250 to
provide the title compound.
MS (APCI) m/e 269 (M+H)+ ;
1H NMR (300 MHz, MeOH-d4) 8 4.45 (d, 1H), 3.7 (m, 2H), 3.5 (m, 3H), 1.7 (m,
9H), 1.5
(m, 4H), 1.3 (m, 4H), 1.0 (m, 2H).
Example 263
(2RS,3R,5'S)-N-f4-(N-Dhenyihydantoyl)butyll-3-amino-2-h~rdrox~5-
~ethvlthio)pentananamide hydrochloride
Ste a
Potassium tert-butoxide (112 mg) is added to a solution of N(epsilon)(tert-
3o butoxycarbonyl)-L-lysine methyl ester hydrochloride (300 mg) and phenyl
isocyanate (110
mL) in 5 ml of tetrahydrofuran. The resulting mixture is stirred at room
temperature for one
day. After a similar amount of potassium tert-butoxide is added, the resulting
mixture is
heated at 65-70 'C for 1 hour. The solvent is removed and ethyl acetate is
added to the
residue, which is washed with successive portions of brine, 10% KHS04, brine,
10%
NaHC03, and brine, and dried over anhydrous magnesium sulfate. After removal
of the
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solvents under vacuum, the product residue is treated with 4N hydrogen
chloride in dioxane
for 1 hour, and again evaporated to dryness.
Step (b)
The product of Step (a) of Example 12 is reacted with the product of Step (a)
of
this Example using the method as described in Example 2 to provide the title
compound.
Example 264
(2RS.3R.5'R)-N f4-(N-phenylhvdanto l~butyll-3-amino-2-hydrox,~r-5-
l0 (ethylthio)pentanamide hydrochloride
Using N(epsilon)(tert-butoxycarbonyl)-D-lysine methyl ester hydrochloride and
phenyl isocyanate, the procedure of Example 263 is used to produce the
stereoisomer
shown above.
Example 265
~2RS,3R,4'R)-N f4-(N (2 4-dimethoxyphenyl)h~dant~l)propyll-3-amino 2 hydroxy 5
(ethvlthio)pentanamide hydrochloride
Using N(epsilon)(tert-butoxycarbonyl)-L-ornithine methyl ester hydrochloride
and
2,4-dimethoxyphenyl isocyanate, the procedure of Example 263 is used to
produce the
compound shown above.
Example 266
2RS,3R,5'S)-N f4-(N (4-triflouramethoxvpheny~
hydantoyl)hutvll-3-amino-2-hydroxy-5-(ethylthio)pentanamide hydrochloride
Using N(epsilon)(tent-butoxycarbonyl)-L-lysine methyl ester hydrochloride and
4-
trifluoromethoxyphenylphenyl isocyanate, the procedure of Example 28 is used
to produce
the compound shown above.
Example 267
(2RS,3R,5'S.R'S)-N f4-l3-Methyl-2 5-dioxopiperazin-2yl)hutvll-3-amino-2-
h~rdroxv 5
fethvlthio pentanamide hydrochloride
Ste a
L-alanyl-N'-benzyloxycarbonyllysine methyl ester hydrochloride is synthesized
by
standard peptide synthesis methods well known in the art. The resulting
dipeptide ester
(250 mg) is dissolved in toluene (20 mL), triethylamine is added, and the
mixture is sealed
in a tube and heated to 140°C for 12 hours. The solvent is removed, and
the product is
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dissolved in ethyl acetate (30 ml) and washed with successive portions of
brine, 10%
KHS04, and brine and dried over anhydrous magnesium sulfate. The solvent is
removed
under vacuum, and the resulting product is deprotected by standard techniques
known in
the art.
~te_p (b)
The product of Step (a) of Example 12 and the product of Step (a) above are
processed as described in Example 2 to yield the title compound.
i0 Utilizing the procedure of Example 32, and employing amino acids with
widely
differing side-chains, a number of substituted diketopiperazines can be
synthesized and
incorporated into compounds of the present invention by the methods detailed
in the
Examples above.
Example 26$
(2RS,3R)-N-f4-(Phthalimido)butyll-3-amino-2-hydrox,v-5-(ethylthio~pentanamide
hydrochloride
t a
Mono-N-(tert)-butoxycarbonyl-1,4-diaminobutane (190 mg) and phthalic anhydride
(150 mg) are dissolved in S ml of toluene and gently refluxed in an oil bath
(117-120°C
until all of the starting material is consumed. The reaction mixture is
diluted with 15 mL of
ethyl acetate, and the organic layer is washed with successive portions of
brine, 10%
KHS04, brine, 10% NaHC03, and brine and dried over anhydrous magnesium
sulfate. The
solvent is evaporated to yield the crude product which is treated with 4N
hydrogen chloride
in dioxane for 1 hour. The solvent is removed, taken up in diethyl ether,
twice with
evaporations to remove the HCI, and dried.
to b
The product of Step (a) of Example 3 and the product of Step (a) above are
processed as described in example 2 to provide the title compound.
Utilizing the method detailed in Step (a) of Example 26$, a number of N-
(aminoalkyl)phthalimides can be synthesized and incorporated into compounds of
the
present invention. Examples of such N-(aminoalkyl)phthalimides include
compounds where q can range from one to six, inclusive, and A can be hydrogen,
halogen,
lower alkyl, lower alkoxy, vitro, or carboxy.
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Example 269
(2RS,3R)-N (2-thien-2- l~yl)-3-amino-2-hydroxy-5-(ethvlthio)nentanamide
hydrochloride
The product of Step (a) of Example 12 and 2-(2-aminoethyl)thiophene are
processed as described above in Example 2 to provide the title compound.
Example 270
(2RS.3R)-fN meths-N-propel)-3-amino-2-hvdroxy-5-(ethvIthio~pentanamide
~ hydrochloride
The product of Step (a) of Example 12 and N-methyl n-propylamine are processed
as described in Example 2 to provide the title compound.
In the same manner, alkylamines and dialkylamines in which the two alkyl
groups
are the same or are different can be~converted to compounds of the present
invention by the
method detailed in Example 35.
Example 271
2RS.3R)-N-f2-(Q-Aminobutyrolactam l~hyll-3-amino-2-hey-5
(ethylthio)pentanamide
The product of Step (a) of Example 12 and 1-amino-2- [g-
aminobutyrolactamyllethane are processed as described in Example 2 to provide
the title
compound.
In a similar manner, aminoalkyl lactams can be incorporated into compounds of
the
present invention my the methods detailed in the Examples given above.
Example 272
(2RS.3S.1'S) N f(1-carboxvl)ethvll 3-amino-2-thio-5-(methylthio)pentanamide
hydrochloride
Example lE (0.40 g, 1.1 mmole) in 3 mL of methylene chloride containing 50 %
molar excess of triethylamine at 0 °C is treated with methanesulfonyl
chloride (O.ImL, 1.31
mmole). After the reaction is completed, the mixture is washed with brine, 10%
KHS04,
dried over MgS04. To a solution of mesylate (0.45 mmole) in 5 mL of THF is
added a
solution of p-methoxybenzyl mercaptan (0.104g, 0.675 mmole) in the presence of
1N-
NaOHi at 0 °C under nitrogen atmosphere. After an additional 30 minutes
at room
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temperature with stirring, the product is purified by silica gel column
chromatography,
eluting with 10% ethyl acetate in toluene.
Obtained p-methoxybenzyl mercapto derivative (0.4 mmole) is dissolved in 3 mL
of
methanol. 2N-NaOH is added to adjust pH at around 12. The reaction is worked
up
according to the general procedure and the product is treated with 4N-HCl in
dioxane for
1.5 hours to obtain the title compound.
Example 273
(2RS.3S.1'S) N f(1-ethoxvcarbonyl)ethyll 3-amino-2-oxo-5-
(meth~rlthio)pentanamide
l~drochloride
Example lE (0.4 g, 1.1 mmole) is oxidized by pyridinium chlorochromate (710
mg,
3.3 mmole) in 5 mL of methylene chloride until the starting material is
consumed. The
obtained diketone is purified on silica gel column chromatography. The
resulting product is
processed as described in step (f) in example 1 to yield the title compound.
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